^ ( ft 55 - M ** ^o ' g X v \ I? i i/wlj ** 1 ? FT M i I l 5 . vTi X, g ==(q u g ?^1 <> o I ^ I i? rfi yi x =c g / f ^^ r ^ < -^ { y *B.'-'-^ So < V^ t^T... ._ >, |>0 1 5 -. id o ^'(/OJ !1V> JO^ %OJ !TV3-dO^ FY s i N %. t-o >- MATERIA MEDICAiPHARMA- COLOGY : THERAPEUTICS PRESCRIPTION WRITING FOR STUDENTS AND PRACTITIONERS BY WALTER A. BASTEDO, Ph.G., M.D. Assistant Professor of Clinical Medicine, Columbia University; Associate Attending Physician, St. Luke's Hospital, New York: Attending Physician, City Hospital, New York; Consulting Physician, St. Vincent's Hospital. Staten Island; Con- sulting Gastro-enterologist, Staten Island Hospital; Fifth Vice-President, United States Pharma- copoeial Convention; formerly Curator of the New York Botanical Garden SECOND EDITION, FiESET PHILADELPHIA AND LONDON W. B. SAUNDERS COMPANY 1918 If Copyright, 1913, by W. B. Saunders Company. Reprinted February, 1914, May, 1914, May, 1915, and September, 1916. Revised, entirely reset, reprinted, and recopyrighted January, 1918 Copyright, 1918, by W. B. Saunders Company Reprinted May, 1918 THE USE IN THIS VOLUME OF CERTAIN PORTIONS OF T H E~ THE UNITED STATES PHARMACOPOEIA!. CONVENTI PRINTED IN AMERICA PRESS OF W. B. SAUNDERS COMPANY PHILADELPHIA TW 121 DEDICATED TO professor ^enrp $)ur& Kusfap, 3OTANIST, PHARMACOGNOSIST, AND DEAN OF THE FACULTY OF THE NEW YORE COLLEGE OF PHARMACY (COLUMBIA UNIVERSITY) Dear Doctor Rusby: Will you do me the honor to accept this dedication as a token of ap- preciation of your high ideals and of your indefatigable efforts in the cause of pure drugs, and as an expression of my great personal debt to you, my earliest and latest preceptor in the field of "materia medica"? Sincerely yours, WALTER A. BASTEDO PREFACE TO THE SECOND EDITION IN addition to bringing the book into conformity with the Ninth Revision of the U. S. Pharmacopoeia, there has been a thorough revision throughout. The sections on alkalies, pitu- itary, salvarsan, bichloride poisoning, emetine, oxygen, and ergot have been rewritten, and new articles have been intro- duced on benzine and gasoline, benzol, kaolin, fullers' earth, glucose, papaverine, ethylhydrocupreine, phenylcinchoninic acid, magnesium sulphate, oil of chenopodium, and the Dakin-Car- rel antiseptic treatment for wounds. Because of its universal use in medical literature the term cubic centimeter (c.c.) has been retained, though, the U. S. and British Pharmacopoeias have substituted the term milliliter (mil.). A milliliter differs from a cubic centimeter by such a small fraction that it is quite negligible. W. A. BASTEDO. 57 WEST 58 ST., NEW YORK, N. Y. PREFACE This book is an adaptation, for the most part, of lectures delivered at Columbia University. In its preparation I have kept in mind that the physician's reason for the study of remedies is the "treatment of the sick"; and I have laid most stress upon those things that bear on practice, even to the exclusion of some matters of great interest in pharmacology. But I have endeavored throughout to emphasize the value of research, both in the laboratory and at the bedside, and to point out any discrepancy between the value of a remedy as. established by research and its supposed value in therapeutics. For I recognize that, as the result of research, many of the hitherto highly valued drugs are falling into merited disuse; and that some that were of little value because of a wrong under- standing of their action have come to have a definite place in our therapeutic armamentarium. Indeed, I have given place to many remedies which I do not recommend, but mention only to condemn. I believe that, as the outcome of critical laboratory research and the adoption of laboratory methods in clinical research, we are at the dawn of a new era of simple and practical therapeutics, an era in which knowledge will supplant credulity on the one hand, and skepticism on the other, and in which fewer drugs will be used but better treatment given. Both because of the importance of digitalis as a drug, and because of the recent great changes in our knowledge of cardiac physiology and therapeutics, I have discussed digitalis at greater length than other drugs; and have drawn my conception of its action as much from recent clinical studies (my own and those of other investigators) as from those of the pharmacologic labor- atory. In the chapter on Prescription-writing I have adopted one method for the students to learn; and to avoid confusion have omitted mention of other methods, without any intention to imply that they are inferior. Recognizing that in a subject which derives so much from research in all the branches of medicine it would be impossible for one person to be equally familiar with all parts, I have drawn freely on the published researches in chemistry, pharmacology, 12 PREFACE physiology, bacteriology, and clinical medicine. But I have felt that citation of authors is, in the main, impracticable in a work of this character; so for the most part have omitted credit unless this was required for authority. Likewise, I have made no attempt to compile extensive bibliographies. However, I should like espe- cially to mention the works on pharmacology by Cushny, Soll- mann, Schmiedeberg, Heinz, and Meyer and Gottlieb; those on physiology by Howell, Starling, Schafer, and Leonard Hill; the sundry publications of von Noorden, Mackenzie, Pawlow, Herter, Lee, Lusk, Meltzer, Hatcher, Hertz, and others; and the Herter and Harvey Society lectures. For the use of a number of tracings I owe my deepest thanks to my colleague, Dr. Charles C. Lieb, whose care about the de- tails of an experiment and accuracy in recording results I believe to be unsurpassed. W. A. BASTEDO. 57 WEST sSTH ST., NEW YORK, N. Y. CONTENTS PART I PAGE INTRODUCTION 17 THE CONSTITUENTS OF ORGANIC DRUGS 19 PHARMACEUTIC PREPARATIONS 37 Definition of the Kinds in Common Use 39 WEIGHTS AND MEASURES 43 ACTIVE PRINCIPLES AND ASSAY PROCESSES 44 THE PHARMACOPOEIA 45 DOSAGE 47 Factors which Modify the Dose 48 ADMINISTRATION 52 The Ways in which Drugs May be Administered for Systemic and Remote Local Effect 53 The Time of Administration 56 Sites and Modes of Action of Drugs 56 Synergists and Antagonists 57 SCIENTIFIC AND EMPIRIC THERAPEUTICS ANIMAL EXPERIMENTATION 58 THE SCOPE OF TREATMENT 60 How MUCH SHALL WE LEARN ABOUT DRUGS? 61 The Pharmacologic Action 63 PART II INDIVIDUAL REMEDIES PROTECTIVES 67 SWEETENING AGENTS 68 NUTRIENTS 68 COUNTERIRRITANTS 72 CAUSTICS (ESCHAROTICS) 78 THE DIGESTIVE FERMENTS 81 THE INORGANIC ACIDS 86 THE ORGANIC ACIDS 88 Fruit Acids 90 ANTACIDS 91 Antacids of Alkaline Reaction 91 Antacids Not of Alkaline Reaction 101 CARMINATIVES 102 BITTERS 107 ANTI-BITTERS 109 CHARCOAL 109 KAOLIN FULLERS' EARTH no EMETICS in ANTEMETICS 112 14 CONTENTS PAGE ASTRINGENTS 113 ANTHELMINTICS 115 CATHARTICS 119 Cathartic Measures 122 Cathartics Acting by Selective Affinity 1 24 Mechanical Agents to Give Bulk and Soft Consistency to the Feces 1 24 Irritants 126 Bile and Bile Salts 126 Fixed Oils, Soaps, and Glycerin 127 Cathartic Mercurials 1 29 Anthracene Derivatives 131 Drastics 135 Saline Cathartics 137 Rectal Treatment 143 ANTI-DIARRHEICS 146 MINERAL WATERS 146 REMEDIES WHOSE CHIEF ACTION is UPON THE CIRCULATION 148 The Physiology of the Circulation 148 General Circulatory Stimulants 157 Mechanical Measures for Raising Arterial Pressure 225 Measures for Increasing the Volume of the Blood 225 Remedies Which Lower Blood-pressure 231 Cardiac Depressants : 231 Arterial Dilators 239 Measures for Decreasing the Volume of the Blood 245 Shock and Collapse 248 REMEDIES WHOSE CHIEF ACTION is UPON THE CENTRAL NERVOUS SYSTEM .. 252 Central Nervous Stimulants 252 Remedies Which Depress the Central Nervous System Narcotics 282 General Anesthetics 282 Intoxicants 316 Hypnotics 356 Antihysterics (Antispasmodics) 393 DRUGS WHICH CHIEFLY AFFECT THE PERIPHERAL NERVOUS SYSTEM 394 Peripheral Depressants 394 Peripheral Stimulants 436 ANHIDROTICS 411 DIAPHORETICS 443 DIURETICS 450 ANTIPYRETICS 461 Analgesic Antipyretics 462 Anti-malarial Antipyretics 470 Antirheumatic Antipyretics 480 DISINFECTANTS AND ANTISEPTICS 488 THERAPEUTIC CLASSIFICATION OF DISINFECTANTS 514 General Disinfectants and Deodorizers 514 Preservatives 515 Disinfectants for Surgical Supplies 515 Disinfectants for Local Use About Body 516 Disinfectants to be Given by Mouth 517 HEAVY METALS 517 PHOSPHORUS 553 IODIDES 555 THYROID (.LAND 560 ANTITHYKOID PREPARATIONS 562 EXPECTORANTS 563 EMMENAGOGUES 567 CONTENTS 15 PAGE CARBON MONOXIDE 574 BENZINE AND GASOLINE 576 BENZOL 577 OXYGEN 578 PART III PRESCRIPTION WRITING LIQUID PRESCRIPTIONS 583 ADMINISTRATION OF LIQUIDS 585 ADMINISTRATION OF SOLIDS 586 LATIN 587 THE FORM OF A PRESCRIPTION 591 FIGURING THE QUANTITIES 593 ABBREVIATIONS 597 PRACTICE IN BULK PRESCRIPTIONS 599 PRACTICE IN PRESCRIPTIONS FOR OBJECTS TO BE COUNTED 601 INCOMPATIBILITY 603 INDEX. 607 MATERIA MEDICA, PHARMACOLOGY, THERAPEUTICS, AND PRESCRIPTION-WRITING PART I INTRODUCTION "Medicine sometimes cures, it often relieves, it always consoles." THE physician's calling has arisen from the needs of the sick, a person who is ill desiring the services of some one who can help him to get well. If the sick man cannot be made well, he wants as much improvement in his health as possible, so that he may do things; for example, attend to his business, or at least get about. If his health cannot be improved, he wants his comfort promoted and his life prolonged. Thus the objects of the practice of medicine are: to prolong life, to secure comfort, to improve health, or to promote recovery. The physician accomplishes these objects by doing something for his patients, i. e., by treating them. Therefore his ability to treat his patients successfully is what constitutes his direct personal value for them, and is the ultimate raison d'etre of the physician's calling. Hence the importance of a familiarity with the available means of treatment, i. e., with remedial or thera- peutic measures. Therapeutics is the science of the use of remedial measures. When a physician orders a patient to bed, he employs a thera- peutic measure. Also when he orders a cold bath, a cathartic, or the application of a mustard plaster; or when he applies a splint to a broken arm, or removes an inflamed appendix, or sits by the bed and calms a nervous patient. Preventive medicine goes a step further than remedial medicine, in that it designs to prevent the appearance or spread of disease. The main therapeutic and preventive measures may be grouped as follows: i. Hygienic those which have to do with cleanliness, dis- infection, the prevention of the spread of contagion, ventilation, the selection of a patient's bedroom, care of bedding, clothing, etc. 2 I 7 l8 PHARMACOLOGY AND THERAPEUTICS 2. Mechanical the use of bandages, splints, ligatures, cath- eterization to empty the bladder, massage, gymnastics, etc. j. Operative the performance of surgical and obstetric oper- ations. 4. Physical the use of physical agents: heat, cold, light, electricity, -rays, radium, etc. 5. Hydrotherapeutic the external use of water and its modi- fications: ice, cold water, hot water, and steam, in the form of baths, packs, douches, etc. 6. Dietetic the modifications of diet for the sick. 7. Suggestive or psychotJierapeutic suggestion, hypnotism, mental buoying, etc. The psychic influence of a physician is of great importance, and to reassure a patient when she is fearing the worst, to encourage, to stimulate the energies and the will, are among the functions of the physician and are therapeutic measures. 8. Pharmaceutic the use of pharmaceutic or drug remedies. Materia Medica. Drug remedies are known collectively as the "materia medica," or medical materials. The science which deals with the properties of drugs is called materia medica or, more correctly, pharmacology. It is a term that is employed in a broad sense to include everything relating to drugs. In connection with drugs, there are several great fields of work, the most important being: /. Pharmacognosy the study of the physical properties of crude drugs. The pharmacognosist studies the methods by which drugs are collected, their appearance on the market, the char- acters by which they may be identified and their quality esti- mated, their adulterants in the whole and in the powdered state, etc. 2. Pharmacy the art of preparing drugs for use. Manu- facturing pharmacy is the art of manufacturing drugs into forms suitable for use in medicine. Dispensing pharmacy is the art of making up prescriptions. The pharmacist makes his knowledge tell on the manufacture of preparations and their combination into prescriptions. He studies weights and measures, solubilities, incompatibilities, keeping qualities, chemic reactions, the extrac- tion of active principles, and the making of preparations suitable for use in the practice of medicine. j. Pharmaceutic chemistry the study of the chemistry of drugs and preparations of drugs. ./. Pharmacodynamics or pharmacology (in its restricted sense) the study of the action of drugs. .The pharmacologist studies the action of drugs on the tissues and structures of living things. The practicing physician does not require a knowledge of INTRODUCTION 19 pharmacognosy, and he needs only such knowledge of pharmacy as may prove helpful to him in prescribing the drugs he desires his patient to have. But his knowledge of pharmacology should be extensive. Drugs are either: (i) Pure chemicals, such as sodium bicar- bonate or potassium iodide; (2) mixed mineral products, such as petroleum oil, vaseline, or ichthyol; or (3) certain animal or plant parts or products. Of animal nature or origin are musk, canthar- ides, adrenaline, lard, honey; and of plant nature or origin are herbs, barks, roots, leaves, fruits, seeds, resins, alkaloids, etc. "Crude drugs" are the commercial forms of the natural animal or plant drugs as they are brought to the market. Their em- ployment in medicine is due to the fact that they contain or yield more or less definite chemic bodies of medicinal value. These bodies are known as the "active constituents." In some cases these constituents are found in all parts of a plant, so that the whole plant is marketed as the crude drug; but mostly they occur in one part only, such as the leaf or root, or are stored in greatest abundance in one part, so that that part is selected for the market and is the crude drug. Sometimes, as in the case of asafetida, an exudate contains the active constituents and is the crude drug, no structural part of the plant being marketed at all. The crude drug of digitalis is the dry leaf, the leaf of the digitalis plant being the chief depository of the peculiar constituents on which digitalis depends for its medicinal activity; the crude drug of rhubarb is the dried root; of peppermint, the leaves and flower- ing tops; of cascara, the bark; of opium, the dried milk juice; of Spanish fly, the whole dried insect. THE CONSTITUENTS OF ORGANIC DRUGS These may be classified into: i. The Active Constituents. 2. The Inert Constituents. The latter are the cellulose, wood, and other structural parts of the drug, and in some instances starch, albumen, fat, wax, coloring-matter, and other substances which have no distinct pharmacologic action, though their presence in a preparation may have a modifying effect on the absorbability and activity of the active pharmacologic constituents. The active constituents may be active in two different ways, viz.: pharmacologically active, i. e., having an action on living animal tissues, and pharmaceutically active, i. e., capable of causing precipitation or otherwise notable chemic changes in a prescrip- tion or preparation. Both kinds are found in cinchona bark, which contains not only quinine and other alkaloids upon which 20 PHARMACOLOGY AND THERAPEUTICS its pharmacologic activity depends, but also tannic acid, an astringent drug. In an ordinary dose of cinchona the tannic acid is too little in amount to have any important astringent effect, and is, therefore, not pharmacologically active; yet if the cinchona preparation is mixed with a preparation of iron, the tannic acid becomes pharmaceutically active and changes the iron salt into ink. Again, the pharmacologically active principles of digitalis are not readily soluble in water, so an aqueous preparation, such as the infusion, would not represent the activity of digitalis were it not for the fact that digitalis also contains a body which possesses the peculiar property of rendering the active medicinal principles soluble in water. This body (digitonin) is, therefore, pharmaceutically active, and as such is important. A constituent is called an active principle when to it may be attributed, either wholly or in part, the physiologic action of the drug. The active constituents of organic drugs may be either: a. Single chemic bodies, or b. Mixtures of such a nature that separation into their com- ponents is not advantageous. The classes of active constituents are: A. The Single Chemicals. 1. Plant acids and their salts. 2. Alkaloids. 3. Neutral principles. 4. Toxalbumins. 5. Ferments. 6. Sugars, starches, and gums. 7. Tannins. B. The Mixtures. 1. Fixed oils, fats, and waxes. 2. Volatile oils. 3. Resins. 4. Oleoresins. 5. Gum-resin^. 6. Balsams. The last three are natural exudations from plants. 1. Plant Acids and Their Salts. The citric acid of lemons, the tartaric acid of grapes, benzoic, cinnamic, salicylic, tannic acid, and some of their salts are of interest pharmacologically. Glycyrrhizin, the sweet principle of glycyrrhiza (licorice), is really glycyrrhizic acid, and is sweet to the taste only in the form of alkaline salts. It is precipitated and rendered tasteless by acids. 2. Alkaloids. -These are a class of organic bodies of alkaline THE CONSTITUENTS OF ORGANIC DRUGS 21 reaction, composed of carbon, hydrogen, and nitrogen, and some- times other elements. The class includes a great many of our most powerful drugs. Their basic or alkaline nature gives the name alkaloid (alkali and eidos, resembling). They possess the power of neutralizing acids with the formation of salts, and in doing so take up the acid without the liberation of hydrogen. In this respect they resemble ammonia, and differ from the alkali metals. Na + HC1 = NaCl + H. NH 3 4- HC1 = NH 3 .HC1 2 (strychnine) + HC1 = C^H^ Some of the alkaloids are strongly basic, while others, such as caffeine, are so feebly basic that they are with difficulty made to form salts at all. Most are monacid, uniting one molecule of the alkaloid for each basic hydrogen in the acid. A few are diacid. Quinine forms two different salts with acid, those with sulphuric acid, for example, being quinine sulphate, the neutral sulphate, in which two molecules of quinine unite with one mole- cule of the dibasic sulphuric acid, (020^24X202)2. H^SC^-f-yH^O, and quinine bisulphate, the acid sulphate, in which only one molecule of quinine unites with each molecule of sulphuric acid, C2oH 2 4N 2 O 2 .H2SO.i+7H 2 O. The uncombined alkaloids, to dis- tinguish them from the "alkaloidal salts," are known as "pure alkaloids," and are not much employed. Nomenclature. To distinguish these basic substances from the neutral principles, the United States Pharmacopoeia makes all the names of alkaloids end in ine (Latin, ina), as quinine (quinina), cocaine (cocaina); and the names of the neutral prin- ciples end in in (Latin, inum), as digitalin (digitalinum), salicin (salicinum). This is a simple device for distinction, and it serves a good purpose. It is to be regretted that this distinctive spelling is not followed in all the text-books. The old form, ending in ia, as quinia, morphia, strychnia, is now obsolete. Solubility. The pure alkaloids are, as a rule, not readily soluble in water, but they dissolve more or less readily in alcohol, ether, chloroform, and the fixed and volatile oils. The alkaloidal salts, on the contrary, are mostly quite soluble in water, and fairly so in alcohol, but dissolve with difficulty in ether, chloro- form, and the oils. For example, atropine, the pure alkaloid, is soluble in 455 parts of water, in 1.5 parts of alcohol or chloro- form, and in 25 parts of ether; while atr opine sulphate, the salt in common use, is soluble in 0.38 part of water (less than its own weight) ; in 5 parts of alcohol, in 420 parts of chloroform, and in 3000 parts of ether. Commonly in practice we employ the 22 PHARMACOLOGY AND THERAPEUTICS salts only, but when a solution is to be made in oil, or chloroform, or ether, we must use the pure alkaloid. Incompatibles. Alkaloids have extensive chemic affinities, and there are many reagents which are used in the laboratory as tests or precipitants for them. As physicians, however, we need know only their common prescription incompatibles, i. e., those substances which form precipitates with alkaloidal salts, and which we would be likely thoughtlessly to include in a prescrip- tion containing an alkaloidal salt. Such common prescription incompatibles are: 1. Alkalies, which combine with the acid radicle and throw the less soluble pure alkaloid out of solution (some of the alka- loids are destroyed by strong alkalies). 2. Tannic acid, which forms the comparatively insoluble tannate. 3. Iodine, iodides, and bromides, which form the compara- tively insoluble iodides and bromides, or double salts. 4. Mercuric chloride, which forms insoluble double salts. In these cases it must be borne in mind that the alkaloid is merely rendered less soluble in water, so if a large volume of water or a fair percentage of alcohol is present, the precipitation may not occur. Physical Character. Most of the alkaloids are solids, as morphine, quinine, and strychnine. A few of them are volatile liquids, as nicotine, pilocarpine, coniine, and lobeline, but these latter mostly form non-volatile solid salts, which can be readily handled. Some are crystalline, some amorphous. Some are deliquescent and liquefy in moist air, as pilocarpine hydro- chloride; others are efflorescent and lose weight in dry air, as the sulphate of strychnine and the sulphate of quinine. Some are decomposed by the heat of boiling water; others can stand much higher temperatures. Cocaine is decomposed at about 98 C. (just below the boiling-point of water), and its solutions cannot, therefore, be sterilized safely by boiling. Some which will stand a higher temperature for a short time are: aconitine, atropine, brucine, cevadine, codeine, morphine, narcotine, and strychnine; so that aqueous or alcoholic liquids containing these alkaloids may be brought to the boiling-point without fear of harm. Taste. The taste of alkaloids is bitter that of strychnine and quinine intensely so; that of morphine, codeine, and caffeine mildly so. Occurrence. Alkaloids occur almost wholly in the higher plants the dicotyledons. A few are found in the lower plants, and one of these, muscarine, is the poisonous principle in a few THE CONSTITUENTS OF ORGANIC DRUGS 23 of the poisonous mushrooms. Some plants furnish many alka- loids, opium, for example, yielding about nineteen, and cinchona about thirty-two. In some cases one alkaloid is found in one part of the plant and another in a wholly different part of the same plant; often several are found together. Where a number of alkaloids occur in one plant they are usually closely related, both chemically and pharmacologically, as in the case of the alkaloids of belladonna; but in some instances they are quite different, and may even be pharmacologically antagonistic, as physostig- mine and calabarine in the Calabar bean. It is of interest that some alkaloids are confined entirely to one botanical family, as atropine, which is not found outside of the potato family (Solanacece) ; or to one plant genus, as pilo- carpine; or to a particular species, as morphine in the oriental poppy, and even then, perhaps, only when it is grown in a par- ticular region. Others, however, are of wider distribution, as caffeine, which is found in various parts of the world in wholly unrelated plants, and berberine, found in the northeastern region of the United States in the barberry, hydrastis, and moonseed. The amount of alkaloid present in different specimens of a drug may vary within wide limits, as might be expected in plants growing under such different conditions of soil, climate, and weather, and subjected to different methods of collecting, drying, preserving, etc. Yet the best quality of most drugs is notably uniform in its alkaloidal content. Alkaloids produced by animals are more commonly known as leukomains and ptomains leukomains, when they are formed by the body-cells, that is, are products of metabolism, for ex- ample, epinephrine; and ptomains, when they result from micro- bic decomposition of dead material, especially the amino-acids. Ptomain-poisoning from decomposing foods may closely resemble poisoning by plant alkaloids; in fact, one ptomain is called ptomatropine, because it gives the symptoms of atropine poison- ing. Certain of the alkaloids, as choline, neurine, xanthine, and some of the ptomains are produced by both plants and ani- mals, so that the dividing- line is artificial and not based on chemic nature. Artificial Alkaloids. A number of alkaloids can be prepared artificially, and theophylline, which occurs naturally in minute quantity in tea-leaves, was the first to be produced synthetically on a commercial scale. Suprarenine, a synthetic with the actions of epinephrine, is also marketed. In addition, the Pharmacopoeia recognizes four bodies which are manufactured from plant alkaloids, viz., apomorphine, prepared from morphine by dehydra- tion; cotarnine, prepared by hydrolizing narcotine; homat rapine. 24 PHARMACOLOGY AND THERAPEUTICS which results from the action of mandelic acid upon tropine, the mother-substance of atropine; and hydrastinine, obtained by the oxidation of hydrastine. Two other artificial substances of the Pharmacopoeia, hexamethylenamine, or urotropine, and antipyrine, have close chemic affiliations with the alkaloid group. That there may be differences in the physiologic actions of the different salts of an alkaloid is suggested by the experiments of O. H. Brown, 1907, on paramcecium. For example, in ~ solutions of quinine salts the paramcecia lived in the sulphate thirty seconds, in the chloride, thirty seconds, in the hypo- phosphite, fifteen seconds, in the bisulphate, three hundred and thirty seconds. In ^ solution of strychnine salts they lived in the acetate five seconds, in the nitrate, forty-five seconds, in the sulphate, seventy seconds, in the hypophosphite, seven hundred and twenty seconds. They were less readily poisoned by ~ solutions of morphine salts, so the percentage of para- mcecia dead at the end of a given time was taken. At the end of two hours, of those in the acetate none were dead, while of those in the valerianate 5 per cent., of those in the sulphate 60 per cent., and of those in the meconate 90 per cent., were dead. 3. Neutral Principles. Besides acid and basic substances, plants furnish a large number of proximate principles which are chemically neutral. Their names end in in (Latin, inuwi), in accordance with the pharmacopceial rule to distinguish them from alkaloids, as stated above. The most important are the glucosides (glycosides) . The glucosides are a class of bodies which, under the in- fluence of certain agents, decompose and yield some form of sugar, together with one or more other bodies. These decom- posing agents may be heat, dilute acids, strong alkalies, enzymes, bacteria, or fungi. Most of the glucosides yield glucose, whence the name; a few of them yield other sugars. Chemically, they are a loose group, and beyond their readiness of decomposition and their power to yield sugar, have no essential characters in common. They follow no rules as to solubility, or taste, or im- portance, some of them being bitter, some not; some soluble in water or alcohol, some not; some inert pharmacologically, and others, such as the active principles of digitalis, strophanthus, and cascara, being among our most valued remedies. The only glucosides official in the United States Pharmacopoeia are salicin, the active principle of willow and poplar barks, and strophanthin, the active principle of strophanthus. The gluco- sidal nature of these bodies may be readily shown, for if they are warmed with dilute hydrochloric acid, the mixture will give THE CONSTITUENTS OF ORGANIC DRUGS 25 the glucose test with Fehling's solution. The products of the de- composition of salicin are glucose and saligenin (salicyl alcohol). C 6 Hn05.O.C6H 4 CH 2 OH + H 2 O = C 6 H 12 O 6 + C 6 H 4 .OH.CH 2 OH Salicin Glucose Salicyl alcohol The ready decomposition of these bodies indicates that prep- arations of drugs such as digitalis, which depend upon glucosides for their activity, must neither be mixed with strong alkalies or acids nor subjected to continued heat. There are two glucosides, amygdalin and sinigrin, which are practically inert pharmacologically, but are of great importance because of the products of their decomposition by certain en- zymes. Amygdalin, with its particular enzyme, emulsin, occurs in bitter almonds, peach-pits, wild-cherry bark, and cherry-laurel leaves. In the presence of water the enzyme emulsin acts upon the amygdalin, causing it to split up into glucose, hydrocyanic acid (prussic acid), and benzaldehyde. The mixture of the two latter constitutes the highly poisonous volatile "oil of bitter almond," which is required by the Pharmacopoeia to contain not less than 85 per cent, of benzaldehyde and not less than 2 per cent, nor more than 4 per cent, of hydrocyanic acid. Amygdalin Water Glucose Prussic acid Benzaldehyde C 20 H 27 NOu.3H 2 O + 2 H 2 = 2 C 6 Hi 2 O 6 + HCN + C 6 H 6 COH + 3 H 2 O The amygdalin occurs in bitter almond to the extent of 1.75 to 3 per cent., so that one ounce of bitter almonds would be a poisonous dose. As enzymes are destroyed by heat and rendered inert by alcohol, no preparation of bitter almond, wild-cherry bark, or cherry-laurel leaves should be made until the drug has first been steeped in lukewarm or cold water to permit this enzyme action and the development of these products. If the crude drug should be extracted in the usual way by alcohol or very hot water, without preliminary steeping, the preparation would be inert. Sweet almonds also contain emulsin, but no amygdalin, hence are inert pharmacologically and may be swallowed ad libitum. Sinigrin, with its peculiar enzyme, my rosin, occurs in black mustard seed, and to some extent in horseradish root. Mustard flour, as purchased, contains nothing irritating, and has the odor of ordinary flour; but as soon as it is mixed with water, it develops the odor and irritant properties characteristic of mustard. This is because, in the presence of water, the myrosin acts upon the sinigrin and splits it up to yield glucose, potassium bisulphate, 26 PHARMACOLOGY AND THERAPEUTICS and allyl isothiocyanate, the last-named substance being the highly irritating "volatile oil of mustard." Sinigrin Glucose Potassium bisulphate Allyl isothiocyanate C 10 H ls NS20,oK = C 6 H 12 6 + KHS0 4 + C 3 H 6 CNS As this enzyme is rendered inert by a temperature above 60 C. (140 F.), very hot water should not be used in preparing a mustard poultice or a mustard foot-bath. It is of interest that this volatile oil of mustard, when shaken with alcohol and am- monia water, deposits more than its own weight of crystals of thiosinamine, a drug which has been used by injection for the removal of excessive scar tissue. (See Part II.) C 3 H 5 CNS + NH 3 = C 3 H 6 CSN 2 H3. White mustard seed also contains myrosin, but instead of sinigrin, it contains another glucoside, sinalbin. Under the influence of myrosin in the presence of water sinalbin splits up into entirely different products, viz., glucose, sinapine sulphate (an alkaloidal salt), and acrinyl isothiocyanate (an irritant but non- volatile oil). Phlorhizin (phloridzin or phlorizin) is a glucoside obtained from the bark of apple, pear, cherry, and plum trees, especially the bark of the root. It is nearly insoluble in cold water, but readily soluble in alcohol and alkaline liquids. Its administra- tion is followed by glycosuria without hyperglycemia, the gly- cosuria resulting from changes in the kidneys by which they are made unable to keep back the normal sugar in the blood; in fact, there is a hypoglycemia. In other words, the "secretion threshold" of the kidneys for sugar (Magnus) is lowered. Phlor- hizin is diuretic, this action, according to Loewi (1903), being due to the prevention of kidney reabsorption by the sugar of the urine. It has been used as a test of the functional power of the kidneys. Besides the glucosides, there are other neutral principles of importance in medicine, such as santonin, aloin, elaterin, chrysarobin, etc. Some of those whose chief characteristic is bitterness, as quassin of quassia, and chamomillin of chamomile, are often spoken of as bitter principles or amaroids. 4. Toxalbumins or Toxins. An extensive class of poisonous compounds, probably protein, of which some occur in plants, some constitute the poisonous products of bacteria, and some are the poisonous agents in the venom of snakes, scorpions, the tarantula, the Gila monster, spiders, and other poisonous animals. It is characteristic of these substances that their poisonous THE CONSTITUENTS OF ORGANIC DRUGS 27 symptoms come on only after a latent period, and that, in suscep- tible animals, immunity to the poison may be established by the repeated administration of small doses. This immunity is spe- cific, the immunity to one toxin conferring no protection from poisoning by another. Aside from those produced by bacteria and animals, the most important known toxalbumins are: 1. Ricin, which occurs in the castor-oil bean, the seed of Ricinus communis. The poisonous ricin is left behind in the extraction of the castor oil; but there have been some cases of poisoning from the ingestion of the whole seeds. The author has met with a case in New York. The symptoms are violent gastro-enteritis and collapse. 2. Abrin, which occurs in jequirity beans (Abrus precatorius) , the little shiny red seeds with circular black spot which one often sees in the shops in baskets of sea-shells. It is used as an irritant in the eye in some cases of corneal opacity. j. Amanita toxin, which occurs in the death's head fungus, Amanita phalloides, and is responsible for many cases of mush- room-poisoning. (See under Muscarine.) Hypersusceptibility to a toxalbumin in the pollen of certain plants would seem to be the explanation of the attacks of hay- fever and hay-asthma to which so many people are subject (Meltzer and Auer and Wolff-Eisner). 5. The Ferments or Enzymes. The enzymes are a class of bodies capable of instituting chemic changes without apparently entering into the reaction or forming a part of the end-products. Their activity is very persistent, but not unlimited. They are unstable bodies, and are nearly all destroyed at a temperature of about 60 C. (140 F.). Examples a,ie:' invertase, which trans- forms cane-sugar into fructose and glucose; lactase, which changes sugar-of-milk into glucose and galactose; maltose, which converts maltose into glucose; emulsin and myrosin, of whose reactions with certain glucosides we have- spoken, and pepsin, trypsin, and the other enzymes of the digestive tract. A number of enzymes have a reversible action, i. e., can, under certain circum- stances, bring about changes just the reverse of the usual. It is not improbable that a great many of the metabolic changes going on in the animal body are brought about by en- zymes. The oxidases, for example, are concerned in the oxidation processes of the tissues. 6. The Sugars, Starches, and Gums. These are carbohy- drates of very slight pharmacologic action and of little importance as remedies, but of importance in dietetics and the arts. Cane-sugar or common sugar (Latin, saccJiarum], CioH^Oii, 28 PHARMACOLOGY AND THERAPEUTICS is employed to make the various syrups and as a sweetening agent. It is found in abundance in the sap of the sugar maple, in sugar-cane, in sorghum, and in the root of the sugar-beet. It dissolves in half its weight of water and is insoluble in alcohol. It ferments with yeast, but does not reduce Fehling's solution. Sugar of milk (Latin, saccharum lactis), C^H^On, is obtained from milk, and requires for solution five times its weight of water. It reduces Fehling's solution, but does not ferment with yeast. It is not very sweet, and is chiefly used as a nutritive in infant feeding and typhoid fever. In pharmacy it is employed as a diluent. Cheap brands of sugar-of-milk may contain lactic acid and traces of milk proteins, which form a nidus for bacterial growth, or they may be adulterated with cane-sugar or glucose. Glwose (Latin, glucosum), C^M^Oe, is described in Part II. Lemtlose, C 6 Hi 2 O 6 , a form of sugar abundant in honey and some fruits, is a carbohydrate which has been found in many instances to be more easily appropriated by diabetics than are cane-sugar, glucose, and many starchy foods (von Noorden). It has been used by Strauss as a test of the functional power of the liver, the assertion being made that if the levulose is re- coverable from the urine unchanged, the liver is seriously im- paired. In Foster's experiments 3 out of 10 normal cases re- sponded with levulosuria, and only 14 out of 20 cases of well- marked cirrhosis. Churchman, Frey, and others obtained similar results. The test cannot, therefore, be depended upon. Manna, derived from a tree of the ash family (Fraxinus ornus), contains the sugar, mannite, CeH^O,;, and is laxative. Comstar ch (amylum), C 6 H 10 O5, is the starch in common use. It is employed as a dusting-powder for the skin, or for pills to prevent their sticking" together, or in the form of starch water as a soothing injection in irritative conditions of the lower bowel. To make starch water, the starch should first be hydrolyzed by mixing about a teaspoonful with two ounces of water, boiling until it forms a translucent paste, then diluting with water to one-half pint. It may be made by simply boiling a teaspoonful of starch with the requisite quantity of water at the outset, but by this method the starch does not so readily hydrolyze. Corn- starch and arrowroot starch (maranta) are used as foods. The latter has long had the reputation of being the best kind of starch for the feeding of children and invalids, but it is not now so much employed as formerly. The gums are chemically closely related to the sugars and starches. There are two official, viz., acacia, which consists chiefly of arabinose, Ci 2 H 22 OnCa, and tragacanlh, which can be made to yield arabinose. THE CONSTITUENTS OF ORGANIC DRUGS 29 Acacia (gum arable) is soluble in water and is demulcent. Its chief uses are pharmaceutic, as in the manufacture of muci- lage and emulsions, and to give increased viscosity to mixtures containing heavy insoluble powders (so that the powder may be held in temporary suspension in the liquid during the pouring of the dose). Its solutions ferment readily, turn sour, and be- come ropy; and it is precipitated from aqueous solution by alcohol. Tragacanth does not dissolve in water, but swells up and makes an adhesive paste. Dextrin (C 6 Hi O 5 ), known as British gum, is prepared from starch, being an intermediate stage in the change of starch to maltose or glucose. It is soluble in water, is sweetish to the taste and slightly laxative, and is the chief ingredient of some of the proprietary infant foods. It is the gum generally used on postage- stamps, and in paste form is frequently employed for attaching labels. Cherry-gum is an insoluble type of gum of no medical interest. A mucilage is an adhesive, aqueous liquid or paste made from a gum. The official mucilages are those of acacia and tragacanth, both used for mechanical purposes. 7. The Tannins or Tannic Acids. These are a class of im- perfectly denned astringent bodies of the aromatic group. They are all acids which form salts, and some of them are glucosidal in nature. They precipitate alkaloids, mercuric chloride, and other salts of the heavy metals, and also proteins and gelatin. With iron compounds they make ink (blue to black in some cases, green in others), and with the connective tissue, protein, and gelatinous material of hides they make leather. This suggests the unwisdom of administering a gelatin-coated pill or capsule at the same time as a tannin-containing drug. They are freely but slowly soluble in water, and readily soluble in alcohol and glycerin. They occur mostly in the bark of trees, and in the plant-galls which result from punctures of insects. The various tannins are given the names of the plants which yield them, e. g., that from cinchona is called cinchotannin, or cinchotannic acid, that from kino is kinotannic acid, etc. The official "tannic acid" is quercitannin, and is derived from oak-galls. It is considered in Part II. 8. The Fixed Oils, Fats, and Waxes. (a) The fixed oils and fats are mixtures of the three bodies, olein (liquid), palmitin (semisolid), and stearin (solid), or close relatives of these, and in addition usually small amounts of other bodies. Olein, pal- mitin, and stearin are compounds of glyceryl, C 3 H 5 =, with radicles of the various fatty acids. With alkalies they form 30 PHARMACOLOGY AND THERAPEUTICS soaps and glycerin. Castile soap, for example, is made by the action of sodium hydroxide on olive oil, which is nearly pure olein: 2)3 + 3NaOH = 3 NaC 18 H 3 3O 2 + C,H S (OH), Olein Sodium Castile soap Glycerin hydroxide The oils differ from the fats only in the relative proportions of these basal ingredients, the oils having more of the olein, which gives them a liquid consistence at ordinary temperatures, and the fats more of the stearin and palmitin, which make them solid or semisolid. The fats and fixed oils have a greasy feeling and are non- volatile, so that they leave a permanent grease-spot. They can- not be distilled, for by heat they are decomposed, with the genera- tion of disagreeable acrid vapors (the familiar odor of burning grease). They are insoluble in water and alcohol (except castor oil and croton oil, which dissolve in alcohol), and are readily soluble in ether, chloroform, and benzin. They are almost all bland, non-irritating substances with nutrient and emollient properties; but on exposure to the air they gradually become rancid by the liberation of odorous and irritating fatty acids. Linseed oil (oleum lini), if exposed to the air in thin layers, will dry like varnish, but most of the oils are of the non-drying type. A few of the fats and oils are of animal origin, e. g., butter, lard (adeps), tallow, suet (sevum), and cod-liver oil (oleum morrhuae) ; but the majority are of vegetable origin, as almond, cotton- seed, cocoanut, linseed, olive and peanut oils, and cocoa-butter. These are found chiefly in seeds or in fruits, the best qualities being usually obtained with the least compression necessary and in the cold; the poorer qualities by expression between heated plates. They may also be extracted by a suitable solvent, such as benzin, which is afterward removed by distillation. Cocoa-butter or cacao-butter (oleum theobromatis) is obtained from chocolate-seeds by compression between hot or cold plates. The fat is the cocoa-butter, and the residue constitutes "cocoa." This fat has a very slight odor and taste of chocolate, is firm and rather brittle at ordinary temperatures, melts at the temperature of the body, and does not readily become rancid. It is used as a basis for the manufacture of suppositories, these retaining their shape at ordinary temperatures and quickly melting when in- serted into a body orifice, such as the rectum. Castor oil (oleum ricini) and croton oil (oleum tiglii) differ from the other fixed oils in being soluble in alcohol and in possess- ing special cathartic properties. (See Part II.) Castor oil is sometimes added to alcoholic hair lotions to prevent drying of the scalp (about 10 minims to a 3-ounce bottle). THE CONSTITUENTS OF ORGANIC DRUGS 3! Glycerin (glycerinum) is a product of the saponification of fats or fixed oils. (See Reaction, page 29.) It is thick and viscid, has a sweet taste, mixes freely with water and alcohol, and has great affinity for water. It has extensive employment in phar- macy as a solvent, as a softening agent and preservative, and as a means for increasing the viscosity of liquids. Action and Uses. Applied in concentrated form to mucous membranes, it is astringent, causing the superficial cells to shrink by abstraction of water. For this reason it is used as an applica- tion to a relaxed uvula or pharynx. Diluted with water or rose- water, as in "rose-water and glycerin" (two parts to one) and in "calamine lotion" (see Zinc Carbonate), it is used upon the skin as an emollient, serving to prevent the drying of the epithelium. With lemon-juice or rose-water it is also used as an application to the dry tongue of fever patients. In mixtures for internal use it serves as a sweetening agent and is slightly laxative. In diabetes it tends to increase the glycosuria. For use in the rectum as a mild irritant and lubricant it may be added to an ordinary enema, or used in the form of glycerin suppositories (suppositoria glyc- erini), which hold 95 per cent, of glycerin. To soften hard feces, | ounce (15 c.c.) may be added to half a pint of soapsuds. Hertz, in "The Sensibility of the Alimentary Canal," 1911, states that glycerin acts as an irritant to the anal canal, but not to the rectum. The glycerites are a class of official preparations in which glycerin is the solvent. Soaps. The soluble or detergent soaps are prepared by the action of an alkali upon a fat or oil, the potash soaps being soft, and those of soda being hard. They contain glycerin unless this is removed by washing, are soluble in alcohol and water, and have an alkaline reaction. Soap (sapo), Castile or hard soap, is prepared by the action of sodium hydroxide on olive oil. It is used in the manufacture of pills, soap liniment, chloroform liniment, and saponified tooth powders. (For the chemic reaction see above, under "Fixed Oils and Fats.") Some time ago a proprietary house put out a preparation described as acid sodium oleate. It was extensively prescribed by physicians, though it was nothing but Castile soap containing free fatty acid. Soft soap or green soap (sapo mollis) is prepared from potas- sium hydroxide and linseed oil, without the removal of the de- veloped glycerin, and is employed extensively for cleansing the hands and skin preparatory to operative work. A liquefied form of it is the liniment of soft soap (linimentum saponis mollis), commonly called the "tincture of green soap," made by dissolving soft soap in alcohol and adding oil of lavender flowers. 32 PHARMACOLOGY AND THERAPEUTICS Lipoids or Fat Allies. Those of interest to us are lecithin and cholesterol. Lecithin is found in certain animal tissues, especially the central nervous system and the yolk of egg. Of the fatty substances of the latter, it constitutes about 70 per cent. It is a compound of glycerin and choline with stearic, palmitic, and phosphoric acids, and is chemically a complex glycerophosphate. It can be saponified by alkalies. (See Phosphorus.) Cholesterol, a monatomic alcohol, C 26 H 4 3OH, is a crystalline body found in all forms of protoplasm, but especially in brain tissue. It also occurs in abundance in the yolk of egg, in milk, cream, and butter, and in the bile. Gall-stones are frequently the result of its precipitation in the bile-ducts or gall-bladder. It has been suggested in anemia, especially pernicious anemia, in doses of 15 grains (i gm.) three times a day; but it is best given in the form of milk and eggs. Quite probably it plays no role in therapeutics. Lanolin (adeps lanae hydrosus), the purified fat of the wool of sheep, mixed with 30 per cent, of water, is made up of com- pounds of various fatty acids with isocholesterin. It is thus not a glyceryl fat, but a cholesterin fat, and is often classed with the waxes. It is yellowish white, of soft, sticky consistence, and, unlike the glyceryl fats, cannot be saponified by boiling with an aqueous solution of potash. Its greatest interest for us consists in its power to absorb more than its own weight of water, which makes it of use as an ointment base for substances in aqueous solution. It is a secretion of the sebaceous type, not absorbable by the sheep's skin. As to its absorbability by the human skin there are conflicting reports, but most observers claim ready absorption. Patschkowski applied an ointment of lanolin and potassium iodide and obtained iodine in the urine in half an hour. Bloor states that it is not absorbed when administered by mouth. The waxes are esters of the fatty acids with hydrocarbon radicles higher in the series than glyceryl. They are of firmer consistence than the fats, have a higher melting-point, and cannot be saponified by boiling with an aqueous solution of potash. Beeswax is from the honey-bee, and is known in pharmacy as yellow wax fcera flava). When bleached it is called white wax (cera alba). It is chiefly myricyl palmitatc, C3oH 6 i.CifiH 3 iO 2 . Spermaceti (cetaceum) is obtained from the head of the sperm-whale, a single whale yielding many barrels. It consists chiefly of cetyl pulinitute, CwHw-CieHsiOs. The best "cold- creams" contain spermaceti and white wax; the poor ones are made of tallow. The ointments or salves in common use are prepared mostly THE CONSTITUENTS OF ORGANIC DRUGS 33 from lard, suet, lanolin, white wax, yellow wax, spermaceti, and petrolatum (a mineral product). The mineral oils do not belong among the constituents of organic drugs, but for convenience may be mentioned with the other oils. They are petroleum products, are mixtures of hydro- carbons, and are not subject to rancidity. The official petroleum products are: Petroleum benzin (benzinum purificatum see Part II). (Kerosene oil is a limpid petroleum product from which, for safety, the more volatile hydrocarbons are removed by distilla- tion. It is not official.) Liquid petrolatum (liquid paraffin) is a much heavier and more oily liquid than kerosene. Trade names for some of its slight modifications are "liquid albolene" and "liquid vaseline." It has a specific gravity of 0.828 to 0.905 at 25 C. That having a viscosity of 3.1 or over is known as "heavy liquid petrolatum/' and that with a viscosity of 3 or less is "light liquid petrolatum." Petrolatum (petrolatum) is practically what we know as vase- line. The Pharmacopoeia specifies "without odor or taste." White petrolatum (petrolatum album), a decolorized product, has been marketed under the trade names of "solid albolene" and "white vaseline." Par a fin (paraffinum) is a white, waxy solid, the purified residue left after the liquid portion of the crude petroleum has been removed. Petrolatum and white petrolatum are of ointment consist- ence, and have the advantage in ointments of not becoming rancid. But their value in ointments is limited, as they are not absorbed through the skin and do not readily penetrate animal and vegetable parasites. In intestinal or pancreatic fistulas, vaseline and paraffin, being non-saponifiable, have been found efficient in protecting the skin from erosion; while the salves con- taining lard or other animal or vegetable fats become saponified by the alkaline secretions and are useless or harmful. Rovsing recommends vaseline as an injection into the joint in dry arthri- tis; and Wilkie, the liquid vaseline to prevent adhesions in ab- dominal surgery. The writer has employed liquid petrolatum in the dry joints of rheumatoid arthritis with temporary benefit. Liquid petrolatum is used as the vehicle in oily sprays for nose and throat, as the agent of suspension of the insoluble salts of mercury for hypodermatic use, as a softening enema for hard feces, and by mouth, as a mild laxative; dose, i ounce (30 c.c.) two or three times a clay. (See Cathartics, Part II.) Kerosene and liquid petrolatum, taken internally, are completely unab- sorbed, and serve merely to increase the bulk of the intestinal 3 34 PHARMACOLOGY AND THERAPEUTICS contents and to soften the feces. They retard the emptying of the stomach. Paraffin with added resorcin, eucalyptol, or other antiseptics is used to make a wax dressing for burns. 9. The Volatile Oils. These are the substances to which many plants owe their characteristic or essential odors. On this account they are often spoken of as "essential oils," or as the "es- sences" of plants. They differ from the fixed oils in that 1. They are volatile, therefore can be distilled and do not leave a permanent grease stain. 2. They do not form soaps with alkalies. 3. They are soluble enough in water to impart to it their odor and taste. 4. They do not become rancid, but on exposure to light and air tend to oxidize and resinify. They mix freely in any proportions with chloroform, ether, and the fixed oils, and are all soluble in absolute alcohol. Some, like oil of turpentine, require several times their own weight of official alcohol for complete solution. They are all mixtures, some of them quite complex. Occurrence. Most of them are found in plants, and each in a definite part of the plant from which it is derived, e. g., oil of orange in the rind of the fruit; oil of cinnamon in the bark; oil of rose in the petals. From these parts they are obtained either by distillation or by means of a suitable solvent, such as benzin, which is afterward removed. Some of the delicate essential oil? used in perfumery, as violet and heliotrope, are obtained by spreading the petals or flowers between wax plates, and after ward separating the absorbed oil from the wax. A few of the volatile oils do not exist in the living plant, ancf are formed either by the action of ferments on glucosides in the presence of water, as the oil of bitter almonds, or by destructive distillation. These latter are known as empyrciimalic oils. For convenience, the volatile oils preexisting in the plant may be grouped according to their nature, and those developed in the plant part by artificial means may be grouped according to their method of production. 11. Terpenes, C X H X (oils of turpentine, juniper, 2. Terpenes + stearoptens (oils of lemon, pepper- mint, etc.). B. Xot existing in plant as f ^. From enzyme action foils of mustard and bitter such, but developed ( almond), from plant constituents: ( 4. Empyreumatic (oil of cade, oil of tar, creosote). Group i is composed of oils which are mixtures of terpenes THE CONSTITUENTS OF ORGANIC DRUGS 35 (hemiterpenes, terpenes, sesquiterpenes, diterpenes, pinene, etc., CioHie), the simplest hydrocarbon oils of the aromatic series. Of all the volatile oils, they are the least soluble in water and the most ready to resinify and deteriorate. Examples are: the oils of copaiba, cubebs, erigeron, juniper, and turpentine. The last named consists almost wholly of dextrorotary pinene. Group 2 includes the mixtures of terpenes which are holding in solution one or more oxygenated bodies (of variable chemic nature, as aldehydes, ketones, ethers, acids, etc.). The terpene portion is known as the eleopten, and the oxygenated portion as the stearopten. The latter is usually solid, though sometimes liquid. It can be separated from the eleopten by cold (as the menthol of peppermint oil) or by fractional distillation. It is not always readily soluble in 95 per cent, alcohol. Examples of stearoptens which are separated and used by themselves are camphor and menthol. It is to the stearopten that the charac- teristic odor of these oils is chiefly due, but the amount of stearop- ten present varies with the different oils. For example, the oils of orange or lemon contain only a small percentage of their pecu- liar stearopten and are nearly all eleopten, while the oils of winter- green and birch are almost entirely composed of a liquid stea- ropten, which chemically is methyl salicylate. The oils of this group are for the most part more soluble in water, and, because of the stearopten, more agreeable in flavor than those of Group i , so they are largely used in the manufacture of the medicated waters and spirits. Some of them are heavier than water, as the oil of cinnamon. Group 3 contains those oils which do not preexist in the living plant, but result from ferment action in the presence of water. The official ones are the oil of bitter almond and the volatile oil of mustard. (For the reactions in the development of these oils see under Glucosides above.) Group 4 contains the empyreumatic oils, those which do not preexist in the plant, but result from its destructive distillation. The official ones are : Oil of cade (oleum cadinum) , from juniper wood, and oil of tar (oleum picis liquidae), from the wood of Pinus palustris and other species of pine. Both have a tarry odor, and are added to ointments for the treatment of chronic skin diseases. The syrup of tar (syrupus picis liquidae), in dose of 15 minims (i c.c.), is also used as an expectorant. Creosote is a mixture of phenols and phenol derivatives, ob- tained during the distillation of wood-tar, and has some of the properties of a volatile oil. The beechwood creosote is considered best for medicinal purposes. The volatile oils have marked pharmacologic actions, but do 36 PHARMACOLOGY AND THERAPEUTICS not belong to a single pharmacologic group. Their action will be considered in Part II. 10. The resins are all, or nearly all, mixtures of several differ- ent substances. They are an ill-defined group, forming amor- phous masses which have a conchoidal shining fracture. They are insoluble in water and soluble in ether, chloroform, and the volatile oils. Many, but not all, of them are soluble in alcohol, and most of them dissolve in alkali with the formation of a non- detergent resin-soap, which is miscible with water. Their com- position is still a subject of study. Some of them, and perhaps all of them, are formed by the oxidation of volatile oils, in association with which in the plant they mostly occur. Common rosin, and the resins of jalap, podophyllum, and scammony are official resins. 11. The oleoresins are the natural plant exudates which con- tain both volatile oil and resin. Balsam of copaiba, Canada bal- sam, and crude turpentine are examples, common rosin and oil of turpentine being the components of crude turpentine. (These natural oleoresins must be distinguished from the pharmaceutic oleoresins, which are artificial ethereal extracts of oily and resin- ous drugs, i. e., extracts made with ether.) 12. The gum resins are generally oleoresins in natural ad- mixture with gum. They are obtained by the evaporation of the milky juices of certain plants. On rubbing a gum resin with water the gum dissolves, and with the oil and resin forms a milky emulsion. Asafetida and gamboge are examples. 13. The balsams are resinous or oleoresinous exudates which contain benzoic or cinnamic acid, or both. These latter impart a "balsamic" odor. Benzoin, storax, balsam of Tolu, and balsam of Peru are official examples. Many fragrant substances are incorrectly called "balsam," e. g., balsam of copaiba and Canada balsam, both of which are oleoresins. In some instances the resins, oleoresins, gum resins, and balsams are the only commercial representatives of their respective plants. Keratin is obtained from horn by dissolving out the albumin- ous matter with artificial digestion, and macerating the residue in ammonia. It is soluble in alkalies and insoluble in acids, and is employed as a coating for pills and capsules which it is desired to have pass through the stomach without action the so-called "enteric" pills. Theoretically, if the pills are given after meals, the coating should not dissolve in the stomach, and the medicinal agents should be set free only when the pills reach the alkaline intestinal contents. As a matter of fact, however, commercial keratin is not always proof against disintegration in the stomach, and as a coat in" must be considered unreliable. PHARMACEUTIC PREPARATIONS 37 PHARMACEUTIC PREPARATIONS The chemicals and the various mineral, plant, or animal crude drugs may be employed in medicine as such without change, e. g., sodium bicarbonate or cod-liver oil, or powdered digitalis leaves; or they may be made into pharmaceutic preparations, as the rhubarb and soda mixture, the emulsion of cod-liver oil, or the tincture of digitalis. Pharmaceutic preparations are the prepared forms into which drugs are made for convenient employment in medicine. It is not convenient, for instance, to administer cinchona in the form of cinchona bark. It would be a disagreeable task for a patient to chew the bitter bark, and difficult, because of the inert matter present, to obtain in this way the full physiologic activity of the drug. But the tincture of cinchona, a pharmaceutic preparation, represents the full physiologic activity of the drug, because the active principles are held in solution, and it is easily administered. In the preparation the drug or drugs (a) may remain un- changed, as in the emulsion of cod-liver oil, rhubarb pills, or powder of ipecac and opium (Dover's powder); or (b) may be changed by chemic reaction, as in Fowler's solution or Basham's mixture; or (c) may be made to yield their active constituents to a suitable solvent, as in preparations made by extraction. Preparations, too, may be employed in the manufacture of other preparations, as cinnamon water in making chalk mixture, and the extract of belladonna in making a belladonna plaster. Extraction is the process of obtaining the active constituents of an animal or vegetable drug by means of a suitable solvent. By this process the inert woody fiber, cellulose, and other matters that are insoluble in the solvent employed are left behind, so that only the soluble matters of the crude drug appear in the preparation. In extraction the solvent is known as the men- struum, and this differs with the different drugs or types of prep- aration. It may be water, alcohol, alcohol and water, alcohol and glycerin, glycerin, wine, acetic acid, ether, chloroform, etc. Official preparations made by extraction are: A. With aqueous solvent infusions and decoctions. B. With alcoholic solvent (in most instances) extracts, fluid- extracts, and tinctures. C. With wine wines. D. With diluted acetic acid vinegars. E. \Vith ether oleoresins. Preparations made by extraction represent the activity of the crude drug, but in addition to the active principles, always con- tain more or less physiologically inert matter which has gone into 38 PHARMACOLOGY AND THERAPEUTICS the solution. Such inert matter is known as the "extractive," and it consists of such substances as fat, wax, oil, tannin, chloro- phyll, etc. Such "extractive" is mostly colloidal in nature, and has a tendency to retard the absorption and the activity of the active constituents. Percentage Strength of Liquids. There are two types of percentage liquids the chemic and the pharmaceutic. The chemic percentage liquid deals only with weight, as chemic reac- tions involve relative weights regardless of volume. To make a 20 per cent, chemic solution, 20 grams of the substance to be dissolved are mixed with So grams of solvent; therefore, 100 grams (weighed) of the solution would furnish 20 grams of the contained ingredient. In the pharmaceutic percentage liquid, however, solids are weighed and liquids measured, so that in making a 20 per cent, pharmaceutic solution 20 grams of the substance to be dissolved are mixed with enough solvent to make the total measure 100 c.c. Of such solution, 100 c.c. (measured) will contain 20 grams of the drug. In the practice of medicine, liquid remedies are always administered by measure, for one can- not carry scales to the bedside; therefore the United States Pharmacopoeia adopts the pharmaceutic percentage liquid, so that a given measure will contain an easily calculated amount of each essential ingredient. The volumetric solutions used in chemic analysis are made on the same plan. By this method a very sol- uble chemical, such as potassium iodide, may be had in 100 per cent, solution. As an illustrative example of the difference between the chemic and the pharmaceutic percentage liquid, let us take a 10 per cent, solution of cocaine hydrochloride in normal saline. In the phar- maceutic solution, 10 grams of the cocaine salt are dissolved in a quantity of normal saline, and sufficient normal saline added to make the finished solution measure 100 c.c. Of this solution, a measure of 10 c.c. will give i gram of the cocaine salt, a measure of i c.c. will give o.i gram, and there is a simple relation between the measure of the solution and the amount of cocaine it contains. In the chemic solution 10 grams of the cocaine salt are dissolved in 90 grams of the normal saline, so that if one wished to use o.i gram of cocaine hydrochloride, one could not get it by measure, since there is no easily calculated relation between the measure ol the liquid and the weight of its dissolved constituents; there- fore, one would have to weigh off i gram of the solution. Such weighing cannot be done in practice, therefore the chemic percent- age method is not suitable for liquids for medicinal use. To conform with the idea of weighing solids and measuring liquids the Pharmacopoeia specifies that in liquid preparations PHARMACEUTIC PREPARATIONS 39 made by extraction a definite weight of the drug shall be employed in making a definite volume of the finished preparation. Hence these preparations have a definite relation in strength to the drug from which they are made, for the active ingredients of a definite weight of the drug are in the solution. The strengths of pharma- ceutic preparations are indicated by the amount of drug used in their making, whether the drugs themselves are in the finished preparation or only their extracted constituents. Thus a measure of TOO c.c. of the tincture of digitalis represents the medicinal activity of 10 grams of digitalis leaves; the tincture is, therefore, of 10 per cent, strength. A measure of 100 c.c. of the fluid- extract of cascara represents the medicinal activity of 100 grams of cascara, hence the fluidextract is of 100 per cent, strength. Pharmaceutic preparations are simple or compound. The simple preparations represent the activity of one drug only; the compound preparations, the activity of more than one drug. For example, rhubarb pills have rhubarb as the only constituent, while compound rhubarb pills contain rhubarb, aloes, myrrh, and oil of peppermint. Nomenclature. The simple preparations are given simply the name of the drug prefixed by the name of the kind of prepara- tion, as: Syrup of ginger (syrupus zingiberis), infusion of digitalis (inf usum digitalis) . The compound preparations have two types of nomenclature. If the active drugs are only two in number, or in some cases three, all are mentioned in the name, as: Pills of aloes and iron (pilula aloes et ferri), elixir of the phosphates of iron, quinine, and strychnine (elixir ferri, quininae et strych- nine phosphatum) . If the important drugs are several in number, especially if one overshadows the others in importance, only one drug is named, and the name of the class of preparation is modified by the term compound. Examples are: Compound tincture of cinchona (tinctura cinchona? composita), which is made of cin- chona, serpentaria, and bitter-orange peel; compound licorice powder (pulvis glycyrrhizas compositus), which contains glycyr- rhiza, senna, and sulphur; and compound rhubarb pills, men- tioned above. A few compound preparations of this kind do not bear a drug name, but the name which indicates their use in medicine, as compound cathartic pills (pilulae catharticae compositae). DEFINITIONS OF THE KINDS OF PHARMACEUTIC PREPARATIONS IN COMMON USE Aqueous Liquids. i. Water (Aqua). A weak aqueous solu- tion of one or more volatile substances (e. g., peppermint or cin- namon water, chlorine water). 40 PHARMACOLOGY AND THERAPEUTICS 2. Solution (Liquor). An aqueous solution of one or more non-volatile chemic substances (Fowler's solution). j. Mixture (Mistura). An aqueous liquid containing in- soluble material (rhubarb and soda mixture). It requires the label, "Shake before using." 4. Syrup (Syrupus). A dense aqueous solution of sugar with or without medicinal or flavoring substances (syrup of ipecac) . 5. Mucilage (Mucilago). An adhesive aqueous liquid or paste made with gum (liquid acacia; paste tragacanth). 6. Infusion (Infusum). A liquid obtained by steeping a vegetable drug in water and then straining. The water may be cold, warm, or hot, but the drug is not subjected to boiling. 7. Decoction (Decoctum). A liquid made by boiling a vege- table drug with water, then straining. 8. Juice (Succus). The juice expressed from parts of fresh plants ("fresh" meaning "undried") ; an example is limonis succus (lemon-juice). Alcohol may be added as a preservative. Alcoholic Liquids. i. Fluidextract (Fluidextractum). An alcoholic or hydro-alcoholic liquid preparation made by extrac- tion, and representing the drug volume for weight; i. e., i c.c. of the fluidextract represents the strength of i gram of the drug. 2. Tincture (Tinctura). An alcoholic or hydro-alcoholic liquid preparation made by extraction and of a strength less than that of the drug; i. e., tinctures are of the same nature as fluid- extracts, but weaker. A few simple alcoholic solutions are in- correctly called tinctures, e. g., tincture of ferric chloride, tincture of iodine. j. Elixir (Elixir). A sweetened, aromatic, hydro-alcoholic liquid (aromatic elixir). 4. Spirit (Spiritus). A simple solution of one or more volatile substances in alcohol (spirit of chloroform). 5. Wine (Vinum). The wines are not now official. They are made like a tincture or solution, but with white wine and alcohol as the menstruum (bitter wine of iron). Miscellaneous Liquids. /. Vinegar (Acetum). Made like a tincture, but with diluted acetic acid as the menstruum (the vinegar of squill is the only one official). 2. Emulsion (Emulsum). A milk-like preparation in which an oil or resin is finely divided and rendered miscible with water by means of some viscous or adhesive substance. Emulsions are: (a) Natural, as in egg-yolk and milk. (/>) Gum resin, as in emulsum asafcctidse; the drug contains gum, oil and resin, and on rubbing with water makes an emulsion, (c) Artificial, in which the adhesive must be added, as emulsion of cod-liver oil. PHARMACEUTIC PREPARATIONS 41 j. Honey (Mel). A liquid or semiliquid mixture of a drug with honey (honey of rose). 4. Oleoresin (Oleoresina) . A semiliquid ethereal extract of a drug which contains oil and resin. The oleoresin contains the ether-soluble constituents of the drug, the ether being evaporated off. It is of greater strength than the drug itself (oleoresin of male fern). 5. Glycerite (Glyceritum). A liquid or semisolid solution in glycerin (glycerite of boroglycerin) . 6. Liniment (Linimentum) . An oily or alcoholic solution or mixture to be applied to the skin (liniment of camphor) . 7. Lotion. An aqueous liquid for application to the skin. There are no official lotions. 8. Collodion (Collodium). A solution of a medicinal sub- stance in collodion (cantharidal collodion). Solids and Semisolids. i. Extract (Extractum). A prepa- ration of dry or plastic consistence, made by extracting a drug with a solvent, and then removing the solvent by evaporation. An extract is of greater strength than the crude drug. Most extracts are about 4 or 5 times as strong as the drug from which they are made (extract of belladonna). 2. Powder (Pulvis). A dry powdery mixture of drugs (pow- der of ipecac and opium) . 3. Trituration (Trituratio). A powdery mixture of a drug with sugar of milk. The only official trituration is trituratio elaterini, of 10 per cent, strength. 4. Mass (Massa). A plastic mixture for division into a num- ber of equal objects, such as pills, troches, etc., and usually ob- tained by incorporating drugs with an adhesive substance. 5. Pill (Pilula). A rounded or oval body of size to be readily swallowed, and made of cohesive drugs or drugs incorporated with an adhesive substance. Pills may be coated with sugar, gelatin, silver, keratin, or salol. The coating may be white, pink, chocolate-colored, etc. t 6. Troche (Trochiscus). A flat body, rounded or lozenge shaped, intended to be dissolved slowly in the mouth. It contains the medicinal substance, and in addition sugar, flavoring and adhesive material (troches of ammonium chloride). 7. Compressed Tablet (Tabella compressa). A solid body made by the compression of a powdered drug or mixture of drugs in a suitable mold. With insoluble powders the hard compres- sion retards disintegration. 8. Tablet Triturate (Tabella triturata). A solid body made of drugs triturated with sugar of milk, and molded with the aid of moisture. It disintegrates as the sugar of milk dissolves. 42 PHARMACOLOGY AND THERAPEUTICS Q. Confection (Confectio). A pleasant-tasting preparation made by mixing medicinal powders and aromatics with syrup or honey (confection of senna). 10. Granular Effervescent Salt (Sal Granulatus Eff ervescens) . A preparation made by adding sodium bicarbonate and citric or tartaric acid to the drug, moistening with alcohol, and passing through a coarse sieve to form granules. It is added to water and drunk during or just after the effervescence (effervescent sodium phosphate). 11. Paper (Charta). A sheet of paper impregnated with a medicinal substance (niter paper) , or bearing it in a state of fine subdivision (mustard paper). There are none official. 12. Plaster (Emplastrum) . A solid mixture which becomes plastic and adhesive on warming; it is spread in a thin layer over muslin, moleskin, etc., for application to the skin (emplastrum belladonna?) . ij. Poultice (Cataplasma). A soft, usually hot and moist paste for external application, as a flaxseed poultice. 14. Ointment (Unguentum). A soft, fatty (unctuous) prep- aration which on rubbing melts at or about the temperature of the body. 15. Cerate (Ceratum). An unctuous mixture of firmer con- sistence and higher melting-point than an ointment (ceratum cantharidis). 16. Oleate (Oleatum). A semisolid solution of metallic salts or alkaloids in oleic acid. It is for external use (oleatum hy- drargyri). 17. Suppository (Suppositorium). A solid which retains its shape at normal temperature, but readily fuses when inserted into a body orifice. Suppositories are usually made with a basis of cocoa-butter and are: (a] Rectal, cone shaped, weight, 30 grains (2 gm.) (b) Urethral, thin, pencil shaped, weight, 30 to 60 grains (2 to 4 gm.) (c) Vaginal, globular or elliptic, weight, 60 grains (4 gm.). Urethral ajid vaginal suppositories are sometimes made of glycerinated gelatin. Small rectal suppositories used for children and in irritative conditions of the anus are made about 15 grains (i gm.) in weight. WEIGHTS AND MEASURES 43 WEIGHTS AND MEASURES In the metric system the liter is a unit of capacity equivalent to the volume occupied by the mass of i kilogram of pure water at its maximum density. It is equivalent in volume to 1.000027 cubic decimeter. Under this definition a milli- liter (o.ooi of a liter) is different from a cubic centimeter by a very minute frac- tion. However, as cubic centimeter is the term used throughout medical literature we shall use it in this book, though both the U. S. and British Pharmacopoeias have adopted the term milliliter (mil) in its place. A. Metric A pproximate Weight Written Equivalent i milligram (mg.) o.ooi ^ grain 10 milligrams = i centigram (eg.) o.oi grain 10 centigrams = i decigram (dg.) o.i if grains 10 decigrams = i gram (gm.) i.o 15 grains 1000 grams = i kilogram (kilo.) 1000.0 2\ pounds Volume i milliliter (mil.) i.o 15 minims i cubic centimeter (c.c.) i.o 15 minims (i c.c. of water weighs i gm.) 1000 cubic centimeters = i liter (L.) 1000.0 34 fluidounces Length i millimeter (mm.) -^ inch 10 millimeters = i centimeter (cm.) ? inch 10 centimeters = i decimeter (dm.) 4 inches 10 decimeters = i meter (M.) 40 inches B. Apothecaries Approximate Weight (Troy Weight) Equivalent i grain (gr.) 0.065 gm. 10 grains 0.7 gm. 20 grains = i scruple O) 1.3 gm. 3 scruples = i dram (5) 4.0 gm. 8 drams = i ounce (3) 30.0 gm. 12 ounces = i pound (ft>) 372.0 gm. Volume 1 minim (rrj) 0.06 c.c. 60 minims = i dram (5) 4.0 c.c. 8 drams = i ounce (5 ) 30.0 c.c 16 ounces = i pint (O) 475-Q c.c. 2 pints = i quart (Oij) 95 o.o c.c. 8 pints = i gallon (Cong.). (i gill = 4 fluidounces.) Length i inch (in.) 2 . 5 cm . Noteworthy Terms ounce avoirdupois 437-5 grains ounce troy 480.0 grains fluidounce of water (the standard of volume) 455-7 grains pound avoirdupois is 7000.0 grains pound troy is 5760.0 grains i minim of water weighs 45 g Q 7 grains = 0.95 grain = 61.61 mg. 15 grains of water = 16 minims; one grain of water measures 1.05 minims = 0.0648 c.c. An imperial pint is 20 ounces; a United States pint is 16 ounces. 44 PHARMACOLOGY AND THERAPEUTICS EXACT EQUIVALENTS OF METRIC AND APOTHECARIES' WEIGHTS AND MEASURES ACCORDING TO THE U. S. PHARMACOPCEIA Volume c.c 16.23 minims liter (1000 c.c.) 33.8 oz. minim (115) 0.061 c.c. fluidram (5) 3-696 c.c. fluidounce (5) 2 9-57 c.c. pint (O) . . 473-i8 c.c. Weight i milligram, o.ooi (mg.) 0.0154 grain i centigram, o.oi (eg.) 0.1543 grain i decigram, o.i (dg.) i-543 grains i gram, i.o (gm.) iS-43 2 4 grains 30 grams, 30.0 462.9 grains 3 1 grams 478.4 grains i grain (gr.) 0.065 g m - 10 grains 0.648 gm. 15 grains 0.972 gm. i scruple 1.296 gm. i dram (5) 3-89 gm. i ounce troy (5) 31-1 gm. i ounce avoirdupois 28.35 g m - ACTIVE PRINCIPLES AND ASSAY PROCESSES As might be expected from the different conditions under which plants grow, the different methods of collecting, drying, and preserving drugs, the effects of age on the drug, etc., crude drugs vary in strength. On this account the use of active con- stituents by themselves has much to commend it, e. g., quinine in preference to cinchona, strychnine in preference to nux vomica, resin of podophyllum in preference to podophyllum. These sub- stances tend also to be more readily absorbed when thus separated from the extractive matter of the crude drug. But in many instances it is impossible or too expensive to isolate the active ingredients in pure form, or there is a preference for the combi- nations or mixtures as they occur in nature, so pharmaceutic preparations, and even the powdered crude drugs, are much prescribed, even though their active principles are available. This being the case, it is a matter of great importance that some of the more potent of these drugs and preparations are standard- ized by the Pharmacopoeia to contain a definite percentage of the active ingredients. For instance, when assayed by the process specified in the Pharmacopoeia, nux vomica must yield not less than 2.5 percent, of alkaloid; jalap, not less than 8 per cent, of resin; the tincture of opium, 1.2 to 1.25 per cent, of morphine. These are known as assayed drugs or preparations. An assay process is a process by which the strength of a sub- THE PHARMACOPCEIA 45 stance or preparation is determined. There are three kinds of assay processes for drug preparations, viz., volumetric, gravimet- ric, and biologic or physiologic. The last-named type of assay has been devised for some of the drugs whose active principles are not readily isolated. For digitalis, for example, one assay process ascertains the amount of digitalis necessary to bring into systolic standstill the heart of a frog of definite weight and of a certain species and sex. THE PHARMACOPCEIA The Pharmacopoeia is a book which defines and standardizes certain drugs and their preparations. Its aim is to establish definiteness for a selected number of those in extensive use by physicians. A number of the more enlightened nations have pharmacopeias, so there are the British Pharmacopoeia, the German, the Swiss, the Japanese, etc. For us, "The Pharma- copoeia" is the United States Pharmacopoeia (written "U. S. P."). Its drugs and preparations are spoken of as official. By the Pure Food and Drugs Act the National Formulary preparations have also official recognition. The official preparations are, therefore, the ones that are standardized; hence they are the preparations that can be obtained of uniform strength throughout the United States; and they are, for the most part, the forms in which reme- dies can be readily supplied by the pharmacist. Hence, the official preparations are the forms to be preferred by the physician in prescribing. To illustrate the character of the Pharmacopoeia, take the drug strophanthus and its tincture. "Strophanthus" is defined as ''the dried ripe seeds of Strophanthus Kombe and of 5. hispidus, deprived of their long awns." The seeds of other species of strophanthus can be procured, but the pharmacist must not employ any but those of the species mentioned, and he must first remove the long awn, a spear-like projection at the apex of the seed which contains none of the medicinal ingredient. Fur- thermore it must respond to the requirements of a biologic assay on frogs, as given in the Pharmacopoeia. For the tincture of strophanthus the Pharmacopoeia directs that 10 grams of strophanthus shall be taken to make 100 c.c. of the tincture, i. e., it shall be of 10 per cent, strength, it must be made with a certain specified menstruum, and it must have a certain physiologic activity. Therefore, when the tincture of strophanthus is prescribed, since it is an official preparation, the pharmacist is not entitled to dispense a tincture of any other strength or method of manufacture. On the other hand, if a 46 PHARMACOLOGY AND THERAPEUTICS physician prescribes an unofficial preparation, the pharmacist may dispense one of any arbitrary strength and made by any method convenient, and the physician is left in uncertainty about what his patient is getting. The United States Pharmacopoeia gives information, also, about specific gravity, melting-point, solubilities, tests of identity, tests for impurities or adulterants, the average dose, etc. It is, therefore, an official formulary and book of standards, and is a working guide and dictator for the supplier of drugs, the manu- facturer of preparations, and the pharmacist. It is not in any sense a book to be memorized by the medical student; but the choice of its preparations in prescribing favors accurate thera- peutics. The Pharmacopoeia is controlled and published by the Na- tional Pharmacopoeial Convention, a gathering of delegates from the various medical and pharmaceutic colleges and state and national societies, and certain other selected societies, and from the Army, Navy, and Marine-Hospital Service. This Re- vision Convention meets every ten years (1890, 1900, 1910, etc.) at Washington, D. C., to determine the principles to govern the next revision. It also appoints a Committee of Revision to carry out the details of the revision, and administrative officers to issue the new edition when it is ready. Three or four years are then spent by the Committee of Revision in research and in the compilation of the revised book, which becomes official on a fixed date after it is issued. It is known as the Pharmacopoeia of 1890 or 1900, etc., the year of the Pharmacopoeial Convention. The present Pharmacopoeia is the Pharmacopoeia or revision of 1910; it became official on September i, 1915. If a physician wishes to prescribe the formula of a previous pharmacopoeia, he must specify on his prescription, "U. S. P. 1880," "U. S. P. 1890," etc. Because it recognizes so many seemingly needless drugs and preparations, the Pharmacopoeia has been much criticized. But it is to be borne in mind that the Pharmacopoeia does not con- sider merely the usefulness of an article, but attempts to stand- ardize those drugs and preparations which are in extensive use by the recognized authorities in medicine in any part of the country. It must also standardize all substances used in making official preparations, whether or not of medicinal value. The National Formulary is a book issued by the American Pharmaceutical Association, with the idea of standardizing some non-pharmacopeia! preparations that are in common use. In a prescription the letters "X. F.'' following the name of a prepara- tion (c. ., lotio plumbi et opii, X. F.) call for the dispensing of a preparation made according to the formula of this book. DOSAGE 47 A dispensatory is a commentary on drugs, a general reference work on the botany, pharmacognosy, chemistry, pharmacy, and therapeutics of drugs. It is an extensive work and is not official. The United States, the National, and King's Dispensatories are the best kno\vn in this country, and Hager's Praxis in Germany. They give a vast amount of information, and are encyclopedic in character, scarcely a known drug escaping some recognition. Useful Drugs is a small book issued by the Council on Phar- macy and Chemistry of the American Medical Association. It presents a brief but practical discussion, from the modern view- point, of the properties, pharmacologic action, therapeutic uses and dosage of a list of drugs of approved worth. It should be in the hands of every practitioner. DOSAGE When we say the dose of a drug, we mean the therapeutic dose for an adult, i. e., the amount ordinarily required to produce a medicinal effect. The Pharmacopoeia gives the average thera- peutic dose, and for convenience this is the dose to learn, in most instances. The minimum dose is the smallest capable of producing a medicinal effect not quite so small, however, as two drops of the ninth dilution of the homeopaths, which Oliver Wendell Holmes estimated to be of the strength of one drop in ten billion gallons. A maximum dose is the greatest dose that can be ad- ministered without probability of poisonous effects. A toxic dose is a poisonous dose. Remedies are administered either in single doses or in repeated doses. A single dose of a medicine may be given all at once, as two compound cathartic pills or an ounce of whisky; or in divided doses, as when one grain of calomel is given in one-quarter grain tablets, one every half-hour for four doses. Repeated doses may be intended to have an effect just at the time of administration, as a bitter before each meal to improve the appetite; or to have a continuous effect, as digitalis for a dis- ordered heart. To produce a continuous effect, remedies are usually given three or four times a day, for, as a rule, it is too great trouble for patients to take medicine more often than this. Even very sick patients should not be disturbed by too frequent medication. Sometimes a powerful drug given for continuous effect is administered in too large amounts for ready secretion, so that it accumulates in the system until poisonous symptoms appear. Such a drug is known as a cumulative poison. The ill effects are 48 PHARMACOLOGY AND THERAPEUTICS dependent upon the failure of elimination to keep pace with the ingestion of the drug. The most common drugs to give cumula- tive effects are digitalis, arsenic, mercury, and lead. Lead and arsenic, indeed, are so slowly excreted that they may accumulate in the system even when taken only in the minutest quantities at a time, as from drinking-water that has lain in leaden pipes, or breathing the air of a room with an arsenic color in the wall- paper. The phrase "pushing a drug to its physiologic limit" is some- times employed when a remedy is given in gradually increasing doses until toxic symptoms begin to appear. FACTORS WHICH MODIFY THE DOSE It must be apparent that the ordinary average adult dose is not the dose for every one under all circumstances. Some of the factors modifying the dose are: 1. Body Weight. In pharmacologic experimentation it is customary to estimate the dosage in proportion to the weight of the animal. Within certain limits this should be a good method with humans, and it is the basis of Clark's rule, which assumes that the average weight of an adult is 150 pounds. The rule is Adult dose X ^!f . But a patient in bed cannot be weighed, and it takes an expert to guess such a one's weight correctly; and a man with dropsy or an adipose patient would have some extra- neous weight to be allowed for. So, as a matter of fact, either on account of our highly organized nervous systems or on account of our ways of eating and drinking and working, or for other reasons, the rule of weight does not seem suitable for practical use. 2. The Age. It is evident that the dose for an adult is not the same as that for a child. Yet to establish a working rule is not easy, for not only is there no regular increase in a child's weight according to age, but there is also unequal development of the different systems of the body. The weight rule would be the best but for its difficulty of adoption, and to multiply the adult close by a simple fraction with the child's age as numerator and the supposed earliest adult age as denominator, will not be correct. It will not do, for example, to take an arbitrary age of twenty or twenty-four as the adult age, and take one-twentieth or one twenty-fourth for each year of the child's age. The fol- lowing table of the average weights at the different ages, taken from Bowditch's statistics in 8008 children in Boston, and Paster's of 14,744 children in St. Louis, as recorded by Holt, shows how absurd it is to estimate the close at two years as twice that at one year, etc. The figures given are for the boys, those for the girls FACTORS WHICH MODIFY THE DOSE 49 being for the most part not more than one to three pounds different. Age Weight Half year 16.0 pounds One year 2 1 .o Two years 27.0 Three years 32.0 Four years 36.0 Five years 41.2 Six years 44.4 Seven years 48.6 Eight years 53.5 Nine years 58.7 Ten years 64.6 Eleven years 70.6 Twelve years 76.7 Thirteen years 83.7 Fourteen years 94.0 Fifteen years 107.3 Sixteen years 1 19.1 From these figures a fairly accurate age-weight rule would be: age p 3 X adult dose. In other words, in writing for 30 doses (4 ounces with i dram dose) put down as many minims or grains as the age + 3; in writing for 15 doses (2 ounces with i dram dose) put down half as many minims or grains as the age + 3. In the metric system put down: the adult dose X (age + 3) X 3, and move the decimal point two places to the left. Two other rules in common use are Young's and Cowling's: Young's rule is: Adult dose X ^,j^~[ 2 ' r* T > * 7 Aiiij xx a e a t n ext birthday T Cowlings rule is: Adult dose X - . In pre- scribing by this rule, all that is necessary is to write for 24 doses and set down for each ingredient the adult dose multiplied by the age at next birthday. Fried' 's rule for infants under one year is: Adult dose X age in months 150 In some cases these rules do not apply, e. g., children react strongly to opium and other narcotics, while, on the contrary, the child's dose of a cathartic or belladonna or arsenic approaches that of an adult. We have seen the same amount of belladonna given to a father and to his son six years of age with equal effect; and a child of three years not one whit more affected by a grain of calomel than was her mother by half the dose. On the other hand, we have seen a child of one year "doped" by one-twentieth of a grain of powdered opium. In old age the dose must be, as a rule, somewhat less than in the prime of life; and especially must skin irritants, irritant 50 PHARMACOLOGY AND THERAPEUTICS cathartics, narcotics, and depressant drugs be used with cau- tion. 3. Sex. Women usually require smaller doses than men, not only because of their average smaller stature and quieter life, but also because of their greater susceptibility to any in- fluences. During menstruation and pregnancy irritant cathar- tics, and during lactation saline cathartics, are to be avoided or used with caution. 4. Temperament, Race, Occupation. The patient of highly neurotic temperament is more susceptible than the phlegmatic person. Such difference may be racial, the excitable Italian, for example, being more easily affected than the stolid Swede; or it may have to do with activity and occupation, the athlete or the man who works all day out-of-dbors and is inured to hard- ship being less readily affected than the man of sedentary habits, the merchant, student, or artist. 5. Previous Habits (Toleration). The morphine habitue can take with impunity a dose of morphine large enough to poison one not habituated, and will obtain no effect from the ordinary dose. An old toper with cirrhosis of the liver will fail to get a medicinal effect from the usual dose of a tablespoonful of whisky. 6. Idiosyncrasy and Susceptibility ,~ Idiosyncrasy is that condition in which a patient develops special and unusual effects from a remedy or food. Some people develop a rash after eating strawberries, others after eating lobster, fish, or buckwheat. Sometimes all the members of a family show such an idiosyncrasy to some special article of food, and it is manifest in successive generations. The same is true of drugs. A minute amount of cocaine dropped in the eye or applied to the nasal mucous mem- brane may cause dangerous symptoms in one patient, though cocaine is used in the eyes and noses of thousands of other pa- tients without any untoward symptoms at all; or a dose of anti- pyrine may be followed by a marked rash, which recurs each time the drug is taken. These are unusual and unexpected effects, and depend not so much on the size of the dose as upon a specific and unusual hypersusceptibility of the patient toward the drug. An ordinary increase of susceptibility means lowered resistance a condition in which the usual or expected effects are produced by less than the usual amounts. For example, two or three grains of quinine sulphate produce in some people the ringing in the ears, deafness, and headache that in most persons do not come from less than 10 or 20 grains. Diminished susceptibility means heightened resistance, the patient showing the usual effects, but only after larger doses than usual. For example, some persons can take two or three cups of coffee and then sleep FACTORS WHICH MODIFY THE DOSE 51 soundly, though this is enough to keep the average person wide awake for hours. 7. The Nature of the Disease. In great pain, as in peri- tonitis, morphine may be borne in doses that would ordinarily be poisonous. On the other hand, in cyanosis or conditions with bad breathing, morphine should be used with caution because of its tendency to depress the respiration. In malaria, quinine can be borne in larger doses than when it is used for other purposes. Again, in Bright's disease or other conditions involving the eliminating organs drugs may more readily accumulate in the system and cause cumulative poisoning; and in functional or organic disturbance of the liver certain substances, like phenol or morphine, may have a more pronounced poisonous effect than otherwise. 8. The Object of the Medication. Quinine as a bitter appe- tizer may be given in doses of one or two grains, while quinine for malaria is given in a single large dose of 15 or 20 grains, fol- lowed by 5 grains three times a day for a month. In a cough mixture for a child syrup of ipecac is given in dose of 2 to 5 minims, but in croup, where an emetic effect is desired, a whole teaspoonful is administered. It is to be noted that preparations for local action are active according to their percentage strength rather than according to the actual amount of drug employed. 9. The Form of the Remedy. As a rule, this makes but little difference; yet, other things being equal, liquids are more rapidly active than solids, and alcoholic liquids more than aqueous. Active principles are more rapid than crude drugs, powders and dry-filled capsules than pills, fresh-made pills than coated pills. Some cathartic drugs, like aloes and cascara, are more effective cathartics than their active principles. This is because of the extractive matter present, which retards absorption and keeps the active principles in the alimentary tract until they reach the colon. 10. The Channel of Administration. It has usually been taught that the hypodermatic dose should be half, and the dose by rectum twice, that by mouth. In a number of instances, how- ever, it has been demonstrated that drugs are as quickly absorbed from the rectum as from the stomach, or even more quickly, and also that, in ordinary circumstances, most drugs are absorbed from the stomach or duodenum with sufficient rapidity to give the full effect of the drug in a short time. Therefore, since rectal and hypodermatic medication are resorted to only under special cir- cumstances, their dose is the same as that by mouth. In rectal medication the strength of the preparation rather than the total 52 PHARMACOLOGY AND THERAPEUTICS dose is usually desired, for the rectum is seldom resorted to for any but local medication. In intravenous medication the dose is a special one for the few drugs that may be so administered, and is usually comparatively small. In conditions of edema, hypo- dermatic medicaments may be retarded in their absorption, and in congestive conditions of the stomach and bowels, mouth doses may be retarded. 11. The Time of Administration. After meals the dose is diluted and absorption delayed by the admixture with the stom- ach contents; so if a rapid effect is desired, a larger dose must be given. On the contrary, the empty stomach allows immediate local action and more ready absorption, as commonly observed in the greater activity of alcoholic drinks taken before meals. 12. The Frequency of Administration. It goes without say- ing that the dose of a powerful drug is less if it is administered every hour or two than if given three times a day. ADMINISTRATION By administration is meant the manner in which the remedy is to be used. Remedies are administered to obtain either a direct local action, a systemic action, or a remote local action. The direct local action is the action at the place at which the drug is applied, as on the skin, or in nose, throat, stomach, urethra, etc. To obtain direct local action, ointments, lini- rnents, plasters, etc., are employed. Local remedies may or may not require to be absorbed. Talcum powder applied to a chafed skin, or bismuth subnitrate given for irritated stomach or bowels, acts by coating the skin or mucous membrane and is not absorbed; while cocaine, to produce a local anesthetic effect, must be ab- sorbed to get at the nerve-endings or nerves beneath the epi- dermis. The systemic action is the action of the drug after its absorp- tion into the circulation, as that of strychnine on the spinal cord, or pilocarpine on the nerve-endings in the sweat-glands. The remote local action is the effect of the drug as it is being excreted, c. ., the irritation of the bowels by mercuric chloride as it is passed out by the colon glands, or the antiseptic action of urotropine as it is eliminated in the urine. To obtain either a systemic action or a remote local action the drug must be ab- sorbed; that is, must become a constituent of the body iluids. ADMINISTRATION 53 THE WAYS IN WHICH DRUGS MAY BE ADMINISTERED FOR SYSTEMIC AND REMOTE LOCAL EFFECT A. By mouth, the usual way, the drug being swallowed and absorbed into the sytem from the alimentary tract. B. Subcutaneonsly (hypodermatically) , the drug being intro- duced beneath the skin by means of a special hollow needle and a syringe. To be used thus, a preparation must be in liquid form, and, as a rule, in complete solution; though in some instances, as in the use of insoluble mercury salts, the drug may be in the form of a fine powder held in suspension in oil. A substance for hypodermatic use must be capable of complete absorption, or it will act as a foreign body; and must be in small quantity, be- cause large amounts will produce too great separation of the tissues. Irritant drugs are only occasionally given hypoder- matically, both because they are painful and because they may produce necrosis of cells with abscess formation. Such ab- scesses are sterile, however, as they are not caused by pathogenic bacteria. For convenience, many drugs are put up in the form of tab- lets called hypodermic tablets. They are made of the drug and finely powdered cane-sugar mixed together, moistened with alcohol, and forced into molds. When dry, they can be handled without disintegration, but are readily soluble. (Tablets made by compression do not dissolve so easily.) Hypodermic tablets of salts of morphine, atropine, strychnine, etc., can be carried in a pocket-case; when wanted, they may be placed in the syringe and dissolved there in sterile water draw^n up to make the solu- tion, or may be made into a solution with a few drops of water in a spoon. For sterilization the water may be heated in a spoon over a spirit-lamp or a gas-burner. Drugs dissolved in normal salt solution (0.9 per cent. NaCl) tend to be less irritant to the tissues and more readily absorbed than those dissolved in plain water, but when the total amount of the solution is very small, tap-water will do. To give a hypodermatic injection, the dose is placed in the hypodermic syringe (many liquids cannot readily be drawn up through the syringe needle), the sterilized needle (it may be sterilized in a test-tube or spoon) is screwed on, and the syringe is turned needle upward so that any bubbles of air may be driven out by pressure on the piston. Thin liquids may be drawn directly into the syringe through the needle. There are two methods of injection for systemic effect, the subcutaneous and the intramuscular. In the subcutaneous method the properly cleansed skin, usually of an arm or a leg, is pinched 54 PHARMACOLOGY AND THERAPEUTICS up between the thumb and finger of one hand, while the needle is quickly plunged in a slanting direction through the skin into the subcutaneous tissue. In the intramuscular method the needle is plunged straight through the skin and subcutaneous tissue into the underlying muscle, usually in the back, buttocks, or chest, though sometimes in the limbs. This method favors ready ab- sorption. By either method, a sharp needle and quick puncture give almost no pain. The fluid is slowly injected, the needle is quickly withdrawn, the point of the puncture is covered to pre- vent the fluid from running out, and the spot is gently massaged to promote diffusion of the liquid into the tissues. The hypoder- matic needle may be cleansed by first forcing water through it, and then allowing a few drops of alcohol to descend through it by capillarity. A fine wire drawn through the lumen keeps it permeable. (In the introduction of cocaine and similar drugs for local anesthesia where a local action only is desired, the needle is inserted just beneath the epidermis and gives a superficial subcutaneous injection, or an intracutaneous injection. This method is not used when a systemic effect is desired.) There are certain advantages and disadvantages in hypo- dermatic medication. The advantages are: j. Certainty of action all the drug gets into the tissues; therefore the dose is more definite. 2. Rapidity of action because the drug in most instances quickly reaches the circulation by means of the capil- laries or lymphatics. 3. Availability when administration by mouth is not feasible, as when (i) the patient cannot swallow, as in uncon- sciousness; or (2) will not swallow, as in drunkenness or delirium or when drugs are taken with suicidal intent; or (3) the alimentary tract is in a state of in- tolerance and non-absorption, as in uncontrollable vom- iting or diarrhea. The disadvantages are seldom encountered. They are: 1. The chance of abscess formation, either a sterile abscess from an irritant drug, or an infective abscess from un- sterile solution, needle, or skin. 2. The chance of injecting the drug into a vein. This would plunge the whole dose into the circulation at once, per- haps with disastrous results. To avoid this the syringe may be unscrewed from the needle; if blood oozes from the needle, this is withdrawn and inserted elsewhere. 3. The chance of injecting the drug into a nerve, with result- ing great pain and even paralysis. ADMINISTRATION 55 Hypodermatic medication has a very restricted employment, because only those drugs whose dose in solution is of small bulk are available for this method of administration. C. By hypodermatoclysis, in which a large quantity of saline liquid (50 to 1200 c.c.) is injected into the loose tissues about the breasts or abdomen, or into the back below the scapula, or into the buttocks or thighs. The liquid is allowed to run in slowly by means of a funnel or reservoir and rubber tube attachment to the needle. If the fluid is not isotonic, or nearly so, with the blood, or if it interferes by pressure with the circulation of the part, it may result in gangrene or abscess. The writer has seen extensive gangrene follow the injection of 200 c.c. of 2 per cent, solution of sodium carbonate in a diabetic. D. By rectum. Drugs may be placed in the rectum by means of an enema, i. e., a rectal injection, or in the form of a supposi- tory or ointment. The uncertainty of absorption and the chance that the drug will be expelled limit the usefulness of this channel and largely restrict it to drugs for local effect only. Proctoclysis is a rectal irrigation or injection intended for both local and systemic effect. It is usually made with saline or medicated saline fluids. (See Rectal Treatment, Part II.) E. By the skin, by inunction, in which an oily or fatty prep- aration is rubbed upon the skin and left to be absorbed. On account of uncertainty of absorption the dose may vary within wide limits. Mercurial ointment is so used in the treatment of syphilis, and cod-liver oil and cocoa-butter in the treatment of malnutrition. F. By the veins, intravenous medication. Drugs administered by a vein act with great promptness, the whole dose passing at once into the circulation. Intravenous medication may be by injection or by infusion. In intravenous injection the drug, di- luted with a small quantity of normal salt solution, is injected from a syringe, the needle being plunged through the wall of the vein in a slanting direction and toward the heart. When the needle is withdrawn, the valve-like opening thus made usually closes of itself, though sometimes there is a moderate extrava- sation of blood into the tissues. In intravenous infusion a large quantity of warm normal saline solution (500 to 1500 c.c.), or some isotonic liquid, with or without the addition of drugs, is slowly passed into the vein through a suitable nozzle. This re- quires tying a vein, so it cannot be repeated more than once or twice, and is employed only in emergencies. G. Through the lungs by inhalation of gas for absorption into the system, as in the use of chloroform or ether as a general 56 PHARMACOLOGY AND THERAPEUTICS anesthetic. (Inhalations of medicated vapors are employed also for a local effect on the respiratory organs.) THE TIME OF ADMINISTRATION This is of some importance, e. g., the saline cathartics act most rapidly after a period of fasting, so are usually adminis- tered before breakfast. Irritant drugs, as arsenic or iron or digi- talis, are best given after meals, when they become well diluted with the stomach contents, and come very little in contact with the stomach-wall to irritate it. Quinine sulphate is given after meals not only because it is irritant, but so that it may be dis- solved by the acid gastric juice; otherwise its absorption is re- tarded or may not take place at all. Sleep producers are most effective at the natural time of sleeping, and when the surround- ings are favorable to sleep; they may have no effect at all if the patient is up and about. Sodium bicarbonate given on an empty stomach, i. e., before a meal, is absorbed as sodium bicarbonate, and furnishes alkali directly to the blood ; but if it is given during the digestive period, it neutralizes the hydrochloric acid of the gastric juice, is changed to sodium chloride, and sets free carbon dioxide. Appetizers must be given just preceding the meal. SITES AND MODES OF ACTION OF DRUGS Drugs may act as such: 1. Independently of the human body, as antiseptics on micro- organisms in disinfection. 2. In or about the human body, but not on its structures, as in the destruction of a tape-worm, skin parasites, etc., or as in the neutralization of a hyperacid gastric juice by an alkali. j. On the structures of the human body. Drugs may act on the tissues (a) Through their physical or mechanical properties, as when cold cream is applied to a chapped face to soften the epithelium and prevent its drying; or when bismuth subnitrate, given for diarrhea, coats the mucous membrane of the bowel and soothes and protects it. Or they may act (b) by their chcmic affinity for one or other constituent of protoplasm, so that either the functional power of the cell or the actual cell structure is changed. Some of these are general in their action, affecting practically all forms of protoplasm (though not all forms to a like degree), and when the action of these drugs is powerful, they are known as general protoplasm poisons. Such are alcohol, chloral hydrate, and quinine. Other drugs are selective, exerting their influence only on special groups of cells and having no effect SYNERGISTS AND ANTAGONISTS 57 upon the vast majority of body structures. This is presumably owing to a chemic affinity for some component of the cell. Such drugs are strychnine, which has a selective affinity for certain portions of the central nervous system, and pilocarpine, which has an affinity for secretory nerve-endings. The effect of drugs on cells is to stimulate them, to depress them, or to change and destroy them. Stimulation is an effect on cells by which their power or their readiness to functionate is increased. Depression is an effect on cells by which their power or readiness to functionate is lessened. Paralysis is the cessation of the power to functionate. Irritation implies an anatomic rather than a functional effect, tending toward the harmful. It has to do with actual changes in the cell structure. In its mild degrees irritation may have the effect of stimulation; in stronger forms irritation may overwhelm the cells and have the effect of depression; while excessive or continued irritation induces inflammation and even actual death of the cells involved. As an example, take cantharides, an irritant to the kidney cells; from small doses the cells are made to func- tionate more actively, and increased urination takes place, but from toxic amounts the irritation results in inflammation, so that nephritis sets in, with destruction of cells, impairment of function, and, perhaps, suppression of the urine. By exhaustion from overwork, continued stimulation may re- sult in depression or even complete cessation of the work of the cells, but this is a functional inactivity from fatigue, and a period of rest and nutrition will usually restore the cells' power. Often a drug will be found to stimulate one structure and depress another, as atropine, which stimulates the vagus center and depresses the vagus endings; or pilocarpine, which stimu- lates the nerve-endings in the sweat-glands and tends to depress heart muscle. SYNERGISTS AND ANTAGONISTS As might be surmised, the same dose of a drug will exert its usual form of activity more easily if given with other drugs of the same class; and sometimes a combination of two similar drugs will gain a result that one alone will not give in any dose. Drugs which help each other in this way are known as syner gists, or mutual helpers, and examples are bromides and chloral hydrate for sleep, calomel and jalap for catharsis. On the contrary, a drug may lose part or all of its power because of some agent that has the opposite physiologic effect. Such opposing agents are known as antagonists. An antagonist may be a drug, or it may be a substance formed in the body, as 58 PHARMACOLOGY AND THERAPEUTICS epinephrine or thyroiodine or some antitoxin. The antagonists may act (a) on the same structures for example, bromides pre- vent the convulsions of strychnine, both acting on the spinal cord; caffeine stimulates the psychic and motor centers of the cerebrum, while alcohol depresses them; pilocarpine stimulates the vagus nerve-endings, which are depressed by atropine; (b) on different structures for instance, digitalis slows the heart by stimulating the vagus center, while atropine prevents this effect by depressing the vagus nerve-endings; adrenaline stimulates the nerve-endings in arterial muscle, causing contraction of the arteries, and this effect can be wholly neutralized by nitrogly- cerin, which depresses the arterial muscle itself. Incompatibility should not be confused with antagonism. It is a pharmaceutic term, and should be confined to prescriptions. Incompatibility may be said to exist between two substances when their admixture in a prescription results in chemic or phys- ical change (other than mere solution). Examples are the pre- cipitation when strychnine sulphate in solution comes in contact with tannic acid, or when lead acetate solution is mixed with a solution of alum. Such a change may or may not be desired in a prescription; hence the physician should know what changes may take place in substances likely to be prescribed together. (See Chapter on Prescriptions.) SCIENTIFIC AND EMPIRIC THERAPEUTICS ANIMAL EXPERIMENTATION Besides the constituents, the preparations, and the pharma- cology of a drug, we are to learn its therapeutics, and we might ask how have our drugs come to have their present uses in medicine? From the employment of hepatica for liver diseases because its leaf suggested the liver, to the employment of drugs because of known actions determined by animal experimentation and therapeutic tests is a far cry, yet it represents only a few years of time, and indicates the rapid strides that are being made toward the establishment of therapeutics on a sound scientific basis. The use of drugs without an adequate scientific explanation of their efficiency is empiric. For instance, colchicum is exten- sively employed as a remedy in gout, though no pharmacologic study has as yet indicated how or why colchicum should be of benefit in this disease. We give it in gout for no other reason than that we believe that it has worked before; in other words, we use it empirically. As a matter of fact, animal experimentation is rapidly rele- SCIENTIFIC AND EMPIRIC THERAPEUTICS 59 gating empiric remedies to the realm of disuse or giving them new uses; and many beliefs in the efficacy of remedies have yielded to the adverse proof of experiment. Indeed, very few of the advances of the last half-century could have been made but for the use of animals in the study of the action of drugs, for detailed experiments on human beings are obviously out of the question. Anrep, working with animals, discovered the effects of cocaine as a local anesthetic; antipyrine, phenacetin, and a number of so-called coal-tar products owe their use to an observation by Filehne that antipyrine reduced the temperature of animals put into fever by experimental infection. The actions of nitrites, of thyroid extract, of saline infusions, of diphtheria antitoxin, etc., are all known as the result of animal experiments. In this connection it is an interesting fact that many of the most important discoveries have resulted from purely academic studies, studies made without thought of finding substances useful to man. For example, the hypnotic power of chloral hydrate was the outcome of Liebreich's attempt to solve the purely physiologic question as to whether or not a substance is broken up into its constituent parts before it is oxidized. The sleep-producing power of sulfonal was discovered in a study of the effects of organic sulphur compounds on metabolism. The power of epinephrine to constrict the arteries and raise blood- pressure was first noted in animal experimentation conducted with no thought .of therapeutic possibilities. And the recent wonderful additions to our knowledge of the irregularities of the heart may be attributed largely to some incidental observations of Cushny and others while performing laboratory experiments without a thought of their ultimate usefulness to man. These illustrations suggest what important discoveries might be lost to us if animal experimentation were to be undertaken only with the definite object of lessening human ills. If to these thera- peutic agents which we owe to experiments on animals we add the knowledge of the body processes, of disease conditions, of the transmission of disease, and of the development of im- munity, it makes enormous the sum of the obligations of medical science and human sufferers to animal experimentation, com- monly known as vivisection. Yet in recent years a goodly number of people who profess to believe that no animal should be sacrificed for the good of human beings, have made the most strenuous efforts to bring about legislation restricting vivisec- tion. Their harrowing descriptions of experiments, their grossly exaggerated statements as to the failure of experimenters to protect the animals from pain, and as to the brutality of the experimenters themselves, have, unfortunately, led many people 60 PHARMACOLOGY AND THERAPEUTICS of prominence to give them support, and have made it incumbent upon all physicians who are in a position to know the facts to combat in every way this retrograde movement. The medical man, of all persons, is in the best position to realize how, in the absence of vivisection to establish exact data, every attempt to treat the sick, especially by the new medical graduate, "would be nothing less than an experiment in human vivisection, which animal experimentation now renders needless." THE SCOPE OF TREATMENT Treatment may be described as either specific, symptomatic, or expectant. Specific treatment is that in which a remedy directly attacks the causative factors of the disease. In the diseases for which such specific remedies are known the diagnosis at once deter- mines the remedy, e. g., in diphtheria the remedy is diphtheria antitoxin; in acute articular rheumatism, salicylic acid; in malaria, quinine; in syphilis, salvarsan and mercury. In each of these diseases there is no question as to the remedy, for it is specific. But for almost all the diseases which a physician is called upon to treat, such as tonsillitis, typhoid fever, cirrhosis of the liver, etc., there is no specific remedy, so that he is forced to con- tent himself with attempts to combat the various harmful symp- toms and their effects as they appear, i. e., he employs symp- tomatic treatment. Thus in typhoid fever, if there is constipation, a drug with a laxative action is given; if diarrhea, a constipating drug; if there is a weak heart, a cardiac stimulant may be ad- ministered, and if the heart is in good condition it needs no drug at all. Hence in many cases of typhoid fever no remedy is re- quired for days at a time, for none of the manifestations of the disease are pronounced enough to demand special antagonizing, and we know of no remedy that will cure the disease itself. Again, in such a disease as cirrhosis of the liver, where certain tissues are destroyed and cannot by any known means be re- stored, treatment is directed, essentially, to combating such symptoms as result from the impairment of the diseased organ, and perhaps, also, to promoting the functional power of such portions of the organ as are still good. These are conditions for symptomatic treatment. In fact, almost all internal treatment is symptomatic treatment, and it is because of this fact that a knowledge of the power of remedies to modify the structure or functions of the various organs of the body is so important to the physician. HOW MUCH SHALL WE LEARN ABOUT DRUGS? 6 1 Expectant treatment is a term applied to the administration of mild and harmless remedies while the development of symp- toms is awaited. For example, if one sees a child with fever but cannot diagnosticate the disease at the first visit, one may pre- scribe some of the official solution of ammonium acetate, which satisfies the patient and the family, tends to do good, does no harm, and does not interfere with the later diagnosis of the disease. Expectant treatment should not be employed if its neces- sity can be avoided. A remedy employed in expectant treatment is known as a placebo ("I placate or please"), and in the selec- tion of a placebo it is well to choose one with some fitness to the case in hand, as the spirit of mindererus in fever, so that the tendency will be good even though its power is slight. In neu- rotic conditions a placebo is often administered for its psychic effect. HOW MUCH SHALL WE LEARN ABOUT DRUGS? The subject of the materia medica is an extensive one, and the text-books contain many things that the physician does not need to know. He need not learn the pharmacopeial definition, where and how a drug grows, the method of its collection, its physical and microscopic characters, its preparation for the market, its adulterants, the process of manufacture of chemic drugs, the shapes of crystals, melting-points, etc. Such data are for the pharmacist, the chemist, and the pharmacognosist, the men upon whom the physician must depend for his proper supply of good drugs. But as physicians we need to know the following: 1. The English and Latin names of drugs and their prepara- tions. In prescriptions we use the Latin names only, but in the literature find both the English and the Latin, so we must know both. We learn, therefore, iha,tficus is fig, and zingiber is ginger, and rhamnus pursJiiana is cascara, and mistura crctcE is chalk mixture. (See also Use of Latin in chapters on Prescription- writing.) 2. The Active Constituents of Organic Drugs. Of particular importance are those active constituents which are isolated from the drug and used by themselves in medicine, as morphine, strychnine, salicin, menthol, etc., or those which make unde- sirable incompatibles, as tannic acid. j. The solubilities and incompatibilities of chemic drugs and of active constituents, where these become of importance from a prescription or utility point of view. 4. Preparations, with their Strengths and Doses. These are 62 PHARMACOLOGY AND THERAPEUTICS the official preparations, and such unofficial ones as are in com- mon use. To know at least some of them is essential to the writing of prescriptions, for not only are the official preparations the ones that are made of uniform strength throughout the United States, but they are the forms in which a remedy can be con- veniently obtained. The average dose is given in the Pharmacopoeia, and this, in most instances, is the dose to learn; and since what is desired for the patient is a therapeutic dose of the drug itself, the dose of the preparation should be such an amount as will represent the desired dose of the drug. The learning of doses is greatly facili- tated by the pharmacopeial custom of having one strength for all the more powerful preparations of a given class. For example, all fluidextracts are of 100 per cent, strength; therefore their dose is that of the drug, but in liquid measure, i. e., each cubic centimeter is equivalent to one gram of the drug. All potent tinctures are of 10 per cent, strength, so their dose is 10 times that of the fluidextract. Most extracts approximate 5 times the strength of the drug, hence have a dose of one-fifth as much. For preparations, therefore, the doses do not have to be carried in mind as separate things, but can be instantly calculated from the percentage strength if the dose of the drug itself is known. On account of pharmacopeial uniformity, the percentage strength is easily learned, as shown above. As an example, take the prep- arations of digitalis; if the dose of digitalis is taken as i grain (0.06 gm.), that of the fluidextract is i minim (0.06 c.c.), that of the 10 per cent, tincture is 10 minims (0.6 c.c.), and that of the 1.5 per cent, infusion is 67 minims, or approximately i dram (4 c.c.). These amounts of the specified preparations each represent the dose of i grain of digitalis. 5. Pharmacologic Action. How the drug acts. This includes the expected or usual action and any unusual actions, from both therapeutic and toxic amounts. 6. Toxicology. The symptoms and treatment in case of poisoning. 7. Therapeutics. An extensive subject of immediate practical importance to every physician, to be studied in a general way with pharmacology, but to be studied in greater detail in con- nection with the individual diseases. It is in therapeutics that there is so much of the traditional, the old-fashioned, the empiric; and the crying need of the medical profession is that drug thera- peutics shall be based directly upon thorough pharmacologic knowledge tried out by clinical tests. S. Administration. How best to prescribe or administer the remedy. THE PHARMACOLOGIC ACTION 63 Q. Cautions and Contraindications. Conditions in which the drug is dangerous, or may be prescribed only with special caution. Indication is a term used in medicine for the kind of treatment "indicated" or "pointed out" by the symptoms or disease of the patient. We say, for example, that "the indications in such a sickness are that the patient shall remain in bed, on a milk diet, and shall have a dose of calomel." Or, to put it in another way, we say that "rest in bed, a milk diet, and calomel are indicated," i. e., "pointed to" by the symptoms as the means of treatment to be employed. Contraindication has the opposite meaning; it is a condition in which the drug should not be employed. THE PHARMACOLOGIC ACTION In this extensive field almost any kind of "aide-memoire" will be of value. It will, therefore, be our general plan to take up in natural succession the actions of each drug as follows: first, its action independently of the body, then its local action, its absorption into the system, its systemic action, its elimination from or disposal by the body, and finally its action (remote local) as it is being excreted. Such a scheme in detail is illus- trated in the following chart : A. On microorganisms and enzymes action away from the body, e. g., antiseptic action. B. Local action 1. On skin and adjacent mucous membranes nose, throat, eye, vagina, rectum, urethra, bladder. external conjunctiva and cornea. Eye^ pupil. internaK^accommodation. eyeball tension. 2. On alimentary tract: Mouth taste, appetite, saliva, astringency. on contents acids, enzymes, food sub- stances. Stomach on wall secretion, movements, absorption of food and drugs, pain emetic, antem- etic. Intestines on contents, secretion, movements, pain, character of stools. Liver, pancreas flow of bile, pancreatic juice, etc. r- u .. f j fat what points or not at all. L. Adsorption o drue{ , " ' } how rapidly. Heart auricles and ventricles 64 PHARMACOLOGY AND THERAPEUTICS D. Systemic action: 1 . On the circulatory organs: Blood corpuscles, alkalinity, coagulability. rate slower, fas- ter, fore e weaker, stronger, rhythm regular or irregular. Arteries contracted or dilated. Arterial pressure higher or lower. Always learn through what mechanisms, and how, an effect is brought about. It is not enough to know simply that the heart is faster or slower, or weaker or stronger. 2. On the respiratory organs: Movements ( de P th - ( rate. Bronchi secretions, muscle. Cough effect of drug depends on whether cough is due to excessive secretion, or lack of secre- tion, or sensitiveness of throat. 3. On the nervous system and sense organs: Cerebrum intellect, emotions, sleep, pain, motor area (motion, convulsions, paralysis). Cerebellum equilibrium . Medullary and basal centers vagus, vasoconstric- tor, respiratory, heat-regulating, pupil-dilat- ing, secretory, vomiting. c,. . , , (muscle tone. Spinal cord reflexes < , I convulsions, paralysis. Peripheral sensory, motor, secretory. Senses sight, hearing, smell, taste, touch. E (external j (Scc Local Actkm } (internal } 4. On muscle and bone. 5. On metabolism and temperature. 6. On secreting glands. male. 7- On genital organs female menstruation, pregnancy, labor, etc. how changed in body, elimination by what route E. Elimination or disposal of drug \ and in what form. rapidly or slowly cumu- lative. THE PHARMACOLOGIC ACTION 65 F. Remote local action on excretory organs during elimina- tion by kidneys, bladder, urethra, skin, bowels, lungs, mammary glands; or in urine, milk, sweat, breath, etc. G. After-effects. H. Untoward effects unexpected or unusual. I. Tolerance habit formation. Such a scheme as the above leads to completeness in the con- sideration of a drug's action. PART II INDIVIDUAL REMEDIES SINCE any or all actions of a drug, whether desirable or unde- sirable, may result from its administration, the proper use of the drug requires a knowledge of all its actions. Hence it is necessary to study each drug either as an independent individual or as a member of a limited group of drugs of nearly identical action. PROTECTIVES A. DEMULCENTS AND EMOLLIENTS These are agents which are soothing and softening to epithelial tissues. Their action is essentially physical or mechanical, and is purely local. Those for application to the skin are called emollients; those applied to mucous membranes are demulcents. The emollients include the unctuous materials, such as lard (adeps), wax (cera), spermaceti (cetaceum), petrolatum, cold cream (unguentum aquae rosae), ointment of zinc oxide, etc.; also cocoa-butter, olive oil and other bland oils, talcum powder, glycerin, rose-water, and various soothing lotions. The object of their use is to prevent drying of the epithelium or to soften and protect dried or irritated tissues. They are employed, therefore, for chapped skin, chafing, dermatitis, burns, etc. Poultices and hot fomentations are sometimes considered emollient, but they are best classed with the hot-water bag under the heading Coun- terirritants. The demulcents are the mucilaginous substances, such as acacia, tragacanth, flaxseed (linum), slippery elm (ulmus fulva), althaea, sassafras pith (sassafras medulla) and Irish moss (chon- drus crispus); also licorice (glycyrrhiza) , sweet almond (amyg- dala dulcis), starch (amylum), milk, white of egg, and the bland fixed oils (almond, olive, linseed, cottonseed, etc.). In the form of lozenges, flaxseed, slippery elm and licorice are employed in sore throat. In liquid form a demulcent may be taken by mouth for esophageal or stomach irritation, as following the ingestion of irritant poisons, or injected by rectum for proctitis or colitis or other irritative conditions. (For Starch Water, see Starch, in Part I.) 67 68 PHARMACOLOGY AND THERAPEUTICS B. MECHANICAL APPLICATIONS These are for local application, and act as protectives in a purely mechanical way. Such are: collodion, adhesive plaster, liquid glass (solution of sodium silicate), plaster-of-Paris (dried calcium sulphate), and the various dusting-powders, such as starch, lycopodium, and talcum, the last being a silicate of mag- nesium. SWEETENING AGENTS These are glycerin, cane-sugar, syrup, saccharin and extract of malt. SACCHARIN Benzosulphinide (saccharin, gluside, C 6 H 4 SO 2 .CONH) is an acid anhydride soluble in 290 parts of water and 31 of alcohol. Sodium-benzosulphinide (sodium-saccharin) is soluble in 1.2 of water and 50 of alcohol. The U. S. P. states that an aqueous solution of i in 10,000 has a sweetness comparable with a i in 20 solution of sugar, i. e., it is 500 times as sweet. But it has a flavor which is not so pleasing as that of sugar. It has been much employed in chewing gum, chewing tobacco, soda-water and can- ned foods as it is slightly antiseptic and is not fermentable; but it is not a food and lacks the caloric value of the sugar for which it is substituted. Mathews and McGuigan considered it deterrent in digestion by ptyalin, pepsin, and trypsin, but Roger and Garnier found that the acid anhydride activated pepsin mildly in the same way as hydrochloric acid. In amounts of not over 5 grains (0.3 gm.) a day for normal adults it was pronounced harmless by the U. S. Referee Board of Chemists, and Folin. a member of the Referee Board, said of their experiments, "The negative character of the results obtained indicates that saccharin in moderate doses is not injurious to the health of normal sound adults." Mercier took 75 grains a day (5 gm.) for 14 days without harm. Further- more, the extensive use of the drug by diabetics has not brought out any deleterious effects. The lethal dose for a rabbit is in excess of 2-, drams (10 gm.) and it is rapidly eliminated by the kidneys in unchanged form. In medicine it is employed as a sweetening agent for the use of diabetics and the obese, and in infants' or children's food when it is desired to omit sugar, as in the "sugar susceptibles" of Kerley. One grain (0.06 gm.) of sodium-saccharin is employed in place of a tablespoonful of sugar. NUTRIENTS From a pharmacologic point of view, the substances coming under this head are sugar, gelatin, cod liver oil, olive oil, and extract of malt. NUTRIENTS 69 SUGAR GLUCOSE Sugar is official in three forms, viz., cane-sugar (saccharum) , milk-sugar (saccharum lactis) and dextrose or glucose (glucosum). A saturated solution of cane-sugar is "syrupus." Cane-sugar. Locally, powdered cane-sugar has been used in dry form as an application to ulcers and infected wounds. It seems to promote osmosis, to dissolve fibrin and to favor local nutrition, and it does not form crusts. Zweifel, Sudeck, and others have employed a 50 per cent, solution in amounts of one ounce (30 c.c.) in the vagina for leucorrhea. As a postoperative measure to lessen shock, vomiting, thirst and gas pains, and fur- nish food, Barbee recommends a i| per cent, solution by rectum by the continuous drip at 30 to 40 drops per minute. Goulston and others consider cane-sugar a valuable cardiac nutrient even when taken by mouth. Finding it non-irritant and readily absorbed, Magnus and others have employed a 10 per cent, solution by hypodermoclysis as a nutrient, and claim that it is utilized as well as glucose. Milk-sugar has no uses except as a diluent in pharmacy and as a food. It is of interest that in Coleman's high calorie typhoid diet as much as i^ pounds (715 gm.) a day has been given by mouth and completely utilized. Glucose, dextro-glucose or dextrose, is the natural sugar of the blood. A 5.4 per cent, solution is isotonic with the blood. Henriques and Anderson maintained goats in good nutrition for 3 weeks by a continuous flow through a permanent canula into the jugular vein, of a solution of glucose, sodium acetate, inorganic salts, and meat digested to the amino-acid stage. Leo states that starving rabbits given 15 grains (i gm.) of glucose daily by the subcutaneous or intravenous route survived 5 days longer than the controls. Woodyat, Sansum and Wilder, by a most careful series of experiments, found that glucose in 10 to 50 per cent, solution can be introduced directly into the veins at rates corresponding closely to 0.85 gm. of glucose per kilogram of body weight per hour, without producing glycosuria or diuresis. This would be 63 gm. per hour for a man of 70 kilograms resting quietly in bed, and at this rate would furnish 6048 calories per day. They call particular attention to the fact that sugar tolerance must be measured by the rate of administration, i. e., the amount per hour. When given more rapidly than at the rate established glycosuria and diuresis result. For example, a lo-kilogram dog given 5.4 gm. per hour passed the amazing amount of 2800 c.c. of urine in 8 hours. They recommend intravenous glucose as among the best of diuretics, the dilute 70 PHARMACOLOGY AND THERAPEUTICS solutions serving to flush the system, and the concentrated solu- tions to abstract water from the tissues. They warn that if large quantities of water are given with the glucose, there is a liability to mechanical failure of the heart, while on the other hand too much of a concentrated solution will over-dehydrate even to the extent of producing death. Burton-Opitz showed that the viscosity of the blood was increased by concentrated solutions and was readjusted by os- motic interchange between the blood and tissues, and Fischer, because of its power to dehydrate colloids, classes sugar with the saline diuretics. The amount of sugar that can be given by mouth or rectum and disposed of is much below the amount that can be given by vein. It is impossible to produce glycosuria by the rectal in- jection of glucose, and Hopkins found that while glucose by mouth produced a hyperglycemia in half an hour, 20 gm. sub- cutaneously took 4! hours and 100 gm. by rectum 4 hours to increase the blood-sugar. Macleod has pointed out that neutral glucose solutions intravenously produce an acidosis, there being twice as much lactic acid in the blood as normal and an increase in the hydrogen ion content. This would suggest the propriety of giving alkali with the intravenous solutions. Therapeutics. i. As food in rebellious vomiting (postopera- tive, in pregnancy or gastric disease, etc.), malnutrition, and car- diac decompensation glucose may be employed by continuous intravenous infusion in 10 to 50 per cent, solution in amounts representing 50 gm. per hour. For convenience a larger amount (300 c.c.) may be given slowly two or three times a day, the resulting glycosuria causing a loss of only a few grams of glucose at most. 2. During or following operation it may be employed as a prophylactic against shock intravenously or in 4 to 6 per cent, solution by hypodermoclysis or the continuous drop proctoclysis. 3. As a diuretic, dilute solutions are used intravenously or by proctoclysis in anuria and uremia, acidosis, diabetic coma (Joslin), and other toxemias; and concentrated solutions in cardiac or nephritic edema. Turretini reports the overcoming of anuria in four cases, two of them mercurial poisoning. GELATIN Gelatin fgelatinum) is obtained by acting with boiling water upon certain animal tissues, as the skin, ligaments, and bones, and allowing the solution to dry in the air. It may be obtained in thin, transparent sheets which are permanent if dry, but when moist, readily putrefy. It is soluble in boiling water, and in the NUTRIENTS 71 proportion of i part of gelatin to 50 of water forms a jelly on cooling. In cold water it does not dissolve, though it absorbs water and swells. It is precipitated from solution by tannic acid as a tough, leathery insoluble mass, a matter of importance in the administration of capsules and of gelatin-coated pills. Be- sides its uses in pharmacy and as a food, a sterilized i per cent, solution in amounts up to 100 c.c. per day has been employed by hypodermoclysis and intravenously in hemorrhage and aneurysm to increase the coagulability of the blood. It is a protein food from which indol is not formed, hence has been thought valuable in intestinal putrefaction, but Mendel considers it an inferior food, useless for growth and poor for the maintenance of nutrition. In shock, Hogan uses it intravenously as a colloidal solution that will remain in the vascular system and so maintain the volume of the blood. Any but fresh gelatin is prone to contain putrefactive products or bacteria. Glycerinated gelatin, a com- pound of equal parts of gelatin and glycerin, is a rubbery mass, used as a basis for vaginal suppositories and urethral bougies. It melts at the temperature of the body. COD-LIVER OIL (OLEUM MORRHU^) This is a fixed oil, obtained from the fresh livers of Gadus morrhua, and of other species of Gadus. It contains faint traces of iodinjs and bromine and sometimes of phosphorus. It also contains a vitamine, for when given with polished rice it prevents beri-beri (Funk), and when substituted in equal caloric value for lard in a standard diet for rats it induced growth which had failed from the lard (Osborne and Mendel). According to Leathes it is a fat with a high percentage of unsaturated fatty acids, so that when taken as food it saves the liver its usual work of desaturation. The cheap oil obtained from putrefactive livers contains various bases, such as choline and tyramine. A watery extract of such has a vasoconstrictor action. Such oils are no longer used. Cod-liver oil has a fishy odor and a bland, fishy taste, which are, at least in part, due to the presence of free fatty acids. These are abundant in the cheaper oils, and in the good oils are more readily produced in hot weather. As the fishy taste makes cod- liver oil especially nauseating to many it is customary to ad- minister the oil in admixture with the extract of malt, or in the form of a sweetened and flavored emulsion. It has been shown experimentally that emulsified oils are more readily absorbable than the unemulsified, especially by persons of poor nutrition, and it is noted clinically that the emulsion is easier to take and 72 PHARMACOLOGY AND THERAPEUTICS is better borne by the stomach than the pure oil. It should be given after meals as an addition to the regular food, or two or three hours after meals, to permit of ready digestion in the duo- denum. It should not be given just before meals. Therapeutics. The great value of cod-liver oil is as a nutrient in states of poor nutrition and poor resistance, hence its use in tuberculosis, chronic bronchitis, and chronic susceptibility to colds. It is also of use in spasmophilia and rickets. In a negro district in New York, Hess showed that rickets could be pre- vented by giving cod-liver oil at an early age. Cod-liver oil is sometimes employed by inunction in cases of severe malnutri- tion, but the usefulness of this procedure is seriously questioned. On subcutaneous injection Mills and Congdon (1911) found that pure oils were slowly absorbed by starving animals, and more rapidly absorbed when made into an emulsion with 3 to 5 per cent, of lecithin. It is probable that such an emulsion would be partly absorbed on rectal administration. Preparations and Doses. Cod-liver oil 2 drams (8 c.c.). Emulsion, 50 per cent, of oil, made with acacia and flavored with sugar and wintergreen 4 drams (15 c.c.). EXTRACT OF MALT (EXTRACTUM MALTI) This is a liquid extract of malted barley. It is of the con- sistence of thick honey, is sweet, and represents a large per- centage of carbohydrate nutritive matter. It contains a small amount of the starch-digesting ferment, diastase. Dose, \ ounce (15 c.c.). Its chief use is to hide disagreeable tastes, as of cas- cara, cod-liver oil, etc. COUNTERIRRITANTS These are remedies which, by irritation of the skin, are in- tended to counter or check deeper-lying affections. Counter- irritation is a very old method of treatment, and it still holds a prominent place in therapeutics. There are several degrees of skin irritation that may be produced, viz., rubefacieni, or red- dening, vesicant, or vesicle-producing, and epispastic, or blistering. Beyond this an irritant may produce death of tissue. There are a few drugs, such as mercuric chloride and croton oil, which attack the gland-mouths and produce pustules (pustulant effect), but these are not now employed as counterirritants. In therapeutics, in almost all cases, it is desirable to confine the irritation to the rubefacient degree. In this the superficial vessels dilate, the skin becomes red and warm, and there may be smarting. If the COUNTERIRRITANTS 73 application is too strong or is allowed to remain too long, little vesicles appear, and presently, coalescing, form blisters. Blistering is very rarely employed as a remedial measure. Until recently blistering of the gums by ammonia was a common practice of dentists; and today a fly-blister over the knee-joint in cases of large inflammatory effusions is more or less employed. However, in almost all cases not only is blistering not desirable, but it is distinctly harmful. For not only is the blister a painful lesion, requiring treatment of itself, but it effectually prevents further applications to the skin at that spot. Hence the more active agents, like mustard and heat, must be carefully watched, especially when the patient is suffering from severe pain or is somnolent or comatose: Unintentional blistering frequently re- sults because of neglect to remove a mustard poultice before going to sleep. In brunets an area of blistering or even vesica- tion may be followed by permanent pigmentation. The mode of action of counterirritants has been the subject of much speculation, but the recognition in recent years of a relationship between the viscera and certain areas of the skin and body-wall through the nervous system has thrown much light upon the matter. Dana (1887) called attention to "referred pains" as being due to the distribution of the nerves, and Head (1893) and Mackenzie (1902) determined that tenderness of the superficial tissues might be a manifestation of inflammation or injury of one of the internal organs. Recent physiologic studies have shown that pain is elicited only in structures supplied by the cerebrospinal nervous system, and that viscera supplied by sympathetic nerves have no proper pain sense. The apparent pain in inflamed viscera is thus due to a reflex effect through the cerebrospinal nerves. Hence the tenderness of appendicitis is mostly localized at one point, though the actual situation of the appendix is very variable; the tenderness of cholelithiasis is spread over an area much greater than that of the gall-bladder; and in pulmonary tuberculosis the superficial tissues are some- times so tender as almost to preclude examination by percussion. Hertz (1911) concluded that pain in disease of the alimentary tract may be situated in the skin, muscles, and connective tissues. Sherrington (1909) demonstrated that on cutting certain nerves passing to the intestines and stimulating the central cut ends, the abdominal muscles contract in a definite manner. Also, it is a well-known physiologic fact that pain tends to cause contraction of the splanchnic arteries. Tice and Larson (1917) found that heat to the abdomen caused a rise in arterial pressure, but cold produced no essential change. These findings all go to show a very close relation, through 74 PHARMACOLOGY AND THERAPEUTICS the nervous system, between the tissues of the body wall and the contained viscera, and tend to explain how irritation of a superficial area may have a decided effect upon a deep-lying or even remote viscus which is in no way in direct connection or contact with the irritated area. In this way may be understood the expulsion of flatus by the intestines as the result of a turpen- tine stupe applied to the abdomen, though the intestines have no direct anatomic connection with the anterior abdominal wall; or the effect of a mus- tard foot-bath in pelvic con- gestion; or of a mustard paste on the chest in pleurisy or pneumonia. Mtiller demon- strated that the application of an ice-bag or a hot-water bag to the abdomen has little if any effect upon the tem- perature of the underlying viscera. But Leonard Hill states that the intrapleural temperature may be decid- edly raised by a hot poultice on the chest wall. As working theories, Head and Hertz adopt the seg- mental relation, i. e., that the spinal cord and brain are in regular segments, and that a lesion affecting a nerve from a given segment affects all the nerves whose centers are in that same segment. "Head's areas," mapped out on the skin by Head as being the areas of tenderness in the va- rious visceral affections, have not, however, been at all constant, and Mackenzie has pointed out that in visceral lesions pain and tenderness do not appear in the whole distribution of any one segment, but in limited areas in the distribution of two or several segments. Therefore, Macken- zie suggests a regional relation rather than a segmental one. Langstroth (1915) finds that the areas over which hyperalgesia may be found in disease of each viscus are numerous. The good action of reflexes from skin stimuli mav be the result of a con- Fig, i. Areas in which pain is some- times felt: (A) In cardiac affections; (B) in affections of the stomach; (C) in affec- tions of the liver, stomach, or duodenum; (D) in affections of rectum or uterus (after James Mackenzie, in "Symptoms and Their Interpretation"). COUNTERIRRITANTS 75 ferred hypersensitiveness to stimuli owing to the visceral in- flammation, to reflex changes in the circulation, or to other so far unknown effects. Rubbing the back will sometimes distinctly affect the viscera, and Mackenzie's picture herewith suggests a reason for the suc- cess, in some instances, of the osteopathic plan of manipulating the spine and its neighborhood. That counterirritation may act in other ways is also possible, for it is well known to every one that pain in a sensitive place results in a diminished sense of pain in a less sensitive region. It is probable, also, that the psychic suggestive effect, as of a thermocautery, may at times be important, and that in the treat- ment of muscular or other tissues in direct contact with the skin changes in the local blood-supply may account for the remedial effect. In this connection it is of interest that Lazarus-Barlow has shown that a muscle on the same side as a blister has a higher specific gravity than the corresponding muscle on the unblistered side. And Wechsberg has demonstrated that when abscesses were experimentally produced in rabbit's legs, they were less extensive and healed more rapidly on the side to which counter- irritants were applied. Oliver found that a mustard paste over the liver sent the blood-pressure from 105 to 135, and Roth, that a large hot application to chest and abdomen sent up the pressure about 8 mm. in each of two cases. But Wood and Weisman (1912) find that irritation of the skin of the hand by a mustard- bath just short of producing dermatitis does not materially increase the rate of blood-flow in the hand, the skin redness being presumably not accompanied by a change in the caliber of the deep-lying arterioles. We may sum up, then, by repeating that the good effects of counterirritation may be due to: (i) A segmental or regional nervous relation between superficial tissues and the viscera. (2) The countering effect of a superficial pain over a deep-seated one. (3) A direct circulatory effect. (4) A psychic effect. Counterirritant Measures. The more commonly employed counterirritant measures are: heat, cold, dry-cupping, and drugs. Heat is applied as an electric pad, a hot-water bottle, a hot stone or flat-iron wrapped in cloth, or a poultice when the desire is to apply something that will keep hot a long time, or for a short time by an electric lamp or the high-frequency current. For a sud- den application of extreme heat the thermocautery or the stupe may be employed. A stupe is a towel wrung out of very hot water; a turpentine stupe is made by sprinkling 15 or 20 minims of oil of turpentine on the hot towel. In the use of the thermo- cautery for counterirritant effect the skin should not be seared, j6 PHARMACOLOGY AND THERAPEUTICS but merely reddened by the rapid passage over it of the red- hot iron or platinum point. Poultices may be made of linseed meal, bread, flour, bran, or hops boiled with water and wrapped in cheese-cloth or any thin fabric. The clay poultice (cata- plasma kaolini, U. S. P., 1900), a proprietary name for which is "antiphlogistine," has kaolin and glycerin as its basis, with added small amounts of boric acid, oil of peppermint, methyl salicylate, and thymol. It has practically no absorption power for water, but acts largely by its heat (Roth); so for use it is heated in its container and smeared over the part with a knife or stick. Roth (1905) showed that it had less power as a counter- irritant and retained heat for a shorter time than a flaxseed poultice. Cold is for the most part secured by an ice-bag or ice-water coil. It has been ascertained that locally applied heat or cold does not affect the temperature of the viscera to any extent, and that their value in internal inflammations is not antiphlogistic but reflex. Cold is often applied directly to an injured or in- fected area with the idea of quieting the inflammation and of checking the activity of bacteria, but it also lessens the resistance of the tissues of the patient, and by so doing may do more harm than good. Fauntleroy (1912) believes that in some cases of appendicitis the ice-bag is responsible for poor walling-off of the lesion and poor resistance on the part of the patient, as shown by the failure of the leukocytes to increase much above the normal. Dry-cupping is a process of suction applied to the skin by means of specially made cups or small tumblers in which a vacuum is created. There are several methods of obtaining the vaccum, such as swabbing out the cup with a cotton probe clipped in alcohol and then lighting the alcohol, or igniting some cotton stuck in the bottom of the cup. The cup must be instantly ap- plied; and in order that it may hold and perform its suction, its application must be in a region where the tissues are soft enough to be drawn upon. Care should be taken not to burn the patient and not to leave the cups on long in one place. Dry-cupping is not now much employed because of its awkwardness, but in extreme cases, as in edema of the lungs or suppression of urine, may be resorted to. Drugs. These are all, in the nature of the case, general protoplasmic irritants. The rubefacients are: camphor, menthol, and chloral hydrate, any two of which solids, when mixed together, become liquefied; the spirit and liniment of camphor, alcohol, chloroform, methyl salicylate (the liquid stearopten which com- poses over 90 per cent, of oil of wintergreen or oil of birch), oil of turpentine, tincture of iodine, ammonia, capsicum, and mustard. COUNTERIRRITANTS 77 The epispastics are: ammonia water (used by dentists for blister- ing the gums) and cantharides cerate. Mustard (sinapis) is the ground seed of black mustard (sinapis nigra). Its use depends upon the development of an irritant volatile oil when the mustard flour is mixed with water. (See Glucosides, Part I.) It may be employed in the form of a mustard-leaf (charta sinapis) dipped in tepid water, or as a thin mustard paste made by wetting a mixture of mustard and flour with tepid water and wrapping in cheese-cloth. For an adult the paste may be made of one part of mustard to two or three of flour, according to the sensitiveness of the skin; for a child, one part to four or five of flour. A mustard paste usually reddens sufficiently in ten to thirty minutes, and its effect must be watched to prevent blistering. As soon as the skin is thoroughly reddened the mustard should be removed. Sometimes with the idea of preventing blistering, white of egg is mixed with the paste, or vaseline is smeared over the skin at the site of application. Whether or not such measures are efficacious we are unable to say. In pelvic congestion with suppressed menstruation a mustard foot-bath is sometimes employed. It is made by adding a tablespoonful of mustard to four quarts of warm water. A mustard-bath for infants is prepared of half this strength. In all mustard preparations very hot water should not be used, as this destroys or retards the activity of the enzyme which forms the irritant volatile oil. The enzyme is destroyed at 60 C. (140 F.). It is to be borne in mind that the "hotness" of a mustard-bath should be entirely due to the mustard oil developed, and not to its temperature as recorded by the thermometer. Cases of poisoning by mustard give the symptoms of volatile oil poisoning. (See Carminatives.) Cantharides (cantharis) is the dried and powdered brilliant green beetle, Cantharis vesicatoria, or Spanish fly. Its active constituent is 0.6 per cent, of cantharidin, an acid anhydride which forms soluble salts with alkalies. The "fly-blister" is a piece of adhesive plaster spread with cantharides cerate. About its only employment is in large inflammatory collections of fluid in the knee-joint, as in acute rheumatism. A fly-blister about two inches in diameter is applied to the skin for twenty minutes, then removed, and replaced by a flaxseed poultice. A large amount of serum collects beneath the skin and is removed by pricking the skin. Internally, the 10 per cent, tincture has been employed as an emmenagogue in dose of 5 minims (0.3 c.c.). From its use to produce abortion, and its administration with the fancied purpose of stimulating sexual feeling, many poisoning cases have resulted. 78 PHARMACOLOGY AND THERAPEUTICS It is a violent irritant, the symptoms following large or undiluted doses being local irritation in mouth, esophagus, stomach, and intestines, resulting in inflammation, blistering, or ulceration, with vomiting, diarrhea, bloody stools, and cramps. The kid- neys and bladder also show intense inflammation, with bloody urine or suppression of the urine. There is sometimes priapism. Pregnant women may abort. The patient may go into profound collapse, resulting in death. The treatment is symptomatic, demulcents being administered by mouth and rectum, and col- lapse treated as described later. Therapeutics of Counterirritants. i. To relieve pain mus- cular, neuralgic, and joint pains, as well as those associated with visceral affections (pleurisy, cardiac pain, biliary and intestinal colic, and dysmenorrhea) . 2. To relieve congestion and inflammation as in the case of inflamed lymph-nodes, pelvic congestion, and pneumonia. 3. To promote absorption as of serous effusions in the pleural or peritoneal cavities or joints, in hydrocele, and in bruises or hematomata. 4. To overcome tympanites as in the use of the stupe in ty- phoid fever or postoperative intestinal paralysis. 5. To overcome collapse as in the use of mustard-bath or alternating hot and cold plunges for infants. 6. To check nose-bleed ice to the back of the neck. 7. To relieve cerebral congestion as the ice-bag in headache, delirium, meningitis, etc., or the menthol pencil in headache. Cautions. Debility and old age, in which conditions irritants of all kinds tend to be depressing. CAUSTICS (ESCHAROTICS) These are substances which act by causing the death of tissue- They may destroy by consuming the tissue, as in the case of sul- phuric acid, or by precipitating protoplasm, as by phenol, or by causing an inflammation which results in a slough, as in the case of arsenic. The caustics are: 1. Acids. Sulphuric, nitric, glacial acetic, trichloracetic. 2. Alkalies. The hydroxides of potassium, sodium, and cal- cium (lime). 3. Metallic Salts. Silver nitrate (lunar caustic), copper sul- phate (bluestone), zinc chloride, burnt alum, chromium trioxide (chromic acid), arsenic trioxide (arsenous acid). 4. Carbon dioxide, liquid or solid. 5. Phenol. Sulphuric acid chars; nitric acid changes the part to yellow, CAUSTICS (ESCHAROTICS) 79 and all acids act by abstracting water and neutralizing the al- kalinity of the tissues. They are direct irritants, even when diluted. The alkalies abstract water and saponify the fatty substances of protoplasm; they are very penetrating, and make ulcers which are slow to heal. Chromium trioxide comes in the form of deliquescent, dark reddish crystals, which decompose or explode on the addition of glycerin, alcohol, or other organic substances. Among chromate workers perforation of the nasal septum is the rule, and deep ulcers of the hands known as "chrome holes" may make their appearance. They may be avoided by protection from the dust. There are also a number of caustic substances, such as mercuric bichloride, which are not used as such in therapeutics. Toxicology. When caustic acids or alkalies are swallowed, they burn and denude the tissues of mouth, esophagus, and stom- ach, and produce shock. To neutralize acids, mild, non-car- bonated alkalies may be used, such as diluted lime or magnesia; the carbonated alkalies set free too much gas. To neutralize alkalies, vinegar and lemon-juice are good. For the burns, de- mulcents, such as olive oil, lard, white of egg, milk, etc., are indi- cated. (For poisoning by metallic salts and phenol, see later.) Therapeutics. To remove exuberant granulations, small polypi, warts, and hypertrophied soft tissues, as in the nose. Caustics are now very little employed except for application to small and superficial areas. Carbon dioxide, in liquid form or in sticks, has been used to remove nevi, and in the treatment of lupus, sluggish ulcers, epitheliomata, and leprosy. To cauterize is to sear the tissues. It may be done with the thermocautery or electric cautery, or by nitric acid, phenol (carbolic acid) , or lunar caustic. Phenol is adapted for infected cavities or sinuses, the area being afterward washed with alcohol to check further penetration of the phenol. For dog-bites, Bartholow, of the New York Department of Health (1911), recommends the following in the order of their merit, viz.: (i) Fuming nitric acid; (2) silver nitrate; (3) the actual cautery. The employment of the thermo- or electric cautery for the removal of tissue is quite different from its counterirritant use, in which the skin should not be seared. SCARLET RED Scarlet red is a name given to several different dye-stuffs, but that recommended for medicinal use is toluol-azotoluol-azobeta- naphthol. It is known as "Scarlet R," and is marketed in powder form and in 8 per cent, ointment. From the many published 80 PHARMACOLOGY AND THERAPEUTICS reports it would seem to have a marked power to stimulate the growth of epithelium over sluggish wounds and ulcers. Bullock and Rohdenburg consider it a chemical irritant of slow absorb- ability and low toxicity. Davis, of Johns Hopkins (1911, 1912), records very rapid covering of the surface of sluggish sores with epithelium having the macroscopic and microscopic appearances of normal skin. On the injection into dogs and rabbits of a i per cent, solution in oil he found it non-irritating and non-toxic, though it was disseminated through the body and stained the fatty tissues. In man he gave it by mouth, amounts of 32 grams, 63.3 grams, and 66.5 grams in about four weeks producing no symptoms, and being apparently unabsorbed, as they did not stain the fat of the body. He therefore recommends its use in gastric ulcer. Hinman recommends a 10 per cent, solution in oil for laryn- geal tuberculosis. Gurbski reported poisoning in a child, and Lyle, in a woman. Both followed application to extensive burns, and the symptoms were headache, dizziness and faintness, followed by nausea, violent vomiting, abdominal cramps, and pain on urination. There was some fever, and albuminuria without casts. Dimazon ointment is a modification that does not stain or irritate. THIOSINAMINE FIBROLYSIN Thiosinamine, or allyl sulphocarbamide, is soluble in 3 parts of alcohol. It is decomposed by water, though this change is retarded by glycerin. Fibrolysin is the trade name for a sterile aqueous solution of a double salt of thiosinamine and sodium salicylate. It is marketed in ampules of 2.3 c.c. of solution representing 3 grains (0.2 gm.) of thiosinamine. Thiosinamine, in dose of 1-3 grains (0.06-0.2 gm.), is ad- ministered by rectum or vagina in suppositories, or subcuta- neously in 10 per cent, freshly prepared glycerin-water suspension or in 15 per cent, alcoholic solution. It is very irritant locally. Fibrolysin is employed subcutaneously, intramuscularly, or intravenously. The injections are given at intervals of one to three days, in some cases as many as 60 injections being given. It is less irritant locally than thiosinamine. The action of the drug is to soften scar tissue, and perhaps to promote its absorp- tion. Starkenstein states that it favors the hydrolysis of collagen into gelatin. There are many clinical reports of its value in hypertrophied scars of the skin; in strictures of esophagus, rectum, and urethra; in fibrous ankylosis; in arthritis defor- mans; in sciatica; in opacities of the cornea, etc. F. Ehrlich THE DIGESTIVE FERMENTS 8 1 has employed it with success to loosen the adhesions of small epigastric and umbilical hernias. Such a drug would seem to be a desideratum in therapeutics, yet it has limitations in its power to affect scar tissue, and its failures are frequent. It is contra- indicated in active inflammatory conditions, in tuberculosis where connective-tissue formation is desired, and in ulceration of the alimentary tract. It is said to be useless in corneal opac- ities of long standing. CHRYSAROBIN Chrysarobin is a neutral principle extracted from Goa powder, a substance found deposited in clefts or cavities of the wood of the araroba tree of Brazil. It is an orange-yellow powder, taste- less and odorless, but irritating to mucous membranes if con- tinuously applied. Practically its only use at present is in psoriasis, the 5 per cent, ointment being employed. This is not used about the face, as it may cause irritation of eyes, nose, and mouth. It sometimes causes an acute dermatitis of arms or legs. THE DIGESTIVE FERMENTS PEPSIN Pepsin (pepsinum) is an enzyme usually obtained from the fresh mucous membrane of the hog's stomach. It is almost entirely soluble in 50 parts of water, and more so in water acidu- lated with hydrochloric acid. It acts in a weakly acid medium to change the insoluble proteins of the food into soluble protein. It is destroyed by o.oi per cent, sodium hydroxide (Sollmann), and it is inhibited by strong acid, human pepsin, for example ceasing to act when the hydrochloric acid reaches 0.3 per cent. By the U. S. P. test it must be able to change 3000 times its weight of coagulated egg-albumin into soluble protein. In other words, one grain of pepsin can digest at least 6\ ounces of coagulated egg-albumin. Dr. Gies has told me of a specimen in existence 2-00 times as powerful as this. The U. S. P. test calls for digestion at 125.6 F. (52 C.) for two and one-half hours in water contain- ing one part of absolute hydrochloric acid in 3000. Pepsin is, therefore, a highly powerful substance; and it would be a very important therapeutic agent were it not for the fact that in almost all classes of digestive disturbances it is a superfluous remedy. For by extensive tests with human gastric contents it has been found that, except in the not very numerous cases of achylia gastrica with atrophy of the gastric mucous membrane, the stomach rarely fails to secrete its specific ferments. 82 PHARMACOLOGY AND THERAPEUTICS Hence its only use as a digestive agent is in atrophic cases, and in these it is not always efficient. (See Pancreatin.) It may be given in capsules, 5 grains (0.3 gm.) at the beginning of a meal and 5 grains at the end, with hydrochloric acid in proper dilution. Pepsin regularly contains some rennin; its solutions, there- fore, will coagulate milk. PANCREATIN Pancreatin (pancreatinum) is usually obtained from the fresh pancreas of the hog or ox. It contains the specific ferments of the pancreas, and represents its external secretion. There is no evidence that it also represents the internal secretion, and it has no power to check pancreatic diabetes. Its notable actions are those of the enzymes, trypsin, amylopsin, and steapsin. It acts best in an alkaline medium. The Pharmacopoeia gives tests of its protein and starch- digesting power. It specifies that i grain of pancreatin with 5 grains of sodium bicarbonate must be able to peptonize com- pletely 3 ounces of cow's milk at 104 F. (40 C.) in thirty min- utes; that is, it must change the proteins so that the milk will not coagulate on the addition of nitric or acetic acid. It further specifies that pancreatin must be able to change 25 times its weight of starch into substances soluble in water, i. e., into dextrin, maltose, etc. Hence pancreatin would be another important therapeutic agent, but that, like pepsin, it is seldom needed in therapeutics. When the secretion of gastric juice fails, as in achylia, the choice is left open of administering pepsin and hydrochloric acid, or pancreatin and sodium bicarbonate, to bring about di- gestion in the stomach. But as a rule no digestant at all is employed. In the milder form of chronic pancreatitis with emaciation, and in the very rare cases of "pancreatic infantilism," a condi- tion of stunted growth and chronic diarrhea, excellent results are recorded from the administration of pancreatin. Byron Bram- well reported a boy of nineteen with development arrested from the age of eleven and chronic diarrhea for the last nine years. He was bright and intelligent and not a cretin. His urine was free from sugar. Under the influence of pancreatin by mouth he grew five inches in two years and gained 22 pounds. Rentoul had a girl of eighteen, in a similar condition of stunted develop- ment, gain 9^ pounds and grow 2 inches in less than five months, at the same time showing decided sexual development and general improvement. Thompson reports two such cases. They are PANCREATIN 83 very rare. These results may be due not to the digestive power, but to an effect which the pancreatin may exert upon the ac- tivity of other glands, for instance, the thyroid or pituitary. Indeed, because of the discovery of a probable antagonism be- tween the internal secretions of pancreas and thyroid, pancreatin has been employed in hyperthyroidism. In chronic pancreatitis pancreatin has been of uncertain value, and in checking a pancreatic diabetes has proved a failure. But in some cases it has overcome the failure of fat and protein digestion which regularly accompanies pancreatitis, and so has resulted in improved nutrition and the disappearance of pan- creatitic emaciation. In some cases of fat indigestion with diarrhea, not especially attributable to the pancreas, as in tu- berculosis, pancreatin has checked the diarrhea and promoted nutrition. The chief use of pancreatin, however, is not as a remedy for internal administration, but as an agent for peptonizing milk (and other protein foods) for invalids. A formula for peptonizing milk is: Pancreatin gr. v (0.3 gm.) Sodium bicarbonate gr xx (1.3 gm.) Water iv (120 c.c.) Milk Oj (480 c.c.) This is kept warm at a temperature never hotter than the hand can bear continuously without discomfort (115 F.). At the end of fifteen minutes enough peptones are present to give the mixture a faintly bitter taste. At the end of an hour, or sometimes in half an hour, the milk is fully peptonized, that is, will not coagulate on the addition of nitric or acetic acid; it is changed in appearance and has a decidedly bitter taste. To obtain the greatest change of proteins to ammo-acids requires twenty-four hours (Short and By waters). For gavage or rectal feeding milk should be "fully peptonized"; for administration by mouth it is usually peptonized only fifteen or twenty minutes because of the taste. At the end of the desired time it should be brought quickly to the boiling-point to destroy the enzyme, and should then be kept on ice. The "cold method" of adding the pancreatin and sodium bicarbonate and allowing the milk to stand without warming is uncertain and unscientific. Pepsin preparations are not suitable for peptonizing, for they invariably contain the coagulating enzyme, rennin, and conse- quently coagulate the milk. 84 PHARMACOLOGY AND THERAPEUTICS RENNIN (Rennet) Rennin is not a digestant, but is the milk-coagulating ferment of the gastric juice. It is obtained from the mucous membrane of the fourth stomach of the calf. Under its influence the case- inogen of milk changes to paracasein, and the latter takes cal- cium and forms an insoluble curd. The calcium is usually fur- nished by the calcium phosphate of the milk, but occasionally must be supplied by the addition of a small amount of calcium chloride or lime-water. The ordinary rennin curd contains 13 per cent, more calcium than the curd of hydrochloric acid (Harris), and is tougher and more cohesive, though less dense and more readily acted upon by pepsin. If the stomach con- tents are highly acid or more than very slightly alkaline, the rennet will not act. Hence if sodium bicarbonate or more than a very little lime-water is added to milk, no coagulation takes place at all; and in marked cases of hyperacidity the curd formed is the dense hydrochloric acid curd and not that of rennet. Its action is retarded by agitation unless in the presence of hydro- chloric acid (Bernegau). It has been found to coagulate from 5000 to 166,000 times its weight of milk. The use of rennet in medical practice is to prepare junket and whey. Junket is the whole coagulated milk, and is a valu- able food for invalids. It is prepared by adding the commercial liquid rennet, or essence of pepsin, or junket tablets dissolved in water, to barely warm milk, and setting aside till the clotting takes place. The process is retarded if the milk is hot. The junket may be eaten plain or with cream and sugar; it may be flavored with sherry, nutmeg, etc. Whey is the liquid portion of the milk after the rennet curd is removed. It is obtained by breaking up the junket and strain- ing through cheese-cloth or linen. It contains some of the rennin ferment, a small amount of soluble protein (lactalbumin) , a slight amount of fat, about 4 per cent, of milk-sugar, and the salts of the milk with the exception of the calcium phosphate. It is used as a nearly protein-free diluent of milk in infant feeding. Before it is added to milk it should be brought to the boiling-point to destroy the rennin; otherwise it will coagulate the new milk. Rennet is used very extensively in cheese-making and in the preparation of junket for the table. DIASTASE Diastase is the starch-digesting agent of barley malt, changing hydrolized or cooked starch to dextrin and maltose. It has also DIASTASE 85 some power to hydrolyze raw starch. The Pharmacopoeia re- quires that it be able to convert not less than 50 times its own weight of potato starch into sugars. It acts in a neutral or shghtly acid medium, is retarded in its activity by alkalies (Chit- tenden and Ely, and Kellerman) , and is destroyed by strong acids. Its digestive power is seldom needed in therapeutics, except pos- sibly in pancreatic disease, or where for some obscure reason starch digestion is definitely defective. The extract of malt is prepared by extracting barley malt with water and evaporating to a thick, honey-like consistence. It contains much maltose and other nutritive matter and a little diastase. As its diastatic activity is not very great, it is really nothing but a form of carbohydrate food (see Nutrients). Owing to its sweetness and thick consistence it is a good vehicle for cod- liver oil, cascara, and other strong-tasting drugs. There are also marketed some "extract of malt" preparations which are really malt liquors of the nature of beer. They con- tain about 2 per cent, of alcohol, by volume, and much nutritive extractive. In some cases they are made bitter with hops. They have very feeble digestant power for starch. Taka-diastase, a ferment with diastatic properties, is obtained from a mold, Aspergillus oryzce, which grows in Japan upon the rice plant. Papain is an enzyme obtained from the juice of the unripe fruit of Carica papaya, a South American papaw plant. It can digest albumin in a medium that is alkaline, neutral, or acid, but acts best in one that is slightly acid. It has no special indications. Ingluvin is the dried lining membrane of the chicken's crop. Its digestive power is not very great. It has been given in doses of 5 grains (0.3 gm.) after each meal in the nausea and vomiting of pregnancy, but its use is purely empiric. Secretin, owing to its unstable nature, has not as yet come into general therapeutic use. It is quickly destroyed by gastric juice and by trypsin (Carlson). Hormonal is a preparation from the spleen of the rabbit. It is said to contain the same peristaltic hormone as the gastric mucous membrane. Reports as to its value differ widely, but a number of authorities have obtained good and continued action of the bowels in postoperative tympanites and obstinate chronic constipation. It tends to cause headache and a marked fall in blood-pressure, and anaphylaxis has occurred. It is given in doses of 15 to 40 c.c. intravenously or intramuscularly, the latter being painful. 86 PHARMACOLOGY AND THERAPEUTICS THE INORGANIC ACIDS The inorganic acids in common use for their acidity are hydrochloric, phosphoric, and sulphuric. Their dose is 5 minims (0.3 c.c.) well diluted. Each has an official 10 per cent, dilu- tion; but, as shown by the following table, the strong acids are not 10 times as strong as the diluted acids. The relative percentage strengths are as follows: Hydrochloric acid. . . .31.9 per cent. . . .Diluted hydrochloric acid. . . .10 per cent. Phosphoric acid 85.0 " . . .Diluted phosphoric acid 10 Sulphuric acid 92.5 " . . .Diluted sulphuric acid 10 Nitric acid is official, but not the diluted nitric acid. Aromatic sulphuric acid (acidum sulphuricum aromaticum) is a 10 per cent, solution (by volume) of sulphuric acid in alcohol flavored with ginger and cinnamon. Nitrohydrochloric acid (acidum nitrohydrochloricum) is made by acting on 82 parts of hydrochloric acid with 18 parts of nitric acid. A violent reaction takes place, the acids being split up to form nitrosyl chlorides and chlorine. The reactions are: HNO 3 + 3HC1 = NOC1 + C1 2 + 2HoO 2HNO 3 + 6HC1 = 2NOC1 2 + C1 2 + 4H 2 O There is a slight excess of hydrochloric acid (Arny), so that nitrohydrochloric acid is a liquid containing free hydrochloric acid, free chlorine, and nitrosyl chlorides, the original acids having lost their identity. It is a corrosive liquid with an unpleasant odor. Diluted nitrohydrochloric acid is about one-fourth this strength. It does not keep. Action. The strong acids are caustic, destroying the cells by the absorption of water, by the neutralization of alkali, and by other destructive chemic changes. Sulphuric acid chars organic matter; nitric acid turns it yellow. The diluted acids induce a reflex flow of saliva. This is especially rich in protein, and serves to take up and neutralize the acid. In the stomach they promote the flow of gastric juice, and secondarily, by their influence in the production of secretin, promote the flow of pancreatic juice and bile. Toxicology. When a strong acid is swallowed, it causes burn- ing and corrosion of the mouth, throat, esophagus, and stomach. The most corrosive acids are nitric and sulphuric. From poison- ous amounts, whether diluted or not, there are the systemic symp- toms of acute acidosis. /. c., dyspnea, twitching, convulsions, coma, collapse, and death. Ewing's conclusions from the experi- mental production of acute acidosis were: It is possible to kill THE INORGANIC ACIDS 87 animals by injection of mineral acids or even of organic acids in large quantity, and such animals die with marked reduction in the acid-neutralizing properties of the blood, and with diminished carbon dioxid content sufficient to explain their peculiar dyspnea. The urine shows marked excess of ammonia nitrogen and diminu- tion of urea. The autopsy findings indicate death from asphyxia. It must be remembered that the basicity of the blood, that is, its acid neutralizing power, depends not alone on alkalies, but also largely upon protein, urea, and other nitrogenous sub- stances (Ewing). Fischer finds acids a cause of urticaria and angioneurotic edema. Treatment. (a) Local. The local antidotes in the ali- mentary tract are mild alkalies, such as soap, lime, and magnesia. The carbonated alkalies, such as chalk, sodium carbonate, and sodium bicarbonate, must be used with great caution, if at all, for with the acid they liberate CO 2 gas, and this may result in collapse from sudden distention of the stomach or rupture of the corroded stomach wall. (b) Systemic. To combat the acidosis half an ounce of sodium bicarbonate dissolved in one to two pints of hot water may be given slowly by rectum; or a 3.5 per cent, solution of sodium carbonate may be administered intravenously (von Noorden). In chronic acidosis the administration of proteins, and especially of amino-acids to furnish NH 3 , the natural antidote to acid excess, has been tried, without great success. The administra- tion of carbohydrates has been of more value. Therapeutics. Nitric acid is occasionally used for the de- struction of warts or small nevi. It causes pain, and often leaves a scar. Its stains of the skin are yellow and indelible. Being a powerful coagulant of albumin, it is not an aid to digestion. Hydrochloric acid is sometimes employed when the natural acid of the gastric juice is deficient or absent. It is then given in amounts of 5-10 minims (0.3-0.7 c.c.) in a glass of water to be drunk during the meal. The throat will not stand a stronger solution. This may be repeated in half or one hour. It is believed by some that in these cases the acid serves as an anti- septic to prevent the development of gas-forming organisms in the stomach and the passage of putrefactive bacteria into the intestines. There is some good evidence against this belief. Rehfuss (1917) finds that these amounts have no perceptible effect on the gastric chemistry, though apparently useful in some cases in overcoming the diarrhea of achyiia gastrica. A great dis- advantage from the long-continued administration of mineral acids is the increased elimination of the alkaline bases, with the development of a comparative acidosis. The diluted hydrochlo- 88 PHARMACOLOGY AND THERAPEUTICS ric acid, it will be noted, is about one-third the strength of the undiluted. Oxyntin, a protein compound of hydrochloric acid, and betaine hydrochloride under the name of acidol, have been introduced for the administration of hydrochloric acid in solid form. Acidol is strongly acid to the taste. It is claimed that 10 grains (0.7 gm.) of oxyntin represent 5 minims (0.3 c.c.), and 10 grains of acidol represent 7.5 minims (0.5 c.c.) of hydrochloric acid (U. S. P.). In a careful research, Long (1915) found that betaine hydro- chloride became dissociated, and its action was almost equal to that of dilute hydrochloric acid of the same concentration. On the other hand, Long found that mixtures made by combining hydrochloric acid with protein, e. g., oxyntin, hold scarcely enough acid to digest themselves. Dilute nitric, nitrohydrochloric, and phosphoric acids are sometimes employed for the same purpose as hydrochloric. There is no reason for preferring them to hydrochloric, which is the natural acid of the gastric juice; and, as noted above, nitro- hydrochloric is an irritant chlorine preparation. Sulphuric acid, both internally, in dose of 5 minims (0.3 c.c.) , and externally, has been employed for the night-sweats of tu- berculosis. In the author's experience it is of no value. It was formerly the custom to employ diluted sulphuric acid or aromatic sulphuric acid to bring quinine-sulphate into solution, but since it does so by changing the insoluble sulphate to the soluble bisul- phate, it would be better to use the bisulphate at the outset and avoid employing an arbitrary amount of acid. THE ORGANIC ACIDS Citric acid (acidum citricum, HsCetLX):) occurs in large quantities in fruits of the citrus family, the lemon, orange, lime, and grape-fruit; and in milk to the extent of 0.1-0.25 per cent. Tartaric acid (acidum tartaricum, H 2 C 4 H 4 O 6 ) occurs in grapes. They are both crystalline solids, readily soluble in water. In the duodenum they form sodium citrate and tartrate. These salts and the acids are not readily absorbed, and have a laxative effect in the intestine. The alkaline salts are changed to car- bonate in the blood, and so serve as systemic alkalinizers. Lemonade and Imperial drink are refreshing drinks in fever. The latter is made by dissolving i^ drams (6 gm.) of potassium bitartrate (cream of tartar) in 2 pints (i liter) of boiling water, and adding ?, ounce (15 gm.) each of sugar and grated fresh lemon- peel. In the duodenum potassium bitartrate, which has an acid reaction, forms Rochelle salt (potassium and sodium tartrate). THE ORGANIC ACIDS 89 When a weak solution of a soluble citrate is mixed with or injected into the blood, it takes up calcium and has a retarding influence upon the clotting of the blood. Because of this action, citric acid has been recommended in the late stages of typhoid fever to prevent thrombosis. But Rudolf and Cole (1911) have determined that citric acid administered by mouth does not essentially influence the time of coagulation of the blood either in typhoid fever or in other conditions; and Addis (1909) has shown that in amounts of 60 to 120 grains (4-8 gm.) a day the drug does not affect coagulability. Janney has administered up to i ounce (30 gm.) with sodium bicarbonate without apparent harm. Formic acid (acidum formicum, HCOOH) has been employed locally and internally in rheumatism. It is present in the secre- tion of the sting of the bee, and has been employed by allowing bees to sting the involved part. Acetic acid (acidum aceticum, CH 3 COOH) is the essential ingredient of vinegar. The Pharmacopoeia recognizes glacial acetic acid of 99 per cent, strength, which is used for the removal of warts; acetic acid, of 36 per cent, strength; and diluted acetic acid, of 6 per cent, strength. The last is of the strength of good vinegar. A 2 per cent, solution is also employed as an intra- uterine hemostatic in postpartum hemorrhage. Trichlor acetic acid, CC1 3 COOH, is strongly caustic, and is employed in the removal of warts, small nevi, and hypertrophied tissue, such as occurs in the nose. The acetates are freely soluble in water, are readily absorbed, and by changing to carbonate act as agents to alkalinize the blood. They are diuretic, and their intravenous administration is followed by a fall in arterial pressure, and dila- tation of the kidney arterioles. Lactic acid (acidum lacticum, C 3 H 6 O 3 ), obtained by fermenta- tion from sugar-of-milk, finds its chief use in 10 to 50 per cent, solution in glycerin as an application to tuberculous ulcers of the throat. Recently, on the theory that putrefactive germs in the in- testines are inhibited by lactic acid germs and their products, the lactic acid drinks have come into extensive use both by physi- cians and the laity. Such drinks are: zoolak, fermillac, kumyss, sour milk, buttermilk, etc. Special strains of lactic-acid bacteria are also sold to be used in making sour milk, or to be swallowed in the form of capsules, tablets, or liquids. In the opinion of Herter, Bryce, Mendel, the author, and others this form of medi- cation has no real value, many researches indicating little if any use for the drinks except for their nutritive constituents. Lactic acid drinks are prone to induce attacks of gastric hyperacidity, 90 PHARMACOLOGY AND THERAPEUTICS and to bring on rheumatic manifestations in those subject to rheumatism. A recent claim that they are of value in diabetes requires extensive clinical testing. Oxalic acid (H 2 C 2 O 4 ) has no use in therapeutics, but is of interest because of the frequency of its poisoning. This usually occurs from the drinking of solutions used in the kitchen for brightening copper boilers. The crystals resemble somewhat those of Epsom salts. There are (i) Severe irritation of the gastro-intestinal tract, with vomiting, diarrhea, and cramps, and (2) nervous manifestations, from twitching of the muscles to complete tetany (continuous cramps of voluntary muscles), and convulsions, coma, and death. When death does not ensue, there may be a remote local effect upon the kidneys resulting in nephritis. The systemic symptoms are those of acidosis, or of the removal from the system of calcium, for which oxalic acid has a great affinity. The chemic antidote for the stomach is a calcium salt, such as lime or the chloride or lactate, to form the insoluble and non- corrosive calcium oxalate. Even wall-plaster may serve if there is no lime at hand. For the systemic symptoms the need is to alkalinize and to supply calcium; therefore a pint (500 c.c.) of a solution of 0.25 per cent, of calcium chloride with i per cent, of sodium bicarbonate may be administered intravenously. Copious drafts of water should be given by mouth to promote the elimination of oxalate by the kidneys. FRUIT ACIDS The acids in fruits are chiefly acetic, malic, citric, tartaric, oxalic, and in some instances salicylic and boric. Malic acid and malates occur in apples, pears, currants, blackberries, rasp- berries, quince, pineapple, cherries, and rhubarb. Citric acid and citrates occur in large quantities in lemons, oranges, grape- fruit, and lime, and slightly in quince, gooseberry, strawberry, raspberry, currant, and cranberry. Tartaric acid occurs in grapes. Bertrand and Agulhon have found traces of boric acid in many fresh fruits and vegetables. According to Blyth, the percentage of free acid present in the various fruits is as follows: Pear, 0.2; grape, 0.79; apple, 0.84; plum, 0.85; cherry, 0.91; peach, 0.92; strawberry, 0.93; apricot, 1.16; blackberry, 1.19; raspberry, 1.38; gooseberry, 1.42; prune, 1.5; mulberry, 1.86; currant, 2.15. Lemon-juice contains about 6 per cent, of citric acid. It must be remembered that the relative acidity cannot be determined by taste, as the proportions of sugar differ in the ANTACIDS 91 different fruits. For example, while strawberries, currants, gooseberries, huckleberries, apples, pears, and prunes contain between 5 and 8 per cent, of sugar, raspberries, blackberries, apricots, plums, and peaches contain less than 5 per cent.; cherries contain 10 per cent., and grapes, from 15 to 24 per cent. (Blyth, Fresenius). The amount of sugar also regularly in- creases with the ripeness of the fruit. ANTACIDS The therapeutically employed antacids are certain salts of the alkalies, potassium, sodium, lithium, and ammonium, and certain salts of the alkaline earths, magnesium and calcium. Of the metals mentioned, K, Na, and Li are ions of ready absorba- bility from the alimentary tract, while Mg and Ca are absorbed with comparative difficulty. Hence after a local action in the stomach the salts of the former for the most part manifest a systemic action, while those of the latter have a special intestinal activity, magnesium salts being laxative and those of calcium constipating. The antacids are of two types: I. Those of alkaline reaction. II. Those not of alkaline reaction. THE ANTACIDS OF ALKALINE REACTION These can neutralize acids, and they have both a local and a systemic effect as alkalinizers. They are chiefly oxides, hydrox- ides, and carbonates, and may be differentiated into two groups, the caustic alkalies and the mild alkalies. (a) The caustic alkalies are the hydroxides of potassium (KOH) and sodium (NaOH) and the oxide of calcium (CaO, lime; Lat., calx}. They destroy tissue by abstracting water, by dissolving albumin, and by saponifying fats. Even in dilute solution the potassium and sodium hydroxides are more pene- trating and more irritant than the other alkalies. The official solutions of potassium hydroxide and sodium hydroxide are of about 5 per cent, strength. They are strongly caustic. (b) The milder alkalies are the carbonates and bicarbonates of potassium, sodium, and lithium, and the carbonates and hy- droxides of magnesium and calcium. The salts of potassium, sodium, and lithium are preferred for simple alkalinity, the mag- nesium salts when there is constipation, and the calcium salts when there is diarrhea. POTASSIUM, SODIUM, AND LITHIUM The official mild alkaline salts of these ions are : Potassium bicarbonate (KHCO 3 ), soluble in 3 parts of water. Potassium carbonate (K 2 CO 3 ), "salts of tartar," soluble in 0.91 part of water. Sodium bicarbonate (NaHCO 3 ), "baking soda," soluble in 12 parts of water. Monohydrated sodium carbonate (Na 2 CO 3 -fH 2 O), dried so- dium carbonate, soluble in 3 parts of water. Washing-soda is crystalline sodium carbonate (Na 2 CO3+ioH 2 O). Both are rather irritating to the tissues. Lithium carbonate (Li 2 CO 3 ), soluble in 75 parts of water. All these salts are insoluble in alcohol. In aqueous solution the bicarbonates slowly change to carbonate by loss of carbon dioxide. When heated, they change more rapidly, hence any liquid containing sodium or any other bicarbonate should not be boiled. Potassium. Since potassium chloride in the blood, in amounts above i : 10,000 slows and weakens the heart and retards the activity of other muscles, the potassium ion has been considered a muscle depressant. But in our food we ingest at least \ ounce (15 gm.) of potassium salts daily, and if the diet is a purely vegetable one, sometimes as much as 3 ounces (90 gm.) daily. Dixon says that we do not get their specific action because they are excreted so rapidly by the kidneys, and Smilie has shown that ordinarily harmless doses of potassium chloride become severely toxic in those with chronic nephritis. It is probable that, other things being equal, the sodium salts should be preferred, unless cardiac depression is an object of the medi- cation. Lithium. Since the lithium salts of uric acid are more soluble than the corresponding sodium salts, lithium has been favored as the alkali in gout and the uric-acid diathesis. But the quadriurate, which seems to be the responsible irritant in attacks of gout, is not rendered soluble by any lithium salt except in concentrated solution; and is not prevented by lithium, so far as known, from forming in gouty subjects. Daniels obtained no effect from lithium citrate alone in a case of gout, but got a greater excretion of uric acid from atophan when lithium citrate was given with it. She attributed a mobilizing effect on deposited urates to the lithium, though it had no power of itself to increase the elimination. The lithia waters on the market are chiefly remarkable for the minuteness of the amount of lithia present. ANTACIDS 93 several gallons, as a rule, containing not more than a single therapeutic dose. Cleaveland (1913) reports lithium poisoning in himself on two occasions. The first time he took 120 grains (8 gm.) of lithium chloride in twenty-eight hours. The symptoms began after the first dose of 2 grams. There were fulness in the head, dizziness, ringing in the ears, and blurring of the vision, followed by tremors and marked prostration. The second time, several months later, he took 60 grains (4 gm.) and the symptoms were repeated. He felt as if he had taken a large dose of quinine. There were no gastro-intestinal symptoms. C. A. Good (1903), in experiments on cats and dogs, found that 60 mg. per kilo daily invariably caused death sooner or later from gastro-enteritis. Sodium. Even sodium chloride is poisonous under certain circumstances, and Jacques Loeb believes that the function of potassium and calcium salts in the blood and in sea-water is to pre- vent penetration of cells by too much sodium chloride. A num- ber of cases of poisoning from concentrated saline used intra- venously or by rectum instead of normal saline have been reported, the symptoms being nausea, vomiting, diarrhea, maniacal delir- ium or coma, fever up to 104 F., collapse, and death. In a fatal case of a woman given 1920 grains (64 gm.) by hypodermoclysis in mistake for normal saline, Combs noted crenation of the red cells in the fresh blood. Barlow reports that the drinking of a pint or more of the saturated solution is a common method of com- mitting suicide in Chekiang Province, China. Campbell cites a case of death in a boy of five w r ho was given a pound instead of a tablespoonful of salt in a quart of water as an enema for worms. Brooks reports death in an adult from an enema of a strong solution. The author has received a report of death in one infant from a colon irrigation of a i : 16 solution, and gan- grene in another from hypodermoclysis with the same liquid, which was labeled "normal saline." The relation of edema to salt retention is a highly important one. Bryant reported the case of a physician who developed serious edema of the legs after eating very large quantities of salt with his meals for several weeks. Stoppage of the habit resulted in cure. Sodium chloride should not be administered as an in- fusion or rectal injection in parenchymatous nephritis, eclampsia, or any condition with edema. On the other hand, too prolonged salt-free diet may result in indigestion, vomiting, absence of acid in the gastric juice, weak- ness, nervous irritability, and cachexia. The author has seen two cases of nephritis with marked edema, in one of which a salt- free diet resulted in convulsive twitching of the muscles all over 94 PHARMACOLOGY AND THERAPEUTICS the body which were relieved by giving salt, and in the other of which it was impossible to obtain diuresis except when salt was given. It is estimated that an adult requires from 2 to 3 grams of sodium chloride a day. Bonninger states that salt has a marked inhibitory action on the secretion of gastric juice, and Hamburger shows that it in- activates pepsin. Best finds 2 glasses of normal saline an effective cathartic, and Miiller an intravenous of 5 c.c. of 10 to 15 per cent, two or three times a day effective against hemoptysis. A peculiar effect of hypertonic sodium chloride (1.5 c.c. of 30 per cent, solution) intravenously is the protection of guinea-pigs against anaphylactic or proteotoxic shock. It acts by lowering the irritability of smooth muscle (Dale, Zinsser, Lieb). (See also Saline Infusion.) Sodium Bicarbonate (Soclii Bicarbonas). For alkalinity ,. the favored salt is sodium bicarbonate (NaHCO 3 ). This salt is extensively employed both externally and internally. Five grains (0.3 gm.) will neutralize 6.2 minims (0.4 c.c.) of hydro- chloric acid (U. S. P.), about 22 minims (1.5 c.c.) of diluted hydrochloric acid, and i^ ounces (45 c.c.) of gastric juice of 0.3 per cent, strength. The alkalinity of its solution increases on standing, owing to the loss of carbon dioxide. On boiling it sets free carbon dioxide with effervescence and loses 37 per cent. of its weight. Externally, in solution, it is a solvent for dried exudates, such as the crusts in seborrheic eczema; and either in solution or paste is a soothing application in erythema, urticaria, itching, insect-bites, and burns. It is not caustic. To mucous membranes its solutions are soothing, and they act as solvents for thick mucus. Alimentary Tract. Sodium bicarbonate neutralizes acids and dissolves mucus. According to Pawlow (1897), it tends to inhibit salivary, gastric, and pancreatic secretion. But in Pawlow's laboratory, Sa witch and Zeliony (1913) have demon- strated that when it is applied to the pyloric mucosa it causes acid gastric juice to be secreted by the stomach in gen- eral. The effect of an alkali in the stomach will vary greatly ac- cording to the nature of the stomach contents at the time of its administration. In the resting period, sodium bicarbonate merely dissolves mucus and is absorbed as bicarbonate into the blood, to increase its alkalinity directly. In the digestive period it reduces the secretion of gastric juice, neutralizes a portion of the hydrochloric acid, liberates the carminative carbon dioxide gas, and is absorbed as sodium chloride. In cases of fermentation or "sour stomach" it may neutralize the organic acids, and so ANTACIDS 95 result in the opening of a spasmodically closed pylorus; while at the same time its CO 2 acts to overcome flatulency. The time of administration must, therefore, be chosen with a definite purpose. Usually for hyperchlorhydria one hour or two hours after meals will be the period of harmful excess of acid. In continuous hyperacidity and in fermentative conditions a dose an hour before meals will tend to prepare the stomach for the next meal; or sometimes a dose will be necessary immediately after eating because of abnormal acid or gas having been present at the commencement of the meal. A dose at bedtime tends to check the early morning acidity, or a dose on arising cleans the stomach of acid and mucus before breakfast. In duodenal ulcer it may be needed when the "empty pain" comes on. In alcoholic gastritis it may be used in solution for lavage to remove excessive thick mucus. Seelig, Tierney, and Rodenbaugh find that intravenous sodium bicarbonate solutions exert an effect beyond those of other alkalies in raising blood-pressure, and Howell states that a less alkaline state of the blood causes relaxation of the blood-vessels, while an increase in the alkalinity improves their tone. But rapid excre- tion makes it difficult to produce more than temporary changes in the alkalescence of the blood. In mild conditions of acidosis the bicarbonate may be given by mouth in quantities to keep the urine only slightly acid. In diabetes, though it favors the excretion of the acetone bodies, its continued use may interfere with the normal acid-neutralizing functions of the body. Underbill found the blood-sugar content of a normal rabbit unaffected by intravenous dilute alkali, but in dogs with hyperglycemia Macleod obtained a distinct lowering of the sugar, and Murlin and Sweet have come to the conclusion that alkalies serve to promote glucose oxidation and to favor the work of the pancreas. In severe conditions of acidosis, as in diabetic coma, uremia, pneumonia, or delayed chloroform poisoning, enormous doses, up to k ounce (15 gm.), have been given by mouth; and by rectum, by the continuous drop method, as much as 2 ounces (60 gm.) per day in 3 per cent, solution. In diabetes these amounts, with sodium bicarbonate intravenously in 3.5 to 4 per cent, solution, give only occasional good results (von Noorden) ; and the reason for this may be that in diabetes there is no change in the alkalinity of the blood as judged by the hydroxyl ions, though in acidosis from mineral acids the blood is acid (Folin). But in the acidosis of uremia the author has successfully employed if ounces (40 gm.) of sodium bicarbonate intravenously in both 4 and 10 per cent, solutions, and there are good reports from its use in the 96 PHARMACOLOGY AND THERAPEUTICS acidosis of pneumonia. Generalized edema, edema of the lungs, and chills are reported following its intravenous use. In rheumatism and sometimes in gout it is given until the urine is alkaline. Von' Noorden believes that in gout alkalies are useless and perhaps harmful. Fauvel states that as much as i| ounces (6 gm.) a day has no effect on the excretion of xanthines or uric acid. By increasing the salts of the blood it is diuretic. In some cases it is distinctly laxative. The other carbonated alkalies have similar actions, but are less employed. Folin suggests that a mixture of sodium, potas- sium, calcium, and magnesium salts would be better than sodium bicarbonate alone. "Fischer's solution" is hypertonic, is ad- ministered intravenously, and consists of i per cent, of crystalline sodium carbonate (containing 10 molecules of water) and 1.4 per cent, of sodium chloride. Following Fischer's recent theory of acid as a cause of nephritis, it has been employed in this dis- ease, but neither the theory nor the treatment seems satisfactory. MAGNESIUM The magnesium antacids are the oxide, the hydroxide, and the carbonate. Magnesium perhydrol is the magnesium per- oxide. The magnesium oxide (magnesii oxidum) of the Pharma- copoeia, or burnt magnesia, is a very light, odorless white powder, which, when exposed to air, slowly changes to carbonate. One part of it, on being mixed with 15 parts of water and allowed to stand half an hour, hydrates and forms a gelatinous mass. The heavy oxide (magnesii oxidum ponderosum) is 3^ times as heavy and does not readily hydrate. Magnesium hydroxide comes in the form of a thick white liquid or magma (magma magnesice), commonly called "milk of magnesia." This is formed by precipitating a solution of magnesium sulphate with sodium hydroxide, which leaves the magnesium hydroxide sus- pended in the water in a line state of subdivision. It contains about 4 grains (0.25 gm.) of magnesium hydroxide in each dram (4 c.c.). Magnesium carbonate (magnesii carbonas), (MgCO 3 ) 4 .- MgfOH^ + sHoO, is a white, insoluble powder, capable of neutralizing acids with the liberation of carbon dioxide gas. These magnesium salts are all very weak alkalies without any caustic action, but they have considerable combining power for acid. The oxide in the hydrated gelatinous form will neutral- ize i.\ times its weight of hydrochloric acid (U. S. P.). Benedict states that magnesium forces calcium from the system and hinders the calcium retention necessary for bone building. This might be a highly undesirable effect from the repeated administration CALCIUM 97 of milk of magnesia to infants. They all act as cathartics, and will be considered further under that heading. (See Magnesium Sulphate under Cathartics and Anesthetics.) CALCIUM Preparations. The mildly alkaline salts are the carbonate and the hydroxide. The carbonate is insoluble in water. The salts for systemic action are the chloride and the lactate, both soluble in water, the former being deliquescent. The carbonate (CaCO 3 ) comes in two forms "prepared chalk" (creta prasp- arata) and "precipitated chalk" (calcii carbonas praecipitatus) . The latter is in the form of a heavy fine powder, may be obtained pure, and is much used in tooth-powders. The former is pre- pared from native chalk and contains impurities, but because of a cohesive tendency has been much used in liquids for internal use. It comes in heavy, cone-shaped lumps, and is often called "drop-chalk," from its method of manufacture. It constitutes 30 per cent, of compound chalk powder (pulvis cretae compositus) ; and this is kept on hand for the fresh manufacture of chalk mixture (mistura cretae), dose, 2 drams (8 c.c.). Unfortunately this mix- ture contains the fermentable substances, sugar and acacia, and does not keep well. The hydroxide is employed in the form of a saturated solution, known as lime-water (liquor calcis). Lime-water is a very weak preparation, containing only 0.14 per cent, of calcium hydroxide, i. e., about n grains to a pint. It is precipitated by heat. To neutralize i minim of hydrochloric acid, \ ounce (15 c.c.) is required. On exposure to air it takes up carbon dioxide and forms calcium carbonate, which precipitates. Hence lime-water tends to deteriorate, and samples sometimes contain almost no calcium hydroxide. Before making lime-water the slaked lime should always be washed thoroughly, to remove soluble impuri- ties, as directed in the Pharmacopoeia. The syrup of the lactophosphate (syrupus calcii lactophos- phatis), dose, 2 drams (8 c.c.), is official. Action. As shown by numerous experiments calcium is necessary not only for the growth of bone, but also for that of the soft tissues. In adults it is required in amounts equivalent to about 15 grains (i gm.) of calcium oxide a day. The body obtains its supply of calcium chiefly from drinking-water, eggs, milk and green vegetables, and slightly from animal flesh, cereals, and fruits. Milk contains about 0.17 per cent., i. e., slightly more than lime-water. There is as much calcium in 400 calories of milk as in 10,000 calories of round steak and white 98 PHARMACOLOGY AND THERAPEUTICS bread (Sherman). The absorption of calcium is not very ready, though it is favored by the acid of the gastric juice. From 60 to 80 per cent, of the calcium taken by mouth passes out with the feces (von Noorden), part of it having been unabsorbed, and part of it absorbed and reexcreted. After a hypodermatic of a cal- cium salt it quickly appears in the colon and as much as 50 per cent, has been recovered in this way. In the urine the or- dinary daily output is from o.i to 0.5 gm. per day, and in the feces 0.4 to 0.8 gm. When Soborow gave 8 to 10 gm. of chalk per day, the calcium of the urine rose to 0.7-0.98 gm. According to Beneker, in sickness and all conditions of debility, and in starva- tion, much more than usual of the calcium and magnesium phos- phates may appear in the urine, and sometimes enormous quanti- ties (2 to 4 gm. a day). Hoppe-Seyler says this excretion is favored by rest in bed, the bones slowly atrophying and giving off lime salts. The bones contain about 4000 times as much cal- cium as the blood and act as a reserve to keep the calcium of the blood normal. In infant feeding both calcium and fat may be lost by the formation of insoluble calcium soaps in the intestines, and Dubois and Stolte suggest for its prevention the giving of sodium or potassium carbonates or foods yielding excess of alkali. Acid conditions favor excretion by the kidneys rather than by the colon, hence in acidosis from diabetes, and when there is much acid in the food, the urinary output of calcium rises to a high figure. Loeb found that calcium salts can stop contact irritability of muscle and the hypersensitiveness of the nervous system induced by various salts. They increase the rapidity of action of the coagulating enzymes, especially of the blood and milk. They antagonize the action of potassium salts on the heart. Loeb has recently suggested that the calcium in the blood is for the protection of the cells from acids and sodium, the potassium and calcium making a relative impermeability of the external portion of the protoplasm of the cells. Meltzer states that cal- cium is capable of correcting the disturbances of the inorganic equilibrium whether these are in the direction of increased irri- tability or the opposite. Loeb noted that the lack of sufficient calcium or the injection into the animal body of a salt capable of precipitating calcium e. g., the oxalate or citrate of sodium- results in muscular twitching. MacCallum, Lambert, and Vogel perfused an isolated limb with normal blood dialyzed to remove calcium, and produced extreme hyperexcitability. With blood similarly dialyzed, but w r ith the calcium retained, there was no hyperexcitability. Tctany has frequently followed removal of the parathyroid glands, and both in tetany and after parathyroidectomy the CALCIUM 99 calcium content of the brain and blood has been found dimin- ished (Quest and MacCallum and Voegtlin). It has also been shown by the last two investigators that the nervous manifesta- tions following parathyroidectomy may be checked by the ad- ministration of calcium salts. They suggest that the absence of the parathyroids causes an "impoverishment of the tissues with respect to calcium, and the consequent development of a hyper- excitability of the nervous system, and tetany." Marine and Lenhart found that 5 c.c. of a 5 per cent, solution of CaCl 2 re- sulted in the recovery of a dog from tetany which came on after a thyroid operation. It is well known that infantile tetany usually appears in those with rickets. Erdheim (1911) reports that extirpation of the parathyroid glands of white rats resulted in the failure of full calcification of dentine and enamel in the growing teeth; but that on transplanting parathyroid glands, the dentine and enamel layers became fully calcified. Erdheim and Canal showed fur- ther that after removal of the parathyroids callus formation is retarded. These facts and a number of reported cases of human tetany relieved by calcium lead one to think that calcium- starvation, or disturbance of calcium metabolism through failure of the parathyroids, is an important cause of tetany, and suggest tl\e intravenous use of calcium salts in this disease (Meltzer). Coagulation of the Blood. It is an old observation that calcium salts added to the blood outside of the body, or intra- venously, increase its coagulability and lessen its coagulation time. But it is still a question whether calcium salts admin- istered by mouth have such an effect. Wright and Paramore (1905) reported a distinct difference within an hour or less; but Addis (1909) found that calcium salts administered by mouth increased the ionizable calcium of the blood, but not sufficiently even from large doses, to alter the coagulability. Rudolf and Cole (1911), after a very careful series of studies, have come to the conclusion that "the free exhibition of calcium lactate by mouth has no appreciable effect upon the coagulation of the blood"; and Van Lier (1912), after taking the coagulation time in 40 per- sons before and after administration of calcium lactate, has ar- rived at the same conclusion. Lee and Vincent (1915), however, after several days of 100 grains (6.6 gm.) of calcium lactate daily noted an increased coagulability, and further that in obstructive jaundice the usual delayed coagulability was overcome. Too high a proportion of calcium delays coagulation. The use of calcium salts as local hemostatics is a failure. In the clotting of milk by rennet, calcium is a necessity. (See Rennet.) However, if an alkaline calcium salt, such as in lime- 100 PHARMACOLOGY AND THERAPEUTICS water, is added to milk, the alkalinity will check the rennet action and the milk will not coagulate. It is probable that, as a rule, any ordinary amount of lime-water is neutralized by the acid of the gastric juice, with the formation of calcium chloride. Januschke (1910) has shown that pleural effusions may be checked by subcutaneous injection of calcium chloride, and Chiari found that transudation and edema were favored by the re- moval of calcium, which normally serves to check the permeabil- ity of the vessels. These experimenters and Meyer were able to check pleural effusion resulting from diphtheria toxin, and to reduce the conjunctival edema resulting from the application of irritants. Other authors have reported good results from the use of calcium salts in serum-sickness from diphtheria antitoxin, in angioneurotic edema, in chilblains, and in other conditions sug- gesting abnormal permeability of the vessels. In the intestines calcium salts have been found to retard or check peristalsis, to lessen intestinal secretion, and to prevent the action of some of the cathartics. In diabetes Kahn and Kahn obtained a fall in the sugar of the blood and Lirine by an intravenous of i to 3! ounces (15-50 c.c.) of a 1.4 per cent, solution of calcium chloride. Calcium Poisoning. Large doses of the chloride intravenously at first increase the contractility of the heart, but soon bring about its stoppage in systole, the arteries being contracted and the pupils pin-point. From 50 c.c. of 1.4 per cent, solution intra- venously, Kahn and Kahn noted great weakness, muscular pain, a fall in systolic and diastolic pressures, and in one case collapse and coma. Towles gave 5 drams (20 gm.) of the lactate daily by mouth for 1 5 days without toxic effects. Therapeutics. Precipitated chalk is used largely for cleaning teeth. Prepared chalk is used as an antacid and in diarrheal conditions. Lime-water is used as an addition to milk to render it more palatable and more readily borne by the stomach, and to increase its calcium content for growing children. Lime-water has also been added to skin lotions for eczema and dermatitis. Calcium chloride and calcium lactate have been employed (a) In hemorrhagic conditions, with questionable results, as hemophilia, the purpuras, scurvy, the hemorrhages of typhoid fever and tuberculosis, mehrna neonatorum, etc. They are not indicated unless the coagulability of the blood is distinctly re- duced, (b) As preliminary to operations in obstructive jaundice. (c] In tetany and the nervous manifestations following para- thyroidectomy or oxalic acid poisoning, (d) In nervous diseases with hyperexcitability, as epilepsy, chorea, spasmophilia, and the tics, (e) In serum sickness, urticaria, angioneurotic edema, THE ANTACIDS NOT OF ALKALINE REACTION IOI chilblains, pleurisy with effusion, etc. (/) In bronchial asthma, to lessen nervous excitability and angioneurotic swelling of the bronchi, (g) In hay-fever to lessen the nerve irritability which leads to sneezing. To gain any effect large doses must be administered daily. Either the lactate or chloride may be used in dose of 15 to 60 grains (1-4 gm.) three times a day. The bitter saline taste of the chloride may be masked by peppermint or lemonade. Hy- podermatically, a 4 per cent, solution may be employed. Intra- venously, a i to 2 per cent, solution of the chloride may be given in amounts of 100 c.c., or a 0.2 per cent, solution of the lactate in normal saline in amounts up to 500 c.c. The chloride must not be confused with the antiseptic, chlorinated lime (chloride of lime) . THE ANTACIDS NOT OF ALKALINE REACTION These do not neutralize acids, so are not locally antacid; but in the blood and tissues they break down into alkaline car- bonates, and as the CO 2 is exhaled increase the alkalescence of the blood. They are, therefore, systemic alkalinizers. These com- pounds are the acetic, citric, and tartaric salts of potassium, sodium, and lithium. The potassium and sodium acetates, KC 2 H 3 O2, NaC 2 H 3 O 2 , and the potassium, sodium, and lithium citrates, K 3 -,Na 3 -,Li 3 ,- C 6 H 5 07, are freely soluble in water. Potassium bitartrate, or cream of tartar (KHC 4 H 4 O 6 ), is of acid reaction, and soluble in 200 parts of water. Potassium and sodium tartrate, or Rochelle salts (KNaC 4 H 4 O 6 ), is very feebly alkaline and is soluble in 1.2 parts of water. The acetates are readily absorbed, and are alkalinizing and diuretic. Dose, 30 grains (2 gm.). The citrates and tartrates are absorbed with some difficulty, and, as a consequence, are more or less cathartic. A portion, however, is absorbed, and this acts as an alkalinizer and diuretic. After very large doses slight amounts of both salts have been re- covered from the urine. In the laboratory tartrates are employed to produce a tubular or tubulo-glomerular nephritis, but from doses taken by humans such an effect does not occur, and Post demonstrates that even in nephritis there is no contraindication to their use. The citrates (see Citric Acid), through their affinity for cal- cium, will retard or prevent the coagulation of the blood and the rennin clotting of milk. They have been employed without any decided success in the late weeks of typhoid fever to lessen the 102 PHARMACOLOGY AND THERAPEUTICS tendency to thrombosis. Lithium citrate, in the form of effer- vescing tablets, each containing 5 grains (0.3 gm.), has been much employed to make a palatable effervescing alkalinizing drink. One tablet may be dissolved in a glass of water. Sodium citrate has been used in infant feeding, one grain (0.06 gm.) to each ounce (30 c.c.) of milk to reduce the density of the curd, and two grains (0.12 gm.) to an ounce (30 c.c.) to prevent completely the rennin clotting. In blood transfusion it is added to the blood in amounts to make 0.2 per cent, which effectually prevents clotting for half an hour. Potassium bitartrate (cream of tartar) is not readily soluble in water. It forms Rochelle salts in the duodenum, and is laxative. It is a constituent of Imperial drink. (See Citric Acid.) The hospital "A. B. C. mixture" is an aqueous solution of which each teaspoonful contains 5 grains (0.3 gm.) each of the acetate, bicarbonate, and citrate of potassium. CARMINATIVES A carminative is a remedy which tends to overcome flat- ulency, that is, distention of the stomach or colon with gas. The aromatics, which depend for their action upon a volatile oil or resinous constituent, form the great bulk of the class; but alcohol, the distilled liquors, chloroform, ether, ammonia, car- bonic acid, as in mineral waters and champagne, and many other local irritants have strong carminative properties. We shall take up here the action of the aromatics. Pharmacologic Action of the Aromatics. Microorganisms.- They are antiseptic, some of them strongly so, as oil of eucalyptus. Their use as antiseptics, however, is very limited, because of their slight solubility in water. In infected tooth-cavities the dentists use oil of cloves or its stearopten, eugenol, or oil of cinnamon. Skin and Mucous Membranes. They are general protoplasmic irritants, so are irritant to both skin and mucous membranes. Applied to the tongue they have a biting effect, and in the eye cause smarting. Rubbed into the skin they are rubefacient, i. e., produce local dilatation of the skin vessels, with redness and warmth of the part. It is probable that they also stimulate the sensory nerve-endings and later depress them, for there is more or less biting and tingling, followed in a number of instances by partial anesthesia or numbness. Peppermint and its stearopten, menthol, distinctly depress the sensory nerve-endings, but at the same time stimulate the ends of the temperature nerves which appreciate cold (loteyko, 1903), hence they give a combined feel- ing of numbness and coolness. CARMINATIVES 103 Alimentary Tract. Many of them are pleasantly aromatic, and these are used as flavors, especially in the dilute forms of the official waters and spirits. They tend to promote the appetite, but in undiluted form are irritant enough to induce a protective flow of saliva. In the stomach they are local irritants, and if given in sufficiently concentrated form, dilate the vessels and produce hyperemia, thus giving a feeling of well-being in the stom- ach region. At the same time they stimulate motor activity and the expulsion of accumulated gases. The less dilute they are, the more prompt is their action. It is generally believed that there is some stimulation of secretion, so that they are contraindicated in hyperacidity; but Korczynski (1901) found that from pepper and mustard there was not only no increased acidity or quantity of the gastric juice, but even a diminution. It may be that, like alcohol, they increase the gastric secretion through an action in the mouth. There seems to be some furtherance of absorp- tion by the stomach, presumably owing to the active hyperemia. Thus the functions of motion and absorption are stimulated, but probably not that of secretion unless they promote appetite. Hertz (1910) has observed by the axrays that very promptly following the administration of a strong carminative by mouth colon peristalsis is set up. This is a reflex action, and it tends to cause the expulsion of accumulations of intestinal gas, and to overcome colic or griping. There is also a direct effect, Muir- head and Gerald finding marked stimulation of isolated segments when various oils were applied in dilutions of i to 50,000. These drugs are regularly added to irritant cathartics as "correctives." Absorption is rapid from stomach and duodenum. Nervous System. From the local irritation in the mouth or stomach there is a general reflex stimulation of the vasoconstric- tor, the accelerator, and the respiratory centers, so that respira- tion is deepened and arterial pressure raised, and momentary feelings of faintness are overcome. In this way carminatives act as restoratives. There is also, after absorption, an apparent cerebral stimulation which may be effective in overcoming hys- teria and other conditions of nervous instability. Circulation. Besides the reflex stimulation, there is flushing of the skin from dilatation of the cutaneous arterioles. Genital Organs. In strong doses these oils tend to be em- menagogue and abortifacient, and many of the cases of poisoning by pennyroyal, rue, savine, and tansy have come from attempts to produce miscarriage. Frequently the victim has died in agony without the abortion occurring, or has developed a severe colitis. Whether the influence on the genital organs could be a factor in overcoming hysteria has not been studied. 104 PHARMACOLOGY AND THERAPEUTICS Elimination. Part is oxidized in the body, and the remainder is eliminated in the urine and the breath, mostly in more or less changed aromatic forms. For example, the odor of the breath of the whisky-drinker is not that of either alcohol, whisky, or fusel oil, but of a derivative of the fusel oil. The urine from turpentine has an odor of violets, and that after peppermint is strongly aromatic, but not minty. In the elimination there is a remote local irritant action on the kidneys and bronchi, with diuretic and expectorant effects. The urine may even be rendered antiseptic, but it is a question whether large enough amounts ever appear in the bronchial mucus to have an antiseptic value. Toxicology. Poisoning results (a) from the irritant ones in concentrated form, with local and systemic symptoms, or (b) from absorption, with systemic symptoms only. From the very irritant types there may be violent gastritis and colitis, with vomiting, diarrhea, and abdominal cramps, and perhaps vomiting of blood and bloody stools. From absorption there may be overstimulation of the cerebrum, with excitement, great restless- ness, delirium, and perhaps cerebral convulsions, or there may be dizziness, stupor, and mental depression similar to that from alcohol or ether. These states may pass into collapse, coma, the convulsions of asphyxia, and death. The kidneys may be the seat of an acute nephritis. The treatment is to empty the stom- ach and administer demulcents, such as white of egg, milk, olive oil, and mucilaginous drinks, and to treat symptomatically for collapse. The inflammatory lesions must be treated as when they arise from other causes. After recovery from the acute symptoms there may be a chronic nephritis or colitis. Poisoning has been reported from asafetida, nutmeg, mustard, and a great many of the aromatics. The colitis cases have mostly resulted from the emmenagogue oils taken for abortifacient purposes. Therapeutics. A number of carminative drugs have other striking actions for which they are of importance in therapeutics, and these we shall study in detail elsewhere. The following is an arrangement in therapeutic groups: 1. As anticolics (in intestinal and uterine cramps). Espe- cially employed for infants are anise, peppermint, and dill water, and for adults the distilled liquors, essence of ginger, spirit of peppermint, aromatic spirit of ammonia, and Hoffmann's ano- dyne (the compound spirit of ether). 2. As odors and flavors anise, bitter almond, caraway, cinna- mon, coriander, fennel, lavender flowers, lemon, nutmeg, orange- peel, peppermint, spearmint, rose, and vanilla. Of the waters, the dose is i dram (4 c.c.); of the spirits, 5 minims (0.3 c.c.). CARMINATIVES 10$ 3. As correctives of irritant cathartics the oils of anise, cara- way, cloves, coriander, fennel, and peppermint. Of the oil, | minim (0.015 c.c.), or of the drug, i grain (0.06 gm.), to each dose. 4. For tympanites, as in typhoid fever, pneumonia, or follow- ing operations. By mouth, oil of turpentine, 10 minims (0.07 c.c.) in capsule, or asafetida, 5 grains (0.03 gm.) in pill or tincture. By rectum, oil of turpentine, \ ounce (15 c.c.), or tincture of asa- fetida or spirit of peppermint, i dram (4 c.c.), added to a soap- suds enema or to 8 ounces or more of infusion of chamomile (an aromatic bitter). 5. As anthelmintics oil of chenopodium and oil of thyme or thymol. 6. As stimulants to mucous membranes of nose and throat eucalyptol, camphor, and menthol, mixed together and inhaled, or diluted with liquid petrolatum and used as a spray. 7. As antiseptics and anesthetics oil of cloves or oil of cinna- mon in decayed tooth, a drop on cotton. Eugenol, the stearopten of oil of cloves, is also used. 8. .4s counterirritants camphor, capsicum, and menthol, and the oils of mustard, rosemary, and turpentine. g. As stimulants in chronic skin diseases, such as eczema the oils of cade and tar in the form of ointment. 10. As stimulants to the growth of hair the oil of mace. 11. As antirheumatics methyl salicylate and the oils of birch and wintergreen, externally as a liniment, and internally in 5- minim (0.3 c.c.) capsules. 12. As antihysterics asafetida, camphor, musk, sumbul, and valerian. 13. As anti-asthmatics powdered cubebs smoked in cigaret form. 14. As bronchial stimulants (and perhaps antiseptics) creosote, 5 minims (0.3 c.c.), oil of turpentine, 10 minims (0.7 c.c.), terebene, 10 minims (0.7 c.c.), and syrup of tar, i dram (4 c.c.). 15. As diuretics oil and spirit of juniper; the fluidextracts of buchu and uva-ursi, i dram (4 c.c.). 1 6. As urinary antiseptics the oils of copaiba, cubebs, and sandalwood, and balsam of copaiba, 5 minims (0.3 c.c.). 17. As emmenagogues apiol, from oil of parsley, and the oils of pennyroyal, rue, savine, and tansy, 3 minims (0.2 c.c.). 18. In leprosy chaulmoogra oil, 5 minims (0.3 c.c.), increased gradually to 30 minims (2 c.c.) two or three times a day by mouth, or 15 to 75 minims subcutaneously every few days. Rogers uses chaulmoogric (gynocardic) acid in 2 per cent, solution intrave- 106 PHARMACOLOGY AND THERAPEUTICS nously, beginning with yV grain (0.006 gm.) and increasing to f grain (0.05 gm.). For simple carminative action the spices are much used, and usually in combinations of several carminatives, as in the com- pound tinctures, compound spirits, and the aromatic fluidextract. A favorite hospital dose for flatulence is compound spirit of ether, aromatic spirit of ammonia, compound tincture of lavender, and spirit of chloroform, of each, 15 minims (i c.c.). Preparations. i. The volatile oils (the Latin name is given in the genitive) are: Allspice (pimentse), anise (anisi), birch (betulae), bitter almond (amygdalas amaras), cade (cadini), cajuput (cajuputi), caraway (cari), chenopodium (chenopodii) cinnamon (cinnamomi or cassias), cloves (caryophylli) , copaiba (copaibas), coriander (coriandri), cubeb (cubebae), dwarf pine needle (pini pumilionis), erigeron (erigerontis) , eucalyptus (eucalypti), fennel (fceniculi), juniper (juniperi), lavender (lavandulae) , lemon (limonis), mustard (sinapis), nutmeg (myr- isticae), orange-peel (aurantii), pennyroyal (hedeomae), pepper- mint (menthas piperitae), rose (rosae), rosemary (rosmarini), sandalwood (santali), sassafras (sassafras), savin (sabinae), spearmint (menthae viridis), tar (picis liquidae rectificati) , thyme (thymi), turpentine (terebinthinae), wintergreen (gaultheriae) . 2. Tlie waters (aquas) are: Anise, bitter almond, camphor, cinnamon, fennel, orange-flower (aurantii florum), stronger orange-flower (aurantii florum fortioris), peppermint, rose, stronger rose, spearmint. 3. The spirits (spiritus) the simple are: Bitter almond of i per cent, strength, dose, 8 minims (0.5 c.c.) ; of 10 per cent, strength, camphor, cinnamon, peppermint, and spearmint; of 5 per cent, strength, juniper, lavender, and wintergreen. The compounds are: Aromatic ammonia (ammonia, lemon, lavender, and nutmeg) , compound ether (ethereal oil and ether) , compound juniper (jumper, caraway, fennel), and compound orange (orange- peel, lemon, coriander, anise). The compound spirit of ether (Hoffmann's anodyne) is no longer official. 4. The elixirs. These are sweetened and aromatic, more or less alcoholic liquids. Aromatic elixir (elixir aromaticum) con- tains the compound spirit of orange, and the elixir glycyrrhiza is aromatic elixir with the addition of 12 per cent, of fluidextract of licorice. The liquors and cordials, as creme de menthe, absinthe, Benedictine, etc., are elixirs. (See Alcohol.) 5. Stearoptens used by themselves are: Benzaldehyde, from oil of bitter almonds; cinnaldehyde, from oil of cinnamon; euca- lyptol, from oil of eucalyptus; eugenol, from oil of cloves; menthol, from oil of peppermint; methyl salicylate, from oil of birch or BITTERS IO7 wintergreen, and also manufactured synthetically; safrol, from oil of sassafras, and camphor. 6. The spices. The spices are not only aromatic, but more or less hot and biting. Some of them yield no oil and depend for their action on resinous ingredients. They are allspice (pimentae), calamus (calami), cinnamon, cardamom, cloves (caryophylli) , ginger (zingiberis) , black pepper (piperis), and red pepper (capsici) . 7. The simple aromatic tinctures are : Asafetida, bitter orange- peel (aurantii amari), sweet orange-peel (aurantii dulcis), capsi- cum, cardamom, cinnamon, ginger, lemon-peel (limonis corticis), musk (moschi), valerian, vanilla. 8. The compound tinctures are: Compound tincture of carda- mom (tinctura cardamomi composita), containing cardamom, cinnamon, and caraway. Compound tincture of lavender (tinctura lavandulae composita) , containing oil of lavender, oil of rosemary, cinnamon, cloves, and nutmeg. Ammoniated tincture of valerian, a tincture of valerian made with aromatic spirit of ammonia as the menstruum. 9. The fluidextr acts are: Bitter orange-peel, buchu, cubebs, eucalyptus, ginger (zingiberis), sumbul, uva-ursi, and the aromatic fluidextract (fluidextractum aromaticum). The last is a fluid- extract of aromatic powder (pulvis aromaticus) which contains cinnamon and ginger, each, 35 parts, and cardamom and nut- meg, each, 15 parts. Doses. These vary somewhat. Where the drugs have no other marked quality, their carminative doses are: Powdered drug, 15 grains (i gm.) ; oils, 5 minims (0.3 c.c.); waters, i dram (4 c.c.); spirits, 10-30 minims (0.7-2 c.c.); tinctures, 30 minims (2 c.c.); aromatic fluidextract, 30 minims (2 c.c.). BITTERS These are substances that are employed to give a bitter taste, the object of their administration being to improve the appetite. When the appetite is below normal, a strong stimulation of the taste-buds will often restore it; and substances with a bitter taste that is not otherwise disagreeable tend to act as stimulants to the taste-buds. That appetite is important for digestion has been demon- strated by Pawlow and his followers. They discovered "that the stomach of a hungry dog would secrete gastric juice if he saw or smelled food, even though there was no food in the stomach. This is known as the "appetite" or "psychic" gastric juice. 108 PHARMACOLOGY AND THERAPEUTICS They also found that some foods would not digest at all, for example, white of egg, if they were put in the empty stomach without arousing the appetite, as through a fistula while the animal slept. That is, they were incapable, by direct action on the stomach wall, of inducing the stomach to secrete. But Pawlow noted further that, on showing the dog food, the appetite juice would form and would act on the egg-albumin; and that the products of this primary digestion would then stimulate the stomach wall and induce the secretion which continued the diges- tion. Hence the appetite juice is of great importance in starting digestion ; and since the formation of the appetite juice is favored by bitters, these may be considered aids to digestion in atonic cases. Moorhead, 1901, found that in normal dogs bitters had no effect or were depressing, while in cachectic dogs they distinctly stimulated appetite, and the secretion of gastric juice. Barisoff gave tincture of gentian to a dog with the end of the severed esophagus opening outside so that substances swallowed did not reach the stomach. He followed this with a meal, and found the average amount of gastric juice increased over 30 per cent, by the bitter. An excess of bitter checked the secretion. Carlson's experiments with normal humans and dogs showed increased ap- petite, but an inhibition of the hunger contractions. He thinks that the effect of a bitter is purely psychic. The bitter effect on appetite is solely the local one on the taste- buds, so it is not obtained if the bitter is hidden, as in capsules or gelatin-coated pills, or if it is disguised by sweetening agents or flavors. It requires for its development that the bitter shall be taken just preceding the usual time for eating; that is, from ten to twenty minutes before. If the appetite is already normal, the bitter may not increase it, and may even lessen it. If the stomach and bowels are deranged, a bitter may nauseate. The bitters are classed as the simple bitters, which have no effect on taste other than bitterness, and the aromatic bitters, which, in addition to the bitter principle, contain a volatile oil or resinous aromatic. The simple bitters are: barberry (berberis), calumba, con- durango, dandelion (taraxacum), gentian, and quassia. These may be used in the form of an infusion, dose, 7} ounce (15 c.c.), or tincture, dose, i dram (4 c.c.), diluted to give a bitter drink. The powerful pharmacologic drugs, nux vomica, with its alkaloid r strychnine, and cinchona, with its alkaloid, quinine, are often employed also as simple bitters. Quassia-cups are used in some households. They are turned out of quassia wood and impart an intense bitterness to water allowed to stand in the cup for ANTI-BITTERS CHARCOAL IOQ fifteen minutes. The cups retain their power for a long time. Infusion of quassia is also employed as a bitter, as an enema for pin-worms, and as an insecticide in agriculture. Orexine hydrochloride and tannate, bitter, crystalline bodies, are also used in dose of 5 grains (0.3 gm.). They are soluble in about 15 parts of water. The aromatic bitters are: wormwood or vermouth (absinthi- um), chamomile (anthemis), German chamomile (matricaria) , bitter orange-peel, and serpentaria. There are two aromatic bitter tinctures which are favorite appetizers, viz., compound tincture of gentian (tinctura gentianae composita), made of gentian, cardamom, and bitter orange-peel, dose, i dram (4 c.c.), and compound tincture of cinchona (tinctura cinchonae composita), made of red cinchona, serpentaria, and bitter orange-peel, dose, i dram (4 c.c.). ANTI-BITTERS There are two vegetable substances that possess the peculiar property of abolishing the appreciation of bitter taste. They are yerba santa (eriodictyon) , a leaf, and gymnemic acid, a whitish powder which is soluble in water, dose, 5 grains (0.3 gm.). The syrup of yerba santa, dose, i dram (4 c.c.), has been much employed as an addition to bitter medicines, especially quinine. It lessens the appreciation of bitter taste, but in swal- lowing hardly acts rapidly enough to check the taste of a bitter substance mixed with it; in fact, to get the real anti-bitter effect, it is necessary to hold the yerba santa preparation in the mouth for several minutes before the bitter is taken. Yerba santa is itself bitter and very astringent. It contains tannic acid in abundance, and it is largely by forming the insoluble tannate that it lessens the bitterness of quinine and other alkaloids. CHARCOAL Animal charcoal (carbo animalis) is prepared from bones, and 85 per cent, of it consists of mineral matter. It is called "bone-black." Purified animal charcoal is bone-black boiled with hydrochloric acid and washed thoroughly with water. It is almost pure carbon. Wood charcoal (carbo ligni) is prepared from soft wood; it is nearly pure carbon. Dose of charcoal, 15 to 60 grains (i to 4 gm.). The larger dose makes a tablespoon- ful and for intestinal infections should be given four times a day mixed with cereal or other thick liquid. Purified animal charcoal possesses the power, in a high degree, 110 PHARMACOLOGY AND THERAPEUTICS of adsorbing organic colors, hence is used largely in pharmacy and the arts for decolorizing, as in the refining of sugar and petroleum. It has a strong affinity for bacterial toxins, and has been used with success in dysentery, cholera, and other intestinal infections. It has also a certain amount of power to remove certain resins, bitter principles, and alkaloids from their solu- tions, and Lebourdais has in this way recovered digitalin, colo- cynthin, strychnine, quinine, and other active principles. Owing to this property, it has been proposed as a remedy in mushroom poisoning, arsenic poisoning, strychnine poisoning, etc. Un- fortunately, this property of adsorption cannot be depended upon. Wood-charcoal and bone-black are very inferior as ad- sorbents. In medicine, wood-charcoal has been used in flatulency be- cause of its known power of adsorbing gases. But when satu- rated with liquid, it loses this power of gas adsorption, hence in fermenting stomach contents is of little or no value. In the study of the stools it is much employed in timing the passage through the alimentary tract. A dose of 30 grains (2 gm.) given with a meal will color the stool resulting from that meal black or gray -black. (See next article.) KAOLIN FULLERS' EARTH These are silicates with powerful adsorptive properties. They have been employed locally as applications to wounds and infected mucous membranes, especially in diphtheria and ozena. Hektoen and Rappaport found that the dry powder of kaolin blown into the nose several times a day for 3 or 4 days removed not only diphtheria bacilli but practically all the nasal bacteria. In the intestinal tract kaolin has been employed to adsorb toxins as in ptomaine and food poisoning, to delay ferment activity, and in conjunction with animal charcoal to adsorb bacteria and check bowel movements in the treatment of severe diarrheal conditions, as in dysentery and cholera. Hess found fullers' earth of more value than kaolin in the intestinal disorders of infants, and Peterson noted that it had a much greater retarding influence on the pro- teolytic, diastatic and lipolytic activities in intestinal contents. In cholera and dysentery Wolff- Eisner recommends a tablespoon- ful each of kaolin and charcoal mixed with oatmeal gruel three times a day, and Stumpff uses 4 ounces (i20gm.) in 4 ounces (120 c.c.) of water every three hours. If it is not well taken thus, he ices it and gives one dram (4 gm.) every two minutes. Fantus experimented with alkaloids and concluded that fullers' earth has decided antidotal value for morphine, cocaine, nicotine and EMETICS III ipecac; less for strychnine and aconitine, and none for colchicine. He noted that the adsorptive properties varied greatly in com- mercial preparations. Fullers' earth is known as terra silicea puri- ficata. For kaolin poultice, cataplasma kaolini, see Counterirri- tants. EMETICS These are drugs employed to induce vomiting. To produce emesis requires the coordination of several mechanisms, the following actions being necessary: viz., closure of the pylorus, opening of the cardia, setting or contraction of the diaphragm, and contraction of the abdominal muscles. If the pylorus re- mains open, the result is "retching." The coordination is pre- sided over by the vomiting center situated in the medulla oblongata. This center is highly sensitive to certain sensory impulses from the stomach, and is also capable of being directly stimulated by certain substances in the circulating blood. The emetic measures in common use may be divided into the local or reflex emetics and the central emetics. 1. The reflex emetics act by irritating the throat or stomach, and are: tickling the throat with a feather, or sticking the finger down the throat, or swallowing one of the following: a large draft of lukewarm water; alum, 30 grains (2 gm.); copper sul- phate, 10 grains (1.7 gm.); zinc sulphate, 15 grains (i gm.); ipecac, 15 grains (i gm.); tartar emetic, 2 grains (0.13 gm.); yellow sulphate of mercury or turpeth mineral, 2 grains (0.13 gm.); mustard, one tablespoonful (about 10 gm.). The drugs mentioned are all local irritants and systemic poisons, and may do great harm if vomiting fails to come on; hence the dose should not be repeated. (See Ipecac.) 2. The only central emetic in common use is apomorphine hydrochloride, apomorphine being an alkaloid derived from mor- phine by dehydration. It is soluble in 40 parts of water or alco- hol, deteriorates and turns green on exposure to light and air, and is considered unfit for use if on being shaken with a little water it imparts at once an emerald-green tint. The emetic dose by hypodermatic is y 1 ^ grain (0.006 gm.), and the expectorant dose is sV grain (0.002 gm.). Quite quickly after a hypodermatic injection of apomorphine nausea comes on, and then, in about five minutes, copious vomit- ing. The drug is not at all excreted into the stomach, and it acts upon the center directly. Smaller closes are expectorant, increasing and fluidifying the bronchial mucus, probably by a nauseant action. Small doses are said to have a mild, morphine- like effect in promoting sleep; but in the author's tests on 16 112 PHARMACOLOGY AND THERAPEUTICS patients for several successive nights, though 3 V grain (0.003 gm.) proved hypnotic, every patient was nauseated. Therapeutics of Emetics. i. To empty the stomach as in acute indigestion, alcoholism, the ingestion of poisons, etc. 2. To remove an obstruction from the esophagus or respira- tory passages. 3. To loosen a ball- valve gall-stone in the biliary passages (nature's way). 4. To relieve spasm or marked congestion in the respiratory passages, as in croup or severe asthma. ANTEMETICS These are remedies designed to check nausea and vomiting In the treatment of nausea and vomiting the recumbent positioi should be maintained. The antemetics are: 1. Antacids, to check hyperacidity; especially sodium bicar- bonate, 20 grains (1.3 gm.), and milk of magnesia, 2 drams (8 gm.); or to check acidosis, large amounts of sodium bicar- bonate. 2. Carminatives. Champagne, brandy, chloroform water, essence of ginger, spirit of peppermint, menthol, etc. In alcoholic nausea and vomiting strong hot carminative mixtures are indi- cated. (See Alcohol.) j. Protectives which mechanically prevent irritation of the mucous membrane, as: bismuth subnitrate, bismuth subcar- bonate, bismuth subgallate, and cerium oxalate, dose of each, 30 grains (2 gm.). 4. Local sedatives, those which depress the sensory nerve- endings: Tincture of belladonna, 15 minims (i c.c.), atropine sulphate, T ^j grain (0.0006 gm.), cocaine hydrochloride, \ grain (0.015 gm.), orthoform, 5 grains (0.3 gm.), anesthesin, 5 grains (0.3 gm.), phenol, 3 grains (0.2 gm.), and cracked ice. 5. Central sedatives. Bromides, chloral hydrate, chloretone, codeine, morphine, sulphonal, veronal, and to some extent other narcotics. 6. Counter irritants to the epigastrium, as a hot-water bag, an ice-bag, a mustard plaster, or the actual cautery. The nausea of pregnancy and that of seasickness are espe- cially resistant to treatment. In pregnancy, alkalies given at the height of digestion or before going to bed, and sometimes a light breakfast before arising, may be effective. Atropine or bromides or cerium oxalate in large doses may also be tried. Frequently no measures are entirely satisfactory. Persistent vomiting in pregnancy is a serious toxic manifestation, usually ASTRINGENTS 113 requiring the termination of the pregnancy. The cause of the vomiting may be acidosis, and this is an indication for abundance of alkalies and carbohydrate food. In seasickness the recumbent position on deck, with eyes pro- tected so that the rolling of the vessel is not seen, is often effective. Another effective measure is thorough purgation with calomel or compound cathartic pills before sailing, and every two or three days during the voyage. The avoidance of much liquid, such as soup, and of tobacco, is also recommended. Bromides, chloral hydrate, veronal, chloretone, champagne, and iced brandy are employed with varying success. A much-vaunted, and at times an exceedingly satisfactory, prophylactic remedy is strychnine sulphate, yi^ grain (0.0005 g m -)> an d hyoscine hydro- bromide, ^7 grain (0.00025 gm.), every hour for five doses before sailing, and, if necessary, repeated every day during the trip. A hypodermic of strychnine sulphate, 3^ grain (0.002 gm.), and atrophine sulphate, y^g- grain (0.0006 gm.), will sometimes bring about a striking improvement in the patient's comfort. ASTRINGENTS These are drugs which tend to shrink mucous membranes or raw tissues. Astringents produce their effects: (i) by con- striction of arterioles, as epinephrine and cocaine; (2) by ab- straction of water, as glycerin and alcohol; and (3) by chemic precipitation of the superficial layers of protein, as the metallic and vegetable astringents. The most employed metallic astringents are: Alum, silver nitrate, ferric chloride, ferric subsulphate (Monsell's salt), zinc sulphate, and copper sulphate. (See Metals.) Potassium chlorate in saturated aqueous solution (i : 16) is employed in relaxed sore throat and in stomatitis, especially that from mercury; but where there is ulceration its solutions are quite irritant. Taken internally it is believed by some to be a specific in ulcerative stomatitis, Holt, for instance, recommending 2 grains (0.13 gm.), every hour the first day, then every 2 hours. Bachem (1912) gave i ounce (30 gm.) daily for six weeks to pups, and there was no effect on growth rate, kidneys, stomach, or blood. The drug was rapidly eliminated in the urine, and acted as any other indifferent salt. Loevenhart in his Harvey Society Lecture, 1914, stated that it does not give up its oxy- gen in the body and is excreted unchanged in the urine, yet it is capable of causing severe irritation of the gastro-intestinal tract, methemoglobinemia, and albuminuria. Buri states that this takes very large doses. Fifteen grains (i gm.) have caused death 114 PHARMACOLOGY AND THERAPEUTICS in a child; i ounce (30 gm.) has been taken without symptoms. Mercier (1902) reports death in a child of three years eighteen hours after taking "a pinch or two" of the chlorate. At autopsy the blood and bone-marrow had a prune- juice appearance and contained methemoglobin ; the bladder was filled with dark brown urine. The treatment for poisoning is lavage, trans- fusion, and measures to overcome shock. Potassium chlorate mixed dry with sulphur, hypophosphites, and oxidizable organic matters is likely to explode. In the form of tablets it has frequently caused fire on contact with sul- phur matches. The vegetable astringents contain either resins or tannic acid. The resinous astringents are myrrh, a tincture of which, diluted with water, is used for soft and bleeding gums, and hydrastis, whose tincture, diluted with water, is used locally in vaginitis and urethritis. The tannic acid astringents are: blackberry root (rubus), catechu, galls, gambir, kino, rosa gallica, sumac fruit (rhus glabra), and witch-hazel bark (hamamelis). They have dropped largely out of use and their only official preparations are the tincture of kino, 5 per cent., and the compound tincture of gambir, dose of each, 30 minims (2 c.c.). A blackberry brandy or cordial is employed by the laity in diarrhea. TANNIC ACID OR TANNIN (Acidum Tannicum) This substance is prepared from nutgalls. It is slowly but completely soluble in less than its own weight of water or alcohol, and, with the aid of heat, in its own weight of glycerin. It is used locally in 5 to 20 per cent, preparations, or internally in dose of 5 grains (0.3 gm.). The ointment and the glycerite are of 20 per cent, strength. The troches contain i grain (0.06 gm.) in each. Tannic acid is incompatible with alkaloidal salts, metallic salts (such as mercuric chloride), lime-water, gelatin, and protein. The precipitation of the gelatin and proteins of hides is "tanning," and changes the hides into leather. In like manner tannic acid renders insoluble the coatings of gelatin capsules and pills. Its astringency depends upon its power to precipitate the proteins of the superficial cells, thus causing shrinking of the tissues and stoppage of secretion. It checks small hemorrhages, /. e., is hemostatic or styptic, by coagulating the blood. In the stomach it precipitates the proteins of the food, but these re- dissolve in the gastric juice. Its effect on mucous membranes is to check secretion. Strasburger believes that the lessening of ANTHELMINTICS 115 intestinal mucus by astringents results in a great diminution in the number of bacteria in the feces. In the intestines free tannic acid is constipating, but it soon changes to sodium tannate and then to sodium gallate, which is not astringent. It is absorbed and excreted as sodium gallate, and has no astringent or styptic power after absorption. Because of the rapid disappearance of tannic acid from the intestines, preparations of the vegetable drugs are preferred in diarrhea, the colloid and other extractive vegetable matters tending to retard the chemic changes and ab- sorption of the tannic acid. If in too concentrated form, tannic acid is an irritant. Therapeutics. i. To harden the skin, as in threatened bed- sore. 2. As a gargle or swab in relaxed sore throat. 3. As a hemostatic for small accessible hemorrhages. 4. As chemic antidote in poisoning by alkaloidal and metal- lic salts, especially those of antimony, with which it forms a very insoluble substance. 5. In the form of suppository, each containing 5 grains (0.3 gm.), in prolapse of the rectum or bleeding internal hemorrhoids. 6. In diarrhea- the vegetable astringents. Tannigen (diacetyl tannin), tannoform (formaldehyde-tannin), tannopin (hexamethylenamine-tannin), and tannalbin (egg-al- bumin tannate) are all compounds marketed for diarrhea. The claims are made for them that they do not act in the stomach, but liberate the tannic acid in the intestines. Dose of each, 10 grains (0.7 gm.). Styptics. The astringent remedies especially used as styptics, that is, to check hemorrhage, are: Solutions of epinephrine, antipyrine, alum, silver nitrate, ferric chloride, ferric sulphate, and ferric subsulphate (Monsell's solution), very hot water, very cold water, glycerite of tannic acid, and 2 per cent, acetic acid. ANTHELMINTICS An anthelmintic is a remedy designed to promote the death or expulsion of intestinal worms. Most of the remedies are also toxic to man, and since the anthelmintic is to attack the worm, rather than the patient, the dose must be as large as one dare risk, whether the patient is a child or an adult. Before the administration of a toxic anthelmintic it is custom- ary to starve the patient for from twelve to twenty-four hours and to give a brisk cathartic, the object being to clean out the intestines and leave the worm in an exposed condition. The dose is then administered, and is followed in four or five hours by Il6 PHARMACOLOGY AND THERAPEUTICS a brisk, rapidly acting cathartic, such as castor oil or salts, to carry out the worm. Castor oil has been objected to on the ground that an oily medium will promote the absorption of the poison by the patient. This may be true, especially in the case of oleoresin of male fern, if rapid evacuation of the bowels does not take place. The different kinds of parasite require different kinds of treatment, as follows: 1. The Pin- or Thread- worms (Oxyuris Vermicular is). These are tiny, thread-like organisms which live in great abun- dance in the colon or the adjoining portion of the ileum, chiefly in the mucus. As they do not cling to the intestinal wall, they are readily carried out by cathartics; or, as they are very vulner- able, may be attacked by colon irrigations. Occasionally they penetrate the mucous membrane of the intestine or inhabit the appendix, and then they cannot be dislodged. The cathartics mostly employed are calomel and castor oil. By mouth both thymol and oil of chenopodium, as used for hookworms, have proved highly effective. A number of substances are used for colon injection, viz., the infusion of quassia, lime-water, a solution of phenol, 0.25 per cent., a solution of quinine bisulphate, i : 2000, a solution of tannic acid or alum, 30 grains (2 gm.) in one pint (480 c.c.), and soapsuds containing \ ounce of the oil of turpentine to a quart. The astringents are effective not only by shriveling the worms, but also by lessen- ing the intestinal mucus in which the worms may lodge. The Hymenolepis or Tcenia nana, which are tiny tape-worms, are sometimes taken for pin-worms. 2. The Round-worms. a. The common round-worm, Ascaris lumbricoides , grows to a length of 6 to 12 inches or even more. They usually inhabit the small intestine, but may be found in the colon or stomach, and have been known to stop up the common bile-duct. The author has had several patients who have vomited round-worms, and in two instances drew up a piece of round-worm through a stomach-tube. These must have been in the stomach. They may be the cause of intestinal hemorrhage. The remedies are: Chenopodium see under "Hookworms." Santonin (santoninum), a glucoside from santonica (Levant wormseed), dose, 2 grains (0.12 gm.) for an adult, and i grain (0.06 gm.) for a child of five years. Santonica, ^ dram (2 gm.), is sometimes taken as it is or in the form of an infusion. Santonin is highly toxic, and death has occurred from 5 grains (0.3 gm.) in an adult, and 3 grains (0.2 gm.) in a child. The symptoms of poisoning are nausea, vomiting, and central stimulation. The reflexes are increased, and there may be headache, dizziness, ANTHELMINTICS 117 delirium, hallucinations, and possibly epileptiform convulsions, followed by collapse and death. A peculiarity of santonin poisoning is partial blindness, accompanied by yellow vision. Baxter reports lost vision in a girl of five after \ grain (0.03 gm.). JellifTe (1906) reports prolonged convulsions, followed by collapse, in a girl, from two troches followed by castor oil which failed to move the bowels. After this she was blind, very restless, and prostrated for three weeks, and showed signs of nephritis. She became a permanent epileptic. The treatment of poisoning is lavage of the stomach, followed by a large dose of Epsom salts, the inhalation of ether, and the management of symptoms as they arise. The central stimulation must be handled with care because of the tendency to collapse. Santonin has come into notice of late as a remedy for the pains of locomotor ataxia and for diabetes, but clinical data do not justify these uses of so dangerous a drug. Spigelia (pink-root) has an official fluidextract, dose, 60 minims, (4 c.c.). It is frequently given with senna (fluidextract of pink-root and senna), the senna furnishing the required, though rather late, cathartic action. In poisoning it causes central depression, with prostration, stupor or coma, muscular weakness, incoordination, and collapse. b. The hookworms ( Lncinaria or Necator or Ankylostoma americana) are treated by thymol or oil of chenopodium. Thymol Public Health Bulletin No. 32 recommends a dose of Epsom salts at night, followed at 6 A. M. by half the dose of thymol, at 8 by the other half of the thymol, and at 10 by another dose of Epsom salts. This treatment is repeated once a week. The dose recommended is 7^ grains (0.5 gm.) for a child of five years, and 45-60 grains (3 to 4 gm.) for an adult, given in 5-grain (0.3 gm.) capsules. It is best mixed with an equal weight of lactose or sodium bicarbonate. Seidell finds insignificant amounts of thymol in the feces and only 50 per cent, in the urine, He notes that absorption is not promoted by its solution in oil. Thymol has also been employed in trichinosis, both while the parasites are still in the intestine and when they are lodged in the muscles. For the latter, 2 to 3 grains (0.12-0.2 gm.) in 30 to 45 minims (2-3 c.c.) of olive oil are injected subcutaneously daily. Musgrave recommends thymol for irrigation in amebic colitis. Thymol has in several instances caused fatal poison- ing of the volatile oil type. Death has resulted from 15 grains (i gm.) in a child; yet in adults as much as 225 grains (15 gm.) have been given in twelve hours (Bozzolo, 1912) without any toxic effects. Oil, of Chenopodium. Since 1915 much has been written Il8 PHARMACOLOGY AND THERAPEUTICS about the great efficacy of this remedy in hookworm disease, and it has been reported of fair value for pin-worms, round- worms, whip-worms and even tape-worms. The oil is constipat- ing and the consensus of opinion is that it should be given in association with castor oil. An acceptable plan is as follows: A dose of Epsom salts or castor oil in the morning is followed by liquid diet for the whole day. The next day a dose of Epsom salts or castor oil is administered, and one hour later oil of chenopodium, 5 to 8 minims (0.3-0.5 c.c) or about 15 drops, in a capsule or dropped on sugar, this dose being repeated twice at one or two hour intervals, i. e., for three doses in all. Two hours after the last dose, i-i| oz. (30-45 c.c.) of castor oil con- taining from 30 to 45 minims (2-3 c.c.) of chloroform is adminis- tered. The chloroform aids in the paralysis of the worms. No food is taken till after this, when a cup of tea may be allowed and later a light supper. The treatment is repeated each week. For a child of 6 years the doses are half the above. A number of cases of poisoning have been reported, but very few in proportion to the enormous number of doses given. Levy collected 12 cases, 9 of them fatal in 2 to 5 days. The smallest doses (reported by Para'more) were 4 drops three times a day for 7 doses resulting in the death of an infant of one year, and 6 drops three times a day for seven doses causing severe poisoning in a child of three years, with recovery. Coutant reports poisoning with recovery in a man of 21 years from two doses of 10 minims (0.7 c.c.) given 24 hours apart. Pole reports recovery of a child of two years after two teaspoonfuls given in one afternoon. The symptoms are those of gastro-intestinal irritation and central depression, i. e., nausea, vomiting, diarrhea, bloody and mucous stools, and abdominal cramps, with headache, drowsiness, mental and physical depression, and -collapse. There maybe tinnitus aurium, ataxia, paralyses, convulsions, and coma. Salant and Livingston, 1915, state that the toxicity is distinctly increased by starvation, and decreased by feeding oils or carbo- hydrates. They also noted cumulative effects. Ascaridole, the active principle of the oil, was 30 per cent, more toxic than the oil. They have shown that solutions of i to 5000 and i to 10,000 of the oil cause a marked decrease of tone in the isolated intestine of rabbits, both muscle and nerve-endings being depressed; also that in intact animals there is a decline in tone of the intestines and a depression of the heart muscle and the vagus center, and an unexplained depression of the respiration. In poisoning the treatment is symptomatic. Motter advises that inordinate sleepiness or -depression call for stoppage of the drug, immediate purgation by castor oil, and central stimulation, as by caffeine and strychnine. CATHARTICS IIQ 3. The tape-worms seen in America are mostly that of beef, T&nia saginata; that of fish, Dibothriocephalus latus; and the dwarf tape-worm, Hymenolepis nana. The remedies are some- times called teniacides and teniafuges. The favorite remedy is oleoresin of aspidium (male-fern), i dram (4 gm.) in capsules. Others are cusso, % ounce (15 gm.) in infusion; granatum (pome- granate root bark), 2 drams (8 gm.) in infusion; pepo (pumpkin- seed), ^ ounce (15 gm.) in infusion; kamala, i dram (4 gm.) mixed with syrup; oil of turpentine, \ ounce (15 c.c.), and chloro- form, i dram (4 c.c.). Pelletierine , an alkaloid from granatum, in the form of the tannate, dose, 4 grains (0.25 gm.), and amor- phous filicic acid, one of the constituents of male-fern, dose, 10 grains (0.7 gm.), are also employed. Power and Salway failed to find any anthelmintic properties in the constituents of pumpkin- seed. Poisoning by aspidium, granatum, and kamala shows in gastro-intestinal irritation, with vomiting, purging, stupor, vertigo, muscular twitching, collapse, and perhaps irritation of the kidneys. There may be hemolysis with jaundice (Grawitz). Hall reports a fatal case from male-fern with r^emorrhagic areas in the upper three feet of intestine. We have several times seen severe gastro-enteric irritation with vertigo and prostration result from the hospital "Early-Bird" mixture. This consists of pumpkin-seed, 2 drams (8 gm.), cusso and granatum, each, i dram (4 gm.), made into an infusion, to which are added kamala, i dram (4 gm.), oleoresin -of aspidium, i dram (4 gm.), glycerin, \ ounce (15 c.c.), mucilage of acacia, \ ounce (15 c.c.), and water to make the total amount 8 ounces (240 c.c.). After the usual preliminary starvation, this quantity is taken in two drafts two hours apart. The "early bird" usually gets the worm. CATHARTICS A cathartic is a measure designed to promote defecation. Such a remedy may be employed (i) In cases of constipation; (2) for the removal of irritating or otherwise harmful material from the intestines, as in food-poisoning, intestinal putrefaction, and some forms of diarrhea; (3) for general depletion, as in plethoric or dropsical states, cerebral congestion, or at the onset of the infectious fevers. Constipation is a condition of insufficient frequency of de- fecation, or of insufficient quantity regardless of frequency, or of hardness and dryness of the feces. The usual number of stools in a day is one or two, but many people maintain health though they habitually depart from this rule in a marked degree. 120 PHARMACOLOGY AND THERAPEUTICS Muscle AuerbochJs Vagus V Mol-or Splanchnic. 1 nhibitory The feces are normally composed of food residue, bacteria, secre- tions, and products of chemic and bacterial activities in the intestinal canal. In some cases the bacteria form as much as one-third of the dried feces (Strasburger) . The Mechanical Factors of Defecation. The Small In- testines. The peristaltic wave is the active force in the propul- sion onward of the contents of the small intestine. Its stimulus depends on the integrity of Auerbach's plexus, and the peristaltic movement is coordinated and purposeful. It involves contrac- tion above the stimulating object and relaxation below it. The wave, once started, is propelled from muscle-fiber to muscle- fiber, directly or through nerve- fibrils, and the wave-like rather than continuous contraction is insured by a short refractory period of the muscle (Magnus). Under abnormal stimuli, as by irritant cathartics, the nor- mal, slow, worm-like peristaltic movement may become a "peristaltic rush" (Meltzer and Auer), with discharge of prac- tically the whole contents of the small intestine into the cecum in a very short time. It is probable that the site of con- stipation is rarely in the small intestines, except possibly in the neighborhood of the ileocolic junction. The Cecum and Colon. These form a great reservoir along which the contents are passed very slowly, and probably in a manner different from that in the small intestines. In the cecum and ascending colon so much liquid is absorbed that by the time the residue reaches the transverse colon it has begun to take on the consistence of feces (Roith). Regular antiperistalsis has been observed in cats and other animals; and, as shown by the x-ray in man, it takes but a few moments for a rectal in- jection to reach the cecum. The time normally required for the passage from stomach- to rectum has been studied under the x-ray by meals mixed with bismuth salts. For the first portion of a bismuth meal to reach the cecum Hertz found the average time to be four and a half hours, and for the last portion nine hours. Satterlee and LeWald, in 27 cases, found two hours the average time for the food to reach the cecum, only one hour being required in 3 cases, Sensory Fig. 2. Chart showing local and central innervation of the small intes- tine (after Dixon) CATHARTICS 121 and the longest time being five hours. In 9 cases it took from four to seven hours for complete emptying of the small intestine. Hertz found that the hepatic flexure is reached in six and a half hours, the splenic flexure in nine hours, the iliac colon in eleven hours, the pelvic colon in twelve hours, and the lower part of the pelvic colon in eighteen hours. At this point is the pelvirectal reservoir in which the contents remain until defecation. Bismuth meal pictures do not, however, tell the rate of a normal mixed meal. In a patient with an ileal artificial anus, Lynch found that a mixed meal appeared in seven hours, while the bismuth meal did not appear for twelve hours. On arising in the morning or on eating breakfast, as observed by Hertz with the x-ra.y, peristalsis begins in the colon and car- ries the feces into the rectum. When the rectum becomes dis- tended, the subject receives subjective sensations of a desire to go to stool. At stool the abdominal muscles are contracted so that more material is forced into the rectum and into the anal canal. This results in the defecation reflex, with relaxation of the anal sphincters, colon peristalsis, and renewed contraction of the abdominal muscles. At stool the whole large intestine from splenic flexure onward is emptied, a relatively long column of feces resulting. In addition, while the act of defecation is taking place, a portion of the contents of the transverse colon may move into the descending colon and pass out. The shape and the size of feces as passed are largely determined by their consistence and by the irritability of the anal canal, and not by strictures high up in the rectum. According to the above, the stool normally contains the food- products which have reached the splenic flexure. Hence the first portions of a meal eaten nine or ten hours before will normally appear in the stool, while a portion of the residue from that meal will not appear until the next stool. If there is but one stool a day, therefore, it will normally contain material from the food eaten as much as thirty-four hours before. Hence, Hertz con- cludes that if, after a morning defecation, the residue of food taken at 4 P. M. does not appear in the feces the second morning after, there is constipation. To check off the material of a given meal, it is customary to give a capsule of 5 grains (0.3 grru) of carmine, or half a dozen lozenges of charcoal, about 30 grains (2 gm.), with the meal. These color the feces from that meal pink or gray-black respectively. (Excellent reference works on the actions of the bowels are: Hertz, " Constipation and Allied Intestinal Disorders," 1909; W. B. Cannon, "The Mechanical Factors of Digestion," 1911.) Griping or cramp is a condition often produced by cathartics. 122 PHARMACOLOGY AND THERAPEUTICS It is probably caused by a spasmodic oontractk>n at the site of an irritant, instead of coordinated peristalsis. The work of Hertz suggests that the distention behind the contracted ring may be the cause of the pain. CATHARTIC MEASURES Cathartic measures are laxative when employed to produce soft stools of about normal frequency, and. purgative when em- ployed to produce copious soft or liquid movements. A hydra- gogMe is any remedy that will result in copious watery stools. The term aperient is sometimes employed for any cathartic, but especially for a saline. The term cholagogue was formerly applied to certain sub- stances which were thought to increase, the production of bile. The amount of bile may be increased by large amounts of ox-gall or bile-salts administered by mouth, and to a slight extent by salicylic acid. It is also increased by the injection of secretin into the blood (Starling). But pharmacologic research has shown that we have no effective agents which, in therapeutic amounts, have this action, so the term had best be abandoned. Cathartic measures include habit formation, response to the desire to defecate, exercise, massage, food, and drugs. 1 . Habit formation is the establishment of a regular time for the daily stool. Usually this time is just after breakfast, both because this is a convenient time and because the activity of dressing and the taking of food both tend to stimulate colon peristalsis. Even when there is no desire to defecate it is ad- visable to make the attempt; for the voluntary effort may force some feces into the rectum and so result in the proper subjective sensations which bring about the defecation reflexes. The after- breakfast smoke tends to promote defecation. 2. That response to the desire to defecate is important is indi- cated by Hertz's observation that the rectum accommodates itself to the presence of a fecal accumulation, so that if the desire is not responded to, it will pass away and the defecation reflex become impaired. Many persons have become habitually con- stipated because their occupation interfered with defecation. Women in business, for example, often suppress the desire to defecate rather than pass a number of men to reach the toilet. 3. The exercises of value are: walking, running, rowing, horseback riding, tennis, golf, gymnastics, and special abdominal exercises. Such are: bending the body forward or backward, or from side to side; lying on the back and raising the legs to a right angle with the trunk, or raising the trunk to a right angle CATHARTIC MEASURES 123 with the legs, etc. It must be noted that there are many persons who live a sedentary life yet are not constipated, and that many athletes and gymnasts have habitual constipation. In fact, exercise is frequently of value only so far as it promotes appe- tite and thus increases the amount of food eaten. 4. Massage may be either superficial or deep. It may be performed by active kneading in the direction of the colon, by a rotary motion of the abdominal wall over the viscera, by vibra- tory massage with the hands or a machine, or by rolling a cannon- ball or ball of clay covered with leather or chamois over the abdomen from cecum to sigmoid below the navel in the direction of the hands of a clock. Such a clay ball may be heated. 5. Foods. There is no sharp dividing-line between food and drugs, certain substances acting as food or as drug according to circumstances. A substance cannot serve as nutriment and act as a cathartic at the same time; for if it is absorbed, it does not act as a cathartic, and vice versa. Those who habitually undereat will be constipated. Foods tend to promote bowel movements by (i) Chemic stimulation, as of sugars and fruit acids and their salts, and di- gestive products, such as proteins, amino-acids, soaps, etc; (2) me- chanical stimulation, as by seeds or husks; (3) increasing the bulk of intestinal contents, as by cellulose, skins, etc., and un- absorbed oils and fats or their soaps. Foods of too ready digestibility are constipating. Of enor- mous importance (Hertz) is cellulose; in fact, Rubner states that "in the absence of cellulose from food almost everything is ab- sorbed." Fruits and vegetables rich in cellulose pass into the intestines as paste and stimulate peristalsis; meat, eggs, and milk pass as liquids and so favor segmentation, but not peristalsis (Cohnheim). Hertz reports that of the dry substance of meat, eggs, white bread, and rice, only 5 per cent, appeared in the feces; while of the dry substance of green vegetables and brown bread 15 per cent., and of the dry substance of carrots and turnips 20 per cent., appeared in the feces. The feces of a mixed diet gave 100 gm. of water and 35 gm. of dry substance; the feces of a vegetable diet gave 260 gm. of water and 75 gm. of dry substance. Vegetables and salads mostly contain fibrous tissue and cellu- lose. Many vegetables are as much laxative as nutritive. Salad dressing contains oil, which tends to be laxative. Cereals contain cellulose. Oatmeal is especially laxative, because of the presence of indigestible husks. Oatmeal water is even said to be more laxative than waters made from other cereals, but no soluble laxative principle has been isolated, and the water lacks the special laxative agent (the husks) of the oatmeal itself. 124 PHARMACOLOGY AND THERAPEUTICS Fruits contain sugar, cathartic acids or salts, indigestible structural parts (fiber, cellulose, skins, etc.), seeds, and non- absorbable colloid pectin bodies. Those most frequently con- sidered laxative are prunes, figs, and dates; but an apple, an orange, a banana, or some grapes at bedtime will often insure the morning stool. The morning coffee also promotes defecation. Water, in copious draughts, may act as a laxative in persons who take too little liquid, but normally it merely serves to acti- vate the kidneys. (See Diuretics.) 6. Drugs. These are usually administered by mouth, but a few may be employed subcutaneously, and some are used by rectum in the form of enemata and suppositories. Cathartic drugs may be loosely classified as: A. Those acting by a selective affinity for the nervous struc- tures. B . Those acting mechanically to give bulk and soft consistency to the feces. C. Those acting as bowel irritants. D. The saline cathartics which have a special action. A. CATHARTICS ACTING BY SELECTIVE AFFINITY In Class A we have: Physostigmine salicylate, dose, ^ grain (o.ooi gm.), which stimulates the ends of the vagus or motor nerves of the intestines; pituitary extract, which stimulates the muscles; and apocodeine, dose, ^ grain (0.03 gm.), which de- presses the ends of the splanchnic or inhibitory nerves, thus freeing the bowel from inhibition and increasing its motor activity. B. MECHANICAL AGENTS TO GIVE BULK AND SOFT CONSIST- ENCY TO THE FECES Sulphur increases the bulk of the feces and makes the stool soft. It is partly changed by the proteins of the alimentary tract into sulphides, sulphites and sulphates, which are mildly stimulating to peristalsis. The intestinal gases are increased in their sulphureted hydrogen constituent, and the feces may have a sulphuret odor. Some of the products are absorbed, as shown by the increase of sulphates in the urine. Sulphur, cream of tartar (potassium bitartrate), and molasses is a favorite household "spring medicine," and tablets may be had containing various proportions of cream of tartar and sul- phur. For the blood, in acne, it is given in the form of calcium sulphide, dose, i grain (0.006 gm.). Precipitated sulphur and potassa sulphiirala are also used in lotions for acne. In scabies CATHARTIC MEASURES 125 sulphur is sprinkled in the bed, and also applied to the skin in ointment form. For room disinfection it is burned to produce sulphur dioxid (SO 2 ). There are three official forms of sulphur, viz. : Sulphur sublimatum (sublimed sulphur, flowers of sulphur), which is preferred as a laxative, as it contains free sulphurous acid and is gritty. Sulphur lotum (washed sulphur), which is freed from acid by washing with ammonia, but is gritty. Its 15 per cent, oint- ment (unguentum sulphuris) is official. Sulphur pr&cipitatum (precipitated sulphur), prepared by precipitation from a solution of alkaline sulphide. It is soft and not gritty, and is preferred in lotions. Agar (A gar -agar} is a form of hemi-cellulose prepared from several species of seaweed. It has the property of absorbing water to form a jelly-like material. After heating 1.5 parts of it with 100 of water it cools to a stiff jelly, which is used extensively in bacteriology as a culture-medium. It is ordinarily unaffected by the digestive fluids, and is not absorbed from the alimentary tract, hence is not a food. But it absorbs water and swells, thus serving the double purpose of carrying water down into the intestines and of increasing the bulk of the colon contents. Its disadvantages are: (i) It is an excellent culture-medium and may favor the development of intestinal bacteria, itself becoming decomposed; (2) it mechanically retards the absorp- tion of food-products ; and (3) by acting as a demulcent it lessens the normal stimulation of the intestine by the food material. To overcome this last disadvantage Schmidt has recommended the addition of cascara, and such a preparation is on the market under the name of regulin. This is slightly bitterish from the cascara, the amount of which is not stated. A teaspoonful to a tablespoonful may be taken at night, or night and morning, dry or with water, or with the morning cereal. Its laxative action is frequently delayed for several days; but after that the patient may continue having a soft daily stool so long as the regulin is taken. Another laxative combination with agar is ptien olphthale'in-agar, of which one level teaspoonful, weighing 15 grains (i gm.), contains | grain (0.03 gm.) of phenolphthalein. Whole flaxseed and psyllium seeds are sometimes taken in teaspoonful dose to increase the bulk of the feces. Their muci- laginous coat absorbs water and swells. They are fermentative, however, and tend to produce gas and acid. Liquid Petrolatum. This petroleum oil, known also as liquid vaseline, liquid albolene, Russian mineral oil, and liquid paraffin, is not absorbed from the alimentary tract (Bradley, 1911, 126 PHARMACOLOGY AND THERAPEUTICS Bloor, 1913), hence serves to soften and to increase the bulk of the feces. It may exert an antiseptic effect on some of the strains of fecal bacteria, but this has not been demonstrated. It has little effect in the stomach, except that, like other oils, it tends to retard stomach emptying and gastric digestion and may nauseate. It is only mildly laxative, and frequently must be given with some stronger laxative, such as cascara. A disagreeable effect in some people is the leakage of free oil from the* anus, especially with the expulsion of flatus. This occurs with both the light and heavy oils, and with those of high and low viscosity. The dose is i ounce (30 c.c.) two or three times a day, the refined varieties being almost tasteless and readily taken. If desired, aromatics may be added. The author, in an investigation for the Council on Pharmacy and Chemistry of the American Medical Association, found that there was no difference in the clinical effects whether the oils were of low or high specific gravity or of Russian or American origin, provided that they were properly refined. The Pharmacopoeia allows a wide range of specific gravity and has adopted viscosity tests (see Part. I) . C. THE IRRITANTS In Class C we have a large and valued list of cathartics, and these may be subdivided for convenience of study into several small groups. These are.: (a) Bile and bile-salts. (&) The fixed oils and their products (soap and glycerin). (c) The mercurials. (d) The anthracene derivatives. (e) Acids, resins, and glucosides with drastic action the drastics. (a) BILE AND BILE SALTS (a) Bile and Bile Salts. The bile salts are sodium glycocholate and sodium taurocholate. They hold lecithin and cholesterol in solution in the bile, and serve as carriers of fats and soaps and their products into the villi of the intestine. They are then reabsorbed by the capillaries and returned to the liver by the portal vein. Owing to their ready excretion by the liver cells they act to increase the quantity of bile. In human bile from a biliary fistula Rosenbloom found i.oi per cent, of total bile salts, and Yeo and Herroun found sodium taurocholate, 0.055 per cent., and sodium glycocholate, 0.165 P er .'nt. In human bile from the gall-bladder Hoppe-Seyler found 0.87 per cent, of the tauro- cholate and 3.03 per cent, of the glycocholate. Fresh ox-gall THE FIXED OILS, SOAPS, AND GLYCERIN 127 contains about 3 per cent, of the salts, but is variable* in its composition. The extract of ox-gall or dried ox-gall and mixtures of the salts are recommended in dose of 5 grains (0.3 gm.) to promote the production of bile, to promote the splitting and absorption of fats, and to enhance the action of the anthracene cathartics. They would seem to be contraindicated in obstructive jaundice, as in this condition the system is already overloaded with bile salts. In cases with biliary fistula Gerster reported that fresh bile through a stomach-tube (it cannot be swallowed) was successful in checking debility. Inouye and Sato find that 8 to 15 grains (0.5-1 gm.) of dried ox-gall, taken one hour before eating, promote the absorption of fat. (b) THE FIXED OILS, SOAPS AND GLYCERIN 1. Olive oil (oleum olivae) is essentially a nutritive and di- gestible fat. However, in amounts of one or two tablespoonfuls it may have a mildly laxative action, being changed to soap and glycerin in the intestine. In large amounts, as ^ pint (240 c.c.), it is only partly saponified, and gets some of its laxative power from increasing the bulk of the intestinal contents. It had at one time a reputation for the cure of cholelithiasis; but as a solvent for gall-stones in the gall-bladder it has no value whatever. In the larger amounts it tends to form soap-lumps which have not infrequently been mistaken for gall-stones in the feces. It dis- tinctly prolongs the emptying time of the stomach. Olive oil is also given by mouth as a demulcent to diminish excessive hydrochloric acid secretion in the stomach, especially in ulcer, and by rectum to allay irritation, as in proctitis and hemorrhoids. Warm oil is often employed by rectum to soften hard feces, but Hertz found that oil does not penetrate the lumps of feces, and that these are much more readily soft- ened by water. 2. Castile soap (sapo) is nearly pure sodium oleate. It is mildly irritant to mucous membranes, hence is laxative. Soap- suds enemata may be made of Castile soap, or if a stronger action is desired, of laundry soap, which contains free alkali and is more irritating. 3. Glycerin (glycerinum), though slightly laxative when ad- ministered by mouth, is chiefly used in the form of the glycerin suppository (suppositorium glycerini), or as a mildly irritating addition to an ordinary enema. Hertz says it is irritant to the mucous membrane of the anal canal, but not to that of the rectum. 4. Castor Oil (Oleum Ricini). This oil is saponified in the 128 PHARMACOLOGY AND THERAPEUTICS small intestine to form glycerin and sodium ricinoleate, a soap which is much more irritant than Castile soap to the intestinal mucous membrane. Its great advantages are its rapidity of action, its thoroughness, its comparative freedom from irrita- tive griping, and its harmlessness if catharsis does not result. A dose of one-half to one ounce (15-30 c.c.) usually produces one or more copious soft or watery stools in from two to six hours. In some of our cases over a quart of stool was recovered afte^r one ounce of castor oil. It has little if any tendency to produce inflammation, hence is not a drastic cathartic; but it is a powerful stimulant of peristalsis. This effect is dependent on the forma- tion of the soap, for castor oil unsaponified is bland and non- irritant. If used by rectum, it should be saponified with an alkali, otherwise it acts like olive oil. In Rowntree's experi- ments, 25 c.c. by hypodermatoclysis had no effect upon the bowels, and merely caused a painful swelling at the site of the injection. Administration. Various methods of administration have been devised to hide the nauseating taste. The prepared oils usually contain saccharin and some aromatic such as peppermint. The three-layer or "sandwich" method in which the oil is sus- pended between two layers of watery or alcoholic liquid, is the favorite. For this purpose compound tincture of cardamom, spirit of peppermint, whisky, orange-juice, lemon-juice, lemonade, ice-water or beer may be employed. Glycerin is sometimes used for the lower layer. The layers should not be stirred together. The favorite drug-store method is to place some syrup of sar- saparilla in a glass and then cause it to foam by carbonic water from the soda fountain, or by a little tartaric acid and sodium bicarbonate. Then the oil is poured in without allowing any to get on the edge of the tumbler. The mixture must not be stirred. The oil floats between some of the syrup below and the foam above, and the whole is drunk without stopping. The oil is not tasted at all. The principle of these methods is to have the mouth and tongue wetted with a liquid (the top layer) upon which the oil will readily slip down. If any oil sticks to the tongue, the taste will be perceived, though it is stated that vichy-lemonade following the dose will prevent this. For infants and children, an emulsion made with acacia and a flavored syrup may be employed. There are some powdered castor oils on the market, such as risiccol and castor-lax, made by absorbing castor oil with magnesia. To get a full castor- oil action they must be taken in very large dose, 2 ounces (60 gm.). Therapeutics. Castor oil is extensively employed in dose of i ounce (30 c.c.) as an occasional brisk cathartic for the thorough Fig. 3. The abdomen of this patient was greatly distended with gas, which seemed as if in his stomach, though unrelieved by belching. After a rectal injection of bismuth this .v-ray picture was taken, the patient being in the standing position. The light areas in the bowel are gas. (Picture taken by Dr. L. T. LeWald.) Fit,'- 4.- The same patient as in l"\x. 3. This .v-ray ])icturc was taken after free movements of the bowels by castor oil. There was complete relief from flatulency. (Picture taken by Dr. L. T. LeWald.) THE CATHARTIC MERCURIALS I2Q cleansing of the intestines. This may be desired in fermentative diarrhea, food or ptomain-poisoning, intestinal flatulency, or mu- cous colitis, or because of continued colonic stasis. Such thorough catharsis is prone to be followed by constipation for a day or two during the refilling of the stagnant bowel. Castor oil in cathartic amounts is not suited for daily repetition. By its activity it tends to congest and stimulate the female pelvic organs, hence must not be employed as a cathartic during menstruation or pregnancy, though it is sometimes administered to bring on labor pains at full term. In colitis and intestinal putrefaction a favorite treatment is a capsule containing 2\ minims (0.15 c.c.) of castor oil and 2\ grains (0.15 gm.) of salol, or twice these amounts, three or four times a day. The effect of such small amounts of the oil is problematic. (c) THE CATHARTIC MERCURIALS Calomel (hydrargyri chloridum mite), the mild chloride of mercury, HgCl, is a bland or unirritating heavy powder, completely insoluble in water. It has few chemic affinities, but is decomposed by alkalies. When it is added to a solution of sodium carbonate, it turns gray with the formation of the carbonate, oxide, or hydroxide of mercury, a change which takes place, as shown by Schaefer, when the calomel passes from the stomach into the duodenum. Some of the salt goes into solution, for the nitrate contains mercury (Schaefer, MacCallum). This gray salt of mercury has more chemic affinities than calomel, is irritant locally, and is antiseptic, and it is upon this chemic change that the value of calomel in the alimentary tract largely depends. This suggests the advisability of dividing the large doses, so that not too much is passed into the duodenum at one time. After cathartic doses mercury is found in the urine. The result of the irritation is increased peristalsis beginning in the duodenum and extending through the whole length of the bowel. In addition, there is a mild antiseptic action, though many more bacteria are carried out by good catharsis than can be killed by an antiseptic. Calomel is not a very powerful colon stimulant, so if the dose is too small, the movement may not be copious; however, if the dose is too large, there may be griping, rectal irritation and tenesmus, and numerous small stools. At times, if the action is not severe enough, the bowels are not thoroughly cleaned out, and the result is autointoxic headache and lassitude. The explanation of this is that the calomel hastens the undigested food through the small intestine to the colon, where the putrefactive bacteria are located. The raw proteins, 9 130 PHARMACOLOGY AlSTD THERAPEUTICS not being carried out, furnish pabulum from which these bacteria generate an extra amount of poisons of the indol type (Herter). Because of this not infrequent sequence to calomel, it is the cus- tom to follow the dose in about eight hours with a saline cathartic to insure a thorough washing out of the colon. The calomel stools may be gray in color from the presence of the mercurous oxide or other mercurous salts; occasionally they are green from the presence of unchanged biliverdin, this being due either to the rapid carrying of the bile through the intestines, or to the prevention of .the usual reduction of the bile-pigment. This prevention may result (i) From the direct chemic action of the mercury salt on the pigment; (2) from an antiseptic effect upon the bacteria which cause the changes in bile-pigment, or (3) from an interference with the oxidases. Frequently re- peated in large amounts, as in 1 extract of belladonna, grain (0.008 gm.); strychnine, the pure alkaloid, T 4u grain (0.0005 gm.) ; and ipecac, \ grain (0.004 g m -) i n each pill. 2. Frangula (Rhamnus frangula), dose, 15 grains (i gm.), has an official fluidextract. 3. Cascara sagrada (Rhamnus Purshiana), dose, 15 grains (i gm.) ; extract, 4 grains (0.25 gm.) ; fluidextract, 30 minims (2 c.c.) ; aromatic fluidextract (cascara, glycerin, 25 per cent., licorice, magnesia, saccharin and aromatics), 30 minims (2 c.c.). Mag- nesia is said to lessen the bitter taste. From the author's ob- servations it seems to lessen the cathartic activity. The fluid- extracts may be given in doses of 10 minims (0.7 c.c.) three times a day, or i dram (4 c.c.) at bedtime, with about equal effect. The aromatic fluidextract was designed to lessen the bitter taste and to prevent griping. 134 PHARMACOLOGY AND THERAPEUTICS 4. Rhubarb (rheum), dose, 15 grains (i gm.); extract, 4 grains (0.25 gm.); fluidextract, 15 minims (i c.c.); tincture, 20 per cent., i dram (4 c.c.); aromatic tincture (rhubarb, 20 per cent., with cinnamon, cloves, and nutmeg), \ dram (2 c.c.); syrup, 10 per cent., i dram (4 c.c.) ; aromatic syrup, 10 per cent, of the aromatic tincture, 2 drams (8 c.c.); compound rhubarb powder or Gregory's powder (rhubarb, 25; magnesium oxide, 65; and ginger, 10), dose, 30 grains (^ gm.); compound rhubarb pills (rhubarb, 2 grains (0.13 gm.), and aloes, i| grains (o.i gm.), with myrrh and oil of peppermint), dose, 2 pills. The syrups are favorites for children. Rhubarb and soda mixture (rhubarb, 1.5; ipecac, 0.3; sodium bicarbonate, 3.5; spirit of peppermint, 3.5; glycerin, 35 per cent., and water), 2 drams (8 c.c.), is no longer pharmacopceial. 5. Senna (senna), dose, i dram (4 gm.); fluidextract, \ dram (2 c.c.); syrup, 20 per cent., 2 drams (8 c.c.); compound syrup of sarsaparilla (senna, 1.5 per cent., with licorice, sarsa- parilla, and aromatics), 4 drams (15 c.c.); compound infusion or black draught (senna, 6; manna and magnesium sulphate, each, 12; and fennel, 2 per cent.), 2 ounces (60 c.c.); compound licorice powder (senna, 18; licorice root, 23.6; washed sulphur, 8; oil of fennel, 0.4; and sugar, 50), i dram (4 gm.). This last is taken stirred up with water. The confection (senna, 10 per cent.; tamarind, cassia fistula, prune, fig, sugar, oil of coriander), i dram (4 gm.), is not now official. Phenolphthalein (dihydroxyphthalophenone) is insoluble in water and soluble in 13 parts of alcohol; dose .2\ grains (0.15 gm.). It has a mild, non-griping, laxative action, mostly by stimulating peristalsis, but also to some extent by pre- venting absorption. The effect is a soft, rather large stool. In a Moreau's loop Wood found it unabsorbed after two hours and the contents of the loop increased in bulk, but he does not say whether this was due to osmosis or secretion. No phenol is liberated, and doses in dogs equivalent to from 60 to 100 grains in humans have proved non-toxic (Wood). Enor- mous doses intravenously have proved non-toxic (Abel and Rowntree). Orland reports 30 grains (2 gm.) taken by a child of 3 years without ill effects. According to Rowntree, it is eliminated by the feces, and none usually appears in the urine, except after a hypodermatic dose. But the author has repeatedly found it in the urine, an alkaline urine after small doses by mouth being of a pink color from its presence. Hydrick, 1914, reports albuminuria from one and two grains (0.06 and 0.12 gm.) in every case in 20 tests, but in the author's extensive clinical use of the drug with frequent urine examinations there has been no albuminuria. In kidney disease a subcutaneous dose of the drug THE DRASTICS 135 is retarded in its elimination by the urine; this is the "phthalein test" of kidney function. A very mild and useful combination is phenolphthalein-agar, of which a level teaspoonful weighs about 15 grains (i gm.) and contains \ grain (0.03 gm.) of phenolphtha- lem. It sometimes produces nausea after a few days' use. Troches of phenolphthalei'n N. F. each contain 1 grain (0.06 gm.). (e) THE DRASTICS These are so named because their action is harsh. In over- doses they tend to produce violent inflammations. Their active principles are chiefly resinous glucosides, such as colocynthin in colocynth and jalapin in jalap, or acids, such as cambogic in gamboge and crotonic in croton oil. Action and Uses. The drastics are strong local irritants, acting to increase both peristalsis and secretion. If one of them is placed in a loop of intestine tied off without injury to the vessels (a Moreau's loop) , the wall of the loop soon becomes con- gested and shows signs of inflammation, and the contents of the loop contain inflammatory products. Their cathartic action is often accompanied by violent cramps and abdominal soreness, and in this event may result in stools containing blood or serum- albumin. After the larger doses in man, if catharsis does not result in a reasonable time, the drugs accumulate in the cecum and colon, and may cause serious inflammation. In such case, too, they may be slowly absorbed and passed out by the kidneys, and these they irritate severely, even to the production of an acute nephritis. The writer saw a case of hysteria which had been treated for obstinate constipation by the administration, in a period of twenty- four hours, of a seidlitz powder, three compound cathartic pills, 2 drams (8 gm.) of compound jalap powder, and 3 minims (0.2 c.c.) of croton oil. These resulted in no movement of the bowels until shortly after the last dose. Then there was a violent diarrhea, with blood in the stools, severe abdominal cramps, bloody urine, and later suppression of urine. The patient went into collapse and died in twenty-four hours. At postmortem examination there was an intense inflammation of the last few inches of the ileum and the whole cecum, in which region some brown drug was visible clinging to the wall of the bowel. There was also an acute hemorrhagic nephritis. The drastics had caused these lesions. On Dr. Theodore Janeway's service at St. Luke's Hospital a girl of nineteen was admitted with similar but less severe poisoning from "bitter apple" (colocynth), given to her by a druggist. She had vomited six hours after the dose, and re- 136 PHARMACOLOGY AND THERAPEUTICS peatedly for twenty-four hours, with almost constant diarrhea and a dull ache across the lower abdomen. She was admitted the following day to the hospital, the temperature being 99.8 F., the pulse 116, and the leukocytes 27,200, with 82.5 per cent, of polymorphonuclears. She still had the gastro-enteritis, and vomited twice after admission; but the kidneys were apparently unaffected, probably owing to the free diarrhea. The patient made an uneventful recovery in four days. In poisoning, the immediate indications for treatment are: (i) To remove the poison by a saline cathartic or castor oil or by colon irrigation, and (2) to check collapse. After the immedi- ate clearing out, bland oils or bismuth salts in large amounts may be given. The subsequent treatment is that for acute colitis, as by bland diet and bismuth salts by mouth, warm oil by rectum, etc. If the kidneys are affected, the treatment for acute nephritis is called for. Therapeutics. It will be seen that these drugs are not suit- able for daily administration. Their repeated use tends to pro- duce ultimate constipation by accustoming the bowel to excessive stimulation, and so lessening its sensitiveness. Their employ- ment should be occasional only, and then only when a thorough cleaning out of stagnating intestinal contents is desired. On account of their tendency to gripe, which is very great, they should also be given with correctives, such as the extract of belladonna and aromatics. In a number of instances a serious drop in blood-pressure has been noted during their action. Of the individuals, podophyllum, euonymus, and leptandra are rather mild and slow in action. Elaterin tends to produce such copious watery stools that it is a favorite in dropsy. Crolon oil is a fixed oil which contains as its active principle crotonic acid, a substance so irritant that a drop of the oil in contact with the skin for an hour or two results in the formation of a pustule. A drop applied to the tongue will sometimes move the bowels, even if the patient is comatose. If the oil is previously freed from crotonic acid, it has an action similar to that of castor oil and a large dose -is necessary to move the bowels. But in the oil as we employ it this action is entirely overshadowed by the action of the crotonic acid; hence the drug as used is not of the castor oil type, but is a powerful drastic. Croton oil is employed only occasionally, and then only in rebellious or coma- tose cases. It was formerly employed as a pustulant in pleurisy, pneumonia, etc., but this use of it has been abandoned. Its dose is 2 minims (0.13 c.c.), and each drop measures practically i minim (0.06 c.c.). Cautions. As the drastics are emmenagogue and aborti- SALINE CATHARTICS 137 facient, they must be used with great caution, if at all, during menstruation and pregnancy. As they are irritant and decidedly depressing, they should not be employed in nephritis, bowel inflammations, hemorrhoids, and low conditions of vitality or in old age. Preparations and Doses. Elaierin, ^ grain (0.006 gm.); resin of podophyllum, % grain (o.oi gm.); colocynth (bitter apple), i grain (0.06 gm.); croton oil (oleum tiglii), 2 minims (0.13 c.c.); gamboge, resin of jalap, and resin of scammony, each, 2 grains (0.13 gm.); podophyllum and compound extract of colocynth, each, 7^ grains (0.5 gm.); jalap, 15 grains (i gm.). Euonymus and leptandra are unofficial, dose, 7^ grains (0.5 gm.). There are official, one drastic powder and one drastic pill, viz., compound jalap powder (pulvis jalapae compositus), composed of jalap, 35 parts, and potassium bitartrate, 65 parts; dose, 30 grains (2 gm.); and compound cathartic pills (pilulae catharticae composite), containing calomel and compound extract of colocynth, each, i grain (0.06 gm.), resin of jalap, T % grain (0.02 gm.), and gamboge, \ grain (0.015 g m -) m each pill. They have not sufficient corrective and may gripe severely. Dose, 3 pills. The compound extract of colocynth is composed of purified aloes, 50 per cent.; extract of colocynth, 16 per cent.; and resin of scammony, 14 per cent., with cardamom and Castile soap. Vegetable cathartic pills (pilula? catharticae vegetabiles) , con- taining compound extract of colocynth, i grain (0.06 gm.); resin of jalap, T % grain (0.02 gm.); resin of podophyllum, \ grain (0.015 gm.); extract of leptandra, j grain (0.015 gm.); extract of hyoscyamus, \ grain (0.03 gm.), and oil of peppermint, \ minim (0.008 c.c.), in each pill, were official in the U. S. P. 1900. They contain sufficient corrective, and the griping is slight or absent. Dose, 3 pills. Subcutaneous Purgatives. A number of active principles will cause purgation when administered hypodermatically, but most of them, such as aloin, cascarin, cathartinic acid, colocyn- thin, and podophyllotoxin (the active principle of podophyllin) are too irritant locally for such use in medicine. (See "Cathartics Acting by Selective Affinity.") D. SALINE CATHARTICS The saline cathartics are certain salts of sodium, potassium, and magnesium. In the study of salts it has been found that their power of penetrating animal membranes, or, in the intes- tines, their absorbability, depends on the nature of the ions of which they are composed. Of ready absorbability, the cations 138 PHARMACOLOGY AND THERAPEUTICS (positive ions) are ammonium, potassium, sodium, and lithium; and the anions (negative ions) are chlorides, bromides, iodides, nitrates, and acetates. Among those that are absorbed -with difficulty are the cations, calcium, magnesium, cerium, aluminium, and the heavy metals; and the anions, phosphates, sulphates, tartrates, citrates, malates, and lactates. Of all these, mag- nesium among the basic ions, and citrates, phosphates, 'sulphates, and tartrates among the acid ions, tend to give cathartic properties to their compounds. To possess this property, the salt must be in solution in the intestines. (Leathes and Starling have found that the pleural endothelium absorbed solutions of magnesium sulphate and sodium sulphate just as quickly as solutions of sodium chloride, but this is not true of the intestinal wall.) Preparations and Doses. 1. Of magnesium the oxide, a very light powder, and the heavy oxide (oxidum ponderosuni) , dose, 30 grains (2 gm.); the hydroxide, in the form of magma magnesia (milk of magnesia), dose, 2 drams (6 c.c.); and the carbonate, dose, 45 grains (3 gm.), are very mildly laxative. The laxative powers of these insoluble magnesium salts are pre- sumably due to the formation of the soluble chloride in the stomach, or the soluble bicarbonate in the intestine. In some cases they fail to dissolve, and in such have been known to form intestinal concretions of dimensions large enough to cause ob- struction of the bowels. The hydroxide is the favorite for children. The citrate (liquor magnesii citratis), dose, half to one bottle of 12 ounces (360 c.c.), and the sulphate (Epsom salt), dose, \ ounce (15 gm.), very soluble in water, are more vigorous. 2. Of potassium the citrate, 30 grains (2 gm.); the effer- vescing citrate, 60 grains (4 gm.) ; the bitartrate (cream of tartar), 30 grains (2 gm.) ; and the sulphate, 30 grains (2 gm.). 3. Of sodium the phosphate, 30 grains (2 gm.); the effer- vescing phosphate, 2 drams (8 gm.); the sulphate (Glauber's salt), 2 drams (8 gm.); and the citrate, 30 grains (2 gm.). Best finds 2 tumblers of normal saline an effective cathartic. The potassium and sodium tartrate, KNaC 4 H 4 O 6 , is Rochelle salt, dose, 2 drams (8 gm.). The seidlitz powder is made by enclosing tartaric acid in a white paper, and a mixture of Rochelle salt and sodium bicarbonate in a blue paper. The contents of the papers should be dissolved separately in water, the two solu- tions mixed, and the liquid drunk as soon as the violent efferves- cence has ceased. It contains Rochelle salt, 2 drams (8 gm.), and some acid sodium tartrate formed during effervescence. Potassium bitartrate, KHC 4 H 4 O 6 , is soluble with difficulty in water, but it forms Rochelle salt in the duodenum. The effervescent preparations are usually preferred, as the SALINE CATHARTICS 139 CO 2 present renders them more palatable and less nauseating. They are the solution of citrate of magnesia, the effervescing citrate of potassium, the effervescing phosphate of sodium, and the seidlitz powder. The laxative mineral waters usually con- tain sodium sulphate or magnesium salts. Pharmacologic Action. Skin and Mucous Membranes. Applied to the skin, solutions of these salts are practically inert, as they penetrate the horny epithelium with difficulty. Applied to mucous membranes, the concentrated solutions are rather irritant because of the abstraction of water. Stomach. Solutions of salts in fairly concentrated form, as they are administered for cathartic effects, have an unpleasant salt taste and are irritant to the stomach, hence they tend to be nauseating. If they lie in the stomach, they promote transuda- tion and secretion, and therefore their own dilution. The view of Otto (1905) that solutions of salts are retained in the stomach until they become isotonic with the body fluids has been in the main corroborated, and Hertz (1910) concludes that "even very concentrated solutions become almost isotonic before their evacu- ation from the stomach." Brown (1912) found that hypertonic solutions were markedly retarded in the stomach, and that iso- tonic and hypotonic solutions leave less rapidly than the very hypotonic tap-water. He agrees with Leven and Barrett that from an otherwise empty stomach 200 c.c. of water leaves in about twenty minutes. In his experiments he ascertained that the strong laxative mineral waters call forth considerable transuda- tion in the stomach and some secretion of gastric juice, and strongly inhibit the motor functions. They are irritant and are capable of inducing an acute gastritis. In their administration, they should be properly diluted to bring them nearly to an iso- tonic condition. For example, Hunyadi and Friedrichshall should be followed by an equal amount of water; magnesium sulphate should be given in 7.5 per cent, solution (isotonic); sodium sulphate, in about 2 per cent., and Carlsbad salts in about 3 per cent., solution. The amount of fluid added by the stomach may be quite large; for instance, by a high duodenal fistula Brown obtained 503 c.c. after 150 c.c. of Hunyadi water, and 250 c.c. after 150 c.c. of 50 per cent. Hunyadi water (almost isotonic). Cobet finds also much fluid added in the small intestine. Intestines. Some years ago Hober, Wallace, and Cushny administered solutions of various salts to dogs. On analysis of the contents of the intestines they found that the salts which were cathartic were regularly the ones not readily absorbed, and that these acted as cathartics even when in solutions isotonic 140 PHARMACOLOGY AND THERAPEUTICS with the blood. By means of a cecal fistula they also measured the fluid that reached the cecum after the administration of isotonic solutions. After 100 c.c. of sodium chloride solution there was none recovered at the cecum in one hour: it had been absorbed. After 100 c.c. of sodium citrate, 75 c.c. were recovered, and after 100 c.c. of sodium sulphate, from 80 to 90 c.c. were re- covered. They concluded that from 75 to 90 per cent, of ca- thartic salts, with the fluid in which they were dissolved, was unabsorbed; and that the catharsis was due to the large bulk of fluid and not to any active stimulation of the intestinal wall. Boas found that, as the solution was more concentrated, it proved less cathartic and more prone to be absorbed and to pro- duce systemic effects. He reports 10 cases of magnesium poisoning from concentrated doses of Epsom salts. Meltzer, Lucus, and Auer have pointed out that when magnesium sul- phate is administered intravenously it reduces the irritability of the intestines and checks the peristalsis aroused by physos- tigmine or barium chloride. Magnus has shown that magnesium sulphate has no power of itself to stimulate peristalsis, and Cohn- heim placed it in the duodenum, with no effect on the motility of the bowel. These findings corroborate the belief that the bulk of unabsorbed or added fluid is the laxative agent. On the other hand, a theory propounded by Aubert (1852), that the salts had to be absorbed in order to act on the intestine,, received some corroboration by the work of J. B. MacCallum (1904). He found that laxative salines (sodium citrate and sulphate) administered intravenously where cathartic. This has not proved, however, to be regularly the case, and investi- gators have considered the theory untenable. However, Hertz (1910), after numerous studies with the #-rays, has revived the theory. He discovered that in two patients with fistula at the end of the ileum the soluble purgative salt traveled no faster than the heavy bismuth salt given with it, so he assumed that it was fair to judge by x-ray pictures and by auscultation of the cecal sounds. The x-rays showed that though a watery stool was passed one and a half hours after the saline was taken, the bismuth given with the saline did not reach the cecum for four hours. He showed further that in the watery stools from sodium sulphate there was no increase in the sulphates; that half the salt was excreted in the urine in eight hours; and that the greater part of the salt of the feces appeared the next day after the liquid stools had ceased. He concluded that the salt must have been absorbed, that it acted through the blood as a stimulant both to secretion and to peristalsis of the colon, and that it acted independently of its own appearance in the colon. SALINE CATHARTICS 141 Sodium sulphate administered intravenously may be slightly laxative, but magnesium sulphate administered by mouth 'but prevented from reaching the colon, or administered hypoder- matically or intravenously is not cathartic; indeed, Auer says that an intravenous or hypodermatic dose definitely checks peristalsis. MacCallum attributed the failure of the intravenous dose to too rapid excretion by the kidneys, and believed that only through the intestines could a sufficient concentration of the salt be absorbed for cathartic effect. He suggested that these salts are purgative by precipitating the calcium salts in the tissues and so neutraliz- ing their depressing action. And, as a matter of fact, the cathartic compounds are, for the most part, the ones that precipitate cal- cium (citrates, tartrates, sulphates, and magnesium), and calcium tends to inhibit their cathartic action. Meltzer's summing up of the intestinal action of magnesium sulphate is as follows: The salt is partly changed in the intestine to sodium sulphate and magnesium carbonate, so that these two salts with some unchanged magnesium sulphate are present. Since peristalsis consists of a coordinated excitation (contraction) above and inhibition (relaxation) below, it is promoted by an increase of the irritability of the excitation phase by the sodium sulphate, and an increase of the irritability of the inhibition phase by the unconverted magnesium sulphate, while at the same time the magnesium carbonate attracts fluid and probably stimulates peristalsis. It is usual that- in one or two hours the dose results in one or more watery stools, which consist of (i) the salt and the water in which it is dissolved; (2) some of the gastro-intestinal contents of which absorption is prevented by the salt; (3) some of the feces already formed in the colon; and (4) liquid added by transudation and secretion. Bayliss and Starling, Magnus, Cannon, and others have shown that the passage of liquids along the intestine is different from that of solid or pasty matter. Solids stimulate peristalsis, whereas liquids simply generate rhythmic intestinal segmentations (Cohnheim). The result of this is that, while the liquid passes along, more or less of the solid contents of the intestine are likely to be left behind. Hence a saline cathartic may not be so thoroughly cleansing as the ordi- nary more slowly acting stimulants of peristalsis. In connection with saline cathartics, Moreau's loop has be- come a classic experiment. It is a loop of intestine tied off with- out injury to the vessels and nerves of the mesentery. Into such loops different salt solutions are injected, and they show that (i) An isotonic solution remains almost unchanged at the end of three hours; (2) a hypotonic solution loses in volume, that is, 142 PHARMACOLOGY AND THERAPEUTICS is absorbed, and (3) a hypertonic liquid gains in volume. It is of interest that in the latter case there is no protein or other evidence of inflammation. The gain in volume is due either to secretion or to osmosis. However, as the loops prevent peristalsis and segmentation, the results of such experiments are not at all conclusive as to the action of saline cathartics. Of saline cathartics as a class it may be said that 1. They irritate the stomach and are prone to produce nausea, an effect which may be largely overcome by administer- ing them as effervescent drinks. 2. Their stools contain much liquid, but no inflammatory products. 3. They are often not thoroughly cleansing. 4. They act most rapidly and best if taken fasting, as before breakfast, and with a large volume of water. Their action comes on in an hour or two. 5. Their catharsis is the effect of the increased bulk and fluidity of the colon contents, and this is chiefly due to the pre- vention of absorption. 6. They do not induce irritant griping; but accompanying their rapid passage through the intestines there may be some griping, much gurgling of the intestines, and more or less faint- ness and nausea. 7. If they are not evacuated, they produce no inflammation and are absorbed. 8. When absorbed, they pass out by the kidneys and act as diuretics. 9. In moderately hypertonic solutions they tend to remove fluid from the body. This may not, however, be the case if the dose is repeated daily, and especially if the patient is on a "dry" diet, as in dropsy. In such cases the salt may be absorbed and only add to the work of the kidneys. 10. Violent purging results in nausea, lowered blood-pressure, and prostration. 11. Small doses taken at night tend to promote and soften the morning stool. Therapeutics of Salines. They may be employed: i. In acute constipation or food-poisoning as a rapidly act- ing non-irritant cathartic. 2. In habitual constipation for a short period only. 3. In intestinal putrefaction. 4. After a dose of calomel. 5. As an occasional purge. Their use in dropsy and obesity and to lessen the secretion of milk in nursing mothers is dependent upon the power of salines to decrease the fluid in the body. For this purpose they are ad- ministered daily, a diet low in liquids being prescribed. But RECTAL TREATMENT 143 they usually very soon cease to carry out excess of liquid, and when profuse watery catharsis does not result, should be stopped. They probably have no influence on obesity; at any rate, of themselves, alone they are unable to cause the body to lose fat. Moderate doses make the stools soft and non-irritant, so have been advised in hemorrhoids, fissure of the anus, etc.; large doses cause such sudden expulsion as to be harmful in these con- ditions. Objections to the habitual use of salines in chronic constipa- tion are (i) That they accustom the intestines to a greater bulk of contents than usual so that the intestines lose their sensitiveness to the usual bulk of intestinal contents; and (2) that they activate the intestine for one or two hours only, and allow it to remain "fallow" for the rest of the twenty-four hours. Poisoning by Magnesium Sulphate. Magnesium sulphate in very concentrated solution does not induce peristalsis, is absorbed, and is poisonous. The toxic symptoms are: marked depression of respiration and a curare-like action on the junctions of motor nerves with striated muscle (Meltzer and his associates and Barbier). The salt is eliminated in the urine and gives this a very high specific gravity, even 1070 or 1080, which of itself is suggestive of magnesium sulphate poisoning. The antidotes are calcium or physostigmine (Meltzer and Joseph). (See Magnesium Sulphate, under Anesthetics, page 313.) RECTAL TREATMENT Enemata, or rectal injections, may be for cathartic, nutritive, or cleansing purposes, or they may be employed to supply liquid to the body, to cause the expulsion of gas, or to carry local reme- dies to the mucous membrane of rectum and colon. The cathartic enema may be employed both as a softening agent for feces and as an evacuant. It has the advantage of affecting directly the rectal reservoir and its contents. (a) The softening agents are water, soapsuds, olive oil, glycerin, and oxgall. Hertz found that hard fecal masses in contact with olive oil were not disintegrated in twelve hours, while in contact with water they disintegrated in four hours. Oxgall, also, he found to have no greater softening power than water. Glycerin increases the penetration of the water. In cases of impacted feces it has been the custom to inject fresh oxgall or a i to 3 per cent, solution of extract of oxgall (extractum fellis bovis), or warm olive oil, sometimes with the addition of castor oil. But, as just stated, neither oxgall nor olive oil is as effective as water in softening feces; and it is a fact that castor oil has little evacuant power unless it is saponified, as in the duodenum. (Inouye and 144 PHARMACOLOGY AND THERAPEUTICS Sato (1911) report that inspissated oxgall, 15 grains (i gm.) by mouth, promotes the absorption of fat.) For softening impacted feces, therefore, the best enemata are plain water, normal saline, and soapsuds, with the addition of glycerin, \ ounce (15 c.c.) to i pint (500 c.c.)- (b) The evacuating enema acts either by constituents capable of irritating the rectum or by the mechanical stimulus of its presence in the rectum. It consists usually of from one pint to two quarts of warm soapsuds, or soapsuds with the addition of glycerin, \ ounce (15 c.c.), or oil of turpentine, \ ounce (15 c.c.). In tlie cat, Cannon has observed peristalsis of the small in- testine as the result of a rectal injection and antiperistalsis of the colon. In tests with bland nutritive enemata of milk, eggs, starch, and bismuth subnitrate he found that in every instance antiperistaltic waves carried the material to the cecum. Small enemata never passed the ileocecal valve, but large enemata of about the capacity of the large intestine would often pass into the small intestine. In man, if a quantity of liquid is introduced three or four inches into the rectum, the patient being in the knee-elbow position or on the back, it will not infrequently reach the cecum; but this happens, as a rule, only when the liquid is bland and is administered slowly, so as not to start the defecation reflexes. In some cases, however, even an irritant enema passes quickly to the cecum, and in rare instances has been vomited. In these cases, of course, the enema fails to act as an immediate evacuant. The evacuant enema is given rapidly, and by a sudden dis- tention of the rectum or by direct irritation of the bowel wall results reflexly in active forward peristalsis, at least of the de- scending colon, with expulsive contraction of the rectum and relaxation of the anal sphincter. In the treatment of chronic constipation enemata should not be given over too long periods, for they accustom the bowel to the stimulus of a bulk of material greater than that of the normal feces. Enemata to induce the expulsion of gas may be of soapsuds made from yellow laundry soap; of soapsuds and turpentine, ^ ounce (15 c.c.); of turpentine, \ ounce (15 c.c.), with olive oil, 6 ounces (180 c.c.); of ice water; of infusion of chamomile; or of tincture of asafetida, 4 drams (15 c.c.), or spirit of peppermint, i dram (4 c.c.), added to a pint of hot water. They are employed in the tympanites of typhoid fever, pneumonia, post-operative intestinal paralysis, etc. Nutritive enemata are employed for feeding when it is neces- sary to spare the stomach. They must be small in bulk, i. e., RECTAL TREATMENT 145 about 6 or 8 ounces (180-240 c.c.), warmed, and slowly adminis- tered so that they will not be expelled. They may be given at six- or eight-hour intervals, and their administration should be accompanied by a daily cleansing enema of normal saline or weak soapsuds. The ingredients of the enema should be made as absorbable as possible. The available foods are dextrose, sugar, sugar of milk, fully peptonized milk, whisky, brandy, and raw eggs. The white of egg peptonized with the milk may be absorbed, but the ingredients of the yolk may not be. Dextrose solutions are absorbable, but in strengths above 5 or 6 per cent, irritate and cause evacuation. Whether the other sugars are inverted and absorbed is a question. Magnus says that cane- sugar is absorbable. The absorption of oils is promoted by emulsification with 3 to 5 per cent, of lecithin (Congdon), and this may apply to egg-yolk. It is possible that the amino-acids, such as tyrosin, histidin, and arginin, may prove useful for rectal feeding, as they represent the end-products of protein digestion. Short and Bywaters found a decided increase in the urinary nitrogen from the administration of amino-acids by rectum. They recommend milk pancreatinized twenty-four hours, with the addition of 5 per cent, of glucose. Colon or rectal irrigations of saline solution slowly admin- istered, using both inlet and outlet tubes, are frequently employed to clean out mucus or the products of intestinal putrefaction, to activate the kidneys, or to supply fluid after hemorrhage. The inlet tube may be inserted 6 or 8 inches, and the outlet tube about half as far. The "continuous drip" irrigation, in which a flow of warm saline 20 to 60 drops per minute, is kept up continuously, day and night, was recommended by Murphy for postoperative tympanites and shock. Potassium acetate or sodium bicarbonate may be substituted for the sodium chloride. The rectum is a favorite channel for the administration of warm normal saline solution to supply liquid to the body after severe hemorrhage. Rectal suppositories may be of wheat-gluten, soap, glycerin, or plain or medicated cocoa-butter. The evacuant ones act largely as a foreign body, mechanically stimulating the rectum to expel it. Even a stick of ice or an undisintegrated stick of soap will often have the same effect. Glycerin suppositories, made of almost pure glycerin, with a little sodium stearate to give a solid consistence, are much employed. The glycerin acts as an irritant in the anal canal, but not in the rectum (Hertz). Suppositories are especially useful where the feces come down to the rectum, but are retarded in their expulsion by a tight or sensitive sphincter. 146 PHARMACOLOGY AND THERAPEUTICS ANTI-DIARRHEICS Diarrhea has so many causes that remedies of entirely dif- ferent action may be required in the different types. In fer- mentative diarrhea castor oil may be indicated, followed by a bland protective like bismuth subnitrate. In severe diarrhea camphor, lead acetate, or opium may be the needed remedy. The anti-diarrheics are : bismuth salts (subnitrate, subcarbonate, and subgallate), cerium oxalate, calcium carbonate (chalk), camphor, lead acetate, opium, the vegetable astringents, and castor oil. They are all studied in detail elsewhere. The Sun Cholera Mixture, N. F., contains in each teaspoonful 6 minims (0.4 c.c.) each of the tinctures of capsicum and rhubarb, and 12 minims (0.8 c.c.) each of the spirit of camphor, spirit of pepper- mint, tincture of opium and alcohol. Dose, f dram (2 c.c.). SquiWs Diarrliea Remedy, N. F., is made of tincture of opium and spirit of camphor, each, 7 minims (o. 5 c.c.), tincture of capsicum, 4 minims (0.25 c.c.), chloroform, 5 minims (0.3 c.c.), and alcohol enough to make i dram (4 c.c.). Dose, \ dram (2 c.c.). Pills of lead acetate, 2 grains (0.13 gm.), and powdered opium, i grain (0.06 gm.), are also employed. A favorite type of pre- scription in simple diarrhea is: bismuth subnitrate, 3 drams (12 gm.), camphorated tincture of opium, ^ ounce (15 c.c.), and sufficient chalk mixture to make 2 ounces (60 c.c.). Dose, a dessertspoonful every two or three hours, or after each move- ment of the bowels. MINERAL WATERS A mineral water is a natural water containing one or more ingredients different from, or in greater quantity than, those in ordinary drinking or washing water. Many bottled waters are not mineral waters. As obtained from the earth, they are thermal when they are distinctly warmer than the average sur- rounding temperature, otherwise non-thermal; some writers adopt 70 F. as the dividing line between these. Warm waters are those from 70 to 98.6 F. ; hot waters are those above 98.6 F. They may be sparkling or effervescent, i. e., impregnated with carbon dioxide, or still, i. e., non-effervescent. They may be sulphurated, containing hydrogen sulphide gas. Their mineral constituents are sodium, potassium, lithium, magnesium, calcium, iron, aluminium, and arsenic, in the form of sulphates, nitrates, chlorides, bromides, iodides, borates, and silicates. In a number of the waters the percentage of the ingredients has been found quite variable at different seasons and in different years. The report of Hay wood and Smith (1905), of the United States MINERAL WATERS 147 Bureau of Chemistry, on the "Mineral Waters of the United States," and that of Francina, on "European Waters," furnish valuable data. A medicinal classification is not readily made because many waters contain more than one ingredient of importance. All are either (i) Alkaline, i. e., having an alkaline reaction; this comes from carbonates and bicarbonates, or in a few instances from borates and silicates. (2) Saline, containing chlorides, nitrates, or sulphates in excess. (3) Alkaline saline, combining the properties of the alkaline and the saline, or (4) Acid, in which there is free sulphuric or hydrochloric acid. Any of these may contain one or other of the special elements, and are known as : Sulphur waters those containing sulphuretted hydrogen and other sulphides. They are usually from "red" or "white" sulphur springs, these names being obtained from the precipita- tion of sulphur. The red sulphur gets its color from iron. Ex- amples are the waters of Richfield Springs or Sharon Springs. Chalybeate or ferruginous waters those which contain iron, usually in the form of the sulphate or bicarbonate, as Spa or Sweet Chalybeate. Arsenical waters those which contain arsenic, as Levico and Bourboule. Alum waters those which contain aluminium salts. Rock- bridge alum water contains 337 grains of aluminium sulphate per million and is astringent. Bromine waters, iodine waters, etc. Lithia waters of these, Haywood and Crook say "lithium seldom or never occurs in waters in large enough quantities to be a predominating basic constituent." In their analyses, Buffalo and Londonderry Lithia Waters show only a trace. Otterburn Lithia, 0.03 part, Geneva Lithia, o.i part, and White Rock Lithia, 12.6 parts of lithium per million. Thus the term "lithia water" is a misnomer. Examples of alkaline waters are Vichy, Apollinaris, Seltzer, Bear Lithia, Great Bear, Manitou. Of alkaline saline are the Saratoga waters (Carlsbad, Congress, Hathorn, High Rock, Vichy, Seltzer) and White Rock Lithia. The Saratoga waters are much poorer in salts now than formerly. The saline waters are those containing abundance of salts and not alkaline, such as Pluto and Mount Clemens. From a medicinal point of view the purgative waters are the most important. In nearly all cases they owe their cathartic action to sodium sulphate (Glauber's salt), magnesium sulphate (Epsom salt), magnesium chloride, or magnesium bicarbonate. 148 PHARMACOLOGY AND THERAPEUTICS The waters which contain a large percentage of magnesium salts are bitter. Those whose action is due to sodium sulphate alone are the Carlsbad waters and Marienbad, which are alkaline, and Villacabras, which is neutral. The published analyses of the Carls- bad waters differ considerably from one another. Those owing their action to both sodium sulphate and the magnesium salts are: Pluto, Friedrichshall, Carabana, Rubinat Condal, and the Hungarian waters, Apenta, Franz Josef, and Hunyadi Ja"nos. "Pluto concentrated" is artificial and does not have its salts in the same relative proportions as Pluto water. It contains about 65 grains (4.3 gm.) of sodium sulphate and 30 grains (2 gm.) of magnesium sulphate, in a dose of 2 ounces (60 c.c.). Mount Clemens water is essentially a solution of magnesium chloride. Mineral waters may be used for the bath or internally. At the various "springs," both the baths and the drinking of the waters are considered requisite parts of the treatment. It is claimed that some of the waters contain radium emanations and are, therefore, more effective when taken fresh. The value of a "cure" taken at one of the mineral spring resorts depends less on the character of the water than on the regulation of rest, exercise and food, the regular taking of the baths, and the influence of freedom from home or business cares amid pleasant surroundings. REMEDIES WHOSE CHIEF ACTION IS UPON THE CIR- CULATION (a) General circulatory stimulants. (b) Measures to increase the volume of the blood. (c) Cardiac depressants. (d) Arterial dilators. (e) Measures to lessen the volume of the blood. THE PHYSIOLOGY OF THE CIRCULATION The following is a brief review from a pharmacologic stand- point: The circulatory organs are for the purpose of carrying certain materials to and from the tissues by means of the blood ; and since all exchanges between the blood and the tissues are made through the capillary walls, it may be said that the function of the circulatory organs is to maintain an adequate capillary blood-flow. Hence the circulatory organs need treatment when they fail to maintain an adequate capillary blood-flow. This capillary blood-flow is dependent somewhat upon the viscosity of the blood, but mainly upon the relation between the general THE PHYSIOLOGY OF THE CIRCULATION 149 arterial blood-pressure (the driving force) and the caliber of the arterioles which lead to the capillaries (the peripheral resistance). These arterioles, being actively contractile, serve as adjustable gates by means of which the amount of blood passing to any given set of capillaries may be regulated. And it is obvious that if the general arterial pressure remains the same an increase in the caliber of any given set of arterioles will result in a greater supply of blood to the capillaries of that set ; and that if the caliber of these arterioles remains the same, an increase in the general arterial pressure will have a similar result. The adjustment of the caliber of individual sets of arterioles without produc- ing the same changes in other sets is, for the most part, im- possible therapeutically; but the caliber of the arterioles as a class may be readily changed by remedial measures. Capillary flow may be altered by changes in (i) The total amount of blood in the arterial system; (2) the heart's output in a given time; (3) the general peripheral or arteriole resistance, and (4) the viscosity of the blood. The amount of blood in the arteries may be decreased by its accumulation in the veins, by its loss from the body (as in hemor- rhage or blood-letting) , or by the excessive removal of other fluid from the body, as in cholera or other severe diarrheal conditions. It may be increased, especially after a preliminary loss, as in hem- orrhage or cholera, by increased receipt from the veins or tissues, by transfusion of blood, by intravenous administration of saline solutions, and by rapid absorption of liquid, e. g., saline solutions, from the alimentary tract or elsewhere. The heart's output may be affected by measures which influence either the filling, the capacity, the rate, or the strength of the ventricles. The peripheral resistance may be altered by measures which change the caliber of the arterioles. It will be obvious that the rate of capillary flow is not to be judged by the degree of general arterial pressure. For example, suppose the heart increases its output, but the arterioles dilate just enough to let the additional blood through. Then, though the general pressure remains unchanged, yet more blood flows through the capillaries and the circulation is more active. As a matter of fact, it has been found in man that the mechanisms which control blood-pressure are so neatly adjusted that it is well-nigh impossible to cause a decided rise in arterial pressure by a therapeutic dose of any slowly acting drug, and yet some such drugs, e. g., digitalis, do have great power to improve the circula- tion. So the therapeutic value of a circulatory drug cannot be measured by its ability lo raise arterial pressure in man. However, in dogs and other laboratory animals we can inject toxic doses 150 PHARMACOLOGY AND THERAPEUTICS intravenously, and thus bring about a concentration of the drug in the blood which will produce effects of sufficient degree and with sufficient rapidity to submerge the dissipating influences. And these give us valuable information as to the real sites and modes of action of a drug. The Heart. The activities of the heart depend upon a num- ber of things, viz., the strength of contraction (contractility), the tone of the muscle, the recuperative power, the irritability, the conductivity of the stimulus from the pacemaker to the vari- ous chambers of the heart, or from one chamber to another, the rate of stimulus production, the rate of the beat, and the rhythm. The heart's action may be affected by remedies directly or indirectly. 1. Directly, by action upon its muscle substance. If the muscle is stimulated, there is an increase in its tone, in its strength of contraction, and in its irritability; if the muscle is depressed, there are the opposite effects. 2. Indirectly, either through its nervous elements, through changes in its coronary circulation, or through changes in the peripheral resistance. The nervous elements of pharmacologic importance are the accelerator and the vagus systems. The accelerators belong to the sympathetic nervous system. The center is presumed to have its seat somewhere in the brain, though it has not yet been clearly located. The fibers from this terminate about certain cells in the anterior horns of the upper portion of the spinal cord. These neurons in turn connect with the sympathetic ganglia, and the cells of these send fibers to terminate in the heart wall at the sinus node. The accelerator system, therefore, is composed of centers, nerves, ganglia, and nerve-endings. The effects of accelerator stimulation are those of direct muscular stimulation, as a rule. Rothberger and Winterberg (1910) have shown that stimulation of the left accelerator results in overaction of the left ventricle, and stimulation of the right accelerator in over- action of the right ventricle. But accelerator influence is not always certain, and at times accelerator stimulation will result merely in an increase in contractility without change of rate, or an increase of rate without change in contractility (Howell). The increase of rate is the result of shortened diastole. The vagus system begins at the vagus center, a collection of cells on either side of the middle line in the medulla oblongata, and from here the nerve-fibers pass as the vagus nerves to groups of cells in the heart wall known as vagus ganglia. From the cells of these ganglia fibrils pass to the sinus node (the normal pace- maker) in the auricle, and to the auriculo ventricular junctional THE PHYSIOLOGY OF THE CIRCULATION 151 tissues at the bundle of His. The vagus system comprises, there- fore, the vagus centers, vagus nerves, vagus ganglia, and vagus nerve-endings. Its chief function, so far as the heart is con- cerned, is that of restraint or inhibition, and it is called the cardio-inhibitory nerve. Stimulation of any part of the vagus system results in slowing and weakening of the heart-beat, with depression of conductivity and loss of tone; while depression of the vagus system sets free the heart and results in increased frequency and strength of the beat and increased tone. The loss of tone is manifested by greater relaxation in diastole; the diminished contractility by less complete contraction in systole. The slowing occurs essentially through a longer diastolic pause. Vagus stimulation and depression are very definite in their effects, and so great is the inhibitory action of the vagus that, under powerful stimulation, it can momentarily bring the heart to a complete standstill in a state of diastolic relaxation. Or excess- ive vagus action may have the effect of partially or completely checking the conduction of impulses from the auricle to the ventricle, with the production of heart-block. The vagus action is primarily on the auricle, and, so far as know r n, is exerted upon the ventricle only through the auriculoventricular bundle, except, perhaps, in a few cases in which the fibers of the right vagus pass directly to the ventricle (Cohn). Robinson and Draper (1912), in electrocardiogram studies made during pressure of the human vagus in the neck, found that while pressure on either vagus slows the rate of contraction and retards conduction from auricle to ventricle, yet pressure on the right vagus has its predominating effect on the rate of the whole heart, while pressure on the left vagus predominates in inter- ference with auriculoventricular conduction. The vagi and accelerators are thus in some ways antagonistic, and as both are in a state of constant activity, they form a sensi- tive balanced control-mechanism which favors prompt response to any influence. (Compare with the antagonistic elements governing the size of the pupil.) The vagus and accelerator systems may be stimulated or depressed directly in any part of the system; or rejiexly, through the center, by afferent impulses coming from other parts of the body. Resistance. Up to its limit of power, a heart will beat more slowly and more strongly in response to increased peripheral resistance; but if the resistance is beyond the cardiac power, the result is weakness and dilatation and cardiac failure. Coronary Circulation. Other things being equal, slowing of the heart means improved supply of coronary blood, resulting in better nutrition and better recuperative power. It has been 152 PHARMACOLOGY AND THERAPEUTICS demonstrated by Stewart and Pike (1910) that the heart will not continue beating unless there is a certain intracoronary pressure. The time of filling of the heart, i e., the diastole proper, de- pends upon the venous pressure, and is usually not much greater than the time of systole. The remainder of the diastolic pause, i. e., the diastasis, is the period during which food and oxygen reach the heart through the coronary arteries and during which the heart recuperates. If the period of diastasis is shortened, the heart beats more frequently, and its output per minute is increased. But if the shortening of the diastasis is too great, or if there is no diastasis, the heart soon fails for lack of a period of nutrition and rest. The maximum output occurs when the period of diastasis is just abolished, but under such conditions the heart cannot long maintain its efficiency. On the other hand, if the period of diastasis is too prolonged, the heart beats so few times in a minute that it cannot maintain adequate arte- rial pressure. Thus it is evident that failure of the circulation may result from too few beats per minute or from too many beats. And it may be assumed that for each heart there is an optimum rate, which is the rate that gives the greatest number of beats consistent with a proper resting period. This optimum rate is neither the maximum rate nor that which allows the great- est output of blood; so that the effect on the rate of the heart is not the criterion of efficiency for a circulatory drug. Regardless of which control mechanism is utilized, the heart's action can practically be modified as regards its rhythm, its rate, its contractility, its tone, its irritability, and its conductivity. The rhythm is either regular, irregular, or intermittent, and may be influenced by changes in irritability and conductivity. If the rate is changed, it must be either slower or faster; if the contrac- tility is changed, it must be either weaker or stronger. If there is an alteration in lone, the degree of relaxation in diastole must be either greater or less. The Vessels. The Arteries. Changes in the caliber of the arterioles may be local, affecting the blood-supply of only one or two organs, or may be general, affecting general arterial pres- sure. The caliber is determined by the activity of the arterial muscles, which, by their contraction narrow the lumen of the artery, and by their relaxation widen it. These muscles may act as the result of direct stimulation or depression, or in response to impulses received through the vaso- motor nerves. Of these vasomotor nerves there are two sets, the vasoconstrictors and the -vasodilators, each set consisting of center, nerves, ganglia, and the nerve-endings in the arterial muscles. The vasoconstrictor centers are masses of cells situated THE PHYSIOLOGY OF THE CIRCULATION 153 on both sides of the middle line in the medulla oblongata; the vasodilator centers are scattered masses of cells in various parts of the central nervous system. The arterial muscles are in a constant state of contraction or tone, which enables them to resist the bursting pressure of the fluid within ; and this resistance tone, though insured to a slight extent by the inherent nature of muscle which makes it contract in response to a demand put upon it, is due in very large measure to the continuous reception of subminimal impulses from the vasoconstrictor center. Thus there is a certain amount of contraction or tone normally present in the arteries, and when the vasoconstrictor centers, ganglia, or nerve-endings are depressed by drugs, this tone is lowered and the arteries dilate. The vasodilators differ from the vasoconstrictors, for, in the first place, they do not act continuously, but only under special circumstances; and, secondly, they produce dilatation only by inhibiting the contractile impulses, for there are no dilating muscles in the arteries. Both the vasoconstrictor and the vasodilator nerves belong to the sympathetic system. When both sets are stimulated to- gether, the vasoconstrictor effect prevails; but under excessive or prolonged stimulation the vasoconstrictor is the first to show exhaustion, so that the constriction may be followed by wide dilatation, even the intrinsic tone of the muscle-fibers being probably somewhat inhibited. Like the vagus and accelerator mechanisms, the vasomotor may be affected by remedies acting directly upon any part of the vasomotor system, viz., center, nerves, ganglia, or nerve-endings; and they may also be affected reflexly by afferent impulses com- ing to the centers from other parts of the body. Besides the muscle itself and the vasomotor nervous mech- anisms, the receptive substance at the neuromuscular junction has specific properties, and may be the site of action of a drug. Summary. The arteries may be contracted by: 1. Direct stimulation of their muscle-fibers. 2. Direct or reflex stimulation of the vasoconstrictor nervous mechanism, or the neuromuscular junction. The arteries may be dilated by: 1. Direct depression of their muscle-fibers. 2. Direct or reflex depression of the vasoconstrictor nervous mechanism. 3. Direct or reflex stimulation of the vasodilator mechan- ism. Some of the arteries do not have vasoconstrictor nerves. At least, nerves connected with the vasoconstrictor center have 154 PHARMACOLOGY AND THERAPEUTICS not been demonstrated in the coronary arteries, those of the brain, and those of the lungs. (See Howell.) These arteries, however, maintain their intrinsic tone. The blood-supply of the lieart is somewhat intermittent, and is dependent upon a proper diastolic pause, for during the greater part of systole the blood is squeezed out of the coronaries, while during the diastolic pause the coronaries refill from the aorta and make an active circulation in the relaxed heart. Dilatation of the coronaries is frequently brought about by drugs that con- strict other arteries. In the brain the supply of the blood is largely determined by the rise and fall of general arterial pres- sure plus the influence of gravity. Of the pulmonary circula- tion we shall speak later. The caliber of the cutaneous arterioles is under a sensitive con- trol mechanism different from that of the other arterioles of the body, so that their dilatation and contraction frequently take place independently of the general arteriole system, as in blush- ing. They are w r eak arteries, however, and regularly tend to be somewhat dilated when general arterial pressure is high. The veins also contain muscles, but their contraction and dilatation seem to be of little moment in pharmacology. The large veins, even the portal vein, as demonstrated by Burton- Opitz, are scarcely if at all influenced through vasomotor nerves. The venous system, however, forms an enormous reservoir for blood, so that by the accumulation of blood in the veins the arterial system may be readily depleted. Venous pressure varies considerably, that in the superior cava being alternately negative and positive, and that in the inferior cava constantly positive and sometimes as high as 50 or 60 mm. of mercury. It must be remembered that the period of filling of the ventricle is shortened if the venous pressure is high, that during the period of diastasis the venous onflow in the large veins is stopped, and that during auricular systole there is some reflux into the great veins. The capillaries have no muscles, and dilate or contract mechanically as more or less blood is forced into them. It is their function to serve as a membranous medium of exchange between the blood and the tissue-fluids, in both directions. Arterial Pressure. The gross factors which go to maintain arterial pressure are four in number, viz., the arteriole or periph- eral resistance, the heart's output in a given time, the volume of blood in the arteries, and the viscosity of the blood. The pressure may be lowered by general dilatation of the arterioles, by decrease in the heart's output, by loss of blood or the fluid of the blood, and slightly by a decrease in viscosity. It may be raised by general contraction of the arterioles, by in- THE PHYSIOLOGY OF THE CIRCULATION 155 crease in the output of the heart, by the addition of fluid to the blood, and by an increase in viscosity. The most important regulators of arterial pressure are the arterioles, but even if the arterioles remain contracted, pressure cannot be maintained if the heart gives out or if there is much loss of blood. Of the arterioles, those of the splanchnic area have most to do with the regulation of arterial pressure. They are strongly muscular, are abundantly supplied with nerves so that they are readily influenced, and have, when dilated, an enormous capacity. Indeed, when these arteries are much relaxed, so much blood passes into them that the brain may be depleted, with fainting or even death as the result, so that a person may be said to bleed into his own splanchnic arteries. On the contrary, they may be so strongly contracted that the weaker arteries of the limbs and skin are forced to dilate to accommodate the blood. It is to be noted that, so far as life is concerned, the main- tenance of adequate cerebral and coronary circulation is the es- sential, for upon these depends the activity of the vital centers in the medulla and of the heart. Many times it is in response to the needs of the vital centers that physiologic changes in the caliber of the arteries take place. The needs of other parts of the body, such as the kidneys, may also greatly influence the general arterial pressure. Hence reduction of what seems ab- normally high arterial pressure may result in a failure of these organs to functionate. (For a resume of theories relating to high pressure in kidney disease see Janeway's Harvey Society Lecture, 1913.) The Pulmonary Circulation. The pulmonary arteries have no vasoconstrictor nerves, but maintain an intrinsic muscular tone of moderate degree. They transmit just as much blood as the systemic arteries, for since the system is essentially a closed one, just as much blood must be pumped by the right ventricle as by the left ventricle, minus a slight loss from the lung capil- laries. But the thin walls and feebler muscle of the right ven- tricle and the inability of the tricuspid valve to withstand high pressures, show that less power is required in the transmission of the blood, and it is evident that the pulmonary arteries give little resistance to the blood-flow. It is estimated that the normal pulmonary arterial pressure is only one-seventh to one-third that in the aorta. In certain cardiac affections, however, where there is back pressure on the pulmonary circulation, as in obstruction at the mitral valve, the right ventricle becomes thick and strong and its cavity larger, and the pulmonary pressure may rise so high 156 PHARMACOLOGY AND THERAPEUTICS as to rupture one or more of the smaller arteries of the lungs. Such a pressure is mechanical, depending upon two factors, viz., increased output of the right ventricle and obstruction to the onward flow of blood in the left heart. So far as we know, all drugs which affect the left ventricle will proportionately affect the right ventricle; and no difference has been noted except in those rare cases in which, through organic narrowing or impairment of contractility in one coronary, the other only is affected by the drug. The degree of filling of the right ventricle depends upon the amount of venous pressure versus the tone of the heart muscle. The rapidity of filling increases with the venous pressure (Hirschf elder). Compensation. A term much employed in connection with disturbances of the circulation is "compensation," which refers to the ability of the heart to maintain arterial pressure in spite of some condition or lesion which tends to make the arterial pressure low. It is the ability of the heart to compensate for some leakage or other adverse condition. We speak of the lack or failure of compensation when the heart is unable to maintain adequate arterial pressure. The effects of failure of compensa- tion are: (i) General venous and pulmonary engorgement, with lymphatic damming up and a tendency to edema and dropsy. (2) Diminished supply of blood to the organs. (3) Poor aera- tion of the blood on account of the sluggish pulmonary circula- tion. The symptoms are: Labored breathing, inability to lie flat, weak and dilated heart, rapid pulse, sluggish peripheral circulation with cold extremities, cyanosis, and perhaps edema or dropsy. Ordinarily, when a lesion, e. g., a defective valve, would tend to interfere with the heart's ability, there is a natural compen- satory hypertrophy of the muscle and a compensatory enlarge- ment of one or other of its cavities, which is spoken of as "dilata- tion"; so that in spite of quite a marked lesion of the heart, compensation may be maintained. Thus if there is a lesion of the mitral valve which permits leakage, then at each systole some of the blood from the ventricle is forced back through the leaking valve into the auricle, instead of forward into the sys- temic arteries. In consequence, the heart would not be able to keep up the systemic circulation were it not for the fact that in response to requirement the cavity of the ventricle becomes more capacious, and the muscular walls become hyper trophied, so that the heart can pump more blood at each systole. It thus provides for the needs of the systemic circulation in addition to the leakage. In other words, by dilatation and hypertrophy the heart compensates for the loss by leakage. DIGITALIS 157 Sooner or later, however, the lesion extends beyond any power of natural compensation; or for some other reason, usually a change of rhythm, the muscle fails, and then there is failure of compensation. A condition of threatened failure of compensa- tion may exist when the heart is on the brink of failure, but remains adequate so long as special pains are taken to pro- tect the body from effort. In these cases there is no reserve force, and failure is constantly threatened. Mackenzie perhaps expresses these ideas better by assuming that the power of the heart may be divided into a working force and a rest force. The rest force is that which meets the needs of the body at rest, while the working force meets the additional requirements when the body is engaged in effort. The begin- ning of heart weakness would then be evidenced by limitation of the working force. It might show by discomfort or distress in performing some act which formerly gave no distress, e. g., short- ness of breath on going up stairs, on running, or on lifting a heavy weight. The working force may be encroached upon to any degree, even to its exhaustion, but if the rest force remains, the patient may still maintain an adequate circulation if put to bed and kept from effort. When the rest force is cut down, there is serious failure of compensation, with the consequences as detailed above. THE GENERAL CIRCULATORY STIMULANTS Besides drugs, various remedial measures are adopted in the treatment of failing circulation, such as rest in bed, light, non- fermenting diet with restriction of liquids, the cold bath, the Nauheim bath, cold air, regulated exercises, etc. The Nauheim bath is a saline bath in the water of which car- bon dioxide is set free. It tends to raise the arterial pressure, in some cases to a dangerous degree. The drugs of the class are : Digitalis and its allies (strophanthus, convallaria, etc.), epinephrine, ammonia, and possibly camphor. There are a few others, such as caffeine, whose dominant actions place them more properly in other groups. DIGITALIS Digitalis (Lat., digitalis), or foxglove, is the dried leaves of Digitalis purpurea (Fam. Scropkulariace(E). It is an ornamental flower of the gardens, grows wild in Europe, Oregon, and Aus- tralia, and is cultivated for the drug market in England and Germany. The wild American plant has been found efficient. Constituents. The active principles are glucosides, and are, 158 PHARMACOLOGY AND THERAPEUTICS therefore, subject to ready destruction. Digitoxin, which most nearly represents the digitalis action, is practically insoluble in water, but soluble in alcohol. It is present to the extent of 0.2 to 0.4 per cent. Digitalin, next in importance, is slightly soluble in water, soluble in 100 parts of diluted alcohol, and read- ily in alcohol. Digitalein, of similar nature, is soluble in both water and alcohol. Under the influence of heat or acids, or when kept some time in aqueous solution, as in the infusion, these glucosides tend to decompose, and may form toxiresins which have a central convulsant action. In addition to these active principles, digitalis contains digitonin, a saponin body which foams with water and possesses the peculiar property of holding the otherwise insoluble active principles in solution in water. It is on account of this that the infusion of digitalis, an aqueous preparation, represents the activity of the drug. Digitonin, administered intravenously, is a physiologic antagonist of digi toxin; but it is not absorbable from the alimentary tract. It crystallizes from solutions in alcohol of over 85 per cent, strength. Besides these principles, digitalis contains an acrid, nauseating substance, digilalosmin, free oil, and digitaleic acid. Preparations and Doses. Official. Digitalis, dose, i grain (0.06 gm.). Fluidextract, i minim (0.06 c.c.). Tincture, 10 per cent., 10 minims (0.6 c.c.). Infusion, 1.5 per cent., i dram (4 c.c.). The doses above may be increased up to four times as much in serious cases. The Pharmacopoeia requires a biologic assay for all digitalis preparations. Unofficial. Digitoxin, dose, y^-g- grain (0.0005 g m -)> is too irritating for hypodermatic use, but may be used by mouth or intravenously. Digitalin, dose, yV grain (0.006 gm.), is moderately irritating, but can be used hypodermatically. (See page 161 .) Digalcn, made according to Cloetta's formula, is a proprietary remedy which, it is claimed, contains ^-g grain (0.3 mg.) of digitoxin in each 15 minims (i c.c.), the solvent being alcohol, glycerin, and water. A number of investigators believe that this is not digitoxin, but probably digitalein. It is moderately irritating, but has been used intravenously. Laboratory experi- ments show its action to be very variable. Digipuratum, made according to Gottlieb's formula, is an extract freed from digitonin and most of the extractive matter, and mixed with sugar of milk to form a powder of the same strength as digitalis leaves. Worth Hale and others have found it a good preparation. In our own experience it is exceedingly uniform. It is marketed in tablet and in o.i per cent, solution DIGITALIS 159 of sodium bicarbonate. The tablets are equivalent to if grains (o.i gm.) of digitalis. The liquid form is for intravenous or hypodermic use, 15 minims (i c.c.) being equivalent to if grains (o.i gm.) of digitalis. Digifolin is a similar preparation of the same strength. Eggleston finds that the total amount to develop effects is the same whether given at one time or in repeated doses. From the large doses the average time to obtain an action was twenty-eight hours, and from the smaller repeated doses, seventy hours. He found that the full dose was about 2 minims (0.146 c.c.) of the tincture, or 2~gV an d the glucosides, apocynin and apocynein. Adonis vernalis is not official. Its dose is 10 grains (0.6 gm.), and it is employed in the form of fluidextract or infusion. Its DIGITALIS l6l active glucoside, adonidin, may also be used in dose of T V grain (0.006 gm.). Ouabam, known as "crystalline gratus strophanthin," is a stable crystalline glucoside of great activity. Its lethal dose is that of strophanthin. Because of its stability it has been sug- gested as a standard for physiologic comparison. It is employed intravenously. The Standardization and Permanency of Preparations. Edmunds, by physiologic assay of 16 different commercial samples of the tincture of digitalis, found that the dose necessary to produce systolic standstill in a 20 gm. frog varied from 0.08 c.c. of the strongest to 0.29 c.c. of the weakest. A tincture made from one batch of drug might thus have three or four times the strength of one made from another batch of drug, and the cor- rect dose of one would be the wrong dose of the other. Haynes, Hale, and others have found similar variation. In addition, all the preparations slowly deteriorate on keeping. It is because of these things that the Pharmacopoeia has adopted the biologic assay, by the "one-hour-frog" method. Unfortunately, this method is not of use for the comparison of different drugs, but only for comparison of different preparations of one drug. Houghton's table of comparisons of the minimum fatal dose of official preparations, as tested by the frog method, is as follows: Digitalis Fluidextract 0.0015 c -c- Tincture 0.015 c - c - Extract 0.0005 S m - Strophanthus Tincture 0.000083 c.c. Convallaria Fluidextract 0.00025 c.c. Squill Fluidextract 0.0012 c.c. This would make the relative toxicity of equal amounts of the drug as follows: digitalis, i : Strophanthus, 18.5; convallaria, 6; squill, 1.2. Hatcher's figures from equal amounts by intravenous dosage in the dog are: digitalis, i; convallaria, |; apocynum, |; squill, gV- These figures do not show the relative clinical efficiency, however, but only their relative toxicity; and the clinical closes bear no relation to the lethal doses. In proportion to the therapeutic dose, except by intravenous administration, digitalis is the least toxic of them all. Worth Hale's comparison of active principles by the frog method is as follows: The minimum fatal dose of strophanthin is o.ooooon; of convallamarin, 0.00000475; f digitoxin, 0.0000085; f French digitalin, 0.000013; of cligitalein, 0.000024; of German digitalin, 0.00007. This would make the relative toxicity of equal amounts as follows: digitoxin, i; strophan- thin, 8; convallamarin, 2; French digitalin, f; digitalein, \\ 162 PHARMACOLOGY AND THERAPEUTICS German digitalin, approximately. Hatcher's comparison of toxicities in cats by intravenous administration is: ouabai'n, 4; digitoxin, i; scillitoxin, i; true digitalin, |; convallamarin, |; digitalein, ; German digitalin, . As to the reliability of preparations of strophanthus we have some evidence. Hatcher tested old and new tinctures of stro- phantus, and tinctures made from recently imported seeds and from very old seeds, and reported them as being fairly uniform. He claims that, unlike digitalis, strophanthus does not deterio- rate with age. Houghton reported that the tinctures of stro- phanthus on the market varied so that the strongest were three times as strong as the weakest; and Edmunds, in testing five specimens of the tincture by their power to bring a 20 gm. frog's heart to systolic standstill, found the strongest four times as strong as the weakest. (It took 0.0012 c.c. of the strongest and 0.005 c - c - f the weakest.) So the possibility of great difference in the strengths of preparations must be borne in mind, and reliable assays taken advantage of when possible. Houghton has also reported that he has found wide variation in the activity of commercial strophanthins, one sample being 90 times as fatal as another. Pharmacologic Action. Local Action. Digitalis has no effect on the unbroken skin, but to mucous membranes and sub- cutaneous tissues is irritant. When administered hypodermati- cally, it causes pain at the site of injection, and through its ir- ritant properties may cause destruction of tissue, with the forma- tion of either a slough or a sterile abscess (sterile because not due to pathogenic bacteria). In a sick patient a number of such irri- tative areas are sufficient to cause fever and depressing reflexes, or at least much discomfort, so that the hypodermatic use of digitalis preparations is to be avoided when possible. Of the active principles, digitalein is the least irritating, digitoxin the most irritating. Alimentary Tract. The taste is bitter and unpleasant. Because of the local irritant effect in the stomach, nausea or even vomiting may result. But in practice, this nausea and vomiting usually come on only after the patient has been taking digitalis for several days; and this is because their chief cause is not the irritation of the stomach, but stimulation of the vomiting center after the drug has become absorbed. This stimulation increases until the center becomes so sensitive that the slight irritation of each subsequent dose results in nausea or vomiting, and requires that the administration of the drug be stopped. This undesirable effect is thus largely central, and it occurs from doses administered intravenously, hypodermatically, or by rectum, DIGITALIS 163 as well as those administered by mouth. But a sensitive vomit- ing center makes the stomach highly susceptible to local irritants, hence doses by mouth are more prone to produce vomiting than doses administered in other ways. Upon the intestines there is ordinarily no effect, but some- times, probably either from the local irritation of unabsorbed drug or from stimulation of the motor nerves of the intestines (the vagus nerves), or perhaps from muscular stimulation, diar- ^ Kj^r^\i\^ Fig. 5. Tracings showing toxic effects of digitalis. rhea is set up. Strophanthin has been shown to be a direct stimulant of intestinal muscle. Digitalis, then, has decided effects upon the stomach and intestines, but they are undesirable ones. Worth Hale has determined that in a period of three hours the acid of the gastric juice invariably causes a diminution of from 25 to 35 per cent, in the activity of the digitalis and strophanthus glucosides. He recommends that to avoid this the official preparations should be 164 PHARMACOLOGY AND THERAPEUTICS neutral; and should be administered with an alkali, and not after meals, but later, when the gastric acidity is low. Absorption takes place from the intestines, and since the drug penetrates the tissues very slowly, is uncertain in rate and degree. Thus twelve to thirty-six hours, and sometimes several days, elapse before the systemic action is manifest. Eggleston states that both digitalis and digitoxin are probably rapidly and fairly uniformly absorbed from the alimentary canal of man, but strophanthus, strophanthin, ouabai'n, and true digitalin are poorly Fig. 6. Tracings showing toxic effects of digitalis. or irregularly absorbed when given by mouth. After deep intra- muscular injections the effects follow more rapidly; but even then, owing to the drug's slow diffusibility, may not appear for hours. In dogs, intravenous toxic doses will produce a prompt response, but in man even intravenous administration of thera- peutic amounts may require one-half to several hours for measur- able results. Where the digitalis principles remain is not yet certain. Cloetta found no digitoxin in the heart muscle of rats and frogs. DIGITALIS 165 Hatcher (1912) states that, after an intravenous injection of a fatal dose in cats, ouabai'n leaves the blood in about three minutes. After the injection of double the lethal dose of digi- toxin death takes place in five minutes; and from an over- whelming dose, may take place during the administration; from less than the fatal dose some of the effect may persist for three or four weeks. Circulation. In a laboratory animal it is observed that a good-sized dose of digitalis has profound effects upon the circu- lation. The striking laboratory effects are given under Tox- icology. In both the laboratory animal and in man the circula- tory effects are known to be brought about through action upon five different structures. These structures are the sinus node, the cardiac muscle, the auriculo ventricular bundle, the coronary arteries, and the systemic arteries. The effects are both nervous and muscular. The following are noted in man: A. The Sinus Node. This is believed to be the normal controller or pacemaker of the rate of the heart. From it impulses are given to the auricles at more or less regular inter- vals of time, and normally at the rate of about 72 in a minute. In response to these impulses the auricles contract together and are followed in about one-fifth of a second by contraction of the ventricles together. A rhythm essentially under the control of sinus impulses is known as "normal rhythm." Slowing. One effect of the administration of digitalis is to inhibit or retard the projection of impulses by the sinus node, the result being slowing in the rate of the whole heart. There may be a sino-auricular heart-block. The same type of slowing may be produced by stimulation of a vagus nerve as is observed in man by pressure on the vagus nerve in the neck, or in animals by electric stimulation of the peripheral segment of a cut vagus. Whether the slowing results from electric or mechanical vagus stimulation or from digitalis, it is abolished by atropine, which paralyzes the vagus nerve-endings in the heart. Thus we have evidence that digitalis slowing may be identical with that from vagus stimulation. (See "effect on auriculoventricular bundle.") Again, in an animal with vagus nerves cut, or in an isolated heart, i. e., a heart severed from all its connection with the centers, the digitalis slowing is very slight. This is evidence that the essential slowing from digitalis does not come from action on the sinus node directly, but from action on the vagus centers. In other words, the effects are vagus effects, and they are not to any great extent produced when the heart is severed from connection with the vagus centers. Therefore we have the evidence that, in a heart with normal rhythm, digitalis may slow the rale by stimulat- 1 66 PHARMACOLOGY AND THERAPEUTICS ing the vagus centers. There is probably also a slight stimulat- ing effect on the ends of the vagus nerves, but this is not im- portant. In therapeutics this type of slowing is not usually obtained; but it may be a toxic manifestation if the slowing becomes so marked that the heart does not beat frequently enough to maintain an efficient circulation. As a matter of fact, except in auricular fibrillation or auricular flutter, any marked degree of slowing is not a usual effect from the therapeutic use of digitalis, hence absence of slowing must not be taken as an indication of the drug's inefficiency. Fever and old age have been said to counteract the vagus effects of the drug, but in 105 pneumonia cases Cohn and Jamie- son found that digitalis acted with full effect even though the fever was high. Jamieson proved the same in other acute in- fections in cats. The author has seen pronounced effects in many old people. In some cases it is possible that digitalis causes complete physiologic standstill of both auricle and ventricle for a moment, as is seen upon electric simulation of a vagus nerve, but this has not been reported as a digitalis effect in man. Arhythmia. Another effect of digitalis upon the sinus node is to change its rhythmic projection of impulses, so that the heart-rate shows regularly alternating short phases of accelera- tion and slowing. That is, the rate rhythmically waxes and wanes, whether the total rate is slowed or not. This is also the effect of vagus stimulation, and it is abolished by atropine. It is known as sinus arhythmia or phasic arhythmia. During forced inspiration and expiration this arhythmia is physiologic, and may be observed in most people, the phases corresponding with the phases of respiration. But when it results from digi- talis it sometimes has no relation to the respiratory rhythm; it is then an indication of beginning poisoning. Summary. Through the sinus node the digitalis effects are either slowing of the rate or sinus arhythmia, or both, or pos- sibly momentary standstill. They result from vagus stimula- tion. B. The Cardiac Muscle. The striking properties of the heart muscle, as viewed pharmacologically, are tonicity, con- tractility, irritability, and stimulus production. i. Contractility and Tonicity. Tonicity of muscle is its prop- erty of maintaining, during its resting period, a state of partial contraction or incomplete relaxation, i. e., a state of tone, which keeps it in readiness to respond promptly when a stimulus comes. In a hollow organ like the heart the tone gives it resistance DIGITALIS i6 7 Normal Weak and dilated to a bursting pressure during the period when the organ is not actively contracting. It is measured by the degree of relaxation in diastole. Contractility is the power to contract against resistance. It is measured by the size of the heart at the end of systole. Tonicity differs from contractility, which has to do with the active contraction, and from irritability, which deals with sensitiveness to stimuli. In a heart whose contractility and tonicity are below the normal, the ventricular chambers are dilated and weak, so that in diastole the muscle is stretched beyond the normal by the venous inflow, and in systole contracts feebly. The result is a decreased output of blood. If we take two concentric spheres and let one represent the capacity of the heart during the resting period of diastole, and the other the capacity at the end of sys- tole, we might represent the normal and the weak heart, as in the illustration, the diminished excursion of the muscle in the -latter lowering the output. Digitalis, by increasing the tone and con- tractility, tends to bring the heart muscle back to normal, and so increases the output. Its site of action in producing this effect may be determined by administering a large dose of atropine to a labor- atory animal to eliminate vagus effects, and a dose of apocodeine Fig. 7. D, Capacity at end of diastole; 5, capacity at end of systole. Fig. 8. Diagram to illustrate "ventricular extrasystole." As, Auricular sys- toles; Vs, ventricular systoles. At x the ventricle beats spontaneously. This beat is followed by a refractory period, during which the regular auricular im- pulse is ineffective, and the ventricle does not beat until the next auricular im- pulse. The auricle beats regularly throughout. to cut off the accelerators. All influences through the nervous system are thus removed, but digitalis still results in striking increase in contractility and tonicity. It must, therefore, stimu- late the muscle itself. It gives these effects with decided force in the laboratory, and probably to some extent in therapeutics. The right ventricle, though its muscular wall is normally much thinner, is stimulated as much proportionally as the left. The papillary muscles are also strengthened and toned, a 1 68 PHARMACOLOGY AND THERAPEUTICS matter of special importance in a weak, dilated heart. For these muscles must contract coincidentally with the ventricle, or Fig. Q. Ventricular cxtrasystoles developing in a heart with normal rhythm and moderate dilatation. This resulted from 10 minims (0.7 c.c.) of tincture of digi- talis and 20 minims (1.3 c.c.) of tincture of nux vomica three times a day. It ceased within two days of stopping the medicine. (Top line, apex; lower, radial pulse.) they will allow the valves to bulge into the auricle during systole and make a relative insufficiency, i. e., a leakage backward. As a matter of fact, the normal ventricular contraction begins in the papillary muscles. An effect on the electrocar- diograph record regularly ob- tained after digitalis is attrib- uted by Cohn to a probable action on contractility (see page 178, Fig. 22). 2. Irritability or excitability is the susceptibility to stimuli. Normally, it does not deter- mine the rate of the heart, for the normal pacemaker is the sinus node. But an increase of irritability beyond the normal tends to result in spontaneous muscular contractions that do not have their origin in the sinus node. The effects of these are harmful. They may be produced by digitalis. Excessive irritability may be confined to a small area and yet be the cause of abnormal beats, "normally inactive points in the heart taking on the power of originating stimuli" (Cushny). Fig. 10. From same case as Fig. Q. Every fourth beat is premature. Top line-, jugular; middle, apex; lower, radial. DIGITALIS 169 Overirritability or aver excitability may show in auricular or ventricular premature beats, in paroxysms of tachycardia, in auricular flutter, in auricular fibrillation, or in ventricular fibrilla- tion. In some excitable hearts there are alternations of premature beats, paroxysmal tachycardia, and auricular fibrillation. (a) Premature Beats. One of the earliest indications of excessive irritability is the so-called extrasystole, a prema- ture or interpolated beat which has its origin elsewhere than Fig. ii. Fig. 12. Figs, ii, 12, and 13. Auricular fibrillation and complete heart-block develop- ing in a case of cirrhosis of liver, with weak heart, but with normal rhythm. Digipuratum, i\ grains three times a day, was given from April iyth to 2oth, when tracing showed auricular fibrillation and complete heart-block, rate 42. The drug was stopped, and two days later tracing 12 showed auricular fibrilla- tion alone, rate about 135. Tracing 13 taken the next day showed return to normal rhythm, rate 100. Similar phenomena followed the administration of dig- italis a month later. at the sinus node. The site of origin may be the auricle, the result being a premature auricular beat, usually followed by a corresponding premature ventricular beat in response to the auricular stimulus. But much more commonly the premature beat has its origin in the ventricle, the ventricle alone giving a premature beat, while the auricular rhythm is not affected. A 170 PHARMACOLOGY AND THERAPEUTICS premature beat may appear at regular intervals or irregularly, and frequently or infrequently. It may follow the normal beats so that the ventricle beats in couples. It may show in the radial pulse or it may not, but it is an irregularity of the heart and not an intermittence. In susceptible hearts it may some- times accompany or follow holding the breath. It is one of the most commonly observed of the toxic manifestations of digitalis. (b) In auricular fibrillation the auricular muscle is in a state of such excitability that muscle groups here and there contract independently, i. e., the fibers quiver or fibrillate, instead of con- tracting coordinately to make an auricular beat. The fibrilla- tions occur at the rate of several hundred per minute, and their effect upon the ventricle is to make it beat in a rapid, irregular, and disorderly manner. In a pulse-tracing of this condition unmodified by drugs (a) No two sections are alike, the radial pulse being irregular and disorderly; (6) the height of the pulse wave- has no definite relation to the length of the preceding pause; Fig. 14. Extrasystoles and auricular flutter. Case with auricular fibrillation. Digitalis, 15 grains four times a day for four days, resulted in alternating periods of halving of the pulse-rate due to extrasystoles (ventricle 140, pulse 70), and very rapid, almost regular pulse at the same rate as the ventricle 186, and half the rate of the auricle 372 (auricular flutter). and (c) the jugular tracing shows absence of the normal auricular waves, and in some instances numerous small fibrillation waves. Auricular fibrillation may exist without serious symptoms, but it is usually serious, is one of the most frequent causes of lack of compensation, and may be the precursor of ventricular fibrillation and death. (c) In paroxysmal tachycardia the heart is regular or nearly so, but very rapid, the rate usually being over 150. The beats may have their origin in the auricle, in the ventricle, or at the auriculoventricular node. If the tachycardial beats originate in the auricle it is known as "auricular flutter." If the beats originate at the auriculoventricular node, there is true nodal rhythm, and the auricle and ventricle receive their stimulus at the same time, and consequently beat simultaneously. If the DIGITALIS 171 beats originate in the ventricle, there may be a reversed or retro- grade rhythm, the excitable ventricle beating prematurely and imposing its rhythm upon an auricle in a similar state of excit- ability. The ventricle may pass into a state of fibrillation, which almost invariably means immediate death. (d)^ Ventricular fibrillation is the usual terminal effect of digitalis poisoning in mammal experiments (Cushny). It Fig- is- U V ; LJ v. Fig. 1 6. Figs. 15 and 16. Complete heart-block. Developing after digipuratum, i grains three times a day for nine days. Fig. 16 shows return to normal rhythm after the digitalis effect had worn off. This block was suspected when a pulse that had been beating between 106 and 116 for several days suddenly changed to a rate between 60 and 70. The auricle was not slowed. corresponds in mammals with the continuous systole in cold- blooded animals. It usually leaves the mammal heart in a state of diastolic relaxation, but Eckler (1912) reports that after death from digitalis, strophanthus, and ouabai'n, 12 out of 62 mammal hearts were found in systolic contraction. C. The Auriculoventricular Bundle. The function of this bundle is to conduct impulses from the auricle to the ventricle, so that normally the ventricular beat follows that of the auricle 172 PHARMACOLOGY AND THERAPEUTICS in practically one-fifth of a second. The effect of digitalis on this bundle may be the retardation or prevention of conduction. This is usually a result of vagus stimulation, and it may be pre- vented by atropine. But in some cases, as demonstrated by Cushny, the effect of digitalis on conduction is not prevented by atropine, and in these digitalis presumably has a direct action upon the junctional tissues, either the auriculoventricular bundle proper, or the junctions of its ramifications with the proper muscles of the ventricles. In therapeutics a prolongation of the auriculoventricular interval, e. g., to three- tenths or three-fifths of a second (incipient heart-block], is not uncommon from digitalis. It is an effect that can be ascertained only by tracings, but it is a toxic manifesta- tion and calls for stoppage of the drug. More rarely seen from digitalis, but much more serious, is a degree of interference with conduction which results in occasional or frequent failure of the ventricle to beat in response to the auricle, i. e., a state of partial heart-block. In this the auricle beats faster than the ventricle. In mild degrees the auriculoventricular interval gradually lengthens, or suddenly lengthens, so that the ventricle intermits at regular intervals, i. e., skips every tenth, seventh, third, etc., beat, the tracings showing an independent auricular beat during the ventricular intermission; and the stethoscope no ventricular contraction. In marked stages the ventricle beats only in response to every second or third auricular beat, i. e., in 2 : i or 3 : i rhythm, the pulse being slow and regular. In these last states fainting spells are not uncommon. Still less frequent from digitalis is complete heart-block, in which the ventricle receives no adequate stimulus from the auricle, and consequently beats at its own intrinsic rate, with entire disregard of the auricular beat. In the complete block of dis- ease the rate of the ventricle is in the neighborhood of 30, and this is the normal intrinsic rate of the human ventricle. But in the complete block from digitalis, owing to the increase in mus- cular irritability, the rate tends to be faster, and may even exceed that of the auricle (Hewlett and Barringer). In this last type, in the absence of a careful study of tracings, the block may re- main undetected. In ordinary cases, however, bradycardia should suggest the possibility of block ; and in any heart a block should always be suspected when there is a sudden slowing of the ventricular rate with regularity. In auricular fibrillation a complete block is shown by the striking change from rapidity and irregularity in the action of the ventricle to slowing and regularity. Shining from digitalis may, therefore, be due to aurkuloventricular heart-block, as well as to an effect upon the DIGITALIS 173 sinus node. Indeed it is to this cause that the slowing obtained in auricular fibrillation or flutter is due. When a partial block is already established by disease, digi- talis is very prone to increase its severity or to change it to complete block. Some of the deaths from the intravenous use of strophanthin, the digitalis ally, have probably been produced in this way. The following is an interesting case of permanently complete heart-block, in which the digitalis had the effect of bringing on 1 ? 3 4 5 6 7 ft ;a in 16 J4 12 IQ \ 'Of \ Of \ Q5 \ 02 v QC \ ^ \ 26 " ^ 34 A }? \ 3C \ to v 36 i4 \ i2~ \ iO \ 7fi \ 7fi \ A; ^--. -a Z4 B ?' ' -^ -a" 5 ^ ? 7? ' / V \ / 70 \ / \ S V * ifl y v ^ 5fi \ 54 *NS 5? Fig. 17. Chart comparing the effect of digitalis on the rate in cases having auricular fibrillation with those having a normal rhythm. The black dots repre- sent the rate with auricular fibrillation and the white with the normal rhythm. The side figures represent pulse-beats. The top figures represent days (James Mackenzie in "Heart," vol. ii, No. 4, 1911). short spells of doubling of the intrinsic rate of the ventricle with retrograde rhythm. It was a case on Dr. Nome's service at St. Luke's Hospital. In one of my tracings from this case the ven- tricular rate shows a sudden jump from 26 to 54, a drop of the auricular rate from 62 to 54, and a change of the rhythm to "reversed" or retrograde, i. e., the auricular systole followed 174 PHARMACOLOGY AND THERAPEUTICS that of the ventricular, instead of preceding it, both having the same rate. At the end of each such paroxysm there was a long pause of the ventricle, lasting some seconds, during which the patient had a passing attack of faintness or light-headedness, though lying flat in bed. Such a pause, sometimes following the doubling of a slow ventricular rate, is prone to occur in partial or complete heart- block, and may be accompanied by feelings of faintness, loss of y y \ Fig. 1 8. Fig. IQ. FiRs. 18 and 19. Complete heart-block developing in a case with auricular fibrillation. On admission (tracing 18) the ventricle was very irregular, rate 146 to 200, with a countable radial pulse of 80 to 94. Infusion of digitalis, 4 drams thrice daily, was given for eleven days, then stopped. At this time the pulse was nearly regular, rate about 72. Four days later tracing IQ was taken, the pulse being quite regular, rate 54. Three days later, /. c., one week after the stoppage of the drug, the complete block was still present, the ventricular rate remaining between 50 and 60. consciousness, or an epileptiform convulsion, the typical Stokes- Adams attack. These effects are due to a momentary anemia of the medullary centers, the result of the ventricular stoppage. They are likely to be more serious if the patient is in the upright position. D. Combined Effects. In cases with auricular fibrillation already established from disease the combined effects on irri- tability and conduction are strikingly to be observed after digi- DIGITALIS 175 tails. The therapeutic effect of the drug in auricular fibrillation is not to overcome the fibrillation, so far as we know, but essen- tially to impair conductivity. It thus checks the passage of the frequent small and irregular auricular impulses, which in this condition serve only to nag the ventricle and make its action disorderly. In other words, it establishes a degree of heart-block. The effect is partly due to vagus stimulation, and pressure on the vagus in the neck will sometimes momentarily produce a similar result, while atropine will prevent it. It is prob- Fig. 20. Coupled rhythm developing in a case of auricular fibrillation. This is an exceedingly common effect. It resulted after five days of powdered digitalis, 2 grains three times a day. Fig. 21. Phasic arhythmia developing in a case of auricular fibrillation. This followed digalen, 10 minims every four hours, for one day, and digipuratum, if grains three times daily for two days. Upper line shows respiration, which is not synchronous with the phases of quickening and slowing of the pulse. ably also, in some instances, clue to a direct action of the digitalis on the junctional tissues (Cushny). The block may become complete, with regularity of the ventricular beats and a much slowed rate, and this is an undesirable effect. But more frequently in auricular fibrillation digitalis results in a condition in which, owing to an area of excitability in the muscle, each beat that occurs in response to an auricular stimulus is followed quickly by another beat which originates in the ven- 176 PHARMACOLOGY AND THERAPEUTICS tricle. Thus the beats appear in pairs or couples, and make "coupled rhythm." In this the distance between the members of a couple is fairly constant, while that between the couples may vary considerably; and the second beat of the pair may or may not be palpable at the wrist. What is probably an early stage of coupled rhythm is an alternation of single beats with coupled beats. A serious stage of it is present when the distance between the couples is short, so that the ventricle beats very rapidly. Coupled rhythm is a common digitalis manifestation in auricular fibrillation, but is sometimes also present with normal rhythm, every second beat being a premature one. Another digitalis effect in auricular fibrillation is "phasic arhythmia," which corresponds in general character with that arising from the sinus, but, so far as known, has its origin not at the sinus, but in the ventricle. Cohn has discovered that in some cases vagus fibers pass directly to the ventricle, and it may be that phasic arhythmia occurs only in such cases and is a vagus effect. E. The Coronary Arteries. (a) Constriction of the coronary arteries is a real digitalis effect, as shown by perfusion experi- ments. In the coronaries of young rabbits a solution of i : 20,000 reduced the outflow from 8 c.c. per minute to 3 c.c. (Dixon), and by the ring and strip methods, Voegtlin and Macht showed contraction by both digitoxin and digitalin. From therapeutic amounts, this action is probably negligible, for, as Hatcher suggests, it seems improbable that the improvements in the circulation from digitalis could occur if the coronaries were constricted. In acute poisoning, however, coronary constriction may be a factor in weakening the muscle; and in cumulative poisoning, it may be the cause of the muscular weakness which manifests itself by alternating weaker and stronger beats, the condition known as "pulsus alternans." This seems probable because the conditions in which pulsus alternans not clue to digitalis is observed are those in which the coronary circulation is probably inadequate, viz., myocarditis with coronary sclerosis, the cardiac hypertrophy of nephritis, and paroxysmal tachycardia, (a) In coronary sclerosis the coronary blood-flow is retarded. (6) In hypertrophy a much larger blood-supply than usual is required, and a time may come when the coronary flow cannot meet the needs of the large mass of muscle, (c) In a rapid tachycardia the diastolic pause is much shortened, and, as the coronary circula- tion goes on essentially during diastole, this shortening obviously causes a serious interference with the cardiac blood-supply. DIGITALIS 177 Pulsus alternans may, therefore, be a coronary effect, and when it results from digitalis, is a decidedly toxic one. (b) Nutrition and Recuperative Power. The increased pres- sure in the aorta invigorates the coronary circulation, and the prolonged diastasis from slowing allows it to last longer. At the same time the greater contraction in systole promotes the emptying of the coronary veins. The result is not only a greater supply of food and oxygen to the heart, to nourish it and permit of recuperation, but also a greater supply of the drug to the heart muscle to keep up its stimulation. Hare (1897) nas shown how digitalis can improve the heart nutrition in growing animals, and, as a result, probably the general nutrition. Of a litter of 10 pigs two months old, he kept 5 as a control, and treated the other 5 with normal liquid digi- talis. The dose was 2 minims twice a day for a month. It was then gradually increased until, at the end of three months, it was 10 minims twice a day. The food was the same for all. There were no poisonous manifestations. After four and a half months the digitalis pigs averaged 4 pounds heavier than the others, and their hearts averaged heavier by more than ^ ounce (15 gm.). On examination by W. M. L. Coplin the ventricular walls were thicker, firmer, and more resistant on cutting, and their mus- cle-fibers measured 0.02 mm. wider (average), i. e., -^ to ^ larger than those of the control pigs. Cloetta (1905) gave digitalis for several months to adult normal rabbits, without effect upon the size of the heart. Then he artificially produced aortic regurgitation, keeping some of the rabbits as controls, while to others he gave digitalis. The hearts of the treated animals were much more hypertrophied and more dilated than those of the controls, and were capable of much greater stimulation. Their aortas were also less dilated than those of the controls. These experiments would go to show that in growing animals and in hearts that required com- pensatory hypertrophy digitalis might improve the coronary circulation and the nutrition of the heart. Electrocardiograms, as demonstrated by Cohn, Eraser and Jamieson, show a change under the action of digitalis (Fig. 22), and this effect has been observed to persist for from 5 to 22 days. It is not affected by atropine. Summary. Digitalis may affect the heart in regard to its rate and rhythm; its tonicity, contractility, irritability, and conduc- tivity; its nutrition, oxygenation, and recuperation. Through its action on the vagus it may produce loss of tonicity, slowing, phasic arhythmia, momentary standstill, or blocking of the auric- ular impulses in their passage to the ventricle. Through its action i 7 8 PHARMACOLOGY AND THERAPEUTICS on muscle it may increase the tonicity, the contractility, and the irritability, the last to a dangerous degree. It makes a specific change in the electrocardiogram. F. The Systemic Arteries. Besides its effect upon the struc- tures of the heart, digitalis in the laboratory may produce another effect on the circulatory organs, viz., contraction of the peripheral arteries. The evidence of this is: If a loop of dog's intestine in situ is inclosed in an oncometer so that any change in its volume can be measured, the administration of a laboratory dose of digitalis is seen to be followed by shrinkage in the volume of the intestine. The shrinkage is synchronous with a heightened general arterial pressure, and is due to contraction of the vessels. If the splanchnic nerves are cut so as to remove connection with ffi Fig. 22. A. The solid line represents the normal outline of the electrocar- diogram. The T wave is directed upward. The dotted line shows the change which occurs in the T wave under the influence of digitalis. B, in a similar way, shows the change in certain cases when the T wave is initially directed downward. Under the influence of digitalis it turns upward (A. E. Cohn, Journal of Experi- mental Medicine, June, 1915). the centers, the shrinkage is less than before, therefore stimulation of the vasoconstrictor center is an effect of the drug. Further, in perfusion of an isolated loop of intestine or of a severed leg, i. c., of organs removed from connection with the nerve-centers, if digitalis is added to the perfusing fluid, the venous outflow is decreased. This effect is due to the contrac- tion of the arterioles, and shows that there is a peripheral vaso- constrictor effect. The peripheral effect may be analyzed (a) by the use of apococleine or ergotoxine, two drugs which paralyze vasoconstrictor nerve-endings; the digitalis still causes contraction, so must directly stimulate the arterial muscle; and (b) by perfusion of a coronary or pulmonary artery; these con- tract under digitalis, though they have no vasoconstrictor nerves. There is a slight stimulation of the vasoconstrictor nerve-endings, DIGITALIS 179 but the main peripheral effect of digitalis is exerted on the arterial muscle. Thus digitalis causes contraction of the arteries by stimu- lating the arterial muscle and the vasoconstrictor center, and slightly by stimulating the vasoconstrictor nerve-endings. The contraction of the arteries occurs mainly in the splanch- nic area, but ordinarily occurs also in the vessels of the limbs. After powerful doses the arteries of the limbs, as shown by the plethysmograph, may be dilated; for they have less power of contraction than the splanchnics and may be forced into dilata- tion when the blood is prevented from entering the splanchnic area (for it must go somewhere). The increased peripheral resistance in itself is a resistance stimulus to the heart, and, in addition, promotes the coronary circulation during the diastolic pause. Richards and Wood report an increased production of epinephrine after digi toxin or strophanthin. Stewart and Scott report that in three cases of auricular fibrillation the blood- flow in the hands was promptly and decidedly increased by digitalis, this being doubtless a cardiac effect. In one case with normal rhythm the blood-flow in the hands was slightly reduced. These are the effects from laboratory doses, i. e., poisonous amounts administered intravenously, and they show the ten- dency of the drug. But in practical therapeutics the effect is not so striking. In fact, it is the consensus of opinion among students of the circulation that in medicinal doses digitalis does not cause constriction of the arteries in measurable degree. Arterial Pressure. In laboratory animals digitalis results in increased output of blood from the heart, increased peripheral resistance, and an increased quantity of blood in the arteries at the expense of that in the veins. Hence we have a decided rise in^arterial pressure. In man the smallness of the dose and the slowness of the drug action permit the sensitive blood-pressure control mechanisms to adjust themselves; hence digitalis in therapeutic amounts may cause no rise in arterial pressure. As Mackenzie expresses it, "contrary to expectation the blood-pressure is raised only in exceptional cases, even when the drug is repeatedly pushed until full physiologic action is apparent, and even when the patient is evidently much benefited by the drug." Price, Lawrence, and others note similar absence of pressor changes. In our own experience, a certain number of heart cases have shown decided improvement in arterial pressure while taking digitalis; indeed, in a few cases there has been a very close rela- tion between the amount of the drug being taken and the systolic pressure. But many other cases have shown no effect at all l8o PHARMACOLOGY AND THERAPEUTICS upon the pressure, though the appearance of poisonous symp- toms demonstrated that full dosage was being given. We have, therefore, reached the same conclusion as a number of other students of the circulation, viz., that frequently the improvement in the circulation under digitalis cannot be fully judged by estimation of the arterial pressure. In auricular fibrilla- tion arterial pressure records are worthless, as no two beats are alike. The Pulmonary Arteries. These tend to be contracted, though the extent or the significance of this effect is not known. The Cutaneous Arteries. The arteries of the face and neck tend to dilate and cause flushing. This seems to have no appre- ciable effect on the general arterial pressure, and is not of impor- tance. It is presumably from a central rather than a peripheral action. The Veins. The effect of digitalis upon the walls of the veins is similar to that upon the arteries, though it is probably of no therapeutic significance. Kidneys. The cardiac effects of digitalis extend further and may be seen in the action of the kidneys. With an unobstructed ureter a normal kidney will secrete more urine if more blood flows through it. And the factors which affect the amount of blood flowing through the kidney are: the general arterial pres- sure, the degree of contraction of the kidney arteries, and the freedom of the venous outflow. Venous back pressure, however slight, or contraction of the kidney arterioles, or a fall in general arterial pressure, will have a tendency to lessen the amount of urine; while a reversal of these conditions favors an increase in the amount of urine. As measured by the oncometer, the normal kidney of an animal shrinks after a laboratory (poisonous) dose of digitalis. This diminution in size is synchronous with the vasoconstriction in other parts of the body and with the rise in arterial pressure, hence it may be assumed that the kidney arterioles, in the same way as the other arterioles, are constricted by poisonous amounts of digitalis. But in human therapeutics, as we have seen, there are presumably no essential constriction of arteries and no striking rise in arterial pressure. It is a fact also that the digitalis prin- ciples apparently reach the kidney in such diluted form that, in therapeutic amounts, they have no direct irritant action upon the kidney structures. Therefore the output of urine in persons with normal circulation is unaffected. Hedinger (1910) gave digipuratum and digalen to rabbits intravenously, and when the kidneys were normal, obtained a slight increase in the volume of the kidney, but a scarcely per- DIGITALIS l8l ceptible diuresis. In the early stages of tubular nephritis he obtained increase in kidney volume (dilatation of the arterioles) and a greater diuresis. In more severe tubular nephritis and in vascular nephritis there was no diuresis. Jonnescu and Loewi obtained a small diuretic effect from digitalis in normal animals. They believed that the drug could cause a local dilatation of the kidney arterioles, as do most diuretics. In cases with normal rhythm and without edema, Cohn emphatically states that diuresis does not follow digitalis. But in cases with low general arterial pressure, venous engorgement and edema, i. e., in persons with failing circulation, there is regularly very little urine formed ; and in these cases the administration of digitalis may be followed by a great increase of the kidney excretion. In response to digitalis, in cases with failure of the circulation we have seen a urine output of 15 or 20 ounces a day change to one of 100 or 200 ounces, at least for two or three days. So digitalis is diuretic only when it brings about improvement in a poor circulation. Digitalis diuresis is dependent upon (a) improvement in the general circulation, through which accumulated tissue fluid passes into the blood to make hydremic plethora, and (b) im- provement in the kidney circulation. It is not due to a direct action of the drug upon the kidney cells. Consequently the marked diuresis lasts only until the excess of fluid in the body brought about by venous stagnation is removed. The urine is very dilute and poorly colored on account of the high proportion of water, but, at least for the first few days, con- tains an actual increase in the total solids, and particularly in the salts and urea. It is probable that this is due to the washing out of stored-up material. In severe poisoning, digitalis may result in the appearance of albumin and blood in the urine. This is due either to a remote local irritant action resulting in nephritis, or to excessive vaso- constriction. Either of these may also be a cause of suppression of the urine. (Suppression is a term to be distinguished from retention. It signifies failure of the kidneys to secrete urine, while retention applies to the bladder, signifying failure of the bladder to empty itself.) Venous Engorgement Edema and Dropsy. In cases with failing circulation there is regularly some degree of venous en- gorgement, z. e., venous back pressure. And venous engorge- ment means: 1. Increased general capillary transudation. This results in increased formation of tissue fluid. 2. Obstruction to the flow of lymph; because the lymph- I 82 PHARMACOLOGY AND THERAPEUTICS atics empty into the veins. This checks the removal of tissue fluid. 3. Lessened capillary absorption of tissue fluid, because of sluggish blood-flow. 4. A lessened amount of urine. This results in lessened excretion of water. The effect of the combined action of these factors is accumula- tion of fluid in the tissue spaces and serous cavities of the body, i. e., edema and dropsy. There is "water retention" in the body, and the patient becomes water-logged. Edema is a condition in which there is an abnormal amount of fluid in the tissue spaces. Dropsy implies edema, but especially refers to abnormal collec- tions of transuded fluid in serous cavities. By improvement in the circulation digitalis removes the venous engorgement. As a result, the general capillary transuda- tion, i. e., the formation of tissue fluid, is lessened, while at the same time improved capillary absorption and a proper flow of lymph remove the excess of tissue fluid. The result is the reduc- tion of the amount of accumulated fluid in the tissue spaces and serous cavities. This fluid passes to the blood, swells its volume, and makes a condition of hydremic plethora. At the same time the rapidity of the renal blood-flow is increased, and this, together with the hydremic plethora, results in diuresis. Thus the excess of fluid is removed from the blood and eliminated from the body. The ultimate result is the disappearance of the dropsy and edema, without the loss to the body of its albumin- ous elements. So digitalis tends to overcome dropsy and edema, not by simply removing the accumulated blood from the veins into the arteries, nor by directly stimulating the kidneys, but (i) By lessening general capillary transudation; (2) by increasing the lymph-flow and promoting capillary absorption, and (3) by increasing the excretion of urine. All these depend upon its power to activate the circulation; or, in other words, its power to lessen venous engorgement. The early stages of edema are not always obvious, for a human being can store a great amount of liquid beyond the nor- mal before edema begins to show. But a greater or less degree of water-logging or water-storage is a regular accompaniment of a failing heart, so that even when the edema is not apparent, digitalis may prove diuretic. Digitalis is of no value as a diuretic in the removal of serous exudations due to inflammatory or local causes, as in cirrhosis of the liver, peritonitis, etc., unless these are accompanied by circulatory inefficiency. DIGITALIS 183 Value of Digitalis. We might sum up the theoretically valu- able effects of digitalis in a failing circulation as follows : 1. On the heart: (a) Slowing, (b) Increased contractility. (c) Increased tonicity. (d) Improved nutrition, (e) In auric- ular fibrillation, slowing and steadying of the ventricular rhythm. 2. On the blood improved oxidation from improved pulmo- nary blood-flow. 3. In venous accumulation the removal of edema and dropsy. Respiratory System. Therapeutic doses have little direct influence on respiration, but they may stimulate the respiratory center through the improvement in the cerebral circulation; or may help the lungs through removal of congestion or edema. Poisonous doses stimulate the respiratory center so that the respiration becomes strong and deep. With the fall in arterial pressure in the late stages of poisoning the respiratory center fails. Nervous System. The brain may be affected through its increased blood-supply. There is no direct action except upon the centers of the medulla. The chief constantly acting medul- lary centers are the vagus, the vasoconstrictor, and the respira- tory, and in this sequence these are stimulated by the drug. If poisonous doses are administered, these centers are eventually depressed. Other centers sometimes affected by digitalis are the heat-regulating, so that temperature in fever tends to be lowered, the vomiting, and the convulsive, which may be the cause of convulsions in the late stages of poisoning. The nerve- endings which are stimulated are those of the vagus and vaso- constrictor nerves. Elimination. The active principles are excreted partly by the kidneys and partly by the intestines. Their excretion is slow, so that continued administration of large doses may give rise to cumulative poisoning. And the administration of a full intravenous dose of one of the active principles of the group during or following shortly after a course of digitalis by mouth has, in a number of instances, resulted fatally. This last state- ment is particularly true of strophanthin, which has been the principle of choice for intravenous use. The Digitalis Allies. Strophanthus would seem to be ab- sorbed from the alimentary tract with less rapidity and more uncertainty than digitalis (Hatcher). It is at least 50 times as poisonous to the heart muscle (Haynes, Edmunds, Houghton). Either strophanthin of the Pharmacopoeia, or ouaba'in (crystal- line grains strophanthin), may be dissolved in salt solution and given by deep intramuscular injection or intravenously. When ^V grain (i mg.), the maximum dose, is passed into a vein of a human being, it may show its results in slowing of the pulse in 184 PHARMACOLOGY AND THERAPEUTICS from one-half to one hour, with strengthening of the heart. Provided that digitalis has not already been given, this treatment may be employed when the symptoms of the cardiac weakness are very severe, and particularly if there is auricular fibrillation. Strophanthin is said to be eliminated much more rapidly by the kidneys than the digitalis glucosides, so that cumulative poisoning does not occur. To test this Frankel gave submaximal doses to a cat for ninety-two days and got no symptoms of over- dosage; Hatcher's work corroborates this. In poisoning, there is no striking constriction of the systemic arteries; and Dixon has shown by a perfusion experiment that while one part of the tincture of digitalis in 2500 was sufficient to constrict strongly the coronary arteries of a rabbit, a similar strength of the tincture of strophanthus had no effect. In a number of cases the ap- pearance of diarrhea is a bar to the use of strophanthus, and this is attributed to a direct action of strophanthin on the in- testinal muscles. Two things in the action of strophanthus must be especially noted, first, its smaller power to relieve conditions due to failure of compensation, except when used intravenously; and, second, its great toxicity to the muscle of the heart. Convallaria has no advantages over digitalis and is more toxic. Hellebore'in, dose, \ grain (0.03 gm.), has been found ex- perimentally to have muscular effects similar to those of digi- talis, but without its vagus effects. Its application in thera- peutics has not been determined. Toxicology. /. Poisoning from an overwhelming dose, as of i mg. of strophanthin per kilo intravenously in a dog, produces a regular sequence of effects in four well-defined stages, with death in a few minutes. (See Plate I.) The stages are: (i) Vagus and vasoconstrictor stimulation, with slowed heart and rapid rise in blood-pressure, the diastolic relaxation indicating diminished tone. (2) Vagus action predominating with greater loss of tone and heart-block, or short periods of vagus standstill, and some- times premature beats from muscular stimulation. (3) Muscular action predominating, with abrupt change to tachycardia, the ventricle beating at a very rapid rate and usually not in unison with the auricle; arterial pressure very high. (4) Muscular weakness with excessive irritability, auricle fibrillating; ventricle losing contractility passes into fibrillation and death takes place. The heart is usually found in a state of relaxation, but Eckler (1912) reports that as many as 12 out of 62 mammal hearts were found in systolic contraction after deaths from ouabain, strophan- thus, and digitalis. Hatcher has had death occur in cats during the intravenous administration; and in a patient in one of the DIGITALIS 185 New York hospitals, death occurred three minutes after an intravenous dose. 2. Poisoning From a Single Large Dose Taken by Mouth. This is a very rare event. Any one of the actions upon the heart, as outlined above, may manifest itself. Excessive vagus action may show in pronounced slowing, sinus arhythmia, periods of momentary cardiac standstill, or some degree of heart-block. Excessive irritability may show in premature beats, auricular Fig. 23. Digitalis poisoning in dog, showing intermittent heart-block. Upper tracing, auricle; lower, ventricle. The down-stroke is systole. fibrillation, or paroxysmal tachycardia. In addition, there may be nausea, vomiting, and diarrhea; discomfort about the heart, coming on early; deep, slow respiration, or, in late stages, dysp- nea; general muscular weakness with prostration. At a late stage the urine may be albuminous or bloody, or may be sup- pressed, and there may be convulsions which are due either to the asphyxia or to stimulation of the convulsive centers. Death takes place with failure of the respiration, following collapse. But the death occurs in spite of artificial respiration, and is due l86 PHARMACOLOGY AND THERAPEUTICS to failure of the circulation from ventricular fibrillation, which in mammals usually takes the place of the continued systole of cold-blooded animals. We have had reported to us one such death from the intra- venous administration of digitalis in a human being, and many deaths following the intravenous use of ^3 grain (i mg.) of strophanthin, death resulting in from three minutes to about an hour. Serious symptoms have also been reported from -^ grain of digi toxin. These deaths have regularly occurred in patients who had been taking digitalis for several days previously. 3. Cumulative Poisoning. This comes from the use of the drug in medicine. The signs of overdosage in the medicinal administration of digitalis should be recognized as soon as pos- sible, for such poisoning is common in hospital and private prac- tice, and its manifestations are not infrequently misinterpreted as symptoms of the heart disease. But there are a number of cases in which we may be unable to say with certainty that digitalis is the cause, until we note the disappearance of the mani- festation shortly after the digitalis is stopped, and its reappear- ance under further administration of the drug. MANIFESTATIONS OF OVERDOSAGE OF DIGITALIS I. SUBJECTIVE MANIFESTATIONS: a. Loss of appetite, nausea, vomiting, diarrhea. b. Oppression about heart, palpitation, tachycardia, con- sciousness of premature or skipped beats. c. Headache. II. OBJECTIVE MANIFESTATIONS: a. Effect on sinus node 1. Excessive slowing. 2. Sinus arhythmia/ Exaggerated respiratory. | Non-respiratory. f Prolonged auriculoventricular in- 7 77 a . j ,, i terval (incipient block). b. bttect on a-v bundle i ^ ,. , , , , , .,, ^ , , rartial or complete block (with or or Tawara s node , , \ ,. ^ without bradycardia). Nodal rhythm. , Premature beats (extrasystoles). . Paroxysmal tachycardia. c. Effect on muscle i 3. Nodal and retrograde rhythms. Overexcitability | 4. Auricular flutter. 5. Auricular fibrillation. 6. Ventricular fibrillation. DIGITALIS 187 d. Combined effects on a-v bundle and on muscle ( i. Complete heart-block, but little or no brady- In auricular fibrillation cardia. 2. Coupled rhythm. 3. Phasic arhythmia. 2. In normal rhythm complete block without brady- cardia (owing to increased excitability). e. Constriction of coronary arteries a possible influence pulsus alternans. These have all been explained in detail above. In this connection the possibility of persistence of effect must be kept in mind, for, as ascertained by Hatcher in cats, the drug action may continue in some cases for as much as three weeks or a month after a single intravenous dose. I have ob- served persistence of partial heart-block for three and one-half weeks after the stoppage of digitalis, and of complete block for at least one week. Conn's electrocardiographic tracings have shown a digitalis effect in man as late as twenty-two days after the drug was stopped. Cushny reports a case of auricular fibrillation in which, through the influence of digitalis, "inhibition had gained a permanent control over the heart," so that the effect persisted indefinitely after the drug was stopped, or was perpetuated by an occasional dose. From my clinical experience I .should judge that such an effect in auricular fibrillation is not uncommon. Except when it is administered intravenously, the margin of safety with digitalis is a large one, so that there is no undue danger in the use of even large doses by mouth or hypodermatically, if the administration is stopped when one of the following condi- tions arises, viz. : /. Nausea becomes marked. 2. The radial pulse goes below 60. The pulse may become pro- gressively slower for a few days after the drug is stopped, hence the necessity for ceasing its administration'before the slowing has become extreme. j. A rapid ventricle with rate unaffected by digitalis for several days suddenly becomes slower (heart-block). 4. A regular ventricular rhythm changes to irregular, as from pre- mature beats or the development of auricular fibrillation; or becomes intermittent, as from partial heart-block. 5. Paroxysmal tachycardia occurs. 6. The absolutely irregular rhythm of auricular fibrillation becomes slow and regular (complete heart-block), or shows coupled rhythm or phasic arhythmia. 1 88 PHARMACOLOGY AND THERAPEUTICS A considerable risk may be avoided by refraining from the use of digitalis (a) When the ventricle is intermitting; (b) when there are premature beats; or (c) when there is bradycardia. Clinical reports of fatalities have borne out Hatcher's findings that an intravenous dose of any one of the principles of the group is much more active if digitalis has previously been administered by mouth or hypodermatically. For, as Hatcher reports, even as late as a month after the intravenous injection in a cat of a nearly fatal dose of digitalis, the test animal may require a smaller intravenous dose for lethal effect than an animal that has had no digitalis. Treatment. In the simplest condition of poisoning, when excessive slowing or irregularity or intermittence of the heart, or tachycardia, begins to show, the treatment is simply to stop the drug and keep the patient quiet in bed until the effect of the drug has worn off. To check excessive vagus action, atropine sul- phate, ^Vg ram (o.ooi gm.), may be employed hypodermatic- ally, but its effect lasts not over an hour. For excessive irri- tability, sodium bromide, i to 2 drams (4-8 gm.), morphine sulphate, | grain (0.015 gm.), and a hot-water bag or ice-bag over the heart may give some relief. In severe poisoning there must be absolute repose and freedom from exertion for several days, the mere effort of sitting up in bed being sufficient in some cases to precipitate failure of the circulation and death. If necessary, body warmth must be maintained by blankets, hot- water bottles, etc. Symptoms are treated as they arise, there being no specific treatment. So far as conduction is concerned, there is some evidence that caffeine tends to antagonize digitalis, hence it may prove a good drug in heart-block. On several occasions I have seen caffeine apparently undo the work of digitalis in auricular fibrillation, an observation confirmed by Barton. Therapeutics. From our studies, it is evident that the only use for digitalis in therapeutics is to modify the action of the heart. And it is to be employed neither to constrict the arte- ries nor to act directly upon the kidneys. It is also evident that among the cardiac disturbances which require treatment there are those in which digitalis has a great value, those in which it has a small value, those in which it has no value at all, and those in which it is distinctly harmful or even dangerous. Discrimina- tion, therefore, is most essential in the use of this powerful remedy. We learn further that the determining factor in our choice of digitalis as the drug to use is not the state of the valves, but rather the functional condition of the various parts of the cardiac DIGITALIS 189 mechanism. According to Lewis, the relative frequency of disorders of the cardiac mechanism in hospital cases would ap- proximate as follows: Heart-block, 5 per cent.; sinus arhythmia, 5 per cent.; pulsus alternans, 5 per cent.; paroxysmal tachy- cardia including auricular flutter, 10 per cent.; premature con- tractions, 34 per cent.; auricular fibrillation, 41 per cent. The role of digitalis in these several conditions is as follows: Heart-block. In incipient or partial heart-block digitalis is contraindicated, for it tends to increase the degree of block. In complete block it has been recommended by Bachmann and others on the ground that it tends to bring the auricular and ventricular rates more nearly together, by slowing the rate of the auricle and increasing that of the ventricle; but in the only one of my cases in which it had any effect (see case report under Auriculoventricular Bundle, p. 173) it brought the auricle and ventricle to the same rate, but in "reversed rhythm," the auricle following the ventricle instead of preceding it; and this was harmful. Sinus Arhythmia. In this condition digitalis is useless and probably harmful. These hearts do best when treated by other measures than drugs. Pulsus Alternans.- In this weakened state digitalis may at times be of some value, but its effects are problematic, and at least in some cases are harmful. Especially is this true of the myocarditis cases with coronary sclerosis. Paroxysmal Tachycardia. As this is a peculiar action of the heart, coming on with great suddenness and ceasing just as abruptly, and lasting from a fraction of a minute even to months, it is difficult to say whether any drug given is effective or not. Some cases cease soon after the commencement of digitalis and some do not. Where the beats arise at the sinus node or in the auricle, digitalis might be expected to be of value by retarding conduction, but when the beats arise in the ventricle, it can only be harmful. In auricular flutter, a condition characterized by an extremely rapid auricular contraction, rate above 300, usually with ven- tricle beating at the same rate or half the rate, digitalis may change the flutter to fibrillation, and this seems to act by submerging the original fast rhythm and eventually restoring the rhythm to normal. Even if it does not do this, digitalis will be of value by establishing some degree of block (Thomas Lewis) . Premature Contractions. Though a few cases have been reported of the disappearance of premature contractions during the administration of digitalis, it is certain that in most cases 1 90 PHARMACOLOGY AND THERAPEUTICS digitalis has a decided tendency to increase these indications of irritability. Auricular Fibrillation. It is in auricular fibrillation, above all other cases, in -which there is an almost ideal effect from digi- talis; in fact, the results of digitalis are dramatic. Lewis says that "in hospital practice, of those with obvious cardiac failure at least 60 per cent, have auricular fibrillation." Large doses should be given at the outset, and if the fibrillation is permanent, should be followed by smaller doses once or twice a week or once a day, for months, or even throughout the life of the patient. The action of the drug is not to overcome the fibrillation, though a slowing in the rate of fibrillation has been noted (Cushny); but, so far as we know, it is to impair the conductivity of the auriculoventricular bundle, i, e., to establish a partial heart- block. The result is that impulses from the auricle get through to the ventricle only at longer intervals, and, as a consequence, the ventricle becomes more nearly regular, is less rapid, and has greatly increased power. The production of complete block, shown by the regularity of the pulse, should be avoided; if it occurs, it is an indication for immediate reduction of the dose. In a case of auricular fibrillation, if the condition is imme- diately serious, an intravenous injection of digipuratum, i^ grains (o.i gm.), or of strophanthin T n to ^ grain (0.0005- o.ooi gm.), may be employed. But usually it suffices to give 15-30 minims (1-2 c.c.) of the tincture three or four times a day, or a corresponding amount of the powdered leaves, i. e., I 2~3 grains (0.1-0.2 gm.), or of the infusion, i. e., 1^-3 drams (6-12 c.c.). It is to be noted that frequently the infusion is given in larger proportional dosage than other preparations. Doses of ounce (15 c.c.) are not unusual, and this dose is made from the same amount of digitalis as 36 minims (2.4 c.c.) of the tincture. Yet such a dose of the tincture is seldom employed. This is perhaps the reason why some thoughtlessly consider the in- fusion the better preparation. The table on p. 191, giving the effects of digitalis as recorded by Mackenzie in a case of mitral stenosis with auricular fibrilla- tion, is typical. The B. P. tincture was used by Mackenzie. Its equivalent in U. S. P. tincture is expressed in the table. In cases in which great excitability shows by varying periods of auricular fibrillation, paroxysmal tachycardia, and premature ventricular beats, digitalis is much less certain than in simple auricular fibrillation. P'or only such beats as have their origin in the auricle, and consequently are affected by depression of conductivity, will be favorably modified by digitalis; while DIGITALIS DATE. TINCT. DIGITALIS, U. S. P. PULSE-RATE. Oz. OF URINE. REMARKS. July 6 1 06 27 8 9 10 ii 12 13 14 37K minims II2# " ii2# " 75 no 73 70 72 72 60 68 41 29 37 52 63 42 16 Headache Headache; nausea Vomited' headache 1C t >7 14 Vomited' headache 16 63 2 7 Better' no vomiting 17 CO 16 18 70 2Q 19 60 26 20 70 3O 21 78 C7 Breathing much easier those arising in the ventricle itself may be made worse by the increase of excitability. I have seen several of these cases. In some, digitalis gave good results; in others it did no apparent good or harm. Normal Rhythm. In the cases in which the heart is beating in normal rhythm and is regular, but rapid and weak, it is quite customary to employ digitalis with the dual purpose of slowing the heart and strengthening its beat. And it is in these cases, in which we desire and might expect so much, that we often meet with disappointment. At times the drug seems utterly lacking in power to check the rate or to add to the strength of the heart, even though, as shown by the development of toxic effects, the digitalis is given beyond the physiologic limit. This may be due either to an affection of the muscle caused by failure of nutrition or the toxins of the disease, or to reflexes of which we do not know the nature. Use in High Arterial Pressure. In this condition the ques- tion may arise as to the advisability of employing digitalis. As the doses administered in therapeutics do not have a strong tendency to raise arterial pressure, high pressure is not of itself a contraindication to the employment of the drug. The author has seen a number of cases with tension between 200 and 260, in which the pressure fell during digitalis administration. Use as Determined by Rhythm and Rate. The rhythm serves merely to determine the functional condition. The most met with rhythms, with their probable significance as judged by rate, are as follows : i. Ventricle regular in frequency (a) Pulse 55 to 140 normal rhythm if rapid, try digitalis, but watch for toxic manifestations. IQ2 PHARMACOLOGY AND THERAPEUTICS (b) Pulse below 55 heart-block? avoid digitalis. (c) Pulse above 140 paroxysmal tachycardia, auricular flut- ter try digitalis. (d) Pulse alternating weaker and stronger beats pulsus alternans try digitalis. 2. Ventricle showing regular waxing and waning of the rate independently of respiration sinus arhythmia avoid digitalis. 3. Ventricle showing premature or abortive beats avoid digi- talis. 4. Ventricle beating in couples avoid digitalis. 5. Ventricle regularly intermittent partial heart-block avoid digitalis. 6. Ventricle persistently irregular and disorderly auricular fibrillation- use digitalis in large doses. The Influence of Conditions of the Heart and Arteries on the Usefulness of the Drug. (a) In Simple Muscular Inability Without Valvular Lesion. Simple dilatation. In this the muscle has lost its tone and become abnormally relaxed, and its contraction is weak; in addi- tion, there may be a systolic leakage through the mitral valves, not due to valvular disease, but to the dilatation of the mitral orifice and the loss of tone of the papillary muscles. Digitalis tends to make the systole stronger and more complete, and, by restoring the tone, prevents the abnormal diastolic relaxation and weakness. At the same time the mitral ring contracts to normal again and the papillary muscles are toned, so that the relative insufficiency of the mitral valves disappears. The result is an efficient circulation. In the moderate dilatation of acute febrile diseases digitalis may be ineffective because of the toxic action of the bacterial products. Chronic myocarditis and fatty degeneration. In these a portion of the muscle substance is changed and replaced by non- contractile tissue (connective tissue in myocarditis; fat in fatty degeneration), so that the drug has less muscle substance to stimulate by direct action. In some of these cases, too, there is impairment of the coronary circulation by coronary sclerosis; and in some the slowing of the heart takes place without a correspond- ing increase in ventricular strength, so that the output is actu- ally lessened instead of increased. Because of these things, therefore, digitalis may be contraindicated, or at least must be used with caution. In acute toxic myocarditis, as in the infectious febrile diseases, digitalis may fail either to slow or to strengthen the heart. In most cases, however, it is effective. (b) Muscular Inability Associated with a Valvular Lesion. DIGITALIS 193 The common valvular defects are those of the left heart, and they either make a valve inefficient so as to permit backward leakage or regurgitation, or cause a narrowing or stenosis of the valvular orifice so as to obstruct the onward passage of the blood. The common valvular lesions which allow regurgitation of blood are mitral insufficiency and aortic insufficiency. The common lesions which cause obstruction to the passage of blood are mitral stenosis and aortic stenosis. In mitral insufficiency there is a systolic regurgitation of blood from the ventricle into the auricle through the insufficient mitral valve. This leakage is ordinarily compensated for by enlarge- ment of the ventricular cavity and hypertrophy of the heart muscle. When the muscle fails, there is a condition of flabby heart wall and papillary muscles, with relaxed mitral orifice, resembling that in simple dilatation, but with a permanent mitral leak. In this condition digitalis may prove valuable. In aortic insufficiency there is a diastolic regurgitation from the aorta through the insufficient aortic valves back into the ventricle. In this condition the left ventricle is usually very large and its capacity enormously increased. In the arterio- sderotic type the aorta is impaired, there is usually more or less myocarditis and general arteriosclerosis, and the failure of the sclerosed coronaries to meet the needs of the very large heart is probable. Hence digitalis should be used with caution. In the endocarditic type the dilatation and hypertrophy of the ventricle through the natural compensatory changes are regularly very marked, the heart is enormous, and there is a very great output of blood at each systole. This factor and the prompt leakage are enough to make a great difference between the systolic and diastolic aortic pressures, hence a sudden great distention of the aorta in systole, a matter of importance if there is aortic disease. In such a case the prolongation of diastole by digitalis does not seem to make any serious difference so far as the leakage is concerned (Stewart), and it allows a longer time for the addi- tional coronary blood-supply needed by the greatly hyper- trophied wall of the heart. The peripheral pressure, however, is not influenced so much by the size of the leak as by reflexes through the depressor nerve which in man runs afferently in the vagus from the heart or from the adjoining portion of the aorta. When the intra-aortic pres- sure is abnormally high, this nerve carries impulses which result in a reflex dilatation of the peripheral arterioles. So in aortic insufficiency, either because of the very high aortic systolic pressure or the sudden overdilatation of the aorta from the great output at a single beat, depressor impulses are set going; and. 13 IQ4 PHARMACOLOGY AND THERAPEUTICS there is immediately a reflex dilatation of the arterioles, which causes greatly lessened peripheral resistance and low diastolic pressure. Whether or not digitalis, through its effect upon the vasoconstrictor mechanism, may counteract this depressor reflex, which is protective by letting off at the periphery the exces- sive pressure caused by the great output in systole, is a question. If it does so, it may be harmful. In mitral stenosis the mitral orifice is narrowed by thickening of the valves or their adherence together so as to obstruct the filling of the ventricle from the auricle. The natural compensa- tion in this case is secured through hypertrophy and dilatation of the left auricle and of the right ventricle, so that, by added pressure, the proper amount of blood is forced through the nar- rowed aperture. Under digitalis, on the one hand, the filling of the left ventricle through this narrowed orifice is favored by a lengthened diastole (and the strengthening of the left auricle and right ventricle), and this has a slight tendency to improve the systemic circulation. On the other hand, digitalis does not re- move the stenosis; and there is always the possibility that while the obstruction to the exit of blood at the mitral orifice remains unchanged, any increased output from a right ventricle already dilated and hypertrophied may result merely in increased pul- monary engorgement. This shows in congestion at the bases of the lungs, transudation of fluid into the pleural cavity, edema of the lungs, or hemorrhage from the lungs. So in mitral stenosis, when the auricle and ventricle are beating in normal rhythm, the systemic circulation gets but little help from digitalis, and the danger of congestion in the lungs is increased. But when there is auricular fibrillation and auric- ular fibrillation is more common with mitral stenosis than with any other lesion of the heart the beneficial effects of digitalis far overshadow any possible disadvantageous ones. In aortic stenosis the aortic orifice is narrowed by thickening of the valves or their adherence together, so that the blood is impeded in its passage into the aorta. The result is that the systemic circulation and coronary circulation tend to be inade- quate. In an attempt to force more blood through the narrowed orifice by an increased power of systole the left ventricle is dilated and hypertrophied. The value of digitalis would not be inter- fered with by such a lesion. So much for the heart lesions. This very brief review of these more common ones will serve to indicate that great judg- ment must be employed in the use of digitalis in heart disease. But it must not be forgotten that the indication for digitalis is failure or threatened failure of compensation, and not at all the DIGITALIS 195 mere presence of a valvular lesion. When there is poor compen- sation, whether there is a valvular lesion or not, digitalis may be the best drug that we can employ. In aneurysm of the aorta, aortitis, or arteriosclerosis, there is no contraindication to digitalis, so with these lesions, as without them, its use would depend on the needs of the heart. In pneu- ? 2 tic r u i ICC K J. f If a te t I f i 7<> VS TIT "3-iYitl w*. Sm>~& Tk^r*, ? r 6 To f f t 00 Z fOu.. /rn. JI/U... fA*. r-. r**. *-,**, A / \ / \ Ori^L r ^ 2 \ 3 /' \ rS , 2 / s\ j r^t 5 * \ o \ ^ / 1 \ f ' tttmt, ri*fc 2 \ (.-, / 10 \ c 3 a- \ i 3 * j J-4- \ '> ^^ \ 5 ^ 3 ^ x / \ / \ 24cJ *C<^U, ;^u>,.' tox \ 3" \ \/ /* //2 , /fce /or loo P6 ?0 72- 7^ fotf. loo foo ?t> f c? r 72- t^ Fig. 24. Case with mitral stenosis and auricular fibrillation. V.S., ventricular systole; R.P., radial pulse. Digipuratum reduced the pulse to normal rate, abolished the "pulse deficit" in the radial pulse as compared with the number of ventricular beats, and increased the urinary flow, as shown above. At the same time there was a very rapid and marked disappearance of dyspnea, cyanosis, and venous engorgement. The auricle continued to fibrillate (author's case). monia and other acute infectious diseases digitalis may be most useful in preventing or checking auricular fibrillation. There is no condition of the kidneys, per se, which calls for digitalis. Any striking diuretic effect is obtained only in condi- tions of venous engorgement from cardiac failure. Summary of Therapeutics. i. The indication for digitalis 196 PHARMACOLOGY AND THERAPEUTICS is failure or threatened failure of compensation. 2. Its most striking effects are seen in auricular fibrillation and when there is venous engorgement. 3. The drug's efficiency is not to be esti- mated by its effects on arterial pressure. 4. The mere presence of a valvular lesion is not a reason for using digitalis. 5. The diuretic effect is entirely due to improved circulation, and may be evident even when the heart weakness has not yet resulted in obvious edema and dropsy. The Digitalis Allies. So far as the circulation is concerned, the uses of these are the same as those of digitalis itself. For administration by mouth not one of them has any advantage over digitalis and its active principles. Convallaria is less cer- tain, and strophanthus is prone to cause diarrhea, while both have a smaller margin of safety between their therapeutic and poisonous doses. The difference between digitalis and stro- phanthus in their action upon the arteries is not observed in therapeutics. Cushny states that the tincture of strophanthus when mixed with water deteriorates and becomes inert in a few days. But for intravenous administration strophanthin and ouabai'n are the most suitable, and have been used with remarkable, and in some instances dramatic, effects. So much as -fa grain (i mg.) should never be employed intravenously at one dose if the patient has just previously been taking any of the drugs of the class by mouth. But it may be employed thirty-six hours after the last dose of strophanthus by mouth, or one week after the last dose of digitalis. If there is any doubt, the beginning dose should not exceed ?$-$ grain (| mg.). If without the desired effect it may be repeated in two hours. EPINEPHRINE Epinephrine, more familiarly known by the proprietary name adrenaline, is an animal alkaloid or leukomain obtained from the medullary portion of the suprarenal glands, chiefly of cattle, sheep, and pigs. So far as we know, it is the same as the normal internal secretion of the gland in man. Its formula is NH.C 6 H 3 (OH) 2 .CHOH.CH 2 CH 3) and it is a distant relative of the vasoconstricting principle of ergot, tyramine. It has the properties of an alkaloid, hence forms salts, is precipitated by alkalies, tannic acid, etc., and is destroyed by long contact with alkalies. In the dried glands it is present to the extent of about i per cent. It is marketed under several trade names, adrenaline, supra- capsulin, suprarenalin, etc., in a solution purporting to have a EPINEPHRINE 197 strength of i part of the chloride in 1000. This solution is not decomposed by a moment's boiling, so it may be sterilized by heat. By prolonged boiling it is quite changed. On long standing, or if diluted, it deteriorates, slowly changing to a reddish color and eventually precipitating. When a precip- itate is present, the solution should be discarded. It keeps better when it contains a slight excess of hydrochloric acid. Tablets of the hydrochloride, the pure alkaloid, and the tartrate are also obtainable. A synthetic substitute, suprarenin, or dioxyphenyl-ethanol-methylamine hydrochloride, has about half the strength (Schultz). The dried suprarenal glands of the sheep and ox, freed from fat, and cleaned, dried, and powdered, are official under the title Suprarenalum siccum. This dried gland is about six times as strong as the fresh gland, and is used either in tablet form or in a mixture with water. The latter must be freshly prepared, as it does not keep. Preparations and Doses. The dose varies according to the method of administration and the effect desired. Dried Suprarenal Gland. Dose, 4 grains (0.25 gm.) by mouth. Solution of epinephrine hydrochloride, i : 1000, used hypoder- matically in asthma, urticaria, etc., 15 minims (i c.c.); used intra- venously, 2 minims (0.12 c.c.); or in shock, 30 minims (2 c.c.) added to saline and very slowly administered. Janeway has administered over i dram (4 c.c.) intravenously in a little more than an hour. On testing the blood-pressure-raising power of the several commercial preparations as compared with pure solutions of epinephrine, Schultz, Hunt, and others found them to be of variable efficiency and poor keeping quality. Pharmacology. General Action. Epinephrine is a stimu- lant of sympathetic nerve-endings or their myoneural junctions. As Langley puts it, "the effects of epinephrine upon any tissue are such as follow excitation of the sympathetic nerve which supplies the tissue." The effects, so far as muscular activity is concerned, depend upon the degree of contraction already exist- ing. Thus, with greatly relaxed arteries, the proportional response is greater than with arteries in normal contraction ; and with contracted bronchi the relaxation is greater than in normal bronchi. Hence a dose which will constrict relaxed arteries may not affect the bronchi; and a dose which will relax contracted bronchi may not constrict normal arteries. Skin and Mucous Membranes. It has no effect on the un- broken skin, but when applied to cuts, open wounds, ulcers, or 198 PHARMACOLOGY AND THERAPEUTICS any mucous membranes which can be reached (namely, those of the conjunctiva, lacrimal duct, nose, throat, mouth, esophagus, stomach, rectum, vagina, urethra, and bladder), it penetrates sufficiently to stimulate the vasoconstrictor nerve-endings of the arterioles at the site of application. The result is a local con- traction of the arterioles ; and this is so marked that the blood is almost shut off from the part, the tissues shrink and appear blanched from comparative bloodlessness, and any moderate hemorrhage is checked. This local contraction of the arterioles is greater and more prompt than from any other drug in use. It follows almost instantly the application of the epinephrine and lasts from fifteen minutes to one or two hours. Repeated appli- cations will continue to keep the arterioles contracted for an indefinite length of time. But besides vasoconstriction, epinephrine has also a vaso- dilator action, so that when the application of the drug is stopped and the vasoconstriction wears off, the arterioles not only relax again, as usual after constriction, but may dilate away beyond the normal in fact, may completely lose their tone, so that there may be a late return in marked degree of the condition which the epinephrine was intended to relieve, viz., the hemor- rhage, or the congestion, or the relaxed mucous membrane. Cannon and Lyman (1913) bring forward some evidence against this dilator effect being due to stimulation of the vasodilator nerves. In the coronary arteries, the dilator effect alone is observed, and this is the effect on other arteries after the adren- aline solution is boiled for a length of time (Lieb). Absorption depends upon the method of administration i. Applied to mucous membranes, or given by mouth, the drug regularly has no systemic effect, or almost none. Possibly by constricting the arteries it prevents its own absorption. It is reported that an aqueous extract of two pounds of fresh supra- renal capsules has been swallowed without apparent ill effect. Osborne and some others claim that it is slowly absorbed from the mouth, though not from the stomach, while some have found that such large doses as ^ ounce (15 c.c.) of the i : 1000 epi- nephrine solution in the stomach have resulted in the character- istic effects on the circulation. A few cases also are reported of marked systemic effects from its application to the conjunc- tiva, the nose, and the urethra. But, as a rule, no systemic effect at all is obtained from the drug when it is given by mouth or applied to mucous membranes, and it seems to be rapidly destroyed at the point of entrance into tissues before it gets into the circulation. Pilcher has shown that the submucous injection in the nose is very rapidly absorbed and may produce dangerous effects. EPINEPHRINE 1 99 2. From subcutaneous injection there may be a slight rise in arterial pressure, but almost always there is no measurable effect. This is the author's experience in tests with students and asthmatics. There is, however, a fairly prompt effect upon contracted bronchi, even though the arteries are unaffected. 3. From deep intramuscular injection enough seems to get into the blood-stream to induce quite frequently a distinct though comparatively small rise in arterial pressure and a re- laxation of the bronchi. These effects are most noticeable when the arteries are relaxed or the bronchi strongly contracted. 4. From intravenous administration there is an immediate and very marked rise in arterial pressure. This is the only method of administration for a sure effect upon the arteries. Circulation. The effect of an intravenous dose upon the circulation is a marked rise in arterial pressure and a momentary increase in rate, followed by strengthened and slowed heart. The rise in pressure is only momentary, but may be maintained by repeating the dose or by continuous slow infusion. A gradu- ated rise in pressure may be obtained by intravenous injection of increasingly large doses. The Vasoconstriction. The most marked constriction is in the arteries of the splanchnic area, where it may be so great that the intestines are almost bloodless. It is produced if the splanch- nic nerves are cut, or if the central nervous system is destroyed; therefore it is due to a peripheral action and not to a central one. The peripheral effect is well shown in an isolated viscus or an isolated limb, by measuring the venous outflow before and after epinephrine. In perfusing a dog's leg, for example, the outflow may be almost entirely stopped by the addition of a few minims of epinephrine solution to the perfusion fluid, but no such action occurs if apocodeine or ergotoxine has previously been used to paralyze the ends of the vasoconstrictor nerves. Therefore the site of the stimulation by epinephrine is the vasoconstrictor nerve-endings or the myoneural junctions (Elliott). After ergotoxine, which paralyzes the vasoconstrictor endings but not the vasodilators, epinephrine is regularly followed by vasodila- tion, an effect known as the "vasomotor reversal" of Dale. Hart- mann, and also Haskins, have shown that after intravenous ad- ministration there is vasodilation in the skeletal muscles, i. e., the blood is shifted from the splanchnic area to the active mus- cles, a valuable effect in shock. The coronary arteries, having no vasoconstrictor nerves, are dilated, or at least their tone dimin- ished so that they become dilated (Janeway and Park). Macht obtained powerful constriction of the pulmonary artery. There is some evidence that the cerebral arteries tend to be dilated. 200 PHARMACOLOGY AND THERAPEUTICS Janeway and Park (1912) have shown that "the effect of epinephrine on an excised artery in a physiologically inert solu- tion is in inverse ratio to the degree of tonus possessed by that artery." In other words, it is to be expected that general arterial relaxation with low arterial pressure, as in Addison's disease, will give a greater proportionate response to the drug than would a normal state of the arteries and normal arterial pressure. In a case of Addison's disease at St. Luke's Hospital, 15 minims slowly administered intravenously caused the pressure to rise from 90 to 1 60 mm. Haskins and Moore have established the fact that normally when there is enough epinephrine in the blood to give a pressor effect, the intestines become paralyzed. Cameron (1906) determined that T ^ grain (0.6 gm.) of nitro- glycerin was just enough to neutralize the pressure-raising power of 0.0075 mg. of epinephrine hydrochloride, i. e., about 8 minims (0.5 c.c.) of the i : 1000 solution. The Slowing. If the vagus nerves are cut, there is no slowing of the heart, or at least if there is slight slowing, it is abolished by atropine; therefore the slowing must be due to stimulation of the vagus, and essentially of the vagus center. But if the arterial pressure is kept low by bleeding or by paralysis of the vasocon- strictor endings by apocodeine or ergotoxine, there is no slowing. It has been shown also that the slowing always follows the rise in arterial pressure. Thus it is evidently due to the reflex stimula- tion of the vagus which regularly occurs when the arterial pres- sure rises, and not to direct stimulation of the vagus center by the drug. Therefore the slowing is reflex, and is dependent upon the rise in arterial pressure, and not upon direct vagus stim- ulation. The Increased Force of the Heart. When epinephrine is slowly added to the perfusion fluid for an isolated heart, a myocardiograph tracing shows increased systolic contraction and lessened diastolic relaxation. In other words, there are increased contractility and increased tonicity. Atropine to paralyze the vagus endings does not change the effect, but apocodeine and ergotoxine, which paralyze the accelerator endings, abolish it. Therefore the accelerator endings must be the site of stimulation by the drug. Some investigators believe that there is a slight muscular stimulation in addition. Thus, in an intact mammal, epinephrine slows the heart, increases its tone, strengthens its beat, and dilates its coronary arteries. It also constricts the systemic arterioles. The manner in which these effects are brought about, and the rapidity of action, are entirely different from those of digitalis. The rise in arterial pressure is very great and very prompt, epinephrine EPINEPHRINE 2OI being the most powerful blood-pressure-raising drug that we employ in medicine. As the effect is peripheral and not central, the rise occurs even when the vasoconstrictor center is paralyzed or exhausted, but it lasts only from one to five minutes. It may be kept up for a long time without apparent harm by frequently repeated doses, or by the very slow administration intravenously of a dilution in normal saline solution. From quickly repeated large doses the very great constric- tion of the arteries may result in failure of the left ventricle with dilatation and weakness, at a time when the right heart is pumping more blood into the pulmonary arteries. The result is pulmonary edema. This effect has frequently occurred in rab- bits from i or 2 c.c. of the solution. It is especially likely to occur when the heart is already impaired, or if the epinephrine is given rapidly with a large saline infusion, for the saline liquid adds to the diffusible fluid in the lung capillaries. Blood. Wiggers was unable to corroborate the finding of Richards and Vosburgh that epinephrine increases the coagula- bility of. the blood, but Cannon and Gray show that small doses, o.ooi mg. per kilo intravenously, and larger amounts subcu- taneously, shorten the coagulation time to one-half or even one- third, though when added to drawn blood it has no effect. Grabfield finds that it increases the prothrombin. Connective-tissue Changes in the Heart and Arteries. In 1903 Josue described sclerotic lesions of the aorta in rabbits to which epinephrine had been administered intravenously for long periods. In 1906 Pearce and Stan ton injected 3 minims of the i : 1000 solution every day for two months, and obtained not only these aortic changes, which they observed to be due to degeneration and calcification in the muscular tissue of the media, but noted also bulging of these weakened areas, the mechanical breaking of the elastic fibers, and the actual formation of aneurysmal dilata- tions. Pearce noted, also, some connective-tissue changes in the myocardium, but none in the peripheral arteries, while Erb found arteriosclerotic changes in the other arteries as well as the aorta. Erb attributes the effects to a toxic action rather than to the heightened blood-pressure, for he obtained them by intra- peritoneal injections which did not raise blood-pressure. The lesions in epinephrine-produced arterioscleroses differ patholog- ically from the lesions of arteriosclerosis in human beings, but furnish valuable material for study. Pearce and Hill have later questioned the role of epinephrine in the production of some of these results, as they found arteriosclerotic changes quite common in supposedly normal rabbits. The fear of producing any such changes by the therapeutic 202 PHARMACOLOGY AND THERAPEUTICS use of the drug need not be great, for we never administer epinephrine repeatedly for long periods except in two conditions, viz., disease of the suprarenal glands and bronchial asthma. The former is so regularly fatal that any risk may be taken for the chance of helping; moreover, the theory upon which epinephrine is given is that it may make up for a pathologic deficiency of the natural epinephrine of the patient, and, therefore, cannot be present in the system in excess. This theory is believed to be incorrect. (See Therapeutics.) In intractable bronchial asthma the drug may be used repeatedly by hypodermatic injection during long periods, and it is well in these cases to think of the possibility of harm to the arteries and heart, and to the nervous system. Respiratory System. Used hypodermatically in small quan- tities, epinephrine causes increased depth of respiration; while if it is used intravenously it quickens respiration, the inspirations being shallower. Park (1912) found that when it was applied to excised rings of the bronchi of the ox, even in a concentration as low as i : 10,000,000, it regularly caused relaxation .without primary constriction. And it may be presumed that this effect is due to stimulation of the bronchodilator (sympathetic) nerve- endings. In man, when it is given hypodermatically, it produces a decided relaxation of contracted bronchi. The rule that the drug acts best where the condition it is opposing is extreme, makes it peculiarly valuable in spasmodic asthma due to exces- sive bronchial contraction, for the effect on the bronchi is out of proportion to the effect elsewhere, and is often evident even when the arterial pressure is not affected in measurable degree. Nervous System. Following a hypodermatic dose, as for asthma, there is frequently an immediate onset of nervous excite- ment and agitation which may last as much as an hour or two. Alimentary Tract. The local astringent effects may be obtained in mouth, esophagus, stomach, and rectum. On intravenous injection the drug stimulates the ends of the splanch- nic or inhibitory nerves (which belong to the sympathetic system), and so lessens peristalsis of stomach and bowels. The contractions of the gall-bladder are said to be inhibited in the same way. The mucous secretions, the saliva, and the bile are increased, as mentioned below. Pemberton and Sweet (1912) have shown that intravenous injections of epinephrine inhibit the flow of pancreatic juice; and Herter found that painting the pancreas with epinephrine resulted in glycosuria. The Eye. A drop of epinephrine solution in the eye causes the conjunctiva to become shrunken and pale, the eyelids to become retracted, and the eyeball to appear more prominent. EPINEPHRINE 203 The drug, if in strong solution, also penetrates to the internal eye, and by stimulation of the sympathetic nerve-endings in the fibers of its radial muscles dilates the pupil. A solution of i : 1000 ordinarily does not dilate the pupil; but Loewi and Rosenberg demonstrated that it does so in pancreatic disease, and in any condition with hyperglycemia, such as hyper thyroidism, diabetes, and after glucose intravenously or freely taken by mouth. Pratt failed to obtain the reaction in three dogs with extreme atrophy of the pancreas. As a test for epinephrine in a liquid, Meltzer and Auer make use of the extirpated frog's eye, which regularly reacts to a strength of i : 1000, or even of i : 10,000. Muscle.- The contraction of striped muscle is not affected, but its relaxation is greatly slowed, as with veratrine. Smooth muscle shows the effects of stimulation of sympathetic nerve- endings. Hoskins claims a vasodilator effect in the skeletal muscles with increased efficiency. Secretion. The sweat, tears, saliva, bile, and mucus are in- creased by stimulation of the sympathetic nerve-endings in the glands. Glands. There is a distinct relation between the thyroid and adrenal glands. Increased thyroid secretion as in exoph- thalmic goitre, or the administration of thyroid appears to sen- sitize the sympathetic nervous system to epinephrine. Hoskins states that feeding adrenal to young male animals leads to hypertrophy of the testes. Uterus. Epinephrine causes constriction of the uterine arteries and of the uterus itself. The latter effect also follows local application (as in an intra-uterine douche). Bladder. Local application produces an astringent effect upon the bladder wall. Intravenous administration results in stimulation of the ends of the sympathetic or inhibitory nerves of the bladder, with the effect of relaxation of the bladder muscles. The ureter shows increase in tone and rate of contraction. Urine. Houghton states that the secretion of urine is in- creased synchronously with the rise in arterial pressure, and continues above normal for several minutes after blood-pressure falls. He believes that the kidney arteries are passively dilated. In five experiments the arterial pressure showed a rise of from 56 to 88 mm. Hg, and the urine an increase of from 8 to 30 minims. But the arterial pressure averaged six minutes for its return to normal, while the urine secretion did not get back to normal until fifteen minutes. Some observers note a decrease or even cessation of the urine production during the epinephrine vaso- constriction. It is an interesting observation that the urine 204 PHARMACOLOGY AND THERAPEUTICS may be found to contain sugar, and this has been proved to be due to an excessive amount of sugar in the blood from lack of dextrose destruction. It is an artificial diabetes, which occurs even if the rise in blood-pressure is prevented. It does not occur if the animal is first starved until its stored glycogen is all used up. Herter and his associates have found that the same effect follows when the pancreas is painted with epinephrine. Kleimer and Meltzer find the increased urination and glycosuria more readily produced by subcutaneous than by intramuscular in- jections. It would seem that the diuretic and sugar-producing actions are quite independent. (See "pupil reaction" above.) Metabolism. Lusk and Richet say, "the theory that epineph- rine causes a production of sugar from fat, decreases the power of the organism to oxidize glucose through inhibition of pancreatic function, and stimulates the thyroid so that protein metabolism is increased is untenable in every particular." Elimination. The fate of epinephrine is not certainly known. Falta says that when it is injected subcutaneously or into the peritoneal cavity, none appears in the urine, while when given by mouth, though it has no systemic effects, it is eliminated in the urine. Toxicology. From the local use of the drug, there have been reports of overacting heart, palpitation, and vomiting. These must be due to idiosyncrasy, for they are unusual. After the hypodermatic or intravenous doses there is frequently excitement, with tremor, and in some cases much anxiety. Cushny says that the hypodermatic injection of very large doses in mammals results in excitement, tremors, and paralysis of the hind limbs, and, in addition, sometimes vomiting, increased urination, or hemorrhages from various mucous membranes or from the kid- neys. Death occurs either from paralysis of the respiratory center or from heart failure, due to back pressure from the constricted systemic arteries. There is no doubt that some post-operative cases of pulmonary edema are due to the use of this drug with saline infusion. Epinephrine and Chloroform. Levy and Lewis (1912) report a research on cats, regarding the simultaneous use of these two drugs. They found that (i) Small intravenous injections of epinephrine chloride, given to an animal under high percentages of chloroform vapor, produce a condition of irritability of the ventricle, with irregular and rapid heart; and that (2) low ten- sion's of chloroform vapor with small intravenous injections of epinephrine chloride ultimately produce the highest grade of ventricular disorder, viz., ventricular fibrillation, which means death. Levy's later studies corroborate these findings. EPINEPHRINE 205 Therapeutics. A. For local effect it is employed i. To cause shrinkage of mucous membrane, whether the membrane is normal, or swollen and hyperemic. In the nose such shrinkage gives a clearer view for examinations, and more room for the passage of instruments, such as a Eustachian catheter. In hay- fever or acute catarrh, i. e., a fresh cold in the head, the applica- tion of an epinephrine solution on a cotton probe almost instantly shrinks the tissues and frees the stuffed-up air-passages. This effect may last half an hour or more, and if the patient then remains quiet and in a warm room, may persist for hours after the adrenaline action is over. In hay-fever the adrenaline solu- tion diluted with normal saline is often used as a spray; but it might be noted that there are some reports of chronic turgescence or hyperemia following its frequent use in this condition. In some operations, as for adenoids and hypertrophies, the shrink- age of tissue may be undesirable. Dropped in the eye, it may lessen a conjunctival swelling, and so favor the finding and removal of a foreign body. In prolapse of the rectum, or hemor- rhoids, the shrinkage may enable the protruding mass to be replaced. 2. To arrest a small hemorrhage at any place where the bleed- ing point is accessible, as in the nose, stomach, bladder, etc. In nose-bleed the hemorrhage may often be checked by a pledget of cotton soaked in epinephrine solution and applied to the bleeding spot. In postpartum hemorrhage the liquid may be added to a hot intra-uterine injection to favor uterine contraction and per- haps to constrict the uterine arteries. 3. To prolong local anesthesia and to prevent local hemorrhage it is added to solutions of cocaine and other local anesthetics. It acts by vasoconstriction, which checks the rapid removal of the anesthetic by the blood-stream. Berry (1905) showed that the toxic action of cocaine is increased when it is administered with epinephrine. 4. To allay itching of vulva and anus it may be applied on cotton. It acts on the moist parts of the vulva, whether mucous membrane or not. 5. In anterior poliomyelitis, in the ascending paralysis types, spinal injection of 15 minims (i c.c.) has seemed to check the progress of the paralysis. B. For systemic effect it is administered hypodermatically or intravenously, according to the condition to be treated. i. Hypodermatically (a) to overcome bronchial asthma, a single dose of 15 minims (i c.c.), (b) to check anaphylactic shock, and (c) in Addison's disease, 5 minims (0.3 c.c.), three times a day. This latter is a condition of weakness and wasting, with pigmenta- 206 PHARMACOLOGY AND THERAPEUTICS tion of the skin and low blood-pressure, and it results from de- struction of the suprarenal glands. It was thought that doses of epinephrine might take the place of the natural secretion of these glands, but reports from its use hypodermatically or by mouth are not encouraging, and intravenous administration several times a day in chronic disease is obviously impossible. Loewi found 2 cases of Addison's disease so sensitive to epineph- rine that dangerous symptoms followed its intravenous use. In our own experience there has been no effect on the course of the disease, though in one case 15 minims (i c.c.) administered slowly intravenously caused a temporary rise in systolic pressure from 90 to 1 60 mm. Others report temporary improvement. Osborne rec- ommends the whole gland in the form of tablets which are allowed to disintegrate slowly in the mouth. As a matter of fact, recent research would seem to indicate that the manifestations of Addi- son's disease are not due merely to absence of epinephrine, but also to the loss of one or more elements from the cortex of the gland; and this would account in part for the lack of benefit from the administration of epinephrine. Epinephrine will not prolong life after the removal of the adrenals. 2. Intravenously it is employed as a rapidly acting circula- tory stimulant of great power in collapse or shock. Owing to its ephemeral action and to the impracticability of frequent intra- venous doses, it is suitable only in emergencies, and is not em- ployed in ordinary conditions of failure of compensation. It should not be given in chloroform collapse (see above). For administration, it may be diluted with normal saline and injected into the vein by a syringe; if there has been loss of blood, it may be added to a saline infusion. If given rapidly with a saline infusion when there has been no loss of blood, it increases the chances of pulmonary edema and heart failure, but a good-sized dose may be given with saline if the infusion is carried on very slowly. T. C. Janeway states that he has seen "the most amazing restoration from apparent imminent death follow the intravenous injection of epinephrine in large doses, in one case over i dram (4 c.c.) of the i : 1000 solution in a little more than an hour." Dangers. A. From Local Use. i. After operations (upon the nose, urethra, etc.) there is risk of late hemorrhage from secondary vasodilatation. 2. In hay-fever there is risk of a chronic state of vascular dilatation following the frequent use of the drug. B. From Intravenous Administration. i. In cerebral arterio- sclerosis there is risk of rupture of a cerebral artery from any sud- den great rise in general blood-pressure. PITUITARY EXTRACT 2O7 2. In internal hemorrhage, especially cerebral or pulmonary, there is risk of increasing the hemorrhage. 3. In pulmonary edema there is risk of increasing the edema. 4. In emergencies there is risk of precipitating heart failure and producing pulmonary edema or general edema. PITUITARY EXTRACT Pituitary extract (hypophysis sicca, desiccated hypophysis} con- sists of the posterior lobe of the pituitary gland of cattle, cleaned, dried, and powdered. Dose, grain | (0.03 gm.). A solution, liquor hypophysis, containing the water-soluble principles from the posterior lobe is also official. Subcutaneous dose, 15 minims (i c.c.). This amount, diluted 20,000 times, is required by the Pharmacopoeia to have the same activity on the isolated uterus of the virgin guinea-pig as a i : 20,000,000 solution of beta- iminazolylethylamine hydrochloride (see Ergot). Roth found commercial preparations exceedingly variable. So far the pos- terior lobe has yielded no active principle. Its activity is not destroyed by boiling (Gushing). The anterior lobe and pars intermedia are not official. (See below.) Pharmacologic Action.- The main action of the drug is to stimulate smooth muscle. It is in some degree antagonistic to the anterior lobe, as it tends to diminish sexual development and activity (Goetsch). Locally. Applied to mucous membranes or injected beneath the skin it causes moderate constricton of the arterioles. Circulation. The intravenous administration induces slowing and weakening of the heart and a rise in arterial pressure, the rise beginnning in a minute or less and lasting usually from 5 to 10 minutes, though occasionally for as much as half an hour. The administration of atropine or cutting the vagi results in strengthening both auricle and ventricle, with an added rise in pressure (Lieb) . The rise in pressure takes place in a decapitated cat and is therefore not clue to an effect on the vasoconstrictor center. The maximum rise in pressure may be as great as that from epinephrine, but is more slowly attained. There is practi- cally no circulatory effect from a subcutaneous dose, and as a rule only a slight one from an intramuscular injection. From intramuscular doses Schmidt obtained regularly a rise in diastolic pressure, though no constant effect on the systolic pressure. Its effects therefore resemble those from epinephrine, but there is a marked difference in the site of action. For after apocodeine or ergotoxine, while the effect of epinephrine changes to vaso- dilatation, pituitary constricts the arteries as much as it did before. Furthermore, pituitary constricts the coronary, pulmon- 208 PHARMACOLOGY AND THERAPEUTICS ary, and cerebral arteries. Hence it must act by stimulating the arterial muscles and not the vasoconstrictor myoneural junctions. T3 ( 3 j_> and Newburgh no effect from ii 4 grains (0.09 gm.) in three days in each of 5 patients. It is possible that strychnine increases the sensitiveness of the center to other drugs. Large poisonous doses overwhelm and quickly exhaust the center. Death takes place from asphyxia, due either to the setting of the respiratory muscles during a convulsion, or to exhaustion of the respiratory center (between the convulsions). Under therapeutic doses, the bronchial muscles are improved in tone, so the drug may be useful in relaxed conditions of the bronchi; while in spasmodic conditions, as in bronchial asthma, it will be harmful. In cough the reflex excitability is increased, so that when there is abundant secretion to be coughed up, strychnine may change a weak, ineffective cough into an effective one. But when the cough is from a dry or tickling throat and cannot be made effective in getting rid of the offending stimulus, strych- NUX VOMICA 277 nine only uselessly increases the cough and distresses the patient. Metabolism. Because of the heightened muscular tone there is some increased metabolism, as shown by increased absorption of oxygen and increased output of carbon dioxide. In convul- sions the metabolism is greatly increased. Temperature. There is greater production of heat, owing to the increased metabolism, and greater dissipation of heat from the dilatation of the cutaneous vessels; the net change is not enough to be important. During a convulsion there is a great production of heat. Excretion. Some of the drug is oxidized and destroyed quite rapidly in the tissues; the remainder is eliminated in the urine. It can be detected in the urine very soon after the dose is ad- ministered, and most of it is excreted within twelve hours, but traces may be present for four or five days. From maximum doses cumulative poisoning may occur, though this is infrequent. In strychnine poisoning the urine, concentrated by boiling and injected into a frog, may give the characteristic convulsions. Tolerance. Hare has given some evidence that there is no tolerance for strychnine (Amer. Jour. Physiol., v). Worth Hale produced it with difficulty in dogs, but more readily in guinea- pigs. In human beings, if the dose is increased very slowly, a certain amount of tolerance may be set up. For example, if a patient is started on -$ grain (0.002 gm.) three times a day, the dose may be slowly and steadily increased until in five or six weeks the patient is getting | or ^ grain (o.oi or 0.012 gm.) three times a day with no untoward symptoms, though such dosage would have been poisonous in the beginning. In loco- motor ataxia, progressive muscular atrophy, optic nerve atrophy, etc., Troisfontaines has reached doses of fV to T G 5 grain (0.018- 0.035 S m -) daily, and Graeme Hammond has been able to in- crease the daily dosage to f or | grain (0.04-0.05 gm.), without untoward effects. Other neurologists have had similar experi- ence in producing tolerance to these large doses. Toxicology. After the repeated administration of large doses of strychnine the patient may become restless and nervous and twitchy, may make abrupt movements, as shrugging one shoulder or twitching the fingers or an arm or a leg, and may feel a stiff- ness of the face muscles, especially when he laughs, or a stiffness in the gait. These are the first signs of strychnine poisoning, and the drug should at once be stopped. If considered neces- sary, spinal sedatives, such as bromides, may be administered. In a more marked stage of poisoning the twitches become spasms, and soon there are general convulsions of the spinal 278 PHARMACOLOGY AND THERAPEUTICS type. During a convulsion all the voluntary muscles are affected, so of two opposing sets of muscles the action of the stronger set predominates. The extensors are mostly the stronger, hence the arms, legs, and back are extended and the head is thrown back; in addition, the hands may be clinched and the eyes wide open, and there is a ghastly grin, the risus sardonicus, produced by the spasmodic drawing out of the corners of the mouth. During the poisoning the mind remains clear, conse- quently there is great anxiety on the part of the patient; and while the convulsions last there is great muscular pain (cramps). The convulsion is at first tonic, that is, the contraction is continuous, making the muscle rigid; it then changes to clonic, i. e., rhythmic intermittent contraction; then it ceases. Before another convulsion sets in there is a moment of great muscular relaxation, with complete prostration and soreness of the muscles. If the poisoning is severe, the convulsions follow in rapid succes- sion, being brought on by the slightest stimulus the slamming of a door, a touch, a flash of light, a puff of air, the moving of a limb, talking or any voluntary effort. In mammals, after a few convulsions, there is complete exhaustion with collapse. Death takes place from asphyxia, due either to exhaustion of the respira- tory center or to continuous spasm of the respiratory muscles. The heart may keep on beating for some time after respiration has ceased. It is put under great strain by the repeated convulsions. Death usually takes place inside of two hours. One-twelfth grain (0.005 gm.) of strychnine sulphate in a woman has given beginning toxic symptoms; -5- grain (0.05 gm.) in a day has been well borne by patients who had become toler- ant to the drug. Shoemaker reports recovery in three hours of a student who had taken thirty T V grain (0.004 g m -) pills of the sulphate. Hewlett reports restoration in a man after 15 grains (0.972 gm.). He recovered over if grains (o.u gm.) from the urine and 4.5 grains (0.3 gm.) from the first stomach washing. A dose of T | (1 grain (0.0004 g m -) P^r kilo intravenously or intra- muscularly is invariably fatal to dogs (Githens and Meltzer). Treatment. If the drug has been swallowed, but symptoms of poisoning have not yet come on, the stomach should be thoroughly lavaged, and tannic acid or even tea administered to form the rather insoluble strychnine tannate, and thus retard absorption. The tannate formed must be washed out at once, as it is slowly absorbed. If tea is employed, immediate lavage is particularly necessary, lest the caffeine of the tea be absorbed and increase the poisonous effect. Most of the caffeine may be got rid of by sleeping the tea in boiling water for three minutes, discarding this water, and then steeping the residue to NUX VOMICA 279 extract the tannic acid (Hatcher). If the convulsions have begun, lavage may also be indicated; but usually, because of the rapid absorption of the drug, it is useless at this stage. Before a stomach-tube can be inserted it may be necessary to administer ether. The systemic treatment consists of 1. Spinal Cord Sedatives. For quick action, chloroform or ether by inhalation. Ether is said to have proved an effective antidote in dogs. Hewlett kept his patient continuously under ether for about six hours and so abolished the convulsions. But general anesthesia must be used with caution; for both chloroform and ether tend to increase the already serious mus- cular relaxation between the convulsions, and chloroform de- presses the respiratory center. Failure of this center in strych- nine poisoning threatens at any moment. For prolonged effect, bromides in large dose, ^ ounce (15 gm.) by mouth or rectum. These are directly antagonistic to strychnine in their action upon the cord. Paraldehyde does not depress the respiratory center, and may be of use in some cases. (Morphine should not be employed, for it not only depresses the respiratory center, but also fails to antagonize the strychnine effect upon the cord. Chloral hydrate is sometimes used; but in safe amounts has too little action upon the cord, and, like chloroform, has the disadvantage of being very depressing to the respiratory center.) Spinal anesthesia with cocaine has been effective in protect- ing the trunk and hind-limbs of animals from the convulsions, but it does not protect the fore-limbs and head, and does not prevent the great relaxation of the voluntary muscles, even in the hind-limbs. Magnesium sulphate intraspinally or intra- venously would be better. 2. Artificial Respiration and the Inhalation of Oxygen. The oxygen acts not only to furnish respiratory oxygen, which is deficient because of the interference with respiration and of muscular activity, but also to increase the rapidity of oxidation of the strychnine in the body. Gies and Meltzer claim that the rhythmic motions of artificial respiration tend to delay the onset of convulsions. j. Cathetcrization of the bladder to remove and so prevent reabsorption of the strychnine passed out by the kidneys. 4. Saline Infusion. Delbert found that if he followed the injection of a lethal dose of strychnine into a dog by an intrave- nous infusion of normal saline, free diuresis promptly resulted and no signs of strychnine poisoning were manifest. Hatcher and Smith found that diuresis hastened the elimination of the drug, 280 PHARMACOLOGY AND THERAPEUTICS but never sufficiently to save an animal given 20 per cent, above the average lethal dose. Githens and Meltzer (1912) recommend the combination of ether anesthesia, intratracheal insufflation, and intravenous administration of Ringer's solu- tion. Therapeutics. Strychnine and nux vomica preparations are extensively employed as tonics in conditions of debility with loss of appetite, and in convalescence from severe illnesses. In these conditions the effect on appetite is of value as well as that on tone. For a more marked action on the reflexes, they are given in atonic conditions of the abdominal viscera, as of stomach, intestines, bladder, and uterus, in the relaxed atonic types of chronic bronchitis, in conditions of weak, ineffective cough, as in severe tuberculosis with much bronchial secretion, and in acute and chronic alcoholism. "Strychnine is to asthenia what morphine is to pain" (Hartenberg) . Further, in serious acute diseases like pneumonia, where there is much prostration, and in narcotic poisoning, as from alco- hol, ether, or chloral hydrate, large doses may be administered for respiratory and spinal stimulation. It is to be noted that while strychnine is good in chloral poisoning, chloral hydrate is not good in strychnine poisoning. In nervous disease strychnine is extensively employed, but its use requires careful discrimination. Its application is as follows : (a) In the postoperative paralysis of stomach or intestine the drug would seem to be the best that we have. (ft) In paralysis from disease of the anterior horn cells (an- terior poliomyelitis, progressive muscular atrophy, amyotrophic lateral sclerosis) moderate improvement may come from in- creased transmission of the regular afferent impulses. (c) In lesions involving the posterior columns of the cord (e. #., locomotor ataxia) the result is problematic. Large doses may bring about improvement in some of the functions, but often are of no value at all. (d) In sexual feebleness without evidence of an organic lesion the effect on the reflexes may be of value. (c] In paralysis due to lesions of the motor area of the brain, or of the motor tract of brain or cord, the tendency of the drug is harmful; for the reflexes of the cord below the lesion are cut off from the normal cerebral control. As a result, they are so height- ened in activity that they approach the incoordinated type. The muscles are in a state of overtone, and in voluntary motion the opposing muscles do not readily relax; so it requires but slight provocation to bring the limb into a state of spasticity or rigidity NUX VOMICA 28l with perhaps clonic contraction of the muscles (as in the spastic gait). Therefore in hemiplegia, multiple sclerosis, transverse myelitis, and other conditions with spastic paralysis, strychnine would tend to increase the already bad condition. The writer found a man with multiple sclerosis who was being given two pills of aloin, belladonna, and strychnine, ^ grain (o.ooi gm.) in each three times a day, together with strychnine sulphate, ^V grain (0.002 gm.), and a dose of Bright's tonic, containing strychnine sulphate, -%$ grain (o.ooi gm.). The amount of strychnine sulphate being administered was thus -^ grain (0.005 gm.) three times a day. He was in such a spastic condition that he could not walk, and could scarcely use his hands to button his clothes. The substitution of bromides for the strychnine re- sulted in a marked improvement in two days. (/ ) In diminished vision, whether functional or from retinitis or partial optic nerve atrophy, large doses sometimes give good results. In these cases the drug may be given internally in the usual way; or, if the eye only is to be treated, may be injected into the neighborhood of the affected eye, or even in i per cent, solution dropped into the eye. Contraindications. Spasmodic conditions of all kinds, as (a) Of smooth muscle spasmodic asthma and biliary, renal, or intes- tinal colic, or spastic constipation; (b) of voluntary muscle hiccup, convulsive tic, epilepsy, and any spastic condition, as from a lesion involving the motor area or tract. Strychnine or nux vomica should not be given if the reflexes are already over- active. Administration. For a bitter effect, the tincture of nux vomica is preferred (10 minims = y^ grain of strychnine, or about -g^ grain of strychnine sulphate). It is given about ten minutes before meals, diluted with water to make a bitter drink. For the purposes of a bitter it is useless if given in cap- sules or coated pills. For a tonic effect any of the preparations may be employed, the strychnine salts being frequently pre- scribed by themselves in the form of tablet triturates. For hypodermatic use, the strychnine salts alone are suitable. As camphor has already been considered, and the other central stimulants, atropirie and cocaine, are at the same time pronounced peripheral depressants, we shall defer their consid- eration for the present. 282 PHARMACOLOGY AND THERAPEUTICS REMEDIES WHICH DEPRESS THE CENTRAL NERVOUS SYSTEM NARCOTICS As the remedies which depress the central nervous system regularly depress the cerebrum, they are known generally as narcotics, a narcotic being a remedy which tends to produce a depressed state of consciousness. Consciousness is a function of the cerebral cortex. The rapidity of the onset of narcosis varies greatly with the different narcotics, but the degree of narcosis increases in a regular way with the amount given. Slight narcosis, for example, shows merely in a tendency to quietness, while greater degrees show in succession drowsiness with mental and physical sluggishness, then sleep, not quite like the natural sleep, then stupor, and finally loss of consciousness (coma). Stupor, or torpor, is a condition of unconsciousness or semicon- sciousness from which one can be aroused, but with difficulty; and coma, a condition of unconsciousness from which one cannot be aroused. The classes of narcotics are: (i) General Anesthetics; (2) Intoxicants; (3) Hypnotics; (4) Antihysterics. Narcosis Theories. There are several theories as to the manner in which narcotic drugs reach the cerebral cell contents, and as to how they act to produce anesthesia. The best known are: 1. The Meyer-Over ton, which was propounded by Meyer and Overton independently. It is that these drugs exert their main action on the central nervous system, because they are taken up by the fats and lipoids which abound there, and so are held in considerable amount in contact with the cell structures. The lipoids are lecithin, cholesterin, cerebrin, protagon, etc. Accord- ing to these authors, the anesthetic property increases with the solubility in fats and lipoids and the insolubility in water. The relation of the activity of hypnotics and anesthetics to their solubility in lipoids is certainly a striking one, and there is a very large amount of evidence supporting this theory, which is the one most generally accepted. It, of course, merely indicates how the anesthetic gets to the nerve-cell, and not what takes place in the cell. 2. The Theory of Moore and Roaf. They believe that nar- cosis or anesthesia is due to a change in the protoplasm of the cerebral cells by the formation of- loose compounds of ether, chloroform, etc., with the cell proteins, and that this results in limitation of the activities of the cerebral protoplasm. On account of the instability of the compounds, these remain formed only so long as the vapor-pressure of the anesthetic in the blood is maintained; so on stopping the administration of the anes- NARCOTICS 283 the tic the narcosis soon ceases. In the words of Moore and Roaf, "that a certain amount of the anesthetic will be taken up by the lipoid in a physical fashion there can be no doubt, because of the high solubility of these anesthetics in such lipoid substances. But we hold that the portion of the anesthetic so taken up and held by the lipoid is passive and not active, and that it is the portion taken up by the protein which is active in paralyzing protoplasmic activity and producing anesthesia. It is a matter of common knowledge that the greater the amount of fatty tissue in a subject undergoing anesthetization, the greater is the amount of anesthetic required. The portion of anesthetic absorbed by the lipoid is imprisoned, and more anesthetic must be given in order to raise the (vapor) pressure of the anesthetic sufficiently to cause combination between cell protoplasm and anesthetic, with resulting anesthetization." The one theory assumes that the ether dissolved in the fats and lipoids is the anesthetic ether; the other considers this ether lost or imprisoned, and the anesthetic ether to be only that which enters into combination with the cell proteins. 3. That of Verworn. He accepts the Meyer-Overton theory as showing the properties necessary for an anesthetic to reach the field of action. But he goes on to give an explanation of the cause of the depression of the activity of the cerebral cells. He shows that in narcosis there is interference with the oxidative processes of the cells, or, in his own words, "the factor which produces the characteristic symptom-complex of narcosis is under all circumstances the suppression of the power to carry on oxidations." His theory is that narcotics render the oxidases (the oxygen carriers) in living tissues incapable of carrying oxygen. He shows that this may take place in any cells of the body, but that the cells of the cerebral cortex are especially sen- sitive to lack of oxygen, and are depressed with very much less of the narcotic than is necessary to depress the nerves and muscles. One of his experiments may be cited: The sciatic nerve of a frog was deprived of oxygen until its irritability was much reduced and its conductivity lost. It was then narcotized with ether. During the ether, oxygen was supplied for a long time, but it had no effect whatever upon the narcosis. Then nitrogen was sub- stituted for the oxygen, and the narcotic was stopped. Still, though the ether passed off, the functions were not restored in the nitrogen atmosphere. After a while the nitrogen was re- placed by air, and in one minute the nerve had recovered its conductivity and its irritability. That is, so long as the cell was under the narcotic influence, oxygen had no power to set the cell functionating, but did set it functionatino; when the narcotic had 284 PHARMACOLOGY AND THERAPEUTICS been removed. Also the mere removal of the narcotic was not enough, but oxygen was necessary to restore the lost functions of the cell. In opposition to this theory is the demonstration by Winter- stein that intestinal parasites keep alive and active in unoxygen- ated fluids, yet respond by narcosis to alcohol and chloroform; and the demonstration by Loeb and Wastenys that in certain low forms profound narcosis can be induced without any note- worthy diminution of the normal rate of oxidation, and that in order to depress oxidation a narcotic must be given in far greater concentration than is required for narcosis. General Anesthetics The ones in common use are: Ether, chloroform, nitrous oxide, ethyl chloride, and magnesium sulphate. As ether and chloroform have uses in therapeutics which do not involve the production of general anesthesia, we shall first take up their general pharmacology and therapeutics, and after- ward their special uses as anesthetics. ETHER Ether, or ethyl oxide, (C 2 H 5 )2O, is obtained by distilling a mixture of sulphuric acid and alcohol. It is a very volatile, light, colorless, limpid liquid, with a burning, unpleasant taste and a characteristic penetrating odor. It boils at about 35.5 C. (96 F.), and should, therefore, boil when a test-tube of it con- taining some broken glass is held for a time closely grasped in the hand. It is highly inflammable, and its vapor mixed with air is explosive. It mixes freely with alcohol and chloroform, and is a solvent of resins, fats, oils, adhesive plaster, and collodion. It is soluble up to about 8 per cent, in water and u per cent, in blood-serum. Its chief impurities are acids, acetaldehyd, and peroxides. Even in originally pure specimens these impurities may develop in the presence of light and air. They are removed if the vapor is passed through water. Preparations and Doses. Ether (aether), by mouth, 15 minims (i c.c.). Spirit, 32.5 per cent., i dram (4 c.c.). The long-used remedy, Hoffmann's anodyne (compound spirit of clhcr, consisting of ether, 32.5 per cent., and ethereal oil, 2.5 per cent.), i dram (4 c.c.), is no longer pharmacopceial. It has a sharp, unpleasant taste, but is the favorite preparation for stomach administration. ETHER 285 Pharmacologic Action. Ether is a general protoplasmic poison. Microorganisms. It is disinfectant. W. H. Park found that a mixture of 3 parts of ether and one part of olive oil would kill colon bacilli in one minute. Skin, Mucous Membranes, and Peritoneum. If applied to the skin and allowed to evaporate, ether blanches and cools the part by its rapid evaporation; if it is applied in the form of a fine spray, it evaporates so rapidly that the part is numbed by the cold or may even be frozen. If applied to the skin and not allowed to evaporate, it irritates and is rubefacient. To mucous mem- branes it is very irritant, so for administration by stomach it requires dilution with water, and for administration by the lungs it requires dilution with air or oxygen. To the peritoneum it is not irritant. Alimentary Tract. It has a burning, unpleasant taste, irri- tates the mouth, and induces a reflex flow of saliva and mucus. In the stomach, if given undiluted, it burns and may induce vomiting. If moderately diluted, it is carminative, tending to promote the expulsion of gas and to relieve with great promptness the reflex and direct effects of a distended stomach upon the heart, the diaphragm, and the abdominal contents. It also over- comes colic. As it is so volatile, it is very prompt in its action, but it may produce eructations of ether-tasting gas, especially in fever or if given with hot water. Absorption is very rapid, whether the administration is by stomach or rectum or lungs. Circulation. From local irritation, whether from inhalation, swallowing, or hypodermic injection, there is a prompt but mo- mentary reflex stimulation of the heart's rate and force with rise in arterial pressure. This is due probably to reflex stimulation of the accelerator center and reflex stimulation of the vasocon- strictor center. It is a slight effect at best, and is proportional to the degree of local irritation produced. Muehlberg and Kramer have shown that the injection of a few minims of undiluted ether into the carotid artery of a rabbit, so that it passes at once to the medullary centers, is followed immediately by intense stimulation of the vagus and vasocon- strictor centers. Thus it causes vagus weakening of the heart, and at the same time excessive peripheral resistance. The result is stoppage of the heart in a condition of dilatation. In laboratory animals death in this manner frequently results if an overwhelming amount of ether is administered at the outset. In man no such deaths are reported, and this may be because ether is so irritant that it needs to be administered gradually. 286 PHARMACOLOGY AND THERAPEUTICS For it is found that if the administration is gradual, whether by inhalation, by rectum, or by vein, the centers become narcotized so that they are resistant to the irritant effect. In careful anes- thesia the effect upon the medullary centers is very little if any at first, but after a time they become depressed. The heart muscle may be temporarily stimulated, as it tends to be by protoplasmic irritants, but after a time, in prolonged anesthesia, or if overwhelming amounts of ether are given, it shows weakening. Loeb found that when the perfusing fluid contained 0.4 per cent, of ether, an isolated dog's heart stopped in extreme diastolic relaxation. With amounts such as are used in the average anesthesia there may be a rise in blood-pressure for the first fifteen minutes, and then a slight lowering to the normal or slightly below normal. The rate is somewhat increased, and there is marked flushing of the skin from dilatation of the cutaneous arterioles. Blood. As administered to man, ether does not reach a concentration to interfere with the oxygen-carrying power of the blood. Viscosity and coagulation are scarcely affected, if at all. Mann says that the number and fragility of red blood- cells and the amount of hemoglobin are unchanged, but the number of leukocytes is regularly increased. Respiration. The reflex stimulation from mouth, stomach, or respiratory passages extends to the respiratory center, and breathing is at first quickened and deepened. Henderson thinks that this, with the resistance in the first stages of anes- thesia, is a possible cause of acapnia. After absorption, ordinary amounts have little effect; but large amounts, as in anesthesia, tend to depress the center. The usual cause of death is asphyxia from respiratory paralysis. In experiments with very dilute ether the respiration regularly fails before the heart, though the latter is very weak and interferes with restitution. Nervous System. Like other strong carminatives, ether tends to overcome hysteric conditions and states of nervous instability. It probably acts reflexly from the stomach as a cerebral stimulant, promoting the control of the highest cen- ters. After absorption it acts as a direct cerebral depressant or sedative, depressing the intellectual centers and the motor areas. Hence small amounts may be hypnotic, and large amounts will induce coma, as in anesthesia. For the nervous structures themselves it has a special affinity, and after an ether death more ether is found in the brain than in any other organ. There are several theories to account for this accumulation in the central nervous system, and the production ETHER 287 of narcosis by ether, chloroform, and similar substances. We shall speak of them later. In poisoning by ether there is a progressive depression of the central nervous system. The higher cerebral functions, those involving intellectual processes, as self-control, judgment, and reason, are the first to succumb, so that the emotions are freed from control. Then the emotions, the perceptions, the motor functions, and coordination by the cerebellum are depressed. Then there is abolition of the spinal reflexes, and finally depres- sion of the vital medullary centers. Sensory centers are affected before motor, so complete insensitiveness to the surroundings and to pain, i. e., complete abolition of the perceptions, precedes complete muscular relaxation. The action of ether upon the brain and spinal cord is directly antagonistic to that of caffeine and strychnine. The sensory nerve-endings are also somewhat depressed. Eye. As affected in the production of anesthesia, the pupil is at first dilated reflexly, either from excitement, from irritation of the nose and throat, or from pain. It has the usual sensi- tiveness to light. In the stage of stupor it contracts as in sleep and is still quite sensitive to light. In the stage of complete anesthesia it is in mid-dilatation (Hewitt says 3.5 to 4.5 mm. in diameter) and almost insensitive to light. This is due to depres- sion of the third nerve center, which in the light reflex controls the constrictor muscle of the iris. In the stage of collapse the pupil is dilated and insensitive to light, owing to the paralysis of this center. Muscle. In perfusion of a limb there is no weakening of the muscle unless the ether concentration is high. Temperature. From large doses the temperature tends to fall, both because of a striking diminution in the production of heat on account of the diminished muscular activity and loss of tone, and of increased dissipation of heat through wide dilatation of the cutaneous vessels and sweating. The fall in temperature will be increased by exposure during an operation. Elimination is rapid and essentially by the lungs; it is prob- able that in prolonged anesthesia some passes out in the urine. Kidneys. During anesthesia there is inhibition of urine formation, owing to contraction of the arterioles; after the anes- thesia there is diuresis (Hawk). After anesthesia the excretion of phenolsulphonephthalein is often considerably retarded and there may be other evidences of kidney retention, notably hyperglycemia without glycosuria. Rarely there is glycosuria, Albuminuria is frequently noticed, perhaps in one-fourth of the cases, the statistics in published reports varying from 5 to 36 per PHARMACOLOGY AND THERAPEUTICS cent. The condition is usually transitory, but occasionally it goes on to an acute nephritis, with albumin and blood in the urine. This would seem to indicate direct irritation of the kidney cells by the ether, but it is a result that may be due to the local contraction of the renal vessels, to partial asphyxia, or to acidosis. Acetone is also frequently found in the urine for one or two days after the anesthesia. Skin. From moderate doses there are flushing of face and neck and a tendency to sweating. From anesthetic amounts there is usually flushing of the whole skin with profuse sweating; and sometimes mottling of the skin or a general erythema of transitory nature the so-called "ether rash." The ether habit is sometimes encountered, the devotee inhal- ing frequently through the nostrils or swallowing the diluted drug. Therapeutics of ether when not employed as a general anesthetic. Externally and Locally. It is used to cleanse the skin preparatory to operations, small or large. It has been em- ployed for peritoneal lavage in tuberculous and purulent perito- nitis. (It does not irritate the peritoneum.) Internally. It is employed in the form of Hoffmann's anodyne. Though the taste is rank and unpleasant, this is one of our most powerful carminatives. On account of the volatility, eructations may keep bringing this taste back into the mouth. The therapeutic uses of Hoffmann's anodyne are: 1. As carminative and reflex stimulant in flatulence, and espe- cially in faintness or fainting following distention of the stomach. 2. To relieve angina pectoris and allied cardiac disturbances. It acts by relieving stomach distention and by its reflex effect upon the circulation. j. To relieve dyspnea (bronchial, cardiac, or that due to a much-distended stomach) . 4. To relieve spasm as in intestinal colic, spasmodic asthma, and hiccup. 5. To allay hysteria and states of nervous instability. Because of the bad taste and eructations it is sometimes mixed with ichthyol and the tinctures of valerian and asafetida to form the "bum mixture," a preparation which is given to hospital bums when they come in on various pretexts of illness merely to get a bed and meals. The repeated gas eructations caused by the ether keep the taste of this mixture in the mouth, and the result is the willing departure of the patient from the hospital. Aur. B.P.I Fig. 38.- Chloroform, 10 breaths, (/>) diminished the contractility of both auricle and ventricle, and caused a fall in blood-pressure from 76 to 56 mm. Caf- feine, 5 mg. per kilo, (a) resulted in increased contractility of auricle and ventricle (down-stroke), and a rise in blood-pressure from 68 to 82 mm. The effect was somewhat lasting. (Tracing made by Dr. C. C. Lieb.) CHLOROFORM 289 CHLOROFORM Chloroform (chlorof ormum) , CHCl a , is a non-inflammable, volatile liquid, which is about i^ times as heavy as water, boils at 141 F., and has a burning, strikingly sweetish taste. It mixes freely with alcohol, ether, and the oils, and dissolves to the extent of about 0.5 per cent, in water (U. S. P.). Moore and Roaf found it to be soluble to the extent of 0.95 per cent, in water, and to the extent of 4 per cent, in blood-serum, and their work indicated that this extra solubility in serum was due to the forma- tion of a loose protein compound. On long standing, or if exposed to sunlight or a flame, chloro- form may decompose, with the formation of free hydrochloric acid, or the poisonous carbonyl chloride (COC1 2 ), or free chlorine, which is very irritating. Alcohol acts as a preservative, as the chloroform does not undergo decomposition so long as there is any alcohol present to be oxidized. Hence the Pharmacopoeia specifies that 0.6-1 per cent, of alcohol shall be present. Preparations and Doses. Chloroform, 5 minims (0.3 c.c.). Water (| per cent.), 4 drams (15 c.c.). Spirit (6 per cent.), 30 minims (2 c.c.). Liniment (chloroform, 30 per cent., soap liniment, 70 per cent.). Pharmacologic Action. Chloroform is a general proto- plasmic poison of considerable destructive power. If concen- trated, it will cause the death of tissues with which it comes in contact; and even when dilute, as in the blood, it can readily produce degenerative changes in various organs of the body. This striking property seems to be common to various hydro- carbons which contain chlorine. Microorganisms. Chloroform is antiseptic, and even in such a dilute solution as "chloroform water" (| per cent, in strength) will retard putrefaction and fermentation, as in urine. Local. It is less volatile than ether, so is less cooling to the skin, and its tendency is rather to irritate than to soothe. If it is dropped on the face from a chloroform inhaler and prevented from ready evaporation, it will make a decided burn. In lini- ments, if evaporation is prevented by covering with flannel or oiled silk, it is counterirritant. Alimentary Tract. Undiluted, it is very irritating to throat and stomach; but its official preparations, being very dilute, are sweet to the taste and pleasant carminatives. They are also soothing to the stomach and antemetic. It is said that the activity of rennet and pepsin is promoted by solutions of less than 0.5 per cent, strength, and retarded by strong solutions. 19 2 go PHARMACOLOGY AND THERAPEUTICS Heart. In perfusing an isolated heart, the addition of a small amount of chloroform results in a momentary strengthen- ing, followed very quickly by muscular weakness, the heart soon becoming dilated and the beats small and ineffective. The drug is a strong poison to cardiac muscle. Sherrington and Sowton found that in a perfusion fluid a strength of 0.05 per cent, of chloroform was sufficient regularly to arrest the heart, but that restoration would take place on returning to pure saline. That is, when the osmotic pressure of chloroform in the cardiac cells is below a certain limit, the heart beats again. If too strong chloroform is used, the heart cannot dissociate itself from the chloroform and death ensues. Levy and Lewis, experimenting with cats, found that light anesthesia, i. e., with the tension of chloroform vapor in the inspired air between 0.5 and 1.5 per cent., regularly produced irregularities in the action of the ventricle, of the types described under "Digitalis" as due to excessive irritability. They observed paroxysmal tachycardia (of ventricular origin), premature ven- tricular contractions, and ventricular fibrillation. The increase of the vapor tension to 2 per cent, was regularly followed by the disappearance of the irregularity. Levy considers this due to muscle weakening and dilatation which he considers protective against fibrillation. With the low-tension vapor, a small intra- venous of epinephrine hydrochloride produced the worst form of irritability, viz., ventricular fibrillation, which usually means immediate death; with the higher tension vapor a small intra- venous of epinephrine produced the irregularities which had been observed to result from the low percentages of chloroform alone. Of considerable importance in anesthesia is the finding of Cushny and Edmunds that the heart may be dilated and very weak before there is any noteworthy change in its rate. Arteries. The vasoconstrictor center, after a primary ir- ritation, is depressed. Bayliss, who has done much work in inhibition, thinks that the vasoconstrictor center is changed by chloroform so that afferent impulses which normally result in vasoconstriction, now result in vasodilatation. (See Sherring- ton's theory under Strychnine.) In some cases the destructive action results in fatty degenera- tion of the heart, the cardiac ganglia, and even the arteries. This is particularly likely to be the case after the prolonged admin- istration of chloroform for anesthesia, or the repetition of its administration as an anesthetic within a day or two. In anes- thesia, death sometimes takes place from collapse, due to depres- sion of the heart and arterial muscles or to ventricular fibrilla- CHLOROFORM 2QI tion. In the early stages of the anesthesia, before the patient is fully anesthetized, death may be due to powerful reflex stimu- lation of the vagus and vasoconstrictor centers, the latter caus- ing abnormal peripheral resistance against a weakened heart. Muehlberg and Kramer, by the injection of a few minims of chloroform into the carotid artery or jugular vein of laboratory animals, obtained intense stimulation of the vagus and vaso- contrictor centers with heart failure. Respiratory. There is a decided depression of the respiratory center, preceded by a very short period of stimulation. In some cases respiratory paralysis is the cause of death, and in experi- ments with the much diluted vapor the respiration regularly ceases before the heart; but the heart is too weak to permit resuscitation. In the throat and bronchi, if the vapor is prop- erly diluted, it is not irritating and may even be soothing, so that cough or bronchial irritation may be less after the anesthesia than before (Bennett). Nervous System. The effects are practically those of ether, the cerebral and spinal depression, however, following more rapidly and from a much smaller amount of drug. The highest intellectual functions are depressed first, then, in succession, the emotional and motor, the cerebellar, the spinal, and finally the medullary. By removing the pia from a portion of the cord to exclude that portion from the action of the drug, Bernstein tried to find the exact site of action of chloroform. On lightly anesthetizing the animal he found that on irritating the afferent nerves whose cells \vere in the excluded area reflexes could be obtained involving motor cells in the chloroformized parts of the cord, i. e., the motor cells where not paralyzed. But on irritating the afferent nerves whose fibers passed through the chloroformized part of the cord, there was no motor response at all. Therefore, he concluded, the action of chloroform must be on the first synapse or the intermediate neuron of the afferent system, the same structure, probably, that is excited by strych- nine. (See Fig. 37.) With larger amounts of chloroform the motor cells or their synapses are also paralyzed. Eye. In complete anesthesia the pupil is rather contracted, and of about 1.5 to 3 mm. in diameter, i. e., two-thirds the diam- eter of the ether pupil. Elimination is chiefly by the lungs and is rapid. Traces are also found in the urine; also in milk and fetal blood. Kidneys. Figures as to the occurrence of albuminuria after ether and chloroform vary considerably with the different writers. After 41 ether anesthesias Babaci and Bebi noted albuminuria in 35 per cent.; while after 54 chloroform anesthesias, albuminuria 2Q2 PHARMACOLOGY AND THERAPEUTICS occurred in only 18 per cent., i. e., ether proved twice as likely to produce albuminuria as chloroform. On following up their observations \vith experiments on dogs, guinea-pigs, and rabbits, these investigators found that though ether more readily causes a passing or functional albuminuria, chloroform is more prone to produce destructive changes, i. c., fatty degeneration and perma- nent inflammatory lesions. Hence chloroform, though less prone to produce albuminuria, is more dangerous to the kidneys than ether. Metabolism. Chloroform tends to produce fatty changes in various organs, in the following order of extent and frequency: liver, kidneys, spleen, heart, arteries and cardiac ganglia, and perhaps the lungs. The main effects on metabolism are due to the marked de- structive changes in the liver leading to necrosis. There is a decrease in the storage of glycogen, and, as a consequence, an increase of sugar in the blood. In the urine there is increase in phosphates, chlorides, sulphates, and total nitrogen, the am- monia nitrogen being increased while the urea is decreased. The urine sometimes contains sugar, acetone, and allied bodies, and cystin, leucin, or tyrosin. These effects are evidences of increased destructive metabolism with incomplete oxidation. Therapeutics of Chloroform, Aside From its Use as Anes- thetic. Externally. (i) In liniments, as a riibcfacicnt for mus- cular, joint, and neuralgic pains. (2) On cotton in a decayed tooth for toothache. Internally. (i) As a mild and pleasant carminative in flatu- lence or colic the \vater or spirit. (2) As an antemetic in re- fractory cases of vomiting one dram of the water every hour. (3) As antihysteric and cerebral sedative the spirit. The Chloroform habit is not uncommon, the sweet taste and narcotic action making the drug a rather pleasant dose. In some cases it is rubbed into the gums. The effects of the habit are similar to those of the chloral habit. (See Chloral Hydrate.) ETHER AND CHLOROFORM AS GENERAL ANESTHETICS When one of these drugs is administered in sufficient amount to put the patient into a state of coma, with muscular relaxation and the abolition of nearly all reflexes, the patient is in a condi- tion of "complete general anesthesia." The study of general anesthesia is, then, a study in toxicology; and the production of ether or chloroform anesthesia is the production of acute ether or chloroform poisoning, the patient being drugged into a state of narcosis bordering on collapse. The objects of general anesthesia are: to abolish pain, con- sciousness, and muscular resistance. To be useful as a general ETHER AND CHLOROFORM AS GENERAL ANESTHETICS 293 anesthetic a drug must be very rapidly absorbable, must act quickly to produce narcosis, and must be very rapidly eliminated; and it must be capable of producing muscular relaxation as well as complete unconsciousness, i. e., abolishing cerebral and spinal activity, without dangerous depression of the vital medullary centers or any permanent effect upon the central nervous system. As these drugs are highly volatile and their vapor is rapidly absorbed by the lungs, their administration by inhalation is preferred as being more controllable and more easily continued for a long time; but a sufficient dose by mouth or rectum or vein will also produce anesthesia. We shall take up ether anesthesia first, then compare chloro- form anesthesia with it. For general anesthesia, ether is regularly administered by inhalation, the vapor being diluted with air or oxygen and ab- 460"""- SATURATION S 22C ASPHYXIAL INDUCTION ZONE RAPID AND DANGEROUS ZONE FOR RESISTANT SUBJECTS /*KnO TNOUCT!ON\ / RELAXATION \ f IN 7-10 MIX \ 7' iow iNoucnoM X- v \ RELAXATION V\ IN 12-15 MIM. A V /TlRRITATION, MUCOUS \ / (SUBCONSCIOUS EXCITEMENT >w /fsLIGHT IRRITATION \. /(CONSCIOUS EXCITEMENT Xv APUNGENT ODOR ^'^^^.^ /(CONFUSION AND SOMNOLENCE ANAESTHETIC 3O mm /ETHER ODOR ' EQUILIBRIUM /[SU6HT CONFUSION 1 1 3-5 NIN. jj 3-7 MIM. |^ 2O-40MIN. ^ MANY HOURS ^ STAGE / ( INDUCTION FULL SURGICAL ANAESTHESIA Fig. 39. Vapor pressure of ether in tidal air for induction and maintenance of full anesthesia. Partial pressure of vapor in millimeters of mercury (Karl Connell in "Operative Therapcusis," edited by A. B. Johnson, D. Appleton & Co. sorbed by the lungs. To avoid dangerous irritation of the respiratory passages and to prevent asphyxia, the ether vapor must be diluted with air for administration by the lungs, just as Hoffmann's anodyne must be diluted with water for adminis- tration by the stomach. "To establish and maintain full surgical anesthesia the blood flowing past the neuron must contain constantly about \ per cent, of ether, or, in terms of tension, 50 mm. of ether and it is only by high percentages of vapor in the pulmonary air that the arterial blood can be recharged 294 PHARMACOLOGY AND THERAPEUTICS constantly to proper anesthetic tension and the central nervous system reduced to a state of quiet anesthesia within reasonable time" (Connell). Therefore to induce anesthesia quickly it is necessary that the air-ether mixture, which is begun at about 4 per cent, to avoid primary irritation, shall rapidly reach 1 6 to 24 or even 28 per cent. To maintain anesthesia it must be kept at about 6 to 7 per cent. With a proper adjustment of the amount of air and' the amount of ether a patient may generally be kept anesthetized for a long period, even for three or four hours, with- out any serious symptoms manifesting themselves. For convenience of study the production of ether anesthesia may be divided into four stages : 1 . Local action and blunted perceptions. 2. Intoxication. 3. Stupor, or partial surgical anesthesia. 4. Coma and muscular relaxation, or complete, surgical anesthesia. Beyond this stage we get collapse, and finally death, a highly regrettable outcome of our voluntary poisoning. It must be borne in mind that there is no sharp line of demar- cation between these several stages, and that some of the symp- 4. ex iZ8X I98X aor. SUBcSot^ "-wya-. MC^WT com* S MOVC vOUHONAL MOVEMENT cO-ORDlMATt THOOOMT Fig. 40. Zones of ether anesthesia (Karl Connell in "Operative Therapeusis," edited by A. B. Johnson, D. Appleton & Co., 1915). toms of one stage may occur with some of the symptoms of another stage. The division into stages is arbitrary, and is purely for convenience of study. The First Stage. This is characterized by local irritation, followed by local numbness and blunted senses. i. Subjective Symptoms. The ether vapor causes irritation of ETHER AND CHLOROFORM AS GENERAL ANESTHETICS 295 nose, throat, and bronchi, producing a sensation of choking or lack of air and a tendency to cough. Soon the lips, throat, and nose become numb, there is ringing in the ears, and the percep- tions become dulled, so that voices sound rather distant and only things close by are noticed ; but the patient can answer questions and may talk. As he loses consciousness he feels as if, no matter what happens, he is powerless to lift even a finger to help himself; but he is in a dreamy, resigned state, and doesn't really care what does happen. 2. Objective Symptoms. The skin soon becomes warm and flushed, the pupils are dilated from excitement or from irritation of the nose and throat, the heart is rapid, and arterial pressure is raised from the reflex stimulation of the vasoconstrictor center. Respiration is also reflexly stimulated, but, because of the cough and the irritation of the respiratory tract, there is resistance to breathing, hence it is irregular. The second stage is characterized by intoxication, or drunk- enness, similar to that from alcohol. The highest centers of the cerebrum those which exert judgment, self-restraint, etc. the intellectual centers, are depressed, and the emotional and the lower animal tendencies are more or less freed from the normal intellectual control. So the patient is childish, or may sing, or shout, or rave, or swear. He may push away the inhaler, or try to get up. He may repeat over and over something that the doctor has said, and may make ugly comments on the char- acters of his attendants in fact, he is drunk. Though his perceptions are dulled, he is still sensitive to pain. On recovery from the anesthesia he has no memory of this stage. The skin is flushed and may show an ether rash; and because of the resistance to respiration and the necessity at this stage of giving rather concentrated vapor, it may become somewhat cyanotic. If the stomach contains food, there may be vomiting. The pupils are dilated and react to light, and there may be rolling of the eyeballs or strabismus, with the eyelids wide open. The heart continues somewhat rapid and there may be raised blood- pressure. If the patient is an alcoholic, very fat; or robust and athletic, this stage is rather prolonged; and a very large amount of ether, or a vapor concentrated even up to 30 per cent., or the addition of chloroform, may be required to complete the anes- thesia. The third stage is that of stupor, i. c., unconsciousness from which one can be aroused only with difficulty. The pupils are contracted as in sleep, the heart is strong and regular and slower than before (though not slower than normal), the breathing is deep and regular, the color of the skin is good. 2Q6 PHARMACOLOGY AND THERAPEUTICS The intoxication stage is over, but there is not complete anesthesia, for if the knife is used in this stage, the patient will wince, or may be aroused by the pain and try to get up. The muscular relaxation is also incomplete. The pupil dilates with pain and contracts readily to light. The patient may be kept in this stage for any length of time, or may quickly be brought into The fourth stage, which is characterized by great muscular relaxation and complete unconsciousness, from which the patient cannot be aroused, i. e., coma. Most of the voluntary muscles are relaxed. An arm or a leg raised in the air falls limp, and the face is expressionless from relaxation of the face muscles. The sphincter ani is one of the last of the voluntary muscles to be paralyzed. The respiratory muscles, of course, are not paralyzed. Smooth muscle loses its tone less readily than voluntary muscle, and intestinal peristalsis is sometimes observed on opening the abdomen. The skin is usually flushed and hot, and is covered with sweat (hence the need of protecting the patient from catching cold) . In the mouth and throat saliva and mucus are abundant. The pupils are in mid-dilatation and react so sluggishly to light that their contrac- tion may be difficult to detect. The eye reflexes disappear, the absence of the corneal or conjunctiva! reflex being one of the indications that the patient is well anesthetized. The heart is regular and of fair force. Its rate is moderately increased. Arterial pressure is good, but in prolonged anesthesia alowly falls. The respiration is regular and may be stertorous or snoring, or may be impeded by the tongue or the collection of saliva and mucus, large amounts of which are secreted in the throat and bronchi (the throat must be kept clean, the jaw and tongue kept forward). The temperature falls, so that the patient must be kept well covered. All sensation and nearly all the reflexes are abolished. This is complete surgical anesthesia, a state in which the patient may be kept for a considerable length of time. The anesthetist recognizes this stage when the corneal reflex is absent, and the raised arm falls limp, i. e., is completely relaxed. If the patient passes beyond this stage, he goes into collapse, with depression of the vasoconstrictor and respiratory cen- ters and of the heart muscle; the pupils usually become dilated and do not react to light. The common danger-signs in ether anesthesia are: 1. Increasing weakness or increasing rapidity or irregularity of the pulse. It should be remembered that the heart may be quite weak before its rate increases. 2. Slow, shallow respiration, with cyanosis. 3. Pupil dilated and without reaction to light. ETHER AND CHLOROFORM AS GENERAL ANESTHETICS 297 Recovery. In recovery from the anesthesia the third and second stages may be passed through slowly, and there is a tendency for the patient to remain asleep until awakened by nausea or vomiting or some other disturbing factor. But there may be a period of struggling and incoherent speech, followed by a deep, quiet sleep; or a period of prolonged quiet with regular breathing as if the patient is deep in anesthesia, and then sud- denly a cry, or vomiting, or an attempt to get up. A careless or inexperienced anesthetist may allow such a partial recovery before the end of the operation, or even before the surgeon begins work, this state of "false anesthesia" being recognized only when the patient moves or gives signs that he is going to vomit. It is a standing rule that if the pupil reacts readily to light, more of the anesthetic is required. Vomiting is expected when, the pulse remaining good, there are a long pause in the breathing and a paling of the face. The vomitus consists of swallowed mucus and saliva, and any other material that may be in the stomach, such as food. As muscular relaxation prevents its full expulsion, the head should be turned to one side, to allow the vomitus to run out of the mouth; other- wise the vomitus may be drawn into the lungs. After-effects. 1. Usual (a) Vomiting is a regular sequel of ether anesthesia; and nausea may persist for two or three days, with disgust for food, headache, lassitude, and sometimes a per- sistent taste of ether. The vomiting may be due to irritation of the stomach by the ether in the swallowed secretions; it is said to be absent usually in rectal or intravenous anesthesia or in- tratracheal insufflation. The taste of ether is due to suggestion, or to the slow excretion of the last portions of the ether. It has been attributed to a condition of acidosis. If it persists after a few hours, the stomach may be lavaged with a solution of sodium bicarbonate; or 3 and quinine bisulphate, gr. \ (0.03 gm.). Another formula is : camphor and quinine sulphate or bisulphate, of each, \ grain (0.03 gm.), and fluidextract of belladonna, \ minim (0.015 c.c.). They are often prescribed "half strength." Of stramonium, the ointment contains 10 per cent, of extract. Of the alkaloids, the dose is yi^ grain (0.0004 g m -)> the maximum beginning dose being ^V grain (0.0012 gm.). The official salts are: atr opine sulphate, hyoscyamine hydrobromide, hyoscyamine sulphate, and scopolamine hydrobromide (hyoscine hydrobromide), all readily soluble in water and alcohol. Atropine can withstand the heat of boiling water without decomposition. Hyoscine and scopolamine are chemically identical, and in spite of claims to the contrary, are considered by pharmacologists to be physiologically identical. Pharmacologic Action of Atropine. The primary actions of the group are those of atropine. They are (a) To stimulate nerve-centers, and (b) to depress nerve-endings. (a) The nerve-centers which atropine primarily stimulates, are the cerebral and the vital medullary centers. Only in highly poisonous doses does it depress these. (b) The nerve-endings which atropine primarily depresses are: 1. The sensory nerve-endings not a marked effect, but tend- ing to lessen sensation and pain. Short and Salisbury (1910) could not detect any cutaneous anesthesia. 2. The motor nerve-endings in the smooth muscle of the viscera (not in striated muscle and arterial muscle) a strong effect, tending to allay abnormal contraction of the muscles of the viscera (bronchi, stomach, intestines, bile-ducts, etc.). 3. The secretory nerve-endings a very strong effect, tending to check the mucous, digestive, and skin secretions. BELLADONNA GROUP 397 4. The ends of the third nerve in the eye a. strong effect. 5. The vagus nerve-endings so that the heart is freed from the usual inhibitory vagus control an effect that is striking but short-lived. Atropine depresses primarily these nerve-endings, whether it is applied locally or given internally, while it has no effect at all upon most protoplasmic structures. It is, therefore, a highly selective drug. In speaking thus of nerve-endings from a practical point of view, it should be noted that atropine acts on muscle after nerve degeneration, though not on the contractile substance of the muscle ; hence it probably affects some material which acts as the receptor of the nerve impulse. It is some part of the neuromuscular junction, though we speak of it crudely as the nerve-ending. Absorption and Local Action. There is slight absorption from plasters, and fair absorption from oily and alcoholic preparations, as ointments and liniments; so the drug may have an effect through the skin on sensory and secretory nerve-endings. In tests with 66 belladonna and scopola plasters Bastedo and Martin (1901) found that these had distinctly more power to stop pain than had the simple plaster without belladonna. That there is some absorption from the plasters is shown further by the oc- casional occurrence of poisoning from them. (See Fig. 51.) Absorption is ready through mucous membranes, the drug rapidly disappearing from stomach and duodenum. Alimentary Tract. The chief effects of the drug are to lessen secretion and overcome colic (spasmodic contraction with pain). The taste is bitter. (a) Secretion. After atropine, stimulation of the chorda tympani results in no secretion of saliva. This is not due to the paralysis of the center or ganglia, for stimulation of the nerve peripheral to the ganglia still produces no secretion. Stimula- tion of the sympathetic, however, continues to cause secretion and vasodilatation, hence there is no paralysis of the secreting cells themselves or of the vasodilating fibers. Therefore the paralyzed portion is the connection between the nerve and the secreting cell, i. e., the nerve-ending. There is some evidence that in large amounts atropine slightly depresses the secretory cells themselves. In the mouth the saliva arid mucous secretions are lessened, and the throat and mouth become dry, an effect which is often noticed from quite small doses. If marked, the patient cannot swallow, though he may be very thirsty. The stomach secre- tion is less affected, but is probably moderately diminished 398 PHARMACOLOGY AND THERAPEUTICS by very large doses. Riegel states that this is especially true of the acid portion of the gastric juice. The intestinal secretions tend to be lessened. The secretion of the pancreas, though under the influence of the vagus, is dependent on the presence in the blood of the chemic substance secretin, rather than on nerve impulses, so atropine has little if any direct effect upon the amount of its digestive elements. But through depression of the vagus endings it may lessen the watery portion of the secretion. The bile production has been shown also to be due partly to a substance in the blood, probably secretin, and its production is little, if any, affected. It was formerly believed that by cutting off certain nerve impulses which induce the change of glycogen to sugar, atropine promoted the storing of glycogen by the liver, therefore it was rec- ommended by Rudisch (1909) in diabetes. Forchheimer (1911) says of it: "In a large number of cases glycosuria, and with it acetone bodies, have diminished or disappeared." But in the very careful studies of two diabetics by Mosenthal (1912) atropine sulphate in amounts which gave beginning poisonous symptoms, i. e., up to T -g-g- grain (0.0045 g m -) three times a day, showed absolutely no effect on the carbohydrate tolerance. (b) Motor Activity. In the stomach, atropine tends to over- come spasmodic contraction of the pylorus, but only when given in large doses hypodermatically. Indeed, Ochsenius in Czerny's clinic found that in a child of one month it required ^ to ^ grain (0.75 to 0.9 mg.) of atropine a day to relax the pylorus. In the intestines, atropine lessens but does not abolish the vagus power (the vagus is the motor nerve of the small intestine), so that the effects of drugs which act as cathartics by stimulation of the vagus, e. g., physostigmine, may be checked; while the peristalsis from cathartics which act by direct irritation of the intestinal wall, and not through the vagus nerves, is apparently not affected. This is because atropine does not affect the auto- matic motor ganglia of Auerbach's plexus. (See Fig. 2, page 120.) It tends, however, to check the so-called "tone-waves" without checking peristalsis; and when from overirritation or from vagus overactivity there is spasmodic contraction with colicky pains, or spastic constipation, atropine tends to overcome this. To understand this action we must understand the difference between normal peristalsis and intestinal colic. In peristalsis a wave of contraction precedes the stimulating body in the intestine by about an inch, while the bowel relaxes below the stimulating body for a foot or two. That is to say, peristalsis is a coordinated, purposeful action involving both BELLADONNA GROUP 399 stimulation and inhibition. It is designed to propel the intestinal contents forward and bring them into contact with the intestinal juices. But if, instead of this coordinated wave of contraction and relaxation, there is a spasmodic contraction of the intestine about some offending body, even about an accumulation of gas, or preceding an obstruction that cannot be moved onward, there is intestinal colic or cramp; at the same time the contents are not propelled along, so there is constipation. In such a case atropine, by allaying the spasm, may permit normal peristalsis to be restored, and, as a consequence, cause a disappearance of both the cramp and the constipation. Irritant cathartics some- Vio 32 14 36 1R 40 47 44 46 48 50 52 54 56 58 ? 4 6 8 .9 10 1? 14 16 18 ?0 22 74, 26 ?fl 30 1? 34- 36J38AO V JC S 7fl I \ / \ 7fi 1 I y \ 74 j V -^ 1 7? y s y 1 I 70 ^ \ Ifl r' f -T 66 1 S4 ^ V \ 52 I fifl \ iR t v v _fc. ifi / 54 / i2 A I in \ 4? 2 HT i T 4fiV *^ V X X 1-4 0. U TJ 4? 3 \n > x 4(1 D < I E: 1- Fig. 49. Chart showing the effects of atropine on the heart-rate of a patient with vagus slowing from digitalis. The numbers at the side represent pulse beats, those at the top, minutes (James Mackenzie, in "Heart," vol. ii. No. 4, 1911). times cause this kind of colic, i. e., they tend to gripe, and to these atropine or one of the extracts is frequently added as a corrective. The constipation and colic of peritoneal irritation, anemia, lead poisoning, or fecal impaction may be overcome by atropine, but if the obstruction is immovable, i. e., of surgical nature, atropine obviously has no value. Heart. The vagus center is stimulated, but any effect from this is soon prevented by depression of the vagus nerve-endings, so that from large doses there regularly results a faster and some- what stronger heart-beat. In the mammal no direct action upon the muscle is distinguished, though in the frog a dose of atropine will temporarily revive an exhausted heart. The largest dose 400 PHARMACOLOGY AND THERAPEUTICS ordinarily employed for humans hypodermatically is -$ grain (0.0012 gm.); its effect on the vagus is seen in about twenty minutes, and lasts less than one hour. (See Fig. 49.) This vagus effect shows both at the sinus node and at the auriculo- ventricular node. Atropine is thus able to check a heart-block brought about by digitalis, and to annul the valuable action of digitalis in auricular fibrillation. In one case (Laslett) of standstill of the whole heart with pauses of five to eight seconds, atropine restored the normal rhythm by cutting off the vagus effect on the sinus node. Arteries. The vasoconstrictor center is slightly stimulated, and this, with the increased rate of the heart, causes a rise in arterial pressure. This is easily demonstrated in a dog. The contraction of the arteries is most marked in the splanchnic area. In man, however, the rise in blood-pressure from even maximal therapeutic doses is usually inappreciable, and if present is entirely due to the increased heart-rate (Sollmann and Pilcher). Berezin found no effect on the pulmonary vessels. In poisoning the vasoconstrictor center tends to be depressed. The Cutaneous Arterioles. From poisonous amounts the arteries of the skin, especially those of the head and neck, are dilated; and a flushed face or an erythematous rash like that of scarlet fever is characteristic of atropine poisoning. The flushed skin is from a central action, as there is no flushing if the sympa- thetic in the neck is divided. The Blood. It has been stated that the eosinophiles are in- creased in number, but Herrick found this not to be the case in the guinea-pig. Respiration. A large dose of atropine is followed by deeper and more rapid breathng and a considerable increase in the amount of air inspired. This is largely due to stimulation of the respiratory center. There is probably also depression of the motor endings of the vagus, resulting in dilatation of the bronchi, and depression of the sensory ends of the vagi in the bronchi, for stimuli through these usually slow respiration. In a number of cases the author failed to obtain a change in the rate of respira- tion from hypodermatic injections of -^ and J 7 grain (1-1.3 m g-)- Edsall and Means by doses large enough to cause marked in- crease in pulse-rate were unable to affect the breathing in Cheyne- Stokes respiration due to cerebral hemorrhage; but in a normal human obtained decided stimulation from a dose that produced toxic symptoms. Higgins and Means go so far as to say that any effect on the respiration is due to dilatation of the bronchi and increased metabolism. The drug is much used in narcotic poisoning, especially that BELLADONNA GROUP 4OI from morphine. Vollmer (1892) reported that a dog inspiring 4500 c.c. of air per minute was given i grain (0.06 gm.) of morphine sulphate at 8.45. At 3.40 the air inspiration was 4000 c.c. Then -$ grain (0.003 S 111 -) f atropine was given, and in fourteen minutes the inspiration was 6000 c.c.; in twenty-one minutes, 10,000 c.c. But excessive doses exhaust the center, and must be guarded against in the use of the drug as an antidote. Exhaustion of the center is the cause of death. The secretions of nose, throat, and bronchi are diminished, so that the membranes are dry and the mucus thick and tenacious. Excessive contraction of the bronchial muscles, as in spasmodic asthma, is overcome by depression of the bronchomotor vagal nerve-endings. Cerebrum. The effect from therapeutic doses is very little, but after poisonous amounts there is psychic stimulation, and the patient becomes talkative and wakeful, without any pronounced intellectual stimulation like that from caffeine. The poisoning may go on to a delirium, usually of cheerful, loquacious type, and may even result in maniacal excitement. Cerebral depres- sion does not generally ensue until the centers have become ex- hausted, and then there may follow mental confusion and nar- cosis leading to sleep, stupor, and coma. In therapeutic amounts the drug is not a narcotic. The motor areas are also stimulated by poisonous doses, as shown by the increased response to electric stimulation of the exposed brain and by the restless activity. The general ex- hilaration observed after overdoses is known as the "belladonna jag," but though it superficially resembles that from alcohol, it is true stimulation, as shown by the increased excitability of the motor areas and the larger doses of narcotic necessary to depress the intellectual powers. The medulla, after large hypodermatic doses, shows stimula- tion of the respiratory center, with weak stimulation of vagus and vasoconstrictor. Death takes place from exhaustion and paralysis of the respiratory center. The spinal cord is stimulated by large doses, the increase in reflex excitability being manifested by twitching of the muscles. In the late stages of poisoning twitching may also result from asphyxia. The peripheral nerves have already been spoken of. Comparing atropine with caffeine and strychnine as central stimulants, we might say that, in therapeutic doses, all three stimulate the medullary centers, and of these chiefly the re- spiratory; but that caffeine, in addition, stimulates the intel- lectual functions, and strychnine the spinal or reflex functions. 26 402 PHARMACOLOGY AND THERAPEUTICS Eye. Atropine has four important effects on the eye: It dilates the pupil, paralyzes accommodation, increases intra- ocular tension, and lessens pain. (a) The Dilatation of the Pupil. The iris consists of two sets of muscles the circular, supplied by the third nerve, and the radial, supplied by the sympathetic fibers from the superior cervical ganglion. These two sets of muscles are in constant action, and by opposing each other constitute an exceedingly sensitive balanced mechanism for the regulation of the size of the pupil. Dilatation of the pupil may result from circular depression or radial stimulation; contraction of the pupil from circular stimulation or radial depression, and these stimulations or depressions may be of center, ganglia, nerve-endings, or muscle-fibers. Fig. 50. Increased convexity of the lens during accommodation. The solid white outline of the lens, /, shows its form when relaxed. The dotted line shows the increased curvature of the anterior surface during accommodation, and its advancement forward into the anterior chamber, a. z is the suspensory ligament; m, the ciliary muscle; and i, the iris (Landolt). When a i per cent, aqueous solution of atropine sulphate is dropped in a man's eye, the pupil dilates in about fifteen or twenty minutes, but takes two hours more to reach the maximum dila- tation. There is no effect on the other eye. If atropine is in- jected into an excised mammal eye, the pupil dilates, and if an animal is atropinized, stimulation of the third nerve, either central or peripheral to the ciliary ganglia, is without effect on the pupil. The action is, therefore, a purely peripheral one. But it is not a direct effect upon the muscle, for in the atropinized animal direct stimulation of the circular muscle results in con- traction; therefore the site of the paralyzing action of the drug must be confined to the third-nerve endings or the neuromuscular junction. BELLADONNA GROUP 403 The dilatation from atropine is, therefore, the result of the unopposed action of the radial muscles. It is, however, fre- quently strong enough to break weak adhesions between cornea and iris, or to make an iris which is strongly attached at two points bow out between the points of attachment. The pupil gradually regains its power, but is not fully restored to normal for one or two weeks. That there is no stimulation of the radial mechanism is evident, for, after atropine, stimulation of the cervical sympathetic results in a still greater dilatation. A drug which causes dilatation of the pupil is called a mydri- atic. Belladonna gets its name from this mydriatic action (bella, beautiful; donna, lady), which makes the eye seem bright and sparkling. (b) Accommodation depends essentially on the curvature of the crystalline lens, and this curvature is regulated by the ciliary muscle. When the ciliary muscle contracts, the capsule of the lens relaxes, and the elastic lens bulges forward and be- comes more convex, i. e., accommodates for near objects. But when this muscle is paralyzed, the capsule of the lens is drawn, the lens is more flattened, and it is impossible to focus the sight on near objects. A drug that paralyzes accommodation in this manner is a cycloplegic. Atropine is strongly cycloplegic. This effect on accommodation does not take place until some time after the pupil has begun to dilate, and it wears off more quickly than the effect on the pupil; but until the power of accommoda- tion is nearly restored, the patient cannot read or see near objects clearly. In fitting glasses paralysis of accommodation is necessary. A i : 200 solution of atropine sulphate usually paralyzes accom- modation in one hour, but restoration does not take place for several days. (c) Intra-ocular Tension. The normal eyeball tension depends chiefly on two factors, viz.: (i) The amount of intra-ocular secre- tion, and (2) the freedom with which fluids may escape through the efferent lymph-channels, i. e., through the spaces of Fontana at the margin of the pupil, into the canal of Schlemm. The tension may be raised either by extra secretion or by dilatation of the pupil which results in shutting off the spaces of Fontana. It is by dilatation of the pupil that atropine causes the increase of tension. In glaucoma, a disease in which the tension is al- ready high, atropine may produce a dangerous condition; and even when there is merely a glaucomatous tendency, it may pre- cipitate an attack of glaucoma. (d) Pain. Atropine gives moderate relief from the pains of iritis and other intra-ocular inflammations. 404 PHARMACOLOGY AND THERAPEUTICS Since atropine is highly selective, the same ocular effects may be seen after the internal administration of large doses. An antagonist of atropine is physostigmine, which stimulates the ends of the third nerve. It is not powerful enough to remove the effects of atropine at once, but greatly lessens the time which the eye takes to return to normal. Muscles. Probably no direct action. The smooth muscle of the viscera is weakened by the depression of motor nerve- endings mentioned above. Secretions. Those of the alimentary tract have already been spoken of. No drug has greater power to check the sweat and mucous secretions. It does not directly affect the amount of bile or urine. Sweat. Stimulation of the sciatic nerve of a normal cat regularly induces sweating of the foot. In an atropinized animal sweating cannot be induced. The profuse sweating of pilocarpine is checked by atropine, also the sweating from certain other drugs, such as aspirin and phenacetin; also the night-sweats of tuber- culosis. Milk. After all the nervous connections are severed, the breasts still have the power to secrete milk, though the secre- tion is less in amount. Hence atropine, which merely cuts off the nervous influences, tends to reduce the milk secretion very little, and cannot cause the complete stoppage of the secretion. The drug acts when applied to the breasts, as well as when taken by mouth. Temperature. In poisoning it is characteristic that the temperature may rise several degrees. The author saw a case with a temperature of 106 F. (41.1 C.). According to Ott, this is due to the absence of sweating, for no rise of temperature takes place in animals, such as dogs, which do not sweat, and are therefore not dependent upon sweating as a means of lowering temperature. Others think it is an effect upon the heat-regulating centers. (See Cocaine.) Elimination. A considerable portion of the drug is oxidized, the remainder being eliminated rapidly by the kidneys. It is said to disappear from the body inside of thirty-six hours, but the prolonged effect on the eye indicates that some is retained in that location. Urinary Organs. The effect from therapeutic doses on the amount of urine is uncertain and unimportant; but in poisoning, both suppression and retention are reported. As the urine is a weak solution of atropine, it will exert a remote local action in the urinary tract to lessen pain and spasm. In poisoning, the urine, concentrated by boiling, will dilate the pupil of an Fig- S 1 - (General eruption following application of a belladonna plaster (W. S. Gottheil in Archives of Diagnosis). BELLADONNA GROUP 405 animal's eye; hence this may be employed as a test for the poison. Tolerance. To a certain degree tolerance may be set up in man by gradual increase in the dosage, so that as much as | grain (0.03 gm.) may be borne without ill effects. Children can take proportionally large doses; in fact, a child of eight may be given the same dose as an adult. I have seen a man of forty-five more affected by doses of 10 minims (0.60 c.c.) of the tincture of bella- donna than was his son of eight by the same amount. Among subhuman mammals it is found that the carnivora are especially susceptible to the drug, while the herbivora are markedly resistant. A cat, for instance, is readily poisoned, while a horse or a rabbit may feed on belladonna leaves with comparative impunity, though their flesh becomes poisonous to the carnivora. Successive lit- ters of healthy rabbits have been reared entirely on belladonna and stramonium leaves, and Calmus found that it took about 15 grains (actually 0.972 gm.) of atropine to kill a small rabbit. In rabbit's serum Doblin and Fleishmann have found a ferment which annuls the toxic action of atropine. Toxicology. In practice, the dilated pupil, the dry throat, and mild cerebral symptoms are the regular warnings of overdosage. In full poisoning there is a stage of central stimu- lation followed by collapse. In this stage of stimulation the skin is warm and dry; the face and neck are flushed, either uniformly or in blotches, to resemble the skin of scarlet fever; the pupils are widely dilated, and accommodation paralyzed, so that vision is disordered; the throat is very dry and red, and there is a feeling of constriction, so that swallowing, even of water, is difficult, though the patient may be thirsty; the breath is foul; the pulse is rapid, with arterial pressure above normal; respiration is rapid and deep; the patient is wide-awake, excit- able, restless, and loquacious or overcheerful, and may pass into a chattering delirium with confused ideas, or even into a condi- tion resembling mania. The temperature may rise several degrees. The concentrated urine dropped in a cat's eye, two drops every five minutes, will dilate the pupil. Belladonna poisoning has been mistaken for scarlet fever and for acute mania; with the latter diagnosis patients have been confined in asylums for the insane. Following this stage of stimulation comes collapse, with heart very feeble, blood-pressure low, respiration slow and shallow, etc. The warm, dry skin may change to a cold, clammy one, and death take place from failure of respiration. A single dose of y^ grain (0.0006 gm.) of atropine sulphate will in some patients cause dryness of the throat and dilated 406 PHARMACOLOGY AND THERAPEUTICS pupil; -gV grain (0.0012 gm.) has produced the delirium, ^ grain (0.03 gm.) has proved fatal, and 3 grains (0.2 gm.) have been recovered from. Poisonous symptoms have followed the use of atropine in the eye. Atropine may remain in the dead body for a long time un- changed. This is of importance from a medicolegal point of view, for the atropine may be mistaken for a ptomain, ptomatro- pine, which has similar chemic and pharmacologic properties. Treatment of Poisoning. The stomach may be lavaged, with or without a solution of tannic acid or tea (Sollmann says that tea is an inferior precipitant for alkaloids). For the delirium and mania an ice-cap may be applied to the head, whisky or bromides administered, and, if necessary, ether inhaled to lessen the ex- citement. (Morphine, chloral, and chloroform should be avoided because of their tendency to precipitate respiratory failure.) In the collapse stage the regular treatment is that for severe collapse. Pilocarpine and physostigmine antagonize the atropine action on certain nerve-endings, but as the poisoning is dependent upon the cerebral and medullary effects, these peripheral an- tagonists are not antidotes of any great value. Therapeutics and Administration. A. To Diminish Secre- tion. 1. Of mucus as in excessive secretion from nose, throat, and bronchi. In bronchitis, in the free running stage of cold in the head, the rhinitis tablets, full or half strength, one every hour for 6 doses, are favorites. 2. Of sweat as the liniment of belladonna in sweating of hands and feet, and atropine internally for the night- sweats of tuberculosis. 3. Of milk when excessive, or when it is desired to dry up the breasts liniment or ointment externally; or the drug internally. 4. Of saliva as in profuse salivation from any cause the drug internally. 5. Of gastric j 'nice as in hyperacidity and hypersecretion, T ^ grain (0.0006 gm.) of atropine sulphate or % grain (0.04 gm.) of extract of belladonna fifteen or twenty minutes before meals. B. To relax over contracted smooth muscle as in spasmodic asthma and the spasm of smooth muscle which results in colic. The latter occurs in the esophagus, cardia (cardiospasm) , pylorus (pylorospasm) , ileocecal valve, or any part of the stomach or intestine, in the bile-passages or gall-bladder (biliary colic), in the pelvis of the kidney or ureter (renal colic), in the neck of the bladder, and in spasmodic dysmenorrhea (in this last mentioned BELLADONNA GROUP 407 the drug may be of little use because of the congestive condition) . Atropine or extract of belladonna may be added to irritant cathartics as a corrective to prevent griping. In the obstipation which occurs in lead-poisoning and in local peritoneal irritation (as in appendicitis, salpingitis, or ovaritis, or renal or biliary colic) atropine may overcome the reflex spasm with resultant catharsis. In intestinal obstruction from suspected spasm, or in fecal impaction, a large dose, -fa grain (0.005 g 111 -)^ nas been recommended. But when there is a real surgical obstruction, such a procedure serves only to delay operation, and sometimes with fatal result. C. To depress the sensory nerve-endings to allay itching (the liniment); to lessen pain, as in ulcer of the leg, anal fissure, or projecting hemorrhoids (the ointment); and the drug by mouth for irritable bladder or urethra, as in cystitis and urethritis, and in enuresis nocturna. D. In the eye as a mydriatic, cycloplegic and analgesic, for the following purposes: 1. To facilitate examination of the internal eye posterior to the pupil. 2. To paralyze accommodation in fitting glasses. 3. In inflammatory conditions of either external or internal eye, to give rest to iris and ciliary muscle, to lessen pain, and to prevent the spread of the inflammation to the iris ; and in iritis, to prevent the formation of adhesions to the lens or cornea, or to rupture newly formed adhesions. It is employed in | to i per cent, solution, and takes a long while for full dilatation. As the dilatation of the pupil and paralysis of accommodation last several days, atropine is espe- cially useful in the inflammatory conditions; while for examina- tions and fitting glasses more rapidly acting drugs are preferred. After the continued use, for a few days, the return to normal may be delayed for twelve to fourteen days (de Schweinitz), but the restoration may be greatly hastened by the use of phy- sostigmine. In a recent symposium (1916) prominent Amer- ican oculists agreed that, to avoid the risk of glaucoma, phy- sostigmine should regularly be employed after the use of atropine or homatropine. De Schweinitz says that in the use of atropine to correct errors of refraction one drop should be dropped into the eye three times during the day preceding the examination; and in hypermetropic eyes, especially those with spasm of accommoda- tion, the drug should be used for several days before the examina- tion for refractive errors. E. In certain spasmodic nervous conditions, as in whooping- cough (perhaps enuresis nocturna under this head). 408 PHARMACOLOGY AND THERAPEUTICS F. In exophthalmic goiter (hyperthyroidism) it probably acts by decreasing the glandular secretion. (Sollmann states that atropine is antagonistic to thyroiodin.) Bromides should be given at the same time, as the cerebral effects of belladonna are undesirable in this disease. G. As preliminary to general anesthesia here it is of use to check excessive secretion in mouth and respiratory passages, to stimulate the respiratory center, and in chloroform anesthesia to prevent excessive reflex vagus stimulation at the onset. H. To stimulate respiration, as in general anesthesia, in pneu- monia, or in collapse from narcotic drugs; to prevent respiratory depression, as when given with morphine. I. To check excessive vagus action, as in the excessive inhibi- tion stage of chloroform anesthesia, and in vagus bradycardia or partial heart-block from disease or from a drug of the digitalis group. It has no value in complete and permanent heart-block. In many human experiments with hypodermatic doses the author was unable to get vagus effects with less than -fa grain (i gm.). The effects last not more than an hour. Thomas Lewis (1911) says that "atropine has never been known to abolish the whole hindrance to conduction." J. In anaphylaxis, as in serum sickness. In experiments on guinea-pigs sensitized with horse-serum, Auer (1910) reports that without atropine 75 per cent, died, and with atropine only 28 per cent. died. All the drugs of the group, viz., belladonna, scopola, stra- monium, and hyoscyamus, have actions of the atropine type, and can be used interchangeably for the ordinary peripheral effects. A special use of the stramonium leaves is in spasmodic asthma, in which condition smoke of the burning leaves is inhaled. The leaves may be burned in a saucer, either alone or with other drugs, or impregnated with potassium nitrate (that is, saturated with a solution of potassium nitrate and then dried); or they may be added to tobacco, lobelia, or cubebs, and made into cigars or cigarettes to be smoked at the time of the attack. The leaves of belladonna will serve as well as those of stramonium. The chief use of hyoscyamus is as a sedative in irritable bladder, cystitis, and gonorrhea, and as a corrective addition to irritant cathartic pills. It has no advantages over belladonna and is much weaker. Hyoscyamine (levo-hyoscyamine) is similar in action to atro- pine, which is a mixture of levo- and dextro-hyoscyamine. Cushny finds that though it acts upon the central nervous system with the same intensity as atropine, it is nearly twice as powerful in its effects upon nerve-endings, especially those of the chorda BELLADONNA GROUP 409 tympani, of the third nerve in the eye, and of the vagus. It is not readily obtained pure, and is little employed in medicine. Dose of its salts, yi^ grain (0.0004 g m -)- Hyoscine or scopolamine acts peripherally like atropine, and therefore will allay pain, will dilate the pupil, and will check secretion. But its action in the eye is more rapid and more powerful, a i : 500 solution dilating the pupil in ten to thirty minutes, and quickly thereafter paralyzing accommodation, while the effect passes fully away in three to five days. Centrally it differs from atropine in that the period of cerebral stimulation is short and is followed by prolonged mild depression of the psy- chic and motor centers that is, the drug is narcotic. It has a peculiar amnesic action, at times completely abolishing the memory of events that occurred during its action. In excitable states, as in delirium or mania, it seems to have great power to lessen restlessness or excessive motor activity. Its use is not without danger, however, for it shows early depression of the respiratory and vasoconstrictor centers, and in a great number of instances has caused collapse. Eshner and O'Hara report cases of collapse after T ^ T grain (0.0006 gm.) of the hydrobromide. The writer has seen fatal collapse from 7 V grain (0.0012 gm.) in an alcoholic man with pneumonia ; and collapse with recovery from 2 V grain (0.0025 m -) m an alcoholic woman verging on delirium tremens. In both of these the hyoscine had been preceded by ^ grain (0.015 gm.) of morphine sulphate. Tileston (1913) says that hyoscine is prone to be followed by Babinski's and Oppenheimer's signs and ankle clonus; in other words, it tends to paralyze segments of the motor tracts. Purves Stewart describes a hyoscine chorea with symptoms similar to those of ordinary chorea. Gregory reports marked delirifacient effects in many cases. Collapse is reported from the use of the drug in the eye. Its chief uses are: 1. As narcotic in the insomnia and excitement of acute mania, uremia, and delirium tremens, in the delirium of pneumonia (especially in alcoholics), and in the insomnia of alcoholism. 2. As a narcotic and peripheral sedative in treating the mor- phine and alcoholic habits. 3. As an anaphrodisiac. 4. As a mydriatic and cycloplegic one drop of a i : 500 solution every fifteen minutes for four to six drops. 5. As a general anesthetic or as a preliminary to general anes- thesia. Scopolamine-Morphine or Scopolamine-Narcophin Anes- thesia. The combination of scopolamine hydrobromide with morphine sulphate or narcophin has been employed in surgery as 4IO PHARMACOLOGY AND THERAPEUTICS a preliminary to general anesthesia and as the anesthetic itself, and in obstetrics. As a preliminary to general anesthesia, a dose of scopolamine hydrobromide, about y^y grain (0.00045 gm.) with morphine sulphate, i to ^ grain (0.015-0.03 gm.), given hypodermatically half an hour before the general anesthetic, is favored by a number, especially in operations upon nervous people, because it promotes a tranquil, drowsy state of mind, lessens the amount of general anesthetic required, diminishes the throat and bronchial secre- tions during the anesthesia, and favors postoperative sleep and freedom from pain. As a general anesthetic about -,^ grain (0.0003 gm.) of sco- polamine hydrobromide and grain (0.008 gm.) of morphine sul- phate or narcophin are injected two and one-half hours, one and one-half hours, and one-half hour before the operation. It is sometimes surprisingly successful, but a great many consider it inefficient and dangerous. In 1988 cases gathered from the literature by Wood the anesthesia proved unsatisfactory in 69 per cent., and in a number of cases had to be supplemented by ether. In addition, though the cases selected for this method were as a rule the less serious ones, there were 9 deaths which could beyond reasonable doubt be attributed to the drug, that is i in 221, a high rate of mortality for an anesthetic. In obstetrics it has come to be known as twilight sleep, though Shears calls it "morphine-stupor." The method elaborated by Kroenig and Gauss at their Freiburg clinic is as follows : When the patient is in active labor with pains every four or five minutes and the cervix admitting two to three fingers, she is isolated in a darkened quiet room and given a hypodermic of scopolamine hydrobromide, gr. y^ (0.00045 g m -) with narcophin, grain | (0.03 gm). An hour later T J- 7 grain (0.00015 gm.) of scopolamine hydrobromide is given. After another half-hour memory tests are instituted; if she does not remember the number of injections given, or when last examined, or objects seen within half an hour, she is in the required state of seminarcosis. If there is still no amnesia, a further dose of ^^ grain (0.00015 gm.) of scopolamine hydrobromide is given, and this is repeated every hour or hour and a half as needed to maintain amnesia. Ordinar- ily only one dose of narcophin is given, but if the patient is very restless, \ grain (0.015 gm.) more is injected. The whole object of the treatment is to abolish retention in the memory of the pains and distresses of the labor. On this account Kroenig recommends ethyl-chloride inhalation as the head is expelled, and the immediate removal of the child from the room lest the crv arouse the mother. ANHIDROTICS 411 In spite of extensive magazine and newspaper exploitation, the method has been largely abolished. It causes a prolonga- tion of the second stage of labor, lessens the strength of the uterine contractions and so favors post-partum hemorrhage, is the cause of an abnormal number of asphyxiated babies, and is uncertain in result (in 500 cases Zwiefel reports successful amnesia in only 31 per cent.). Furthermore the mother requires constant watch- ing, for there may be nausea, vomiting, headache, great mental excitement or delirium, or collapse. A few maternal deaths and quite a number of infantile deaths are reported. Homatropine hydrobromide (U. S. P.) is the hydrobromide of an artificial alkaloid allied to atropine. It is made by the condensa- tion of tropine and oxytoluic or mandelic acid. It is soluble in 5.7 parts of water, and is used solely for its ocular effects, one drop of the i per cent, solution being dropped in the eye every fifteen minutes for 4 to 6 drops. Dilatation of the pupil comes on quickly, reaches its maximum in one to two hours, and is followed very soon by paralysis of accommodation. The restoration of the accommodation to normal occurs in twenty-four hours, and full restoration of the pupil in forty-eight to seventy-two hours i. e., much more quickly than after atropine. Homatropine is, therefore, preferred to atropine for fitting glasses and in ophthalmoscopic examinations; while atropine is preferred where continuous mydriasis is desired, as in inflamma- tory conditions of the eyeball. Physostigmine will hasten the restoration of the eye, and it is the consensus of opinion among ophthalmologists that, to avoid a possible glaucoma, homatro- pine should always be followed by physostigmine. ANHIDROTICS An anhidrotic (anhydrotic) is a remedy which tends to reduce sweating. For local sweating, as of the hands and feet, alcohol, eau de cologne, spirit of camphor, a 25 per cent, solution of aluminium chloride, and belladonna liniment are favorites. For odorous perspiration of the feet alcohol may be used as a wash, and a mixture of boric and salicylic acids placed in the shoes or stockings. The chief use of a general anhidrotic is in the night-sweats of tuberculosis. (See discussion under Antipyretics and Dia- phoretics.) The anhidrotic measure may be a hot bath on going to bed, or a body sponge with alcohol, vinegar (or acetic acid), or a solution of alum; or it may be a drug taken internally. Atropine is our most powerful anhidrotic. It has the advantage of stimulating respiration, but it has the undesirable effects of 412 PHARMACOLOGY AND THERAPEUTICS drying the throat and increasing the cough, and may even dilate the pupil. In very extensive tests the author found that for internal administration in tuberculosis the best general anhidrotic is agaricin. Strychnine is also of value. Ergot, which has been highly recommended, seemed to have no effect at all. Calcium chloride is sometimes effective. Agaricin is an unofficial extract obtained from the fungus, Polyporus albus, which grows on the European larch. It is really an impure form of the crystalline principle, agaric acid. Its dose is -^ grain (0.006 gm.). In this dose it strongly de- presses the ends of the secretory nerves of the sweat-glands, has no undesirable side-effects, and is strongly anhidrotic; but its effects are not lasting, so it must be given within four or five hours of the expected sweat. If the sweat comes on toward morning, the dose may have to be repeated once in the night. In larger doses it sometimes induces nausea, vomiting, diarrhea, and perhaps dryness of the throat, but it does not dilate the pupil. Doses large enough to produce nausea do not give the anhidrotic action. Camphoric acid, C 8 Hi 4 (COOH) 2 , is an oxidation product of camphor. It is soluble in alcohol and the fixed oils, and slightly in water. Its dose is 15 grains (i gm.), given in cachet or powder. Its taste is disagreeable, and its systemic action is mildly that of camphor; but practically its sole use in medicine depends upon its anhidrotic property. Roth (1911) found it to be without any direct effect upon the sweat-glands, and was disposed to attribute its action in the night-sweats of tuberculosis to stimu- lation of the respiratory center. COCAINE Cocaine is an alkaloid obtained from the leaves of Erythroxy- lon coca, or of Erythroxylon truxillcnse (Earn. Erythroxylaced). The coca shrub is extensively cultivated at an elevation of 3500 to 6000 feet in the mountains of Peru, Bolivia, and Ecuador, and to some extent also in Mexico and the East and West Indies. It has been estimated that 100,000,000 pounds of the leaves are used annually in South America. They yield cocaine and several other alkaloids, all compounds of ecgonine. Cocaine is the methyl-benzoic acid compound; cinnamyl-cocaine is the cin- namic acid compound, and truxilline is the truxillic acid com- pound. Coca itself is used to some extent in the form of a wine, but the only pharmacopccial representatives are cocaine, soluble in oil, and cocaine hydrochloride, soluble in 0.4 part of water and COCAINE 413 3.2 of alcohol, but insoluble in oil. This alkaloid al salt is decom- posed at a temperature of about 98 C., so its aqueous solution cannot be sterilized by boiling. Its solutions are not antiseptic, and frequently show a growth of mold. This mold development may be retarded by the addition of boric acid. The following formulae show the close relation between atropine, cocaine, and tropacocaine. Tropine CH 2 CH CH 2 Atropine CH 2 CH CH 2 / I NCHs Ecgonine :H 2 CH CH.COOH c NCH, CHOH \ 1 Cocaine >fr ptr ^n 2 v_,n / NCH 3 \ CH 2 CH CH, CH 2 -CH- CH.COOCH 3 -CH 2 Tropacocaine CH 2 CH CH 2 / I NCH 3 CH.O.CO.C 6 H 6 \ I CH 2 CH CH 2 Pharmacology. Cocaine is of great importance pharmaco- logically, for it is very extensively employed as a local anesthetic, has marked poisonous properties, and is one of the "vicious habit" drugs. Local. Cocaine is a general protoplasmic poison, capable of irritating and destroying cells, or of stopping .the motions of leukocytes, amebae, and ciliated cells. Solutions above 5 per cent, in strength injected hypodermatically may result in death of tissue, which shows either as a necrotic area of the skin or as a sterile abscess; the application to the eye may, for the same reason, result in cloudiness or ulceration of the cornea. This effect is not usually seen, but it occurs often enough to be of importance. From application to mucous membranes or injection beneath the skin there promptly follows complete abolition of pain, from depression of the ends of the sensory nerves or their ad- jacent nerve-fibrils. In addition, there is local constriction of the arterioles from stimulation of both muscle and vasocon- strictor nerve-endings. The constriction of the vessels is not so great as that from epinephrine. The anesthesia and constriction come on in one to four minutes and last from fifteen minutes to one hour. 414 PHARMACOLOGY AND THERAPEUTICS The drug cannot penetrate the unbroken skin. The author kept a finger for fifteen minutes in a 20 per cent, aqueous solution of cocaine hydrochloride, and it showed neither anesthesia nor blanching, though one drop of the liquid on the tongue was quickly followed by loss of sensation. But cocaine is readily absorbed through mucous membranes or the moist parts of the vulva. After the injection or application there may be a momen- tary irritation, but very quickly there is complete loss of the sense of pain, with shrinkage and paling of the part from compara- tive bloodlessness. Any mucous membrane to which the drug can be directly applied becomes shrunken and anesthetic in this way, e. g., membranes of the nose, throat, mouth, esophagus, stomach, rectum, vagina, urethra, bladder, and conjunctiva. In the hypodermatic use the drug is injected just beneath the epidermis, and its action is prolonged and intensified by the addition of epinephrine. This further constricts the vessels and prevents the too ready removal of the cocaine by the circulation. For the same reason it tends to make the skin incision bloodless. In a finger or toe prolonging of the local action may result from the application of a tourniquet or band to impede the venous return flow. In the anesthesia, though the sense of pain is promptly lost, the sense of touch is not so readily abolished, and the tempera- ture is scarcely affected, if at all; hence the touch of an instru- ment or the heat of a cautery may be felt, though pain is absent. The drug at first tastes bitter, but the taste for bitter soon be- comes completely abolished, while that for sweet and sour merely becomes dulled, and taste for salt is not affected. If applied in the nose, the sense of smell is abolished. It has been found that anesthesia is produced if the drug is applied to any part of the nerve, from the nerve-ending to the posterior root; so anesthesia in therapeutics may be obtained (a) by the application of the solution to a mucous membrane; (b) by its injection beneath the mucous membrane or skin; (c) by its injection into the nerve; or (d} by its injection into the spinal canal, so that it may reach the posterior roots. This last method is known as "spinal analgesia" or "spinal anesthesia." Cocaine has not the marked selective action of atropine, but from 10 c.c. of i to 3 per cent, solution Ritter (1909) obtained in dogs a general anesthesia lasting from fifteen to thirty minutes. The dogs were fully awake, but quiet and indifferent and insensitive to pain. Meltzer, Kast, and Meyer obtained similar effects in animals. The drug affects sensory nerves very readily, but not so readily the motor nerves. If both sciatics of a frog be exposed COCAINE 415 high up in the thigh, and a little cocaine injected into the sub- stance of one of them, an electric stimulus to the nerve on the uncocainized side (or above the cocainized area on the other side) produces the usual reflex results, notably contraction of the splanchnic arteries. But no such results follow the electric stimulation of the cocainized nerve below the area of injection. Evidently, then, the afferent impulses on the cocainized side are blocked and do not pass the cocaine. But the electric stimulation of the sciatic above the cocain- ized area produces the usual muscular contraction in the leg be- low, so that motor impulses are not Hocked by the cocaine. There is, perhaps, a slight hindrance to the passage of motor impulses, as mentioned by Crile. Spinal Analgesia. To obtain spinal analgesia, \ or | grain (0.015-0.03 gm.) of cocaine hydrochloride in aqueous solution is injected into the spinal canal, the needle being inserted between the third and fourth lumbar vertebrae into the region of the cauda equina. The toes and perineum become anesthetic in about three or four minutes, and the anesthesia rapidly ascends until it reaches about to the umbilicus, the whole of the body below this point being anesthetized. There is little or no muscular relaxation; the sense of touch may not be altogether abolished, and the sensations of heat and cold are unchanged. (See also Shock and Collapse.) Jonnesco has recently made the injections higher up in the spinal cord, using a mixture of stovaine and strychnine. He reports using the method without a fatality in 1005 patients, ranging from one month to eighty-two years. Transient arrest of respiration occurred seven times. He reports 1958 cases of its use by others with safety. But this method has not met with favor in this country, and after many trials has been abandoned as unsafe. Gray and Parsons and Smith and Porter obtained a pronounced fall in blood-pressure from the high injec- tions and not from the low. Experimentally, it has been shown that cocaine injected into the spinal canal can absolutely block the strychnine convulsions of that region, but the strychnine con- vulsions come on in the muscles supplied by the uncocainized parts of the cord. Gabbett (1910) reports a death from the injection of novocaine, i| grains (0.6 gm.), and strychnine hydrochloride, % grain (o.ooi gm.). The convulsions affected the arms, but not the lags. The Eye. If a drop of 2 or 4 per cent, aqueous solution of cocaine hydrochloride is dropped into the eye, the immediate effect is marked irritation, with reflex contraction of the pupil. But this is followed quickly by anesthesia of cornea and conjunc- 416 PHARMACOLOGY AND THERAPEUTICS tiva, with blanching, retraction of the eyelids, and absence of the winking reflex hi response to an irritant. A few minutes later the pupil becomes dilated, and remains so for one or two hours. The pupil still reacts to light, though only partially, and there is neither paralysis of accommodation nor decrease in intra-ocular tension, so the effect on the eye is different from that produced by atropine. This is further shown by the fact that in a fully atropinized eye cocaine still further dilates the pupil, and that in a cocainized eye the pupil contracts on electric stimulation of the third nerve, either centrally or distally to the ciliary ganglia. These experiments show that it does not act on the third nerve. The action of the cocaine is evidently a peripheral one. If it is injected into an excised eye, it causes the same dilatation of the pupil. If the superior cervical ganglion (from which the pupil-dilating fibers emanate) is removed from one side of an animal, and after the wound has healed and the nerves have had time to degenerate, cocaine is dropped in each eye, there is a dilatation of the pupil on the intact side, but on the other side only slight dilatation if any. Hence, though there may be some depression of the circular muscles, the main action is stimulation of either the radial muscle-fibers or some part of their (sym- pathetic) nerve-supply. Accommodation is not paralyzed, as the ciliary muscle is not affected; so cocaine is not available in fitting glasses. The intra-ocular tension is not increased, and in spite of the dilatation of the pupil, which lasts only an hour or two, may be diminished. This effect is thought to be due both to the shrink- age of the vessels of the eyeball and to the consequent diminu- tion in secretion. If one drop of a 4 per cent, cocaine solution is dropped in the eye every minute for five minutes, the pupil will be fairly dilated in about five minutes more, and the dilatation will last for from one to two hours. A danger is the drying of the cornea, with ulceration or clouding. The Stomach. Cocaine is locally anesthetic, and will prevent vomiting from local irritants. It is of interest that in the Andes Mountains the natives chew coca leaves, and if they have a plentiful supply of coca, can continue to work for several days without food. They seem to have no feeling of hunger so long as food is kept out of their sight, but the appetite returns if they see or smell appetizing food. Probably there is diminished sensation in the stomach and in the mouth, and consequent absence of the effect on appetite of reflexes from these regions, while the psychic elements in the production of appetite (the sight or smell of food) remain intact. The psychic stimulation COCAINE 417 is also probably a factor in producing increased power to work. It is said that 100,000,000 pounds of the leaves are used annually in South America, the people chewing them with the addition of a little chalk or lime. These effects have not been obtained in other localities, and consequently have been attributed to some unexplained property which is confined to the fresh or freshly dried coca leaves. But Sollmann thinks that these effects have failed in northern regions because the drug has not been tried in conditions of marked hunger and fatigue. Miiller and also Schlesinger found little or no abolition of hunger by cocaine, though it abolished the feeling of weakness. Disagreeable central effects upon the alimentary tract which not infrequently follow the absorption of cocaine, as in spinal anesthesia, are nausea, vomiting, and diarrhea. The cause of these is not known. Systemic Effects. The systemic effects are not made use of in therapeutics, and may be studied rather because of their mani- festation in poisoning. Heart. In perfusing the isolated heart the addition of co- caine does not change the rate or force of the beat, therefore neither the muscle nor the accelerator endings nor the vagus end- ings are affected. But in the intact mammal, after a moment of slowing from slight vagus center stimulation, the heart beats faster, and as it does not do so when both accelerators are cut, the effect must be stimulation of the accelerator center. The vagus endings retain their sensitiveness, for even late in the poisoning stimulation of a vagus nerve results in slowing. After lethal doses the heart eventually becomes weak and slow from direct muscular depression (or perhaps vagus stimulation), and death may take place from cardiac failure. Occasionally, an unexplained, almost instant, collapse follows the absorption of the drug, even when it is used locally. In the hearts of cold- blooded animals, C. C. Lieb has repeatedly obtained auriculo- ventricular dissociation (heart-block). Arteries. The vasoconstrictor center is stimulated and blood- pressure rises; in severe poisoning this center is depressed. From ordinary amounts there is no direct effect upon the arteries, such as occurs from the local application, as the drug is not suf- ficiently selective in its great dilution by the blood. Kuroda (1915) showed that perfusion of an organ resulted in dilatation of the arteries. Crile calls attention to the important fact that after an in- travenous injection of cocaine the splanchnic arteries arc more resistant to influences which usually cause their dilatation, e. g., 27 41 8 PHARMACOLOGY AND THERAPEUTICS shock, handling the viscera, etc. Hatcher and Wilbert state that an intravenous dose of cocaine too small to affect the circulation will increase the sensitiveness of the vasomotor system to epinephrine. Respiration. The respiratory center is strongly stimulated, and the respiration is increased both in rate and in depth. Death is usually due to respiratory failure, though it is not so always. Cerebrum. This is stimulated in much the same way as with atropine, even the local use of the drug being followed by talka- tiveness and cheerfulness, and even delirium and cerebral con- vulsions. But as an intellectual stimulant it seems to rank higher than atropine, for the cocaine jag is characterized by in- creased intellectual power and self-possession, in addition to loquacity. The reaction time is shortened, and it is more dif- ficult to put and keep an animal under chloroform or ether, i. e., cocaine antagonizes narcosis. The motor areas of the brain are stimulated, and also the re- flex centers of brain and cord, and there is a tendency to motor activity and restlessness, so that the patient wants to walk about. A dog will run amuck, usually in a circle, and quite in- different to his surroundings. The ergograph shows an actual increase in muscular power. All these things are evidences of true central stimulation, exactly the opposite of the effect of alcohol or morphine. After highly poisonous doses the stimulation is followed by depression, stupor, cerebral (not spinal) convulsions, and coma. Medulla. The respiratory, vasoconstrictor, and accelerator centers are stimulated. Whether the vagus center is stimulated to any great extent or not is a moot question. In poisoning, the thermogenetic center in the caudate nucleus is affected, so that the temperature may rise several degrees. Muscle. There is no direct effect, but the motor areas are stimulated so that muscular power is increased and fatigue is lessened. Temperature. See under Medulla. The rise in temperature has probably the same explanation as that after atropine. The temperature does not rise in chloralized animals. Excretion. Some of it is destroyed in the body, though experiments at the University of Berlin (1913) would indicate that cocaine is in some degree excreted unchanged by the kidneys. The urine is sometimes increased, sometimes diminished, prob- ably through changes in the kidney circulation. The effect upon it is unimportant. Untoward Effects. Untoward effects following its use for anesthesia are: COCAINE 419 (a) From protoplasmic irritation cloudiness or ulceration of the cornea; necrotic area or sterile abscess at the site of injection. (b) After absorption (i) Talkativeness, excitement, and wakefulness. (2) A profound narcosis instead of excitement. (3) Nausea, vomiting, and diarrhea, sometimes distressing. (4) Sudden collapse without warning. Acute Poisoning. A number of cases are reported. An over- whelming dose may cause prompt stoppage of heart and respira- tion, or complete relaxation of the arteries with collapse (Smith and Porter) . In some cases there is great susceptibility and there are many reports of sudden collapse and death in the physician's office after the local use in nose, throat, eye, and urethra. Great excitement, collapse, and respiratory failure have resulted from 2 drops of a 4 per cent, solution in the eye; also conjunctivitis. One of my cases has twice, following cocaine in the eye, had a dilatation of the arterioles on that side of the face, so that it was flushed and hot, an effect which regularly follows sympathetic paralysis. Harris reports death from very small amounts in a case \vith status lymphaticus. In ordinary poisoning the central symptoms resemble those from atropine. They are often observed after a cocaine debauch in a habitue. These symptoms are garrulousness, restlessness, motor activity, with incoordination like in a drunken man, ex- citement, hallucinations, and delusions; nausea and vomiting; rapid heart with raised blood-pressure; respiration quick and deep, or even panting; pupil dilated; throat dry. There are frequently great anxiety and fear that death will take place, and anginal pains about the heart. Magnan's sign is a subjective sensation as of pimples or worms beneath the skin or of vermin on the skin. Following the excitement there are drowsiness, stupor, coma, collapse, cerebral convulsions, and death from failure of the heart or respiratory center. It may be distinguished from atropine poisoning by Magnan's sign and the reaction of the pupil to light, and by the fact that atropine checks sweating, and may be found in the concentrated urine in sufficient amount to dilate the pupil of a cat's eye. Failure of the heart to react to pressure on the vagus in the neck would suggest atropine. Treatment. Because of the marked anxiety it is of great im- portance to reassure the patient. In the excitement stage an ice-bag to the head and whisky or large doses of bromides may be supplied, or even inhalations of ether. In the collapse stage the treatment is for collapse, especial attention being paid to the respiratory center. C. C. Lieb has repeatedly checked cocaine heart-block in isolated turtle hearts by caffeine; but caffeine 42O PHARMACOLOGY AND THERAPEUTICS increases the poisoning of the central nervous system and is ordinarily contraindicated. Cocaine Habit. The cocaine habit is quite common, espe- cially among nurses, physicians, and druggists, who have easy access to the drug, among prostitutes, and among the negroes of the South. The drug is taken as snuff, or is rubbed into the gums, swallowed, or injected hypodermatically. The habit may be diagnosed by the nervousness and twitching in the absence of the dose, by the marks of a hypodermatic needle, by ulceration in the nose, with epistaxis, if the snuff is taken, and by the effects of a "fake" dose of some other drug. Blue atrophy of the skin at the site of the injections has been reported by Gottheil (1912). When without his usual dose the habitue feels irritable, de- pressed, and restless, and cannot concentrate his attention; on getting the dose his spirits brighten and he experiences a return of his mental and physical energies. By degrees he passes into a state of poor nutrition, wasting, and anemia, with loss of appe- tite, deranged digestion, constipation, and insomnia. He grad- ually reaches a state of mental and moral weakness without self-control, far beyond those of the morphine or heroine habitue, is easily depressed, develops careless and debasing habits, and lacks the inclination to work. He may develop various mental and nervous symptoms, such as tremor of hands and lips, ir- regular twitching of the shoulder and other muscles, queer sensa- tions in the skin, and hallucinations and delusions. The delusions cause great viciousness, and perhaps attempts to harm others. Mania and chronic dementia and other forms of insanity as results of the habit are reported. Treatment. Isolation, the rapid or even the immediate with- drawal of the drug, with the substitution of atropine or hyoscine, and attention to nutrition, digestion, bowels, and sleep. Therapeutics. The wine of cooa is employed to some extent as a tonic and appetizer in run-down conditions, or in convales- cence from acute illnesses. Since it has the taste of wine and contains \ grain or more of cocaine and allied alkaloids in each ounce, it is not surprising that a number of cases of cocaine habit have resulted from its use. It is not now Pharmacopceial. Cocaine hydrochloridc is employed very extensively as an anes- thetic, either by application to mucous membranes in 2 to 10 per cent, solution, by hypodermatic injection in 0.2 to 4 per cent, solution, or by injection of \ grain (0.03 gm.) in solution into the spinal canal. In the nose, besides its use as an anesthetic, it is employed to shrink the tissues so as to favor the passage of instruments, to increase the view, to stop hemorrhage, or to free the nasal passages COCAINE 42 1 and to lessen engorgement in rhinitis and hay-fever. It is inferior to adrenaline for these purposes. Many cases of cocaine habit can be traced to the use of sprays and powders in hay-fever, and not a few to the use of proprietary asthma cures and catarrh snuffs. In the throat it may be sprayed over a hypersensitive pharynx before examination with a laryngoscope, or to check a distress- ing dry cough, or in tuberculous laryngitis to abolish pain and permit the swallowing of food. In affections of the esophagus (ulcer, cancer, esophagitis, spasm, cardiospasm) cocaine solution may be swallowed just be- fore eating, to lessen the pain and spasmodic contraction which results from the passage of food. A 10 per cent, solution is applied to the pharynx and larynx in direct laryngoscopy or esophagoscopy to prevent pain and shock. In the stomach it is employed to allay pain, nausea and vom- iting; in the eye, as anesthetic for operations and the removal of foreign bodies, and as a transient pupil dilator to facilitate ex- amination of the internal eye; in the urethra, to allay spasm and permit the passage of instruments; at the anus, in ulcer or fis- sure, to allow a painless examination or painless defecation; on the vulva, to overcome intractable itching, and in the entrance to the vagina in vaginismus. In irritable rectum or anus it may be employed in ointment or suppository form. In the external ear the aqueous solution is not absorbed, but some anesthesia may be obtained from the pure alkaloid dis- solved in aniline oil. It is reported that a 10 per cent, solution in ether will be absorbed. When cocaine is used hypodermatically, it is not injected deeply like other drugs to hasten absorption, but is placed im- mediately beneath the epidermis. The addition of epinephrine lessens the systemic and prolongs the local effects, and checks hemorrhage; so in this admixture it has recently come into ex- tensive use for quite large operations, as amputation of a limb or laparotomy. It does not, however, abolish the perception of the patient or produce full muscular relaxation. In major opera- tions under general anesthesia Crile and others are attempting to lessen shock by cocainizing the operative area in advance of cutting. Allen Starr uses cocaine hypodermatically as a diag- nostic agent in painful tic, the drug being injected at the site of that branch of the fifth nerve which supplies the painful area. If the pain disappears, the lesion is peripheral; if not, it is central. Spinal analgesia with cocaine or one of its relatives, es- pecially novocaine and stovaine, may be employed for opera- tions about the perineum and lower extremities when a general 422 PHARMACOLOGY AND THERAPEUTICS anesthetic is contraindicated, as in severe diabetes and severe nephritis. It has also been used to a slight extent in obstetrics. A very important use of it is to prevent shock in severe traumatism of the lower extremities. Its value for operations is limited for the following reasons: (i) The extent of the anesthesia is beyond the control of the anesthetist, in some cases the whole body, even the head and face, being affected. (2) There is frequently vomiting and diarrhea and excitement, effects which may persist for hours. (3) The patient remains conscious, and is made keenly alert by the drug. (4) There is little or no mus- cular relaxation. (5) Cocaine collapse sometimes occurs. A number of deaths are reported. Systemically, cocaine is not ordinarily employed at all, but, if other remedies are not at hand, it may be used as a central stimulant in collapse from narcotic drugs. Intravenous Injection of Cocaine. A method of producing local anesthesia by injecting cocaine into the veins has been more or less used (Bier's vein anesthesia), a tourniquet above and be- low the area to be anesthetized preventing the loss of cocaine and causing the localized action. A danger is clotting in the vein. Ritter's (1909) experiments with dogs, in which he produced general anesthesia by an intravenous of a i to 5 per cent, solu- tion, and Meyer's similar results with cats have not been followed by any extensive use in man. Harrison (1911) reports the effects on himself of 5 grains (0.3 gm.) of cocaine hydrochloride in 2 per cent, solution introduced intravenously. Cerebration was normal except for a restless inability to keep the mind long on one subject. Mo.tor power was unimpaired. There were dizzi- ness and palpitation. There was marked analgesia everywhere, though slight twinges of pain were felt on making a f -inch incision through the skin. Two hours later there was still a slight im- pairment of feeling. The experimenter says that the results are not good enough to justify this use of cocaine. COCAINE SUBSTITUTES The drawbacks in the use of cocaine are: 1. Its general poisonous action. 2. The frequency of undesirable idiosyncrasy to it. 3. Its decomposition at boiling temperature, which prevents effective sterilization. 4. Its poor keeping qualities in solution. 5. Its tendency to vicious habit formation. Because of those alleged drawbacks to the use of cocaine, a number of other local anesthetics have been brought forward as COCAINE SUBSTITUTES 423 cocaine substitutes. Of these the following are closely related chemically, and are employed in the same strength as cocaine: Eucaine, beta-eucaine chloride or lactate, trimethyl-benzoxy- piperidine, which is irritant locally, but may be boiled without harm, does not constrict the arterioles, and has very slight effect upon the pupil and accommodation. The chloride is soluble in 30 parts of water, and the lactate in 20 parts. Stovaine, di-methyl-amino-benzoyl pentanol chloride, which is soluble in its own weight of water, is more irritant locally, di- lates the arterioles on local application, and in spinal analgesia induces muscular relaxation. It is too irritant for use in the eye, and has shown a greater tendency than cocaine to produce local gangrene. Alypine, benzoyl-tetramethyl-diamino-ethyl-isopropylic alco- hol chloride, readily soluble in water. Its solutions will not stand boiling. It dilates the arterioles, and has no effect on either pupil or intra-ocular tension. Novocaine, para-amino-benzoyl-diethyl-amino-ethanol chlo- ride, soluble in its own weight of warter, not decomposed by boiling, and without effect upon the arterioles. Schley found that large doses administered to guinea-pigs produced practically the same poisonous symptoms as cocaine, but it required about six times as much of the novocaine. As it is not absorbed readily by mucous membranes or the eye, it must be used hypodermat- ically. To prevent shock, Crile uses a solution of i : 400 to anes- thetize the field of operation in advance of cutting. Hatcher and Eggleston find the symptoms less persistent than those from cocaine; also that slow continuous intravenous injections of large amounts fail to produce lasting effects. Toxic amounts quickly administered cause immediate stoppage of heart and respiration. Tropacocaine, the benzoyl ester of pseudo-tropine chloride, is more irritant locally, and does not dilate the pupil or affect the arterioles. Its solutions can be boiled. These drugs are all chemically related to cocaine. They are found to be less irritating to the tissues and less destructive if dissolved in normal saline rather than pure water. They are all prompt in producing anesthesia, and their effects last only from fifteen minutes to half an hour; but they all maintain anes- thesia for a much longer period if used with a small amount of epinephrine, the anesthesia being a little slower in coming on. The epinephrine acts by constricting the arterioles so that the drug is not carried away so rapidly by the blood-stream; a further advantage is that, by the blanched area, it shows exactly where the drug has been injected. 424 PHARMACOLOGY AND THERAPEUTICS SOME OTHER LOCAL ANESTHETICS NOT USED HYPODERMAT- ICALLY Orthoform, methyl-para-amido-meta-oxybenzoic ester, is ap- plied as a powder to painful ulcers, or in ointment form to pro- jecting hemorrhoids or to the vulva in pruritus; or is used in suppositories in anal fissure or ulcer, or in the form of lozenges to be dissolved in the mouth to overcome dry cough, or in tubercu- lous laryngitis to permit swallowing. It may be taken inter- nally for ulcer of the stomach. Dose, 5 grains (0.3 gm.) in suppository, lozenge, capsule, or powder. A 5 or 10 per cent, ointment is also employed. The author has seen a spreading der- matitis of the fingers and hands after the use of an orthoform ointment. It occurred twice in the same person and was doubt- less due to idiosyncrasy. Anesthesin, the ethyl ester of para-amido-benzoic acid, has the same uses and dosage as orthoform. It is slightly soluble in water, and more readily so in alcohol and the oils. Propaesin, para-amido-benzoic-acid-propyl ester is a crystal- line powder, slightly soluble in water and moderately so in al- cohol. It is used in the same way as the last named, in doses of 5 grains (0.3 gm.) or in 10 per cent, ointment. Dipropcesin is a combination of one molecule of urea with two of propaesin. It is anesthetic in an alkaline medium. Chloretone, chlorbutanol, is sometimes employed in the same way (see under Hypnotics), in powder, tablets, spray, etc., as a local anesthetic. Holocaine, para-diethoxy-ethenyl-diphenyl-amidin chloride, is very soluble in water, but more irritant and more toxic than cocaine. In forty-five seconds a i per cent, solution produces an anesthesia of the eye which lasts ten or fifteen minutes, with- out any effect on pupil, accommodation, intra-ocular tension, or the arterioles. Dionine, di-ethyl morphine chloride, is soluble in 7 parts of water, and is used in 5 per cent, solution to dilate the pupil, to lessen intra-ocular tension, and to abolish pain in the eye. Snycler prefers it to eserine in glaucoma. At first it causes great irritation and even chemosis, but this soon disappears. Its sys- temic effect is similar to that of codeine. (See Morphine.) Yohimbine is an alkaloid yielded by a tree of the Apocynacece of German West Africa. Its solutions decompose on boiling and deteriorate on keeping. It is less anesthetic than cocaine and dilates the pupil, but it so strongly dilates the vessels that to prevent hyperemia a 2 per cent, solution requires to be mixed with an equal quantity of epinephrine solution. OTHER ANESTHETICS NOT USED HYPODERMATICALLY 425 Taken by mouth, yohimbine is said to cause a dilatation of the cutaneous vessels, to stimulate the lower part of the spinal cord, to increase sexuality, and to induce erections of the penis which may or may not be accompanied by sexual desire. Dose, | grain (0.008 gm.), or in 2 per cent, solution hypodermatically 8 minims (0.5 c.c.). A number of veterinary writers have re- ported aphrodisiac effects in cows, pigs, and horses. Vasotonin, a preparation of yohimbin and urethane designed to lower arte- rial pressure, was found to have the opposite effect (Lawrence). Schleich's infiltration anesthesia was famous at one time. He used solutions of the hydrochlorides of morphine and cocaine in three different strengths in 0.2 per cent, solution of sodium chloride. The strongest of his solutions contained 0.2 per cent, of cocaine and 0.025 per cent, of morphine. Other local anesthetics are the ethyl chloride spray, which freezes the part, and is only momentary in its effects, and phe- nol, a 5 per cent, solution of which, kept in contact with the part, will slowly numb and anesthetize. Eriodictyon (yerba santa) is an astringent, resinous, bitter drug, of which the fluidextract is official; dose, 30 minims (2 c.c.). It possesses the peculiar local action on the taste-buds of abolish- ing the taste for bitter, though not that for sweet, salt, or sour. If the mouth is rinsed with a little of the fluidextract di- luted with water, a dose of quinine or strychnine taken three or four minutes later gives scarcely any bitter taste. It is sometimes made into a syrup and used as a vehicle for the administration of quinine to children; but in such admixture it has no time to act on the taste-buds, and really lessens the bitterness of the quinine salt by changing it to the tannate, an almost insoluble and therefore almost tasteless salt. Intravenous Local Anesthesia. This method, introduced by Bier, gives complete anesthesia of a limb. The blood is squeezed out of the veins between two Esmarch bandages, and a 0.5 per cent, novocaine solution injected into a vein. The solution reaches all parts of the segment, and produces complete anes- thesia of the segment in five minutes, so that even an amputation may be performed without pain. In an adult 50 to 100 c.c. of the solution are required for the arm, and somewhat more for the leg. Quinine and urea hydrochloride has come into extensive use as a local anesthetic. It is mostly used hypodermatically and is described under "Quinine." 426 PHARMACOLOGY AND THERAPEUTICS SOME PERIPHERAL DEPRESSANTS NOT OF GREAT MEDICINAL IMPORTANCE 1. HYDROCYANIC ACID AND CYANIDES Preparations. Diluted hydrocyanic acid, HCN, a 2 per cent, solution; dose, i minim (0.06 c.c.). It rapidly deteriorates on keeping. Undiluted hydrocyanic (prussic) acid is not employed in medicine. Polassium cyanide, KCN; dose, \ grain (o.oi gm.). In addition, hydrocyanic acid is present in preparations of wild-cherry bark (Prunus virginiana), the oil of bitter almond (Amygdala amara), and cherry-laurel leaves (Laurocerasus). In these it does not occur in the crude drugs, but is developed in the presence of water by the action of the ferment emulsin on the glucoside amygdalin, both of which are present. (For the re- action, see Part I, Glucosides.) The official oil of bitter almond contains 2 to 4 per cent, hydrocyanic acid and 85 per cent, benzaldehyde; dose, i minim (0.06 c.c.). The preparations of these are: Infusion of wild cherry, 4 per cent.; dose, 2 ounces (60 c.c.). Syrup of wild cherry, 15 per cent.; dose, i dram (4 c.c.). Fluidextract of wild cherry; dose, 30 minims (2 c.c.). Bitter almond water (aqua amygdalae amarae), o.i per cent.; dose, i dram (4 c.c.). Spirit of bitter almond, i per cent., 3 minims (0.2 c.c.). Action. Cyanides are general protoplasmic poisons, highly toxic to all living things, and antagonistic to the action of the body ferments. Locally, they tend to depress the ends of the sensory nerves. Poisoning. Large doses so affect the protoplasm of the body that it is unable to absorb oxygen from the blood. As a conse- quence, the venous blood is like the arterial blood, i. e., red and oxygenated. This is, so far as we know, due to inhibition of the activity of the oxidases (oxidizing ferments), through whose action the oxygen of the blood is utilized in the cells. This property of cyanides has been established by Richards as of value in the study of the action of certain oxidizable poisons. After a toxic dose of cyanide there is a passing stimulation of the vagus, vasoconstrictor, and respiratory centers, followed by marked depression of these. There are widely dilated pupils, and vomiting from stimulation of the pupil-dilating and vomiting centers, then convulsions, probably of medullary origin, collapse, and death from failure of the respiraton. Very large doses taken when the stomach is empty are followed almost immediately by a few convulsive movements and death. The fatal dose is vari- CONIUM 427 able because of differences in the strength of preparations. An amount of dilution equivalent to about i minim of pure hydro- cyanic acid, or 2 1 grains (0.16 gm.) of potassium cyanide, is reckoned to be a lethal dose (Taylor). For an elephant in Cen- tral Park it required 9 ounces (180 gm.) of potassium cyanide to produce death. The poison may be detected by the characteris- tic odor, which is perceptible in the mouth or the emptied bottle, or at postmortem on opening the body. Treatment. Prompt emptying of the stomach, and the ad- ministration by mouth of oxidizing antidotes, such as hydrogen peroxide, potassium permanganate, or, perhaps, much better, freshly prepared ferric hydroxide (the arsenic antidote). Intra- venously i per cent, sodium hyposulphite, and 0.5 per cent, co- baltous nitrate have been recommended. In addition, are indi- cated artificial respiration and the general treatment for collapse. Therapeutics. It -has been employed locally to allay itching and to stop nausea and vomiting. It is also used to check cough. There is no evidence to justify its employment for these purposes, and it would seem that the medicinal use of hydrocyanic acid or potassium cyanide might with advantage be abandoned. The syrup of wild cherry is much used as a flavor in cough mixtures. Cherry-laurel water and the water and spirit of bitter almond are used as flavors. CURARE Curare, containing the alkaloid curarine, is a South American arrow-poison. It is probably obtained from a species of Strych- nos, the genus to which the strychnine-yielding plants belong. Its essential action is to paralyze the motor end-plates in striped muscles, and for this purpose it is largely used in physiologic and pharmacologic laboratories. It has been used in certain convul- sive or spasmodic conditions of striped muscle, but its dosage is very uncertain, and its tendency to paralyze the respiratory muscles is marked, hence it is too dangerous. CONIUM Conium, or "poison hemlock" (not "hemlock"), contains the volatile liquid alkaloid, coniine. It is not official, but the fluidextract is employed, dose, 3 minims (0.13 c.c.). There is some medullary depression and slight sensory depression, but the main effect is a curare-like but mild depression of the motor end-plates. For this it has been used somewhat in certain spasmodic nervous affections, such as chorea and whooping- cough, but has been found of little value. It was by conium that 428 PHARMACOLOGY AND THERAPEUTICS Socrates, the philosopher, was put to death; and as his mind remained clear until near the end, he wrote a description of his condition. There was paralysis with slight numbness, beginning in the toes and gradually ascending until it involved the trunk. Death from conium is due to respiratory paralysis, either of the respiratory center or of the terminals in the respiratory muscles. GELSEMIUM Gelsemium, yellow jasmine, has as its active principle the alkaloid, gelseminine. The fluidextract, dose, i minim (0.06 c.c.), and the 10 per cent, tincture, dose, 10 minims (0.6 c.c.), are official. Peripherally it acts like conium, but centrally is more de- pressing. It is somewhat analgesic, and has an atropine action on the pupil and accommodation. Therapeutically, it has been employed with reputed good effects in refractory trifacial neu- ralgia, but just how it checks the neuralgic pain has not been explained. SPARTEINE SULPHATE Sparteine sulphate, dose, i grain (0.06 gm.), is the sulphate of an alkaloid obtained from Scoparius, or broom. It slows and weakens the heart by stimulating the ganglia on the vagus nerve and by directly depressing the heart muscle; it also slightly stim- ulates the ganglia of the vasoconstrictor nerves. Sparteine was formerly believed to have a digitalis action, but laboratory experiments prove it to be a decided cardiac depressant. It may be used to quiet an overacting heart, and on the theory that it depresses the ganglia of bronchoconstrictor nerves may be employed in spasmodic asthma. LOBELIA Lobelia, Indian tobacco, the active principle of which is the volatile liquid alkaloid lobeline, resembles nicotine or real to- bacco in its action. Its chief use is in spasmodic asthma, to depress the bronchomotor nerve-endings or their ganglia. Small doses taken repeatedly cause an unexplained persistent increase in the frequency of the heart-beat. The fluidextract , dose, 2 minims (0.13 c.c.), and the 10 per cent, tincture, dose, 20 minims (1.3 c.c.), are official. The leaves are a constituent of some of the proprietary asthma powders, which are used for burning, the smoke being inhaled. They are sometimes made into cigars or cigarettes with stramonium, cubebs, or tobacco, and these smoked during an asthmatic attack. Lobelia has also been employed as an emetic, the dose required being four times that mentioned above. TOBACCO (TABACUM) 429 TOBACCO (TABACUM) Tobacco is the leaves of Nicotiana tabacum (Fam. Solanacece), subjected to a process of fermentation to remove certain proteins and fats that would make the smoke disagreeable, and then to another process of fermentation by which 25 or 30 per cent, of the nicotine is lost and the aroma developed. The chief constituents of the cured leaves (not the smoke) are the volatile liquid alkaloid, nicotine, some related alkaloids, and a volatile oil to which most of the aroma is due. (For the constituents of the smoke see below.) The Havana tobacco is noted for its delicate aroma, and usually contains only i to 3 per cent, of nicotine; while some of the Virginia and French tobaccos may yield as much as 6 or 7 per cent. An examination of Virginia tobaccos by the Virginia Agricultural Experiment Station in 1898 showed 1.68 to 6.17 per cent, of nicotine. Turkish tobacco comes from Nicotiana Rustica, and contains about 2.5 per cent, of nicotine (Kew Bulletin). The cured tobacco is used for smoking; or, mixed with molas- ses, extract of licorice, and other flavoring materials, is used for chewing (chewing-tobacco). When powdered, also sometimes scented and flavored, it constitutes snujj, which is used by snuffing into the nose or rubbing upon the gums. For smoking, tobacco is burned in a pipe, or in the form of cigarrete or cigar, the smoke being drawn through the tobacco into the mouth, or sometimes "inhaled," that is, drawn into the lungs. A method of drawing the smoke through water or rose- water, as in the "hookah," is in vogue in eastern countries. It is said that this takes out about half the poison and cools the smoke. The smoke contains nicotine, pyridine, quinoline, hydro- cyanic acid, irritant aldehyds, ammonia, furfurol, phenols, carbon dioxide, carbon monoxide, and some volatile oil. How much of the nicotine of tobacco is destroyed in the smoking is a question. Allen says that "the greater part of the nicotine is converted into pyridine and other pyrogenous compounds," and Bush, and Vohl and Eulenberg found no nicotine at all in the smoke. As pyridine is only one-twentieth as poisonous as nicotine this would explain the absence of serious acute symptoms from smoking. Other investigators, however, report the recovery from the smoke of one- to four-fifths of nicotine. Lehmann (1912) has shown that the hydrocyanic acid is not a factor in the tobacco effects; but the investigations of the London Lancet (1912) point to furfurol aldehyd and other aldehyds as harmful constituents. Furfurol is a constituent of the fusel oil of alcohol, and the Lancet experiments show that a single cigarette may contain as much of 430 PHARMACOLOGY AND THERAPEUTICS it as two ounces of whisky. Furfurol, of which a dose of ij grain (o.i gm.) is capable of producing a persistent headache, is practically absent from the smoke of Turkish cigarettes. In medicine, tobacco has been employed externally in the form of a poultice, and internally as an emetic, and the smoke has been inhaled in spasmodic asthma; but, owing to its great toxicity and to the great difference in human susceptibility to its action, it is dangerous as a remedy and has been omitted from the Phar- macopoeia. Tobacco is still used more or less in asthma, and in addition to stramonium, lobelia, or cubebs, forms a constituent of many of the asthma cigarettes and cigars. As its value is so limited, tobacco is to be considered chiefly because of the effects of the tobacco habit. The world's output has been placed at 2,000,000,000 pounds a year. In the United States alone in 1913, according to the internal revenue reports, the output of manufactured tobacco was 410,976,513 pounds, while the cigarettes numbered over 15,000,000,000 and the cigars over 8,500,000,000. That would be over 4 pounds of tobacco and over 85 cigars and 150 cigarettes for each inhabitant. In addition, 33,000,000 pounds of snuff were manufactured. Pharmacologic Action of Nicotine. Nicotine is rapidly absorbed from skin and mucous membranes. Its main action is a brief stimulation of the cerebrum, medulla, and cord, of the ganglia on the vagus and sympathetic nerves, and of the motor end-plates in voluntary muscle, the stimulation being followed by depression. Alimentary Tract. The saliva is increased and there may be biting of the tongue from the irritant nicotine. Either from the local effect of the swallowed saliva or from its systemic effect after absorption there may be nausea, vomiting, and increased peristalsis with diarrhea. Circulation. The stimulation of the vagus center and ganglia results in a slowing of the heart, and that of the vasoconstrictor centers and ganglia in a great rise in blood-pressure; the sub- sequent depression shows in a rapid heart and lowered blood- pressure. From smoking, a preliminary rise is not uncommon during the first fifteen or twenty minutes, but it may be absent in those who are very tolerant of the drug. To one who is not habituated the subsequent fall in pressure may result in mild collapse. A fall of 50 mm. has been noted. Cannon, Aub, and Binger (1912) have shown that nicotine can cause increased activity of the adrenals. Respiratory. This center is also stimulated, then depressed. The bronchial muscles, from stimulation followed by depression TOBACCO (TABACUM) 431 of the ganglia of the motor nerves, undergo a transient contrac- tion, followed by persistent relaxation; hence the use of tobacco in spasmodic asthma. Smooth muscle of all kinds is affected through the ganglia of the supplying nerves. The pupil is contracted at first and subsequently dilated. This is from an effect on the third-nerve ganglia. The cerebrum is only slightly stimulated, and this effect so quickly passes into depression that the drug is a true narcotic or cerebral sedative. Tobacco is not an intellectual stimulant, but just the reverse. The medullary centers and the reflexes are at first stimulated, then depressed. Toxicology. The poisonous effects of tobacco (not tobacco smoke) are due chiefly to nicotine. Two drops of nicotine placed on the tongue or rubbed into the gums of a small dog or cat will produce death in one or two minutes. A large mastiff died almost instantly when ten drops were placed on his tongue, and a canary when one drop was held near its bill. In man death has followed the use of tobacco as a poultice, the application of an infusion in skin disease, the injection of an infusion into the rectum for worms, the plugging of a wound with a quid of tobacco to stop the bleeding, etc. In fact, a cigar may contain enough nicotine to kill two unhabituated adults. Fortunately in smoking the nicotine is changed, at least to a considerable degree, and much of that present is exhaled and lost. Acute nicotine or pyridine poisoning is frequently seen after the first cigar, or when an unusually large quantity of tobacco is consumed in a short time. The symptoms are those of mild collapse, viz., pallor of the skin, sweating, nausea, and perhaps vomiting, diarrhea, muscular weakness, faintness, dizziness, and lowered arterial pressure. Tedeschi reports epileptic seizures. Treatment. Fresh air and rest lying down, with reflex stimu- lants, such as whisky, brandy, or aromatic spirits of ammonia. If the symptoms are severe, the treatment is that for severe collapse; but this degree of poisoning is rare from smoking, as the stomach symptoms or the mild collapse come on early and check the further use of the drug. Were the drug to manifest its symptoms more slowly, so that a larger dose might be consumed before the smoker becomes ill, many serious poisonings would result. Tolerance is readily established up to a certain limit, which differs widely with different persons, e. g., the limit of tolerance for one person is a single cigar in an evening, while another person may smoke ten cigars in the same time without being upset. After 432 PHARMACOLOGY AND THERAPEUTICS the use of tobacco has been abandoned for a time the tolerance to it is found to have decreased. The Tobacco Habit. As a habit drug, tobacco is peculiar in that the effects desired are not to be attributed in any great degree to its most active constituent, nicotine. Indeed, the best tobaccos are not by any means those with the highest percentages of the alkaloid. To the beginner in smoking the pleasure is sadly lacking; and it is not until the habit is established that smoking becomes a source of comfort and pleasure. But to the habitue tobacco is narcotic, its use in moderation promoting the feelings of ease and relaxation. Strangely enough, its pleasurable effects seem quite unrelated to the extent of the physiologic action, for to most smokers there is little satisfaction from smoking in the dark or from using the tobacco in some unaccustomed way, as in a pipe instead of cigarettes, or as snuff; and a weak Havana tobacco often gives more pleasure than a two or three times as strong Virginia or Kentucky variety. It is a fact, also, that those who have the habit of inhaling, and are, therefore, accustomed to bringing the smoke in contact with a large surface of mucous membrane, get little satisfaction, no matter how strong the tobacco, unless they inhale to bring the smoke to the accustomed membranes. The same may be said of the use of tobacco in the form of snuff smoking will not satisfy the snuff user. Another noteworthy fact is that there is no great physiologic demand for the usual dose of tobacco, so that the habit of smok- ing can be stopped suddenly without any striking physiologic reaction. Also, a moderate smoker one who is accustomed, say, to one cigar after his dinner can get along very well without his smoke, and will have less craving for it two or three hours later than he had at the usual time for it. This is not true of morphine, cocaine, or the other habit drugs, for which the craving becomes worse and worse as the deprivation continues. It is evident, then, that the demand for tobacco is not so much the physiologic demand of the body for its dose, as it is the psychic demand for the satisfaction of a habit. The smoker's pleasure seems to be derived largely from the presence of some- thing in the mouth, from the studied inhalation and exhalation, and from the soft circling up of the smoke. The fact that the presence of something in the mouth with rhythmic motion of the jaw, as in gum-chewing, gives a pleasure that is similar, though weaker, places the use of tobacco in a psychic habit class with chewing gum, eating chocolate, or perhaps sucking a tooth- pick. In attempting to break the tobacco habit we take advan- tage of this fact and advocate the chewing of gum, or of some TOBACCO (TABACUM) 433 substance of strong taste, such as gentian or lovage, or the eating of candy at the usual smoking time. Many an old smoker speaks of smoking as "a fool habit." That the effect is not all psychic, however, is suggested by the failure of any other substance to give the satisfaction that tobacco does, either for smoking or chewing. Every one prefers to smoke tobacco, for example, rather than cabbage leaves, though the smoke of cured cabbage leaves contains pyridine bases. This preference for tobacco may, however, be merely a matter of the greater delicacy of the tobacco taste and aroma. The method of smoking makes some difference. The Lancet has shown that the pipe smoke contains the most alkaloid and the cigarette smoke the least. The pipe has the disadvantage that owing to the heat of the tobacco and the bowel of the pipe, oily nicotine and pyridine substances tend to distil into the smoke without combustion. Some of these are inhaled and some accumulate in the stem of the pipe, so that an old pipe gets "strong." The pipe-smoker tends to keep more or less under the influence of tobacco by frequent, short smokes, but he seldom inhales. The cigarette smoker is prone to inhale, i. e., draw the smoke into his lungs. The cigar is less rapidly consumed than the cigarette, and its area of ignition is greater, so that the tobacco just in advance of the area of combustion gets hot; consequently there is some vol- atilization of the raw nicotine, and this is drawn in with the smoke. This is not so much as in the pipe; but the fatter the cigar, the greater will be the volatilization, and therefore the less the destruction, of the nicotine. Hence the smoke of a thin cigar, and still more so that of a cigarette, will contain less of the raw, volatile poisons than that of a thick cigar. W. E. Lee (1908) has tested the relative potencies of cigars and cigarettes as fol- lows: A Manila cigar and a cigarette of Virginia tobacco of nearly double the strength of the Manila tobacco were burned so that the same amount of tobacco in each was consumed in the same time. The smoke of the cigar made of the weaker tobacco was about twice as toxic as that from the cigarette. As a matter of fact, the cigarette fiend does not consume any more tobacco than the cigar or pipe fiend, for 10 average cigars represent the tobacco of 50 or 60 cigarettes, and, as we have seen, the cigarette is the least harmful form of tobacco. Yet there are real objections to the cigarette, viz., that it makes smoking easy for the young, that it has a strong tendency to induce the habit of inhalation, and that, being small, it can be smoked at odd moments, so that the excessive cigarette smoker tends to keep himself under some influence of the drug all day long. The 28 434 PHARMACOLOGY AND THERAPEUTICS charge that the rice-paper of the cigarette produces harmful fumes has been repeatedly shown to be without foundation. Indeed, if the paper is impregnated with potassium nitrate to make it burn evenly and without bursting into a flame, as is frequently the case, it has a tendency to overcome the primary rise in blood-pressure which is brought on by the nicotine. Those who lead an open-air life can smoke much more than those who remain indoors. Especially bad is constant smoking in an ill- ventilated room, for more or less of the smoke is reinhaled. Moderate smoking is a psychic depressant, favoring ease and comfort and "laissez-faire," rather than effort and work and energy. It is truly narcotic. In so far as it is a habit the smoker may feel ill at ease if he fails to get his usual smoke; yet excessive smoking may be given up at once and absolutely without any rebellion on the part of the body. It is easier for the patient if he keeps away from smokers and has cheerful company, and if he chews something bitter or strongly flavored, such as gentian-root, lovage, chewing-gum, or chocolate. Blood- pressure. Many investigators have noted a decided rise in arterial pressure during smoking, even in persons habitu- ated to its use. But this is not a constant effect. In 17 men from sixteen to thirty-one years of age, Aikman got a rise in 5 and a fall in 12, from smoking one cigarette. Thompson and Sheldon (1917), experimenting on 58 patients in middle or advanced life with high arterial pressure and arteriosclerosis, found that smoking a cigar produced a rise in systolic pressure in 35 per cent., a fall in 45 per cent., and no change in 20 per cent., the results being variable in the same patient. Efficiency. Seaver while physical director at Yale estimated that smoking an ordinary cigar resulted in one hour in a marked drop in muscular po\ver. Of 500 boys at school, Taylor found the grades of the smokers invariably lower than those of the non- smokers. Of 201 students at Clark University, of whom 46.3 per cent, were smokers, Clark noted that 68.5 per cent of the non- smokers and only 18.3 per cent, of the smokers won academic honors. Meylan, in a study of the tobacco habit at Columbia University, concludes that "the use of tobacco by college stu- dents is closely associated with idleness, lack of ambition, lack of application, and low scholarship." Of course one must concede that the men of poor calibre and lack of application are more prone than ambitious workers to carry the tobacco habit to excess. Bush, in a series of 120 tests in each of fifteen men in several different psychic fields, shows that tobacco smoking was followed by a 10.5 per cent, decrease in mental efficiency, most marked in the fields of imagery, perception, and association. Habituation TOBACCO (TABACUM) 435 lessened the degree of mental inhibition resulting from the smok- ing, and the men of the higher intellectual rank seemed to have the greater susceptibility. Fisher and Berry found that even a single cigar lessened the accuracy of baseball players in throwing a base- ball at a target. From a study of the irritable heart of soldiers, Parkinson and Koefod (1917) conclude that excessive cigarette smoking is not the essential cause in most cases, but is an impor- tant contributory factor in the breathlessness and precordial pain. Chronic Tobacco Poisoning. Much smoking for a length of time may cause various disturbances, viz. : 1. Derangements of digestion, as lack of appetite, nausea, heartburn, constipation. 2. Headaches, depressed states of the mind, lack of energy, irritability of temper (auto-intoxication), restlessness, nervous- ness, and impaired memory. 3. Tobacco heart rapid or slow, irregular, very susceptible to nervous influence. There may be palpitation, precordial distress, and dyspnea on exertion. Syncope may cause death in high altitudes, and a number of persons with tobacco heart have died in the train while crossing mountains. Tobacco-smoking has been the cause of bradycardia, tachycardia, extrasystoles, auricular fibrillation, auricular flutter, sino-auricular block, and auriculoventricular block. 4. Arteriosclerosis atheroma of the aorta has been reported as produced in rabbits by nicotine, by infusion of tobacco, and by inhalation of tobacco smoke. It is to be remembered that atheroma of the aorta is common in rabbits without tobacco. 5. Tobacco amblyopia. This results from a chronic retrobul- bar neuritis in which it may not be possible to detect anything wrong with the optic disc, but vision is dulled and is not im- proved by glasses. Vision is often better in a dull light than in a bright one (de Schweinitz). In some cases the optic disc may be pale and somewhat atrophied. 6. Deafness either from the production of catarrhal con- ditions in the nasopharynx and Eustachian tube, or from an effect on the nerve. Most of the bad effects are removed by the stoppage of the drug and proper hygiene, i. e., exercise, fresh air, baths, etc. The local irritation of the smoke upon the tongue has been charged with the production of epithelioma; that on the throat with the production of catarrhal conditions or hoarseness; that of the swallowed saliva with gastric hyperesthesia and gastritis. Cigarmakers show a high proportion of cases of anemia, tuberculosis, brachial neuritis, sciatica, hysteria, and cardio- vascular affections. 436 PHARMACOLOGY AND THERAPEUTICS THE PERIPHERAL NERVOUS STIMULANTS We have already spoken of the peripheral sympathetic stimu- lation of cocaine and epinephrine, and the primary stimulation from nicotine. PHYSOSTIGMA (CALABAR BEAN) The ripe seed of Physostigma venenosum (Fam. Leguminosce) , yielding, when assayed, not less than 0.15 per cent, of alkaloid soluble in ether. The plant is a woody twiner of western Africa, and the calabar beans were used by the native medicine men for "trial by ordeal." The person accused of a crime was given a paste made of the seeds; if he recovered, he was declared innocent; if he died, he was guilty. It is said that if enough cattle were made over to the priests they were prone to mistake harmless seeds for the calabar in making the paste. Constituents. The alkaloid physostigmine or eserine is the essential ingredient. There are also minute quantities of two or three other alkaloids, of which eseridine or isophysostigmine has the action of physostigmine, and calabarine that of strychnine. Physostigmine in solution is decomposed by light or heat, and a reddish color indicates diminished activity. Preparations and Doses. Physostigma, 0.15 per cent, of alkaloid; dose, i| grains (o.i gm.). Extract, 1.7 to 2.3 per cent, of alkaloid; dose, f grain (0.008 gm.). Tincture, 10 per cent., 15 minims (i c.c.). Physostigmine salicylate, soluble in 75 parts of water and 16 of alcohol, is given in dose of ^-^V grain (0.001-0.002 gm.). Pharmacologic Action. Physostigmine stimulates the se- cretory nerve-endings of glands and the nerve-endings of striated and smooth muscle. It therefore antagonizes the effects of atro- pine upon secretion, upon the action of smooth muscle, and upon the eye; and antagonizes curare in its effects upon striated muscle. It has no effect on sensory nerve-endings. Secretion. Physostigmine is not employed in medicine to increase secretions, for by arteriole constriction and the cutting off of the blood-supply of the glands the amount of the secretion is limited. Muscle. Its effect upon the action of smooth muscle is strongest in the alimentary tract, so that it may be employed, either by mouth or hypodermatically, as a cathartic. It also tends to cause contraction of the bladder, ureters, bronchi and spleen, and perhaps also of the uterus. PHYSOSTIGMA (CALABAR BEAN) 437 Its effect upon the action of striated muscle is shown in the isolated gastrocnemius by increased irritability and increased power to lift a load. Irregular stimulation in man is also indicated by peculiar fascicular spasms or twitchings of the muscle, as in the temporal or orbital muscles when the drug is used in the eye, or in the muscles of the limbs in poisoning. It is directly antidotal to the peripheral action of curare, and presumably acts upon the same structures. The Pupil. If a drop of i : 200 aqueous solution of eserine is placed in the eye, contraction of the pupil begins in one or two minutes and reaches its maximum in one-half to one hour. The marked contraction lasts from twelve to thirty-six hours, and the normal size of the pupil is regained in from two to four days. The contraction is due to stimulation of the ends of the third nerves, physostigmine not contracting the pupil after degeneration of the nerve (Anderson). Accommodation. Through similar action on the ends of the third nerve, the ciliary muscle contracts like the circular muscle of the iris, and allows the lens to bulge forward. This causes the sight to be fixed in accommodation for near objects, while objects more than a few feet away are out of focus. There is sometimes supra-orbital or eyeball pain from continued overaction of this muscle. The accommodation returns to normal somewhat more quickly than the pupil. Intra-ocular tension is much lowered, without any essential pre- liminary rise in tension. This lowering is usually considered due to the increased escape of fluid through the spaces of Fontana, which are promptly opened up by the contraction of the pupil; but Gronholm attributes much of the fall of tension to contraction of the vessels and the resulting diminished secretion. The use of the drug in the eye may be followed by disagree- able or painful twitchings of the eyelid, or fascicular spasms of the adjoining face or temporal muscles. Physostigmine is much more powerful than pilocarpine as an antagonist of atropine. Circulation. The effect upon the heart and arteries is but poorly understood. Small doses slow the heart, and as this effect follows large doses of atropine, it cannot be due to vagus center stimulation. Some authors believe there is a stimulation of the vagus nerve-endings. In the frog there are direct muscle stimulation and increased irritability, but in mammals strengthen- ing is not usually seen. The arterioles are contracted from per- ipheral stimulation, probably chiefly of the ends of the vaso- constrictor nerves, for Dixon says there is no contraction after apocodeine. Arterial pressure is raised. There is apparently no effect upon the vasoconstrictor center. In poisoning, both 438 PHARMACOLOGY AND THERAPEUTICS heart muscle and vasoconstrictor mechanism are depressed so that the arterial pressure falls. Respiration is at first quickened and deepened, from stimula- tion of the center and probably of the afferent vagus endings in the bronchi. In poisoning there is depression of the center, and there may be asthmatic breathing from contraction of the bron- chial muscles. Death is due to failure of the respiratory center. Neroous System. The cerebrum is little affected, conscious- ness in fatal poisoning remaining until near the end. The vital medullary centers are at first stimulated, then depressed. The reflexes are depressed, and in poisoning there may be an ascend- ing paralysis, beginning in the legs. The effect on peripheral nerves has been spoken of; there is no effect on sensory nerves. Excretion is rapid by the urine. A slight amount appears in the saliva and bile. Toxicology. Noteworthy are the marked muscular weakness without loss of consciousness. The pupils are markedly con- tracted, the skin covered with sweat, there are vomiting, diarrhea, and cramps in the abdomen. The loss of muscular power begins in the legs and ascends, and is accompanied by twitching or tremor. The heart is at first slow and the arterial pressure good ; later the heart becomes weak and slow, and the blood-pressure is lowered. The respiration is at first rapid and deep, then becomes shallow and labored or perhaps asthmatic. Death occurs from paralysis of respiration. The antidote is atropine for the asthma, the diarrhea, and the intestinal cramps; if necessary, the patiejit must be treated for collapse, bearing in mind that the heart itself is very weak. Joseph and Meltzer recommend magnesium sul- phate as partly antidotal. It can be used subcutaneously or in the spinal canal, the dose being i dram (4 c.c.) of a 25 per cent, solution. Therapeutics. The extract in pills, and the salts of physostig- mine hypodermatically, are used as cathartics. Since not many drugs will act as cathartics when administered hypodermatically, a knowledge of this power of physostigmine may be of value in some severe illnesses or postoperative conditions. The physostigmine salts, usually in a solution of i : 200, arc much employed in the eye to lessen the high intraocular tension of glaucoma, and, after drugs of the atropine class, to hasten the return of the pupil, accommodation and intraocular tension to normal. They are preferred to pilocarpine because their action lasts longer and is more complete, and there is no noteworthy preliminary rise of intraocular tension. A dis- advantage is the nervous spasm of the eyelid and temporal muscles, which may occur frequently during several hours; and PILOCARPUS (jABORANDl) 439 the contraction of the ciliary muscles, which may cause a blurring of the vision. Physostigmine is employed as an antidote in magnesium sulphate poisoning. PILOCARPUS (JABORANDl) The leaflets of Pilocarpus jaborandi or of Pilocarpus micro- phyllus (Fam. Rutacece), yielding, when assayed, not less than- 0.6 per cent, of alkaloids. It is a Brazilian shrub. Constituents. The alkaloid pilocarpine, also isopilocarpine and pilocarpidine, with similar action, and jaborine, which acts like atropine, but occurs in too minute quantity to have any effect. Preparations and Doses. Pilocarpus, 0.6 per cent, alkaloid; dose, 30 grains (2 gm). Fluidextract, dose, 30 minims (2 c.c.). Pilocarpine hydrochloride and pilocarpine nitrate; dose, \ grain (o.oi gm.), the former being readily soluble in alcohol and water, the latter in water but less readily in alcohol (i : 60). Pharmacologic Action. Pilocarpine is directly antagonistic to atropine in its effects upon the ends of the secretory nerves, the ends of the nerves governing smooth muscle, the ends of the vagus nerves, and the ends of the third nerve in the internal eye. In strong solution it slightly stimulates the gland and muscle cells. It does not affect the sensory nerve-endings or the striated muscle or their motor end-plates. As with atropine, pilocarpine acts after nerve degeneration, and is presumed to affect a material which serves as receptor of nerve impulses. For practical pur- poses we can speak of its acting on the nerve-endings. Secretion. The secretion chiefly affected is that of the sweat, pilocarpine being a very powerful diaphoretic. According to Edmunds and Cushny, a man may lose from 4 to 9 pounds in weight after a single dose; other observers also have estimated that the sweat may amount to a gallon, the solid as well as the liquid portion being increased in total quantity. The sweating takes place after the nerves to the glands have been cut peripheral to the ganglia, so the drug must act on the nerve-ending or the cell. The sweating is completely checked by atropine. As it takes much more atropine than normally, it is believed that pilo- carpine stimulates the structures that atropine depresses, viz., the receptor substance between nerve-ending and muscle. There is some evidence that pilocarpine also acts slightly on the ganglia. The sweat is acid or neutral from the fatty acids of the sebaceous secretion, the sebaceous glands sharing in the stimulation. 440 PHARMACOLOGY AND THERAPEUTICS The saliva and bronchial mucus are also considerably in- creased, and to some extent also the ear-wax and tears, the gastric, pancreatic, and intestinal juices, and all the mucous secretions. In very weak conditions the bronchial mucus may accumulate to such a degree as to interfere with the breathing and favor the development of edema of the lungs. All these secretory effects are prevented by atropine. The quantity of milk, of bile, and of urine are not directly affected. It is stated that the sugar in the blood and the sugar in the milk are increased in amount. It is an interesting fact that, both from the local application of the drug to the scalp and its internal administration, the hair, in some cases, increases in abundance. This result is due, prob- ably, to the increase of the scalp secretions. The new hair may be of a lighter shade and give a patchy appearance. As a test, Pringle (1908) injected \ grain (0.03 gm.) of pilocarpine nitrate into the scalp, and got a growth of hair as the result. Smooth muscle shows its increased activity only after poisonous doses, the chief manifestations being increased peristalsis in the alimentary tract and contraction of the bronchi, bladder, and pupil. The effects are due to stimulation of the nerve-endings, and are prevented by atropine. The arterial muscles are not affected, and probably not the uterus. The Eye. A 0.5 to i per cent, solution, dropped in the eye, has the following effects: (a) Pupil. There is stimulation of the third nerve-endings, with contraction of the pupil, the maximum contraction being reached in one-half to one hour, and lasting only three or four hours. (b) Accommodation. The ends of the third nerve in the ciliary muscle are stimulated; hence this circular muscle con- tracts and causes bulging of the lens and fixation of the eye in ac- commodation for short distances. There may be a dull pain from the continued muscular contraction. (c) Intraocular Tension. After a preliminary rise, lasting sometimes as much as half an hour, and probably brought on by increased secretion, the tension falls. The fall is more or less coincident with the pupil contraction, and results from the in- creased escape of fluid which follows the opening of the lymphatic outlets (spaces of Fontana) when the pupil contracts. Circulation. From large closes the heart is usually slowed and slightly weakened, this action being due solely to stimulation of the vagus endings, and being preventable by atropine. From very poisonous closes, the vagus ends may become paralyzed, but the heart muscle itself is directly depressed, so that the beat continues slow. Sometimes the heart beats faster at first from PILOCARPUS (jABORANDl) 441 vagus center depression. After toxic doses the arterioles are dilated by depression of the vasoconstrictor center, and blood- pressure falls. Pilocarpine is, therefore, a cardiac depressant, both vagus and direct, and in excessive doses an arterial dilator. Its margin of safety is small, and its administration in conditions of cardiac weakness has been followed in some cases by collapse and death. The author has seen two cardionephritic cases die from the combined effects of pilocarpine hydrochloride, T ^ grain (0.006 gm.), and a hot-pack. Respiratory Tract. Owing to the increased bronchial secretion and contraction of the bronchial muscles from stimulation of the ends of the bronchomotor nerves, the breathing in poisoning may be labored or asthmatic; at the same time there is depression of the respiratory center. These factors, joined to weakness of the circulation, tend to promote edema of the lungs, asphyxia, collapse, and death. Nervous System. The mind remains clear in pilocarpine poisoning, but there is depression of the medullary centers and of the spinal reflexes, and there may be muscular weakness or paralysis. Elimination. In the sweat, urine, and saliva. Toxicology. As in physostigmine poisoning, there is prostra- tion without loss of consciousness. There is at first excessive vagus action and depression of the vasoconstrictor center, with slowed or intermittent heart-beat (vagus standstill or vagus heart-block) and low blood-pressure. Later there is slow, feeble heart-beat and collapse. The pupil is strongly contracted, the skin flushed and pro- fusely sweating, and the saliva abundant. There may be nausea, vomiting, diarrhea, and abdominal cramps. The respiration may be labored, asthmatic, with the physical signs of increased bron- chial mucus or edema over both lungs; there may be muscular relaxation, beginning in the lower limbs and ascending. Con- sciousness, though dulled, persists until near the end. Death takes place in collapse, with edema of the lungs. The treatment is atropine hypodermatically, and the general treatment for collapse, especially artificial respiration. The atro- pine serves to overcome the asthmatic breathing, to lessen bron- chial secretion, to diminish cramps in the abdomen, and to check excessive vagus action. Therapeutics. The fluidextract is added to hair-washes, the pilocarpine salts being, as a rule, considered too expensive. In the eye, a i : 200 solution of pilocarpine hydrochloride is 442 PHARMACOLOGY AND THERAPEUTICS used in glaucoma, and to hasten contraction of the pupil after mydriatics. Internally, it has been employed in chronic congestive con- ditions of the middle ear, in labyrinthine affections, and in con- gestive conditions of the eye. Its good effects seem to depend largely on the resulting diaphoresis. It has also been used as an expectorant in the dry stage of bronchitis, but it makes profuse sweating and salivation. Its chief use is as a diaphoretic in nephritis with uremia and in dropsy. Tyson recommends 10 minims of the fluidextract three times a day, or a daily dose of \ grain of pilocarpine hydro- chloride. Because of its tendency to depress the heart or produce edema of the lungs, its effects must be watched; and it should not be employed if the heart is weak. MUSCARINE AND MUSHROOM POISONING Muscarine is an alkaloid contained in the mushroom known as the fly agaric, Amanita muscaria, and in some other agarics. Its actions are very similar to those of pilocarpine, but stronger, hence in poisoning by the fly agaric we get the same symptoms as from pilocarpine poisoning. The symptoms come on very quickly. Muscarine is not destroyed by cooking. Atropine is the best antidote, and the stomach should be washed out or an emetic given, and general treatment for collapse instituted. Muscarine is not used in medicine, as it is more dangerous and more irri- tant to the stomach than pilocarpine. Most of the cases of mushroom poisoning, however, are due to the death's-head fungus, Amanita phalloides, and related species, which contain little if any muscarine, but depend for their poison- ous action upon a substance which has the nature of a toxin. It is characteristic of a toxin that the symptoms are manifested only after a latent period, and that immunity may be established toward it in susceptible animals by the repeated administration of non-lethal doses. This toxin is destroyed by prolonged cook- ing. Ford has prepared a serum which is antitoxic and anti- hemolytic to the amanita toxin. The symptoms come on after a latent period of ten or twelve hours. They are great thirst, vomiting, diarrhea, cramps in the stomach and limbs, headache, cerebral stimulation up to a state of delirium, and sometimes suppression of the urine. After twelve to twenty-four hours there may be jaundice from extensive hemolysis, or collapse from a toxic action upon the heart muscle ; or the sickness continues for several days, resembling an infectious disease. Later there may be an interstitial nephritis with uremia. Fig. 54. Amanita phalloides, white form, showing cap, stem, ring, and cup. (From Atkinson's "Mushrooms," Henry Holt & Co., Publishers.) 'K- 55- Agaricus campestris. View of under side, showing stem, ring, gills, and margin of rap. (From Atkinson's "Mushrooms," Henry Holt & Co., Publishers.) fj. 56. Fly amanita, Amanita muscaria. Poisonous. Nearly one-half natural size. (From Circular 139, Third Series, U. S. Department of Agriculture.) DIAPHORETICS 443 The treatment is to wash out the stomach and the colon, apply an ice-bag to the head, and give morphine by hypodermatic. If collapse ensues, treat for collapse. Atropine is of no value, and Ford's serum would hardly be obtainable when wanted. Ford has attempted to divide the poisonous fungi into three groups, viz. : 1. Those containing poisons acting on the nervous system, as Amanita muscaria. 2. Those producing degenerative changes in the internal organs, as Amanita phalloides, Amanita verna, etc. 3. Those causing gastro-intestinal irritation with violent manifestations, as Lactarius torminosus, Clitocybe illudens, Entoloma sinuatum, etc. The Amanita muscaria, or fly agaric, is highly colored with yellow and orange and reddish tints. Its stem is longer than the diameter of the cap, bulges at the base, and bears a collar or ring of tissue. The cap is deep yellow or orange or greenish yellow, and bears numerous scattered white or yellow scales. The gills on the under surface of the cap are white. It has a fungous odor and grows in open woods or along roadsides near trees. The Amanita phalloides (death's-head fungus, deadly agaric) is white throughout or slightly brownish. The stem often arises from a cup the so-called "death's-head" or "poison-cup"- bulges at the base, is longer than the diameter of the cap, and near the cap is surrounded by a collar of tissue (the annulus or ring) ; it tends to turn dark where bruised. The cap is white, or slightly yellowish or greenish white, or brownish, and its under surface bears the persistently white gills. It has a typical fungous odor, and grows in open woods or along the borders of woods. The common edible mushroom or field mushroom is Agaricus campestris. It is stubby in growth. Its stem is shorter than the diameter of the cap, is cylindric, and instead of being bulbous is narrowed at the base; it does not emerge from a cup, and, except for the first hour or two after maturity, is usually without an annulus or ring. Its cap is white to brownish, and bears on its under surface the notably pink gills, which become purplish brown when a few hours old, and turn blackish brown on keeping. It has an earthy smell, like potatoes, rather than a fungous smell, and grows in fields, lawns, or by roadsides. DIAPHORETICS A diaphoretic is a remedy which tends to induce profuse sweating. Profuse sweating is diaphoresis. The measures employed to produce diaphoresis are either drugs 444 PHARMACOLOGY AND THERAPEUTICS or methods of raising and keeping raised the body heat. We do not here consider terror, nausea, great weakness, and other causes of profuse sweating, as these are not therapeutic agents. 1. The drugs in common use are: pilocarpine, whisky, Dover's powder (pulvis ipecacuanhas et opii), the spirit of Mindererus (liquor ammonii acetatis), and the sweet spirit of niter (spiritus aetheris nitrosi), all of which we have already studied. Many other drugs tend to increase the sweat, but are not employed for that express purpose in therapeutics. 2. Methods of raising body heat and keeping it raised for diaphoretic purposes: (a) Increasing the production of heat, as by exercise. (6) Prevention of heat loss, as with blankets or extra bed- clothes, or heavy woolen sweaters, as during exercise. (c) The use of artificial heat, either internally or externally internally, by hot drinks, and externally, by hot air, hot baths, vapor baths, electric baths, etc. A full Turkish bath involves remaining about five minutes in a room at 230 F. (110 C.), five minutes at i9OF. (8y.8 C.), and fifteen or twenty minutes at about 140 F. (60 C.), the air being kept as dry as possible by good ventilation. A Russian bath is similar, but the air is sur- charged with aqueous vapor by steam. Water taken internally is both diaphoretic and diuretic. It is not cathartic (except perhaps in those who habitually under- drink), for the intestines can absorb such enormous quantities that, in normal conditions at least, the excess does not pass out by the rectum, but is excreted by the kidneys and skin (Starling). Cold water alone is essentially diuretic rather than diaphoretic, the sweat being increased to only a slight degree. But large drinks of hot water, as in the form of hot lemonade or chamomile tea, or large drinks of cold water plus measures which increase body heat and set in action the heat-regulating mechanism (as hot air, hot baths, exercise, etc.), result in a copious out- pouring of sweat. It is our custom in therapeutics to combine the measures. For example : 1. In exercising to remove fat a sweater or two is worn to prevent heat loss by evaporation of the sweat. 2. To check a cold, a liberal draft of hot lemonade or water at bed-time, with or without whisky, is assisted by extra bed-cloth- ing, and sometimes a preliminary hot bath. 3. In nephritis and dropsical conditions the hot-pack or hot- air bath is employed, with sometimes, in addition, a hypoder- matic of pilocarpine hydrochloride, y 1 ^ grain (0.006 gm.). The hot-pack gives a combination of increased external heat DIAPHORETICS 445 with prevention of heat loss. In giving a hot-pack the patient, all except the head, is wrapped in a blanket or sheet (the arms being separated from the body by a layer of material) , then suc- cessively in two blankets which have been wrung out of very hot water, then perhaps in a rubber sheet, with the bed-clothes over all. He is kept thus for from fifteen to thirty minutes. If the hot-pack is not for dropsy, a copious drink of water or lemonade may be administered; if it is for dropsy, liquid must not be given. To prevent headache, an ice-bag or wet cold cloth should be applied to the head. In dyspneic conditions the pack should not be extended high on the chest. The electric bath, the hot-air bath, and the vapor bath are sometimes used for the same purposes. The electric bath is given in a cabinet in which the patient sits (head out), surrounded by electric lights. In the hot-air and vapor baths the patient, wrapped in a sheet, sits in a cabinet or tent with the head out; or if in bed, may have a sheet hung over him in the form of a tent. A heater in the tent or cabinet, or hot air conducted into the tent by a pipe, makes a hot-air bath; the steam from a kettle makes a vapor bath. Cold applications to the head during these baths tend to prevent headache. By any of these methods copious sweating is produced, even to the amount of several quarts ; and if the skin is not exposed to cold, the production of sweat may continue above normal for as much as twenty-four hours. If, however, sweating does not result, there may be headache and feelings of faintness, and even collapse, as sometimes occurs in the Turkish bath. Even when there is profuse sweating, collapse sometimes takes place in a hot- pack, and especially is this likely after pilocarpine; so in serious heart conditions, or if there is a tendency to edema of the lungs, diaphoretic measures must be used with caution. Nevertheless, as a rule, profuse sweating is not so exhausting as repeated ca- tharsis. During or immediately following a copious sweat, exposure to cold may result in chilling of the surface, with contraction of the skin vessels and internal congestion, i. e., a cold. Therefore, be- fore going out after a heavy sweat one should have a cold sponge or shower with a good rubbing down of the skin and a short period of rest. The Rationale of Sweating. Normally, the loss of heat through the skin is due to radiation and convection from the sur- face of the body, and to the cooling effect of the evaporation of sweat. Radiation and convection are promoted by cold, and by dilatation of the skin vessels, as in exercise; but it is largely by sweating that the heat loss of the body is normally increased. 446 PHARMACOLOGY AND THERAPEUTICS Ordinarily the evaporation of the sweat keeps pace with its production, so that the sweat does not gather into perceptible moisture. But when the sweat cannot evaporate as rapidly as it is produced, as during exercise, or in a humid atmosphere, or for other reasons, the perspiration collects and becomes visible. Perspiration that is visible indicates that the heat-regulating mechanism has overdone the production of sweat, and that more is produced than under the existing circumstances can be utilized for cooling purposes. When the surrounding medium is hotter than the body, as in these hot-bath methods, radiation and convection are abolished, and consequently the only cooling mechanism left is sweating. But as the heat-regulating centers do not discriminate, the sweat continues to form so long as the body is hotter than normal, even though the conditions are such that the sweating cannot serve its usual purpose in cooling the body. Just so long, therefore, as there is a heightened body temperature the sweating continues, in a futile attempt of the heat-regulating mechanism to bring the body temperature to normal in the usual way. In the methods for inducing diaphoresis it is this tendency of the sweating mechanism to respond to raised body heat of which advantage is taken. For so long as the sweat is prevented from accomplishing its object of cooling the body, the sweating will continue indefinitely. Hence the use of exercise, hot drinks, and hot-air and hot-water baths to increase the body heat; and of blankets, sweaters, etc., to lessen the heat radiation and to absorb the sweat and prevent its evaporation at the surface of the body. Fat. In a sense there is a protective garment about a fat per- son, the thick, poorly conducting layer of fat interfering with heat loss; so that if the internal temperature is raised, an excessive amount of sweat is poured out in the effort of the body to cool itself. On a hot, dry day a fat man may lose by evaporation as much as 3200 calories; on a hot, humid day a fat man sweats more profusely, yet suffers more from the heat than the thin man. If a fat person ingests no water while carrying out diaphoretic measures, the body tends to form water from the fat, and so lessen its adipose deposit. Von Noorden says that 100 grams of fat yield 107 grams of water, and he states that restriction of the water intake produces a loss of fat. But he quotes Heilner and also Henneberg as authorities for the statements that in experi- mental animals abundant water-drinking increases fat catabolism, and in stock-raising renders it very difficult to fatten animals. Hawk says that water increases protein metabolism. Yet by vigorous daily exercise, wearing heavy sweaters, limitation- DIAPHORETICS 447 of the fluids, and regulation of the food ingested a fat man may lose 40 or 50 pounds of his weight in a few months and yet feel in splendid condition. The Character of the Sweat in Diaphoresis. The normal se- cretion of the sweat-glands is of low specific gravity and of faintly alkaline reaction, and there are various salts present. The slight acidity sometimes noted is due to admixture with the fatty acids of the sebaceous secretion. It is frequently stated that the copious sweat produced by methods to raise body heat is slightly alkaline, but in many tests by the author of the sweat of nephritics in the hot-pack it has been, without exception, acid. The Relation of Diaphoresis to Nitrogenous Excretion. The ordinary insensible perspiration does not contain any appreciable nitrogenous matter (Lusk). The average of many tests by dif- ferent experimenters gives 0.068 gm. nitrogen per day in skin elimination. Benedict (1906) got 0.071 gm. nitrogen per day in the whole cutaneous secretions, both sebaceous and sweat, of a resting man. "But when the sweat was increased, as in a man at moderate work, the nitrogen from the skin rose to 0.13 gm. per hour, and in a man at hard work to 0.22 gm. per hour. The nitrogen of these larger quantities represented urea, uric acid, creatinin, and other constituents of urine." Therefore, copious sweating from hard work, which Atwater and Benedict found might be eight times the normal sweating, represented the loss of i gm. of nitrogenous excreta in five hours. This shows that the sweat-glands of normal persons can, to some degree, be made to take on a func- tion of the kidneys. But in this work there was greatly increased muscular activity, i. e., increased metabolism, and consequently the results are not indicative of the real excretory value of diapho- resis in sick people. Some of the striking experiments on diaphoresis are worth noting: Hoelscher, in 22 experiments with hot-air baths, obtained 6719 c.c. of sweat, containing a total nitrogen of 0.48 gm. per looo c.c. Eijkmann studied three medical students at light occu- pation in the climate of Java. In three hours he obtained 0.222 gm. nitrogen; in twenty-four hours, 0.761 and 1.362 gm. nitrogen. Benedict experimented with a man twenty-four years old, 75 kilos in weight, at rest in the respiration chamber during four days of fasting and then three days with food. The average daily nitrogen excreted by the skin was 0.103 S m - When such a man did eight hours' work on a stationary bicycle in the respiratory calorimeter, his clothes extracted with distilled water gave an average of 0.29 gm. nitrogen per day for eighty-eight days' work. 448 PHARMACOLOGY AND THERAPEUTICS Lawnius estimated that in a circus athlete the loss in the sweat was 1.8 gm. nitrogen per day. Zuntz calculated that the loss of nitrogen to the perspiration, including shed epithelium, is 0.46 gm. per day. Atwater and Benedict with a professional bicyclist twenty- eight years of age and 62 kilos in weight, placed in the bicycle ergometer for four hours, found that the heat output was about 600 calories per hour, and that the total nitrogen increase in the sweat was roughly proportional to the work done. In the sweat of 6 normal humans and 3 nephritics Riggs (1911) failed to find uric acid. But Plaggemeyer and Marshall (1914) tested normal passive sweat, obtained during 25 min- utes of hot-air sweating, and filtered to eliminate shed epithe- lium, and found urea, uric acid, ammonia, and diastase as con- stant constituents, the urea being 0.05-0.3 per cent, and the uric acid 0.00005-0.00018 per cent. The total output of nitrogen ranged from 34 to 640 mg., the ratio of ammonia nitrogen to the total nitrogen being considerably higher than that in the urine. In Sickness. In uremia, a condition of poisoning in which the molecular concentration of the blood is increased as a result of impaired kidneys, the sweat poured out may contain a much greater proportion of nitrogenous material than that from hard work. In fact, in nephritis crystals of urea have actually been found deposited upon the skin ; though this was only in terminal conditions of collapse with abnormal capillary permeability. That in uremia profuse sweating is of great value in carrying off nitrogenous material was the contention of Bendix (1904), who claimed to be able, by profuse sweating alone, to bring to normal the greatly depressed freezing-point of the blood of uremic patients, i. e., to reduce its molecular concentration to normal. But Austin and Miller (1914) observed no effect from sweat-baths on the non-protein nitrogen of the blood in nephritics with hypertension. Tachau (1912) gave one-hour sweat-baths to nephritics and determined that the nitrogen excreted amounted to 0.2 to 0.49 gm., while the chlorides were 1.31 to 2.05 gm. Von Noorden says that the perspiration of nephritics contains a maximum of i to 1.3 gm. of urea from profuse sweating, and this is too little to be of moment to the kidneys. Thus from an excretion point of view sweating in nephritis must be considered chiefly of use in re- moving water and perhaps chlorides rather than urea or other nitrogenous waste. But by draining the blood of water it has the additional effect of mobilizing the tissue fluids, of promoting the visceral circulation, and perhaps also of bringing into the blood antibodies to be utilized or toxins to be excreted. Hunt has DIAPHORETICS 449 demonstrated that normally the reserve of water in the body is so great that even when several liters of water have been lost by sweating, the percentage of water in the blood is not appreci- ably diminished because of supply from the tissue fluids. More- over, the dilatation of the skin vessels results in a diversion of the blood from the congested internal organs. In intestinal putrefactive toxemia with indicanuria, indol has been detected in the perspiration. By the chlorides excreted Spitta has determined that sweat- ing is as great in a hot bath as in hot air of the same temperature; therefore by a simple hot bath, as by the more elaborate baths, profuse sweating may be produced, and afterward may continue for many hours in excess of normal if the person remains in a warm room or in bed. Therapeutics and Administration. i. To lower temperature, in mild fevers the liquor ammonii acetatis, 2 drams (8 c.c.), or spiritus setheris nitrosi, i dram (4 c.c.). The effect of these is probably almost nothing. 2. To overcome chill or cold by relieving internal congestion and reestablishing proper cutaneous circulation. Hot lemonade at bedtime, whisky and hot water, Dover's powder, and a hot bath are the favorites, with extra bed-clothes. Dover's powder is in extensive use by both physicians and the laity to produce sweating, especially if there is pain or restlessness. But unless it is given with a copious hot drink and the patient uses extra bed- clothing, the chances of its producing profuse sweating are very small. It is given in 5 or lo-grain doses, and is often followed the next morning by nausea, headache, and a feeling of lassitude. 3. To lessen obesity exercise with heavy woolen clothing, Turkish baths, hot baths, restriction of liquids ingested. 4. To assist the kidneys in the removal of accumulated poisons, as in uremia, and possibly in gout, rheumatoid conditions, eclamp- sia, and other toxemias. Hot-pack, vapor baths, etc., with or without pilocarpine, and, if there is no edema, with copious drafts of water. A hot-pack is often followed by a decided in- crease in kidney activity. 5. To lessen edema and promote the absorption of dropsical effusions hot-pack, vapor baths, etc., with dry diet, very little water being ingested; sometimes with pilocarpine. It must be understood, of course, that dropsical fluid is reabsorbed from the tissue spaces when by sweating the blood loses water. An added factor in lessening edema may be the excretion of sodium chloride in the sweat. 6. To lessen congestion of the internal eye and of the middle and internal ear especially by pilocarpine. 29 \ 450 PHARMACOLOGY AND THERAPEUTICS 7. To hasten the outbreak of the rash in measles and other exan- themata. Hot baths for this purpose are in common employ- ment. Local sweating with high temperature is used in chronic rheumatism, rheumatoid and gonorrheal arthritis, and other joint affections. In the ordinary baking-box for an arm or a leg, such as Bier's, the temperature can be borne for half an hour up to about 1 80 F., the heat of a baking oven, and this induces a marked hyperemia of the limb, with profuse perspiration. With the Sprague apparatus, in which, by a special arrangement, the evaporation of the perspiration keeps pace with its production so that there is never any visible perspiration, a temperature of 300 to 350 F., the so-called "superheated air," can be borne without discomfort or burning. At this temperature, if a drop of water should collect on the skin, it would instantly form steam and scald the skin. A limb, or even the whole body except the head, can be kept at this temperature for fifteen or twenty minutes, the body temperature rising from i to 4 degrees. Cold applications should be kept upon the head. DIURETICS A diuretic is a remedy which tends to promote the flow of urine. Diuresis is copious flow of urine. The kidney is a highly vascular organ, with numerous vaso- motor nerves and readily influenced arterioles. Its function is to preserve the normal composition of the body fluids by ridding the blood of certain substances which are present in excess or are not normal constituents, hence it reacts readily to changes in the blood composition. The blood from the renal artery passes along the afferent arterioles into the capillaries of the glomeruli, and there loses a certain amount of water, containing substances in solution. This escapes through the endothelium of the capillaries and their covering membrane of Bowman's capsule into the uriniferous tubule; while the blood, thus concentrated, leaves the glomerulus by an afferent vein, which is smaller than the afferent arteriole (perhaps only two-thirds the size). "This vein divides into branches after the manner of an artery, and from these arises a dense network of capillaries which everywhere ramify over the wall of the uriniferous tubule" (Quain). The blood in the capil- laries surrounding the tubule is, therefore, blood with a diminished total of dialyzable substances and concentrated by the loss of water; and it differs by so much from the blood in the capillaries of the glomeruli. DIURETICS 451 The average daily urine amounts to about 1500 c.c., is of acid reaction, and contains about 33 gm., i. e., 2.2 per cent, of urea; while the blood from which it is derived is alkaline and contains only 0.05 to o.i per cent, of urea. The liquid must, therefore, undergo striking changes in its passage from the glomerular capillaries to the ureter. We might review very briefly the functions of the different parts of the kidneys: The Glomerulus. While there seems to be no doubt that this acts largely as a mechanical filter, there is some evidence that its cells may, in addition, select and secrete certain of the elements of the blood. Brodie believes it to be an expulsor organ, capable of expansion and contracton. The Tubules. That the tubules have the power to reabsorb water and some of its dissolved substances is apparent from a number of experiments. Cushny showed not only that water was absorbed, but that there was a differential reabsorption of certain of its salts, apparently in proportion to their diff usability, e. g., sodium chloride more readily than sodium sulphate. He found also that in marked diuresis the proportion of these salts in the urine was more nearly equal; and he figured that reabsorption failed to take place because of the rapidity of the passage of the liquid through the tubules. Moreover, destruction of the tubule cells experimentally or by disease is regularly followed by increase of urine excretion. That the tubules have also a specific secretory power is sug- gested by the results of the injection of sodium sulphindigotate into the blood. Within a minute or two the urine secreted is blue, showing that the pigment passes out in the urine. If the kidney is at once removed and the coloring-matter fixed by perfusion with alcohol, microscopic examination shows the tubule cells deeply stained with blue, while the glomeruli are not stained at all. This suggests that the pigment has passed through the tubule cells (presumably was excreted) rather than through those of the glomerular capillaries. Again, if the blood-pressure is reduced below 40 mm. mercury (below which pressure all urine flow ceases), the cortex alone is blue, and the pigment is found deposited in granules in the striated epithelial cells and the lumen of the first and second convoluted tubules. After the injection of uric acid in a solution of piperazin Starling found uric acid in the cells and lumen of the convoluted tubules. Nussbaum's experi- ment on the reno-portal vein of the frog and some experiments on poisoned kidneys also point to a specific secretory power. By injecting acid indicators into the blood it may be shown that the glomerular fluid is alkaline, and that the urine becomes 452 PHARMACOLOGY AND THERAPEUTICS acid in the convoluted tubules ; if it is hurried through the tubules by active diuresis, it is less acid and may be alkaline. Without entering further into the theories of kidney action, which are not yet soundly established, and can be read up in any recent book on physiology, we will assume that the function of tlte glomerulus is to pass from the blood to the uriniferous tubules large quantities of an alkaline fluid which contains urea, chlorides, phosphates, sulphates, and under some circumstances sugar and other substances, in the proportion in which they occur in the blood. And that the functions of the tubules are: (i) To change the reaction of the glomerular fluid to acid. (2) To add to it cer- tain substances by excretion, such as urea, uric acid, creatinin, urinary pigment, phosphates, and, under certain circumstances, water. (3) To concentrate the urine, by the reabsorption of much of its water and of some of its dissolved substances. These are reabsorbed somewhat according to their absorption power, i. e., sodium chloride readily, sulphates less readily, and urea not at all. But it has been demonstrated that the excretion of various sub- stances reaches its maximum at different times and not necessarily when diuresis is greatest. As the function of the kidneys is in large measure to keep the blood of normal composition, even minute quantities of foreign substances, such as potassium iodide, or excessive quantities of normal constituents, such as sodium chloride and sodium bi- carbonate, may be rapidly excreted without any apparent re- absorption. The urine is, therefore, made up essentially of (i) water, (2) such dissolved substances as have been removed from the blood in the glomeruli and have escaped reabsorption, and (3) the substances excreted by the tubule cells. Either its quantity or its quality may be changed by an alteration (i) in the con- stituents of the blood; (2) in the nitration or secretory power of the glomeruli; (3) in the secretory power of the tubules; or (4) in the reabsorptive power of the tubules; but in the production of diuresis we are not always certain which of these are the factors involved. On account of these complex factors we must not forget, in treating patients, that the volume of the urine is made up of water, and that, therefore, the quantity of urine excretion is not necessarily a measure of the cxcrementitious materials that are being removed from the body. Indeed, von Noorden states that a con- centrated urine may carry out just as much deleterious matter as one less concentrated. As the normal powers of healthy kidneys are vastly more than sufficient to maintain a proper blood com- position, our endeavor in disease must be to restore the kidney DIURETICS 453 functions or to minimize the amount of kidney activity required. We have no proof that the removal of edema by diuresis benefits the kidneys themselves, however much it may benefit the patient. We cannot confer upon the kidneys any abnormal powers, or functions new to kidney tissue. Walker and Dawson, Christian, and others have shown that the life of rabbits with severe acute experimental nephritis may be definitely shortened by the repeated administration of diuretics, at least those of the caffeine series, and potassium acetate. Their experiments would suggest that diuretics are contraindicated in acute nephritis, but the success of diuretic methods in mercuric bichloride poisoning points otherwise. Christian says that following an active diuresis there may be for a day or two a decrease in renal function as measured by the index of urea excretion. This is probably due to renal fatigue and not to renal damage. The Therapeutic Production of Diuresis. From these re- marks it will be seen that the site of the diuresis may be the glomerulus or the tubule, or both; and that diuresis may be brought about by: I. Measures which increase the glomerular fluid. (a) By increasing the blood-flow through the kidney. (b) By lowering the osmotic pressure of the blood. II. Measures which increase the tubular secretion. III. Measures which decrease the tubular reabsorption. I. Measures Which Increase the Glomerular Fluid. (a) By Increasing the Blood-flow Through the Kidney. It is evident that constant replacement of the blood of the kidneys must take place or the urine will cease to flow. It is evident, also, that glomerular filtration is dependent upon the maintenance of a certain capil- lary pressure, for experiments show that when general arterial pressure falls below about 40 mm. of mercury, the urine ceases to flow. The capillary pressure in the glomerulus is maintained by the general arterial pressure, by the small size of the efferent vessel of the glomerulus as compared with its afferent vessel, and by the friction of the second set of capillaries. About the pressure in the efferent vessel, and about its dilatation and contraction, we know nothing; but it is found by experiment that even a moderate resistance to the venous outflow from the kidney checks the flow of urine. We know at present, therefore, that the flow of urine is readily influenced by changes in the amount of blood ~ passing through the kidneys; and that this amount of blood is j regulated by the general arterial pressure, by the caliber of the kidney arterioles, by the back pressure in the kidney - veins, and by the viscosity of the blood. Digitalis is one of 454 PHARMACOLOGY AND THERAPEUTICS the best of diuretics in conditions with impaired circulation. (See Digitalis.) The kidney arterioles are the sluice-gates to the capillaries. If general arterial pressure remains constant, dilatation of the kidney arterioles allows a greater blood-flow through the kidney capillaries, and contraction of the arterioles determines a lesser blood-flow. If the caliber of the arterioles remains constant, a rise in general arterial pressure causes more blood to pass through, and a fall in pressure causes less blood to pass through. It is a general rule that diuresis is accompanied by dilatation of the kidney arterioles through a local action, and in most in- stances it is observed that diuresis is dependent upon such dilata- tion. But there are exceptional instances where diuresis has occurred in the absence of dilatation of the renal arterioles, or where diuresis has failed even though the arterioles were dilated. In experimental vascular nephritis Pearce reports dilatation of the vessels from caffeine and from 5 per cent, sodium chloride, but diuresis from the caffeine only. Also, if the kidney is pre- vented from expanding, i. e., the vessels not allowed to dilate, there is diuresis from caffeine, but not from various diuretic salts and dextrose. (b) By Lowering the Osmotic Pressure of the Blood. If sodium chloride, sodium acetate, urea, or dextrose in hypertonic solution is injected into the blood, the osmotic pressure of the blood is at once raised. Fluid passes to it from the tissues, the blood swells up, and a condition of hydremic plethora with lowered osmotic pressure is brought about, i. e., the quantity of blood is greater than normal, the tissues or tissue spaces having been drawn upon for a diluting fluid. If an isotonic saline solution is injected into a vein, swallowed, or administered by rectum, this hydremic plethora results without the imbibition of fluid from the tissues or tissue spaces. In hydremic plethora, under the influence of the slightly raised arterial pressure and the lessened viscosity of the blood, this swollen volume of blood tends to promote rapid blood-flow, and, as a consequence, to favor transudation of the excess of fluid through capillaries. The kidney capillaries are the ones by which the body gets rid of excessive fluid ; therefore if the kidneys are functionating properly, there is diuresis, and the excess of water with certain dissolved materials is rapidly got rid of. Hydremic plethora and its resulting diuresis may be the con- sequence of the absorption of dropsical fluid, as under the adminis- tration of digitalis. It may be produced intentionally by the ingestion of water, or of solutions of dialyzable substances. DIURETICS 455 The result in any case is diuresis, unless the molecular concentra- tion of the plasma is decreased. For example, a hypotonic sodium chloride solution intravenously, because of its low salt content, will make a hydremia without diuresis (Davis). Of dialyzable substances, those with a pronounced diuretic action are: (a) Inorganic Salts. Sodium sulphate, sodium chloride, and sodium or potassium bicarbonate, but the only ones employed as diuretics are the bicarbonates. (6) Organic Salts. The acetates, citrates, and tartrates, which break down into carbonates in the blood. They are po- tassium acetate, potassium citrate, potassium bitartrate, potas- sium and sodium tartrate, liquor ammonii acetatis, and liquor ferri et ammonii acetatis (Basham's mixture). The best of these is potassium acetate. (See Imperial Drink, page 88, and A. B. C. mixture, page 102.) (c) Urea, (d) Dextrose. (See Glucose.) All these substances tend to have an effect upon the urination in direct proportion to the osmotic pressure which they exert. In hydremic plethora, if the kidneys are not functionating well, as in chronic nephritis, and there is water retention, the excess of water tends to transude through the systemic capillaries and to favor the production of edema and dropsy. Water. Ordinary drinking-water is hypotonic, and is prac- tically unabsorbed by the stomach. But it imbibes salts from the food or mucus, or from the superficial cells of the alimentary tract, or takes up the sodium chloride which is formed in the duodenum by the neutralization of the hydrochloric acid of the gastric juice. Hence it becomes a salt solution, and, instead of passing on through the intestine to the rectum, is absorbed. Therefore when excess of water is ingested the excess does not normally pass out with the feces; and under ordinary conditions of absorp- tion, no matter how much is drunk, does not produce a movement of the bowels (Starling). So the ingestion of large quantities of water leads to a condition of hydremic plethora, which results in increased urination. Water in large amounts is, therefore, diuretic, and in its elimination tends to carry out certain dis- solved substances, especially urea, sulphates, and phosphates. Leonard Hill says it only washes out the urea stored in the tissues and does not provoke increased destruction of tissue protein; but Hawk has gathered some evidence that copious water drink- ing results not only in a removal of stored-up urea, but also in increased protein destruction. The body has a great capacity for the storing of water, so that even when the excretory apparatus is impaired, excessive amounts 456 PHARMACOLOGY AND THERAPEUTICS of water can be taken for many days before dropsy sets in. In these cases it is evident that a diuretic is indicated before dropsy is apparent. But water should not be given, for in dropsical conditions large quantities of water serve only to increase the already "water-logged" condition of the patient. II. Measures Which Increase the Tubular Secretion, and III. Measures Which Decrease the Tubular Absorption. Be- tween these two, we cannot at present discriminate. The diuretics which act upon the tubules, however, may be divided for practical purposes into 1. Those which are non-irritant to the kidney, and conse- quently in the larger doses do not produce inflammation caffeine, theobromine, theophylline, diuretin, agurin. (See Caffeine.) Caffeine itself, because of its dominant other effects, is little employed as a diuretic, but the action of the series is obtained by theobromine and theophylline (theocine) and their soluble combinations. Usually in conditions with undiseased kidneys, as in the edema of cardiac insufficiency, and less often in kidney cases, they are effective diuretics, and the author has in several instances seen the urine flow for twenty-four hours reach 200 to 300 ounces (6 to 9 liters) after two or three doses of 20 grains of theophylline or theobromine sodio-salicylate. In one dropsy case at the City Hospital the drug was continued for seven days with a high daily urine output and a total loss of 60 pounds in the patient's weight. However, because of their tendency to cause renal fatigue, Christian recommends that they be given in full dosage for a period of two or three days only, followed by a similar period without any diuretic. Both drugs are irritating to the stomach, theophylline being more so than theobromine; and in such case their soluble compounds in 5 per cent, solution may be given intravenously. In acute and chronic nephritis the indication for the use of these drugs is not so clear as in the cardiac cases; indeed, with theophylline in renal cases Christian found that kidney efficiency as judged by the index of urea excretion was more often decreased by their use than increased, and with caffeine even in normal persons Benedict noted a degree of nitrogen retention. In a case of kidney disease at St. Luke's the urine rose to 300 ounces (9 liters) the first day, and remained high for the seven days during which the drug was administered (see Caffeine). 2. Those which are irritant, and in overdose may produce inflammation. They are: ((/) Volatile oils, and resinous or aromatic drugs, especially the oils of sandalwood, juniper, turpentine, the balsam of copaiba, and the drugs buchu, cubeb, kava-kava, matico, uva ursi, and DIURETICS 457 cantharis. These are less prescribed as diuretics than as urinary antiseptics. The oil of jumper is present in "gin." (b) Certain drugs which contain irritant glucosides and are mostly used in the form of infusion; for example, scoparius or broom, which contains scoparin, asparagus, which contains asparagin, and triticum, which contains triticin. (c) Calomel. A dose of calomel at the beginning of diuretic treatment will often hasten, or at least appear to hasten, the on- set of diuresis. This is particularly true in venous stagnation. It may act by irritating the kidney cells; but its action is more probably due, not to direct diuresis, but to the relief of the kidneys through the removal of fluid by the bowels. To compare the various diuretics, Raphael (1894) placed him- self on a uniform diet for a long period, the daily allowance of fluid being 1 180 c.c. His twenty-four-hour urine ranged between 750 and 960 c.c. When, in addition to his uniform diet, he took diuretics, his urine increased as follows: INCREASE. 0.4 gm. oil of turpentine 1 1 per cent. 0.2 gm. oil of juniper + 1000 c.c. water in 0.5 gm. caffeine and sodium salicylate 42 0.5 gm. theobromine and sodium salicylate (diuretin) 2 1.5 gm. theobromine and sodium salicylate 14 3.0 gm. theobromine and sodium salicylate 53 30.0 gm. sugar of milk 34 1000.0 c.c. water 100 1000.0 c.c. carbonic water 73 1000.0 c.c. beer 100 1000.0 c.c. claret 80 1000.0 c.c. milk 153 As a general rule, the following things are true about diuresis: 1. The filtered substances, urea and salts, are increased in proportionally greater amount than the secreted substances, uric acid, creatinin, pigment, etc., and there may be no increase in the latter substances at all. The excretion of phosphates is increased by water (Hawk), and that of uric acid by atophan. 2. Substances which are ordinarily partially reabsorbed are passed out in greater proportion to the other substances than normally, their proportional reabsorption being prevented either by the more rapid flow which takes place through the tubules, or by impairment of the reabsorbing power of the cells. 3. Frequently for the first day or two of diuresis there is a great increase in the amount of some of the solids excreted, as if there had been accumulation of these in the body and they were being washed out. Magnus says that for each salt (substance) there is a "secretion threshold," a certain degree of concentra- tion in the blood, above which an increase leads to the elimina- 458 PHARMACOLOGY AND THERAPEUTICS Fig. 57. Drawing made to scale from tracings taken from a dog by C. C. Lieb. Horizontal line of figures, time in minutes. Black line, arterial pressure; dotted line, urine flow. The close relation between general blood-pressure and urine flow is striking. The drugs, in the order used, with dose per kilo, are: Caffeine, 2 mg., urine little affected. Theophylline acet-sodium, 3 mg., urine much increased. Spirit of nitroglyccrin, 0.3 c.c., urine decreased. Thcobromine sodium salicylate, 3 mg., urine increased. Caffeine and sodium benzoate, 4 mg., continues theo- bromine effect. Animal bled, 20 c.c. per kilo, great fall in urine. Saline infusion, 25 c.c. per kilo, great increase. Camphor in oil, 20 mg., decided fall. Pituitary extract, o.i c.c., fall followed by rise. Epincphrine solution, o.i c.c., fall followed by rise. Tincture of caniharides was then given in amounts large enough to produce inflammation of the kidney. DIURETICS 459 tion of the excess with an increased secretion of water. It may be that in diuresis the level of this "secretion threshold" is lowered. By atophan, for example, it is possible to reduce the uric acid of the blood away below normal. 4. Without abundant supply of water there is no diuresis. 5. The continued use of diuretics results in fatigue of the kidney cells. Therapeutics of Diuresis. The two great uses of diuresis are (i) To promote the elimination of toxins, usually of bacterial or metabolic origin, and (2) to cause the removal of dropsy. In the first case copious amounts of water must be administered to serve as the medium of excretion; in the second, the ingestion of water is kept below normal. When the human kidneys are im- paired, as in nephritis, there may be abnormal retention of various substances, i. e., the kidney loses its power to excrete to the full degree. Such substances may be water, chlorides, urea, creatinin, uric acid, etc. In such cases the application of this or that diuretic is purely experimental. 1. To promote the elimination of toxins. Assuming that the kidneys are functionally good, diuresis brought about in any manner tends to increase the excretion of any dialyzable substance in the blood; for the water in passing out must carry with it some of each of the filterable substances of the blood. If the poisons are not filterable, they pass out in the urine only if the tubule cells, or perhaps the cells of the glomeruli, can take them from the blood and excrete them. The tubules are exceedingly sensitive to foreign substances in the blood, and are probably competent to excrete many of the unusual deleterious substances of the body, such as toxins of disease or abnormal products of metabolism; but we have no satisfactory data to indicate just how much of a role they do play in such elimination. To promote the elimina- tion of drug poisons, such as strychnine, a saline infusion or 2 per cent, sodium sulphate intravenously may be administered. For metallic poisons see the Lambert-Patterson treatment for mercuric bichloride poisoning. This is also a method for over- coming suppression of the urine in acute kidney cases. By promoting absorption of tissue fluid, diuresis may have an additional value by getting the tissue toxins into the blood stream to be excreted. 2. To cause the removal of dropsy and edema i. e., the removal of fluid from the potential tissue spaces. The treatment of drop- sical or edematous conditions is of the greatest interest from a diuretic point of view. There are four great causes of edema, viz., venous engorgement from cardiac disease, kidney impermeability, tissue retention, and abnormal general capillary permeability. 460 PHARMACOLOGY AND THERAPEUTICS As a rule, a combination of diuretics is advised, and a diminution of the water intake. (a) Venous engorgement has been discussed at length under Digitalis. At times the best results are obtained with digitalis to activate the circulation, and diuretin or a saline such as potassium acetate to activate the kidney or dilate the kidney arterioles. (b) Kidney impermeability is a difficult thing to overcome, because it depends on kidney disease. The impermeability for salts, urea, uric acid, water, etc., may depend largely on the type of affection of the kidney. Much experimental work has been done on forms of acute nephritis produced by poisons. Thus poisons affecting the tubular epithelium are uranium nitrate, mercuric chloride, and the alkaline chromates; poisons affecting the glomerular capillaries are arsenous acid, cantharidin, and rat- tlesnake venom ; and a poison that will affect both capillaries and tubules is diphtheria toxin. The glomerular capillaries seem to be affected beyond all other capillaries, probably by a remote local action in the elimination of the poisons. In the experimental acute tubular nephritis there is copious urination, increased by most diuretics. In the experimental acute glomerular nephritis there is no polyuria and deficient response to diuretics. In either case, after a few days' exposure to the poison, the lesions tend to extend and become combined; but when the poison is stopped, the kidneys heal and do not show the lesions of chronic nephritis (Pearce). In acute or chronic nephritis with edema we have little in- formation to guide us in our choice of diuretics, and our best plan is to use a saline diuretic with one of the caffeine series, such as theobromine sodio-salicylate. Because of the danger of producing kidney fatigue, Christian and others recommend large closes for only two or three days at a time. Pearce has shown that kidney injury alone is insufficient to cause edema. There must be, in addition, general capillary per- meability and hydremic plethora. (c) Tissue retention of water as a cause of edema is a subject not fully understood. In chronic edematous states it is customary to put the patient on a diet very low in sodium chloride, the so- called "salt-free" or "salt-poor" diet. This reduces the sodium chloride in the urine, but seems to make little alteration in the percentage of sodium chloride in the blood-plasma. It is, how- ever, an effective measure in many cases. The author has seen cases in which the salt had been so reduced that diuresis occurred only after the administraton of sodium chloride. (d) Abnormal permeability of the capillaries of the body may result from poisons, as in arsenic and food poisoning and uremia. ANTIPYRETIC DRUGS 461 It is to be remembered that diuresis requires water as its medium, so that to promote the elimination of poisons copious drafts of water should be administered with the diuretic. If, however, there is edema or any degree of water retention, all fluids should be restricted. (See also Caffeine, Theobromine, and Theophyllin.) ANTIPYRETICS Antipyretics are remedies which tend to reduce the tempera- ture in fever. The reduction of temperature may be brought about by cold or by drugs. Cold. Some of the methods for applying cold are the cold bath, the cold-pack, and the drip sheet; and for local use the cold compress, the ice-water coil or ice-bag, rectal irrigation with ice-water, the cold spinal douche, etc. The cold bath is employed in typhoid fever. In the tub-bath the patient is covered with a sheet and lifted into a bath contain- ing water at about 70 F. The primary shock is less if he is placed in the bath at 85 or 90 F., and the water cooled rapidly to 70 F. by the addition of ice. The head should be cooled with ice-cold compresses, and the body rubbed vigorously during the bath. A preliminary dose of whisky tends to dilate the cutaneous vessels and increase the output of heat. The bath is continued for from ten to fifteen minutes. The bed-bath is made by having the patient on a large piece of rubber sheeting, of which the edges are raised over pillows or rolled-up sheets. Cold water is poured in around the patient, ice added, and the patient's body soused with the water by means of a large sponge. In the cold-pack one or two sheets are wrung out of cold water and wrapped around the patient, the first layer of sheet passing beneath the arms and being tucked between the legs. The patient lies on a blanket, in which he is then completely enveloped up to the neck. After fifteen minutes these coverings are removed. If desired, the sheets may again be wrung out of cold water and the process renewed. When the drip-sheet is used as an antipyretic measure the patient is wrapped in a sheet in the same manner as above, but sits up and has cold water poured over him. These methods of applying cold, whether followed by a good reaction or by shivering, cause an increase in the viscosity of the blood (Determann, Austrian). ANTIPYRETIC DRUGS The group known as antipyretics includes only those drugs whose most pronounced property is to reduce the temperature of fever. It does not include aconite, alcohol, digitalis, phenol, 462 PHARMACOLOGY AND THERAPEUTICS and other drugs which possess the power to lower temperature in fever, but have other important activities that lead us to class them elsewhere. For convenience, the essential antipyretics may be divided into three therapeutic groups, viz., the analgesics, the antimalarials, and the antirheumatics. THE ANALGESIC ANTIPYRETICS The official ones are antipyrine, acetanilid, and acet-phenet- idin. Some of the quinoline derivatives, among the so-called coal-tar drugs, have been employed largely as antipyretics (kairin, thallin, etc.), but have been discarded in favor of more certain remedies. Antipyrina, antipyrine, phenyl-dimethyl-pyrazolon, NC C H 5 CH 3 N/\CO CH 3 C CH is freely soluble in water and alcohol, and has a slightly bitter taste. It is a body closely resembling the alkaloids, and is pre- cipitated by tannic acid, alkalies, and some other alkaloidal pre- cipitants. With calomel it forms a poisonous compound. With spirit of nitrous ether or other nitrites it gives a deep-green color (iso-nitroso-antipyrine) ; with ferric salts a deep red ; with chloral hydrate, naphthol, phenol, and sodium salicylate it liquefies; with caffeine, quinine, and some other alkaloids it forms soluble double salts. Dose, 4 grains (0.25 gm.). For local application it is employed in 5 to 25 per cent, aqueous solution. Close relatives are pyramidon, dimethyl-dimethyl-amino-pyrazolon, and sali- pyrine, antipyrine salicylate. Acetanilidum, acetanilid, phen-acetamide, C 6 H 5 .NH.CH 3 CO, has a slightly biting taste, ancl is soluble in 190 parts of water and in 3.4 of alcohol. Its solubility in water is increased by acids and decreased by alkalies. Dose, 4 grains (0.25 gm.). Close relatives of acetanilid are exalginc, methyl-acetanilid, and salophen, acetanilid-salicylic acid. Acet-phenetidinum, C 6 H 4 .OCoH 5 .NH.CH3CO, more familarly known under the proprietary name "phenacetin," is a derivative of phenol. It is soluble in 1310 parts of water and 15 of alcohol, and is almost tasteless. The chemic formula shows that phen- acetin might properly be called oxyethyl-acetanilid, but it is not a direct derivative of acetanilid, and may better be placed in a separate group with other phenetidin compounds. It is not readily soluble in water. Dose, 5 grains (0.3 gm.). The other THE ANALGESIC ANTIPYRETICS 463 phenetidin compounds worthy of note are lactophenin, a lactic- acid derivative; malakin, a salicylic-acid derivative; and apolysin and citrophen, the mono- and tri-phenetidin citric acids. Pharmacologic Action. These drugs all reduce temperature in the same way, are all analgesic, are all nerve sedatives, and are all antiseptic. This antiseptic action is mild, but is the same in kind as that of the phenol group of antiseptics, to which they are closely related chemically. Their antipyretic action is powerful, as exhibited in the reduction of temperature in the infectious fevers. Their analgesic action is chiefly shown in headache and nerve and muscle pains. Locally, antipyrine differs from the others in that a 10 to 25 per cent, solution applied to a mucous membrane acts mildly like cocaine, inducing vasoconstriction with shrinkage of the mem- brane and the checking of small hemorrhages, and lessening pain. Acetanilid is slightly irritant locally, and phenacetin is bland. The Antipyretic Effect.- It seems probable that in many cases hyperthermy or fever is a protective reaction on the part of the body, and in these cases moderate degrees of fever require no antipyretic treatment. There are some cases, however, in which even mild degrees of fever seem disadvantageous, and others in which the protective fever reaction overshoots the mark and pro- duces a high and dangerous body temperature, and it is in these that antipyretic measures are indicated. Hektoen believes that fever is an indication that foreign protein is being broken down. In fever the temperature may be reduced either by lessened production of heat or by increased output of heat, or by both. The tendency of the body is to keep itself at a normal tempera- ture. If the body is too warm, there is a dilatation of cutaneous blood-vessels and an outpouring of sweat, so that the body will undergo heat loss by (i) Radiation and convection of heat, more heated blood from the interior being brought to the surface ; and (2) the evaporation of sweat. At the same time there is a tendency to lessened muscular activity with diminished heat production. This combination of lessened heat production and greater heat dissipation tends to bring the overheated body to a normal temperature. If, on the contrary, the body is too cool, there is stimulus to greater muscular activity, the muscular act of shivering takes place, sweating stops, and the cutaneous vessels are contracted. So there are greater heat production and lessened heat dissipa- tion, and the too cool body becomes warmed. This heat production and heat-dissipation are, to a certain extent, under the control of some central structures spoken of collectively as the heat-regulating centers, the function of which 464 PHARMACOLOGY AND THERAPEUTICS is to keep the body temperature normal. There are probably thermogenic centers governing the production of heat, and thermolytic centers governing the dissipation of heat, and it is believed that they are situated in the corpus striatum and optic thalamus. Barbour and Wing have shown that heat applied directly in these regions results in body cooling, and cold results in body warming. Any variations from the normal affect these centers; and they at once send out impulses which influence the mechanisms for the production or the dissipation of heat, as may be needed. In active muscular exercise much heat is produced; but through the heat-regulating mechanism heat dissipation is in- creased to correspond, so that the temperature scarcely rises, and if it does, is soon restored to normal. The extra loss of heat is brought about by dilatation of the cutaneous vessels and sweating. But in some of the infectious fevers that have been studied the heat production has been found very little increased, and the hyperthermy to be due to the failure of the heat-dissipating mechanisms to do their work. For example, in one case of malaria Liebermeister estimated the increase in heat production during the hot stage to be 21 to 24 per cent., much less than the increase during active exercise; but during the malarial chill, owing to the muscular activity of vigorous shivering, the heat production rose 147 per cent. At the same time, owing to the constriction of the cutaneous vessels, the mechanisms for heat dissipation were in abeyance. It would seem in such cases that the fever results from the failure of the heat-regulating centers to make the heat loss keep pace with the heat production. Whether or not the toxins of the disease affect the center directly is still a question. A chill is considered to be the result of surface cooling from constriction of the cutaneous arterioles, the skin being the site of the nerve-endings through which temperature changes are perceived. In a chill, shivering is the heat-producing response of the regulators to the cold at the surface rather than to general body temperature. The subsequent fever results from this excessive heat production at a time when the skin vessels are still constricted and sweating absent, i. c., when heat loss is at a minimum. In those of the infectious fevers which have been studied in this regard there is a great increase in the nitrogen elimination during the fever, but no material increase in the amount of fats and carbohydrates oxidized, as shown by the elimination of CO 2 ; therefore heat production is not greatly increased. Just the opposite condition is found in active exercise, in which there is THE ANALGESIC ANTIPYRETICS 465 great increase in the elimination of CO 2 and only a moderate increase in the nitrogen of the urine. Liebermeister has likened the heat-regulating centers to the heat-regulator of a room. The heat regulator is set at a certain temperature; if the room gets warmer, the mercury rises or a metallic band expands, and by making an electric connection operates on one or more dampers in the furnace so that the fire burns less briskly, or shuts down the registers so that the room receives less heat. If the temperature of the room falls below that at which the regulator is set, the dampers or registers are opened and more heat comes into the room. Now, to carry out the analogy, the heat-regulating centers in the human body may be thought of as being normally set for a temperature between 98 and 99 F. If the temperature goes up a degree or two, the centers send out impulses which result either in a lessening of heat pro- duction, i. e., by diminution in muscular and circulatory activity, or an increase in heat loss, i. e., by dilatation of the cutaneous vessels and sweating. On the contrary, if the temperature falls a degree or two, the heat production may be increased by muscular activity, shivering, etc., or the heat loss diminished by contraction of the cutaneous vessels and the stoppage of sweating. The temperature-regulating centers have little discriminating po\ver, and a surface chill may induce the centers to constrict the vessels and lessen heat loss, and at the same time to increase the production of heat, so that fever may result. To what extent the body reaction which results in fever is beneficial or harmful, we are not yet able to state. Recently certain infections seem to have been cured by the repeated artificial production of a chill with high fever, as by the intravenous administration of foreign protein, usually typhoid vaccine. In some fevers the regulating centers may lose their control at certain times of the day only. In tuberculosis there is a tendency to afternoon fever, accompanied by headache, discomfort, and weakness from failure of heat loss, while at night there may be an overaction of the mechanism for cooling, with diminished metabo- lism and the production of profuse sweat, the result being chilling of the surface (cold night-sweats) and a fall of temperature to subnormal. Frequently, in tuberculosis fever cases, the morning temperature is normal and the patient feels at his best at that time. But in tuberculosis the centers are incompetent, so that a slight exertion tends to produce fever at any time. In malaria there is a severe chill with contraction of the skin vessels and the generation of much heat (by shivering). After a time this results in great fever and discomfort, the contraction of the skin vessels and the absence of sweating preventing heat 30 466 PHARMACOLOGY AND THERAPEUTICS loss. But presently the centers gain control, and great activity of the cooling mechanism follows. The result is dilatation of the skin vessels and profuse sweating, with a fall in temperature to normal or even subnormal, and the restoration of the patient's comfort till the next chill comes on a day or two later. In a continuous fever like typhoid, apparently the heat- regulating centers are set at a high point, 102 F., 103 F., 104 F. The centers are just as sensitive to changes as ordinarily, for shivering follows a drop of 2 or 3 degrees in the temperature, and sweating results from a rise of i or 2 degrees. But the tempera- ture at which the centers tend to keep the body is not 98.6 F., but 102 F., 103 F., or 104 F., as the case may be. But even in typhoid fever there is a tendency to a morning remission of temperature, with rise to the highest point in the afternoon or evening. And it would seem as if, preceding the rise in temperature in these cases, the heat regulators are affected by the poisons of the disease, so that they allow the temperature to rise above normal; but that, at a certain point, the centers gather themselves together and are able to assert themselves and regain their control, and the temperature is brought backjx>ward normal. This makes a daily rhythm. Action of Drugs. A drug may tend to lessen the temperature in fever by decreasing metabolism, as quinine, by lessening the activity of the circulation, as veratrum, by dilating the cutaneous vessels, as whisky, or by inducing perspiration, as solution of ammonium acetate. But antipyrine, acetanilid, acet-phenetidin, and their allies act centrally, and they result in a lowering of the temperature in fever either by increasing the resistance of the regulating centers to the disease poisons, or by lowering the degree at which the heat-regulating centers are set (if we may use such an analogy). Meyer regards them as mild narcotics to irritated thermogenic centers. The effect of these drugs is not to any extent to reduce heat production, for they do not diminish metabolism, and acetanilid even increases metabolism. They act by enabling the center to improve its control over the mechanisms of heat dissipation, which are the ones at fault in the infectious fevers. That they act through the centers is shown by their failure to affect the temperature in health, by their failure to reduce tem- perature if the spinal cord is severed, and by the fact that there is no attempt on the part of the body, as the temperature falls, to manufacture more heat by shivering, etc., as occurs when the temperature is reduced by external cold (cold baths, etc.). The lowering of temperature by these drugs may be accompanied by profuse sweating, but this is a result of the action upon the centers, Fig. 58. Acetanilid, 0.4 mg. per kilo. Ventricle (upper tracing) shows increased lonicity and diminished contractility (down-stroke, systole). Arterial pressure, lower tracing, falls from 75 to 42 mm. The pulse-rate drops from 130 to 120. (Tracing made by Dr. C. C. Lieb.) Fig. 59. Urticarial eruption following antipyrinc (\V. S. Gottheil in Archives of Diagnosis). Fig. 60. Kxfoiiative dermatitis following the administration of large doses ot antipvrme. JIair and nails shed (Schamberg). THE ANALGESIC ANTIPYRETICS 467 and they are still antipyretic if the sweating is prevented by atropine. Occasionally, as the result of their action, the centers reassert themselves too strongly, overshoot the mark, and carry the temperature away below the normal. In some cases this results in collapse. Schutze has shown that antipyrine does not prevent the forma- tion of antitoxins in the body, so it does not interfere with the natural forces of protection against disease, except as fever is beneficial. The other parts of the nervous system are also affected prac- tically alike by these three drugs. Cerebrum. This is somewhat depressed, all three remedies being useful in overcoming nervous irritability and restlessness. They have also a notable power in lessening pain, especially that from neuralgia or neuritis, or a lesion of the central nervous system. They are especially useful in headache. Head suggests the hypothesis that the analgesia is the result of an action on synapses in the pain-conveying tract in the thalamus adjacent to the heat center. Stekel believes that the action in headache is due to the regulation of the balance between heat production and heat loss. In migrainal headache, for example, he noted that there was diminished surface temperature, as noted in the axilla, though normal rectal temperature, and that after small doses of antipyrine the axillary temperature rose as much as one degree with the disappearance of the headache. Martin, Grace, and McGuire found a marked lowering of general electrocutaneous sensitiveness within one hour of mouth doses of acet-phenetidin, 5 to 15 grains (0.3-1 gm.). These remedies are not strongly hypnotic, and do not pro- duce somnolence if the patient is up and about; yet if taken at bedtime, they favor the onset and maintenance of normal sleep. The cerebral cortex, then, is partly depressed ; yet even large doses seem to have very little depressing effect on the intellectual functions. This distinguishes them markedly from morphine, the bromides, and other central depressants. Phenacetin, being an ethyl compound, is more hypnotic than the others; antipyrine is the least hypnotic. But antipyrine is said to be more depress- ing to the motor areas, so that it has been used in epilepsy, chorea, and whooping-cough with more or less benefit. The centers of the medulla are scarcely, if at all, affected. In poisoning, convulsions may occur, clue probably to stimulation of the spinal cord centers, or perhaps to asphyxia. Circulation. A number of cases of collapse following the use of antipyrine, acet-phenetidin, and acetanilid have been reported, so that these drugs have acquired a bad reputation as circulatory 468 PHARMACOLOGY AND THERAPEUTICS depressants. In experimental work the heart muscle is directly stimulated by ordinary doses, the beat being stronger and more rapid. But from large doses the muscle is weakened, and the beat may be slow and irregular, causing collapse. The skin vessels are dilated in fever, apparently as a result of the action of the heat-regulating centers. The collapse action is most pronounced with acetanilid, and when it occurs from moderate doses, would seem to be due to idiosyncrasy. Nearly all the fatalities or cases of serious collapse from these drugs have come from very large doses taken in the form of proprietary headache and anti-pain remedies. Many of these cases have occurred from preparations containing caffeine, which is often added as a heart stimulant, and it has been shown by Worth Hale that they are more dangerous with caffeine than without, and less dangerous with sodium bicarbonate. Employed in proper dosage, these drugs are practically as safe as any other powerful depressants, but must be used with equal caution. Acetanilid, NaHCO, . . , Acetanilid. . | Acetanilid, caffeine, NaHCO. . . | Acetanilid, caffeine . . . . I Fig. 61. Toxicity of acetanilid increased strikingly by caffeine, decreased by sodium bicarbonate. Experiments on mice by Worth Hale. The degree of toxicity is represented by the length of the bars. Metabolism. Antipyrine and acet-phenetidin have probably no appreciable effect on the metabolism in health, as shown by the elimination of N, the absorption of O 2 , and the elimination of CO->. Acetanilid increases metabolism, as shown by an increase in the urea and total nitrogen of the urine. In fever, in association with the reduction of the temperature, the metabolism is lessened. Excretion is by the kidneys. Antipyrine appears n the urine either unchanged or as oxyantipyrine in combination with glycu- ronic and sulphuric acids. Acetanilid appears as para-amidophe- nol. Acet-phenetidin appears as phenetidin compounds. Untoward Effects. From idiosyncrasy, antipyrine not infre- quently has produced a scarlatiniform rash with edema of the face and fever; or urticaria, or a vesicular, bullous, or eczematous eruption. The chief untoward effects from acetanilid and acet- phenetidin are cyanosis and collapse; a petechial eruption has been noted from acet-phenetidin. Toxicology. Acute poisoning shows in affections of the alimcn- THE' ANALGESIC ANTIPYRETICS 469 tary tract and nervous system. There are: burning and swelling of the whole alimentary tract, with stomatitis, nausea, vomiting, gastritis, perhaps enteritis, mental dulness, tremors, convulsions (cerebral), and coma. Death results from failure of the respira- tion. With acetanilid and acet-phenetidin cyanosis and collapse may occur early. Toxic effects in a girl of twenty have been reported from 10 grains of antipyrine. The treatment is by demulcents for the gastro-intestinal tract, and, if necessary, meas- ures to combat collapse. A common result of poisoning by acetanilid and acet-phenet- idin is a marked cyanosis, with which there may be more or less dyspnea, rapid heart, and even collapse. There is some destruc- tion of red cells, and some formation of methemoglobin by reduc- tion, but the cyanosis seems to be out of proportion to the meth- emoglobin formation and out of proportion to the patient's symptoms. There is probably some other reduction compound present in the blood, and Bachmann says that it is aniline. Ten grains of acetanilid taken internally have produced cyanosis, also acetanilid powder applied to ulcer of the leg. The author saw one case from a phenacetin powder, probably 10 grains, given by a pharmacist for headache. Chronic Poisoning. Many nervous patients have the habit of taking these drugs. The habit does not have a hold upon them, like the morphine habit, and can be broken without any systemic rebellion; yet it is a difficult habit to overcome, for the symptoms are never startling, and the friends, not perceiving any harm from the drug, note the apparent suffering when the drug is stopped (headache, irritability, restlessness, sleeplessness). There is a proneness to digestive disturbances, to neuroses, to neuralgic pains, to various skin rashes, as erythema and eczema, or simple itching without a rash, and to mild forms of neuritis. There may be dyspnea on exertion, and other evidences of cardiac weakness. Impotence has been reported. We have had under our care one striking case of chronic poisoning with cyanosis which persisted for weeks after the stoppage of the acetanilid. Many chemic and spectroscopic tests of the blood revealed no foreign chem- ical other than methemoglobin. Antipyrine does not have this effect upon the blood. Therapeutics. Antipyrine, in 10 to 25 per cent, solution, is employed locally to stop nasal hemorrhage, and as an application in the painful throat of tuberculous laryngitis. Systemically, it has been used with moderate success as a motor depressant and general sedative in cl/orca and whooping-cough. It has also some employment in diabetes insipidus and diabetes meUitus. Its other uses are those of acetanilid and acet-phenetidin. 470 PHARMACOLOGY AND THERAPEUTICS All the drugs of the group are employed very largely for their effects upon the nervous system and in fever. Their general therapeutic powers are: (a) To overcome fever. In the high temperature of influenza, tonsillitis, etc., these drugs not merely reduce the temperature, but also greatly promote the comfort of the patient by lessening pain, if present, by lessening nervousness and headache, and by promoting quiet and rest. There are cases of typhoid fever in which these antipyretics have a decidedly better effect than the cold bath, as when there are shivering and cyanosis during the bath and for some time afterward, and discomfort both physically from the cold and mentally from the dread of the next bath. The drugs are much used where cold baths are not prac- ticable, and their antipyretic and quieting effects usually last from four to eight hours. In the afternoon fevers of tuberculosis, also, they promote the comfort of the patient. (b) To relieve pain in conditions without fever , as in dysmenor- rhea and muscular rheumatism; headache, migraine, neuralgia, sciatica, peripheral neuritis; the lightning pains of locomotor ataxia, and the pain of an intracranial or spinal tumor. They have little influence on pain from traumatism. (c) To allay nervous excitability and promote sleep in conditions without fever emotional shock, hysteria, and nervous conditions in general. Administration. Usually in capsules or tablets. If they cause too much perspiration, atropine may be added. THE ANTI-MALARIAL ANTIPYRETICS CINCHONA There are two medicinal varieties of cinchona, one the bark of several species of calisaya, and known officially as Cinchona, the other the bark of the red cinchona, known as " Peruvian bark," and with the official title, Cinchona rubra. These are natives of South America, but many species are cultivated in various tropical countries. Constituents. There are about 19 alkaloids, the important ones being quinine, cinchonine, quinidinc, and cinchonidine. In addition there are quinic, quinovic, and tannic acids. Red bark contains more tannic acid and less quinine than calisaya, but both are required to contain 5 per cent, of total alkaloid. Preparations and Doses. Fluidextract (calisaya); dose, 15 minims (i c.c.). Tincture, 20 per cent, (calisaya) ; dose, 30 minims (2 c.c.)- Compound tincture (tinctura cinchona; composita), 10 CINCHONA 471 per cent, red bark with serpentaria and bitter orange peel; dose, i dram (4 c.c.). The alkaloidal salts, dose, 5 grains (0.3 gm.), are: Quinine sulphate, (CzoHziNaOa^-HaSCX, soluble in 725 parts of water and 107 of alcohol. It is readily soluble in dilute hydrochloric, sulphuric, or phosphoric acids, as it forms the soluble double salts, or in the case of sulphuric acid, the soluble bisulphate. Quinine bi- sulphate, C 2 oH24N2O2.H 2 S04, soluble in 9 parts of water and 23 of alcohol. Quinine hydrobromide, soluble in 40 parts of water and 0.9 of alcohol. Quinine hydrochloride, soluble in 18 parts of water and 0.8 of alcohol. Quinine dihydrochloride, soluble in 0.6 part of water and 12 parts of alcohol. Quinine and urea hydrochloride, soluble in 0.9 part of water and 2.4 parts of alcohol. Quinine salicylate and quinine tannate, very slightly soluble salts. Cincho- nine sulphate, soluble in 60 parts of water and 12.5 of alcohol. Cinchonidine sulphate, soluble in 65 parts of water and 90 of alcohol. Euquinine, not official, is the ethyl carbonic ester. It is insoluble in water and not bitter. Its dose is twice that of the official quinine salts. Tinctura antiperiodica, N. F. (Warburg's tincture), is a bitter, aromatic laxative, sedative and antimalarial "shot-gun" prescription. It is made of quinine sulphate, aloes, rhubarb, angelica seed, elecampane, saffron, fennel, prepared chalk, gentian, zedoary, cubeb, myrrh, camphor, white agaric, opium, black pepper, cinnamon, ginger, alcohol, and water. Each ounce contains opium, | grain (0.008 gm.); quinine sulphate, 10 grains (0.6 gm.), and extract of aloes, 8 grains (0.5 gm.). The dose is i dram (4 c.c.). Warburg's tincture without aloes (sine aloe) is the same with the omission of the aloes. Pilula antiperiodica, N. F.. and Pilula antiperiodica sine aloe, X. F., represent i dram (4 c.c.) of the corresponding tinctures. Ethylhydrocupreine hydrochloride, a proprietary remedy with the name optocJiin, is a close chemical and pharma- cologic relative of quinine. It is derived from the al- kaloid cupreine of China cuprea bark or is made from hydroquinine. It is fairly soluble in water and alcohol. Pharmacologic Action. Quinine is a protoplasm poison. Microorganisms. Quinine is strongly antiseptic, and retards the development of bacteria and yeasts. In very dilute solution (i : 10,000) its first tendency is to stimulate or irritate protoplasm; 472 PHARMACOLOGY AND THERAPEUTICS but the stimulation is soon followed by depression, and in motile organisms, especially protozoa (ameba, paramecium) and ciliated cells, all motion very soon ceases. Strong solutions cause instan- taneous cessation of movement and kill the organisms. The spirochetes of relapsing fever are more resistant, and can live in a solution of i : 500. (See page 24.) It is an interesting fact that various cells, under the influence of quinine, will undergo asymmetric cell division, e. g., the ova. In certain low vertebrates, as the salamander, dilute solutions of quinine applied to the epithelium will produce cells of atypical mitosis like those of cancer. This effect is produced by other pro- toplasmic poisons, such as chloral and cocaine (Wilson). The enzymes seem to be slightly retarded, but are not nearly so much affected as the living organisms. Of the digestive fer- ments, ptyalin and diastase are little, if any, affected, and pepsin and trypsin are distinctly retarded in their activity. Other fer- ments, such as the blood-coagulating and the oxidizing, are re- tarded; and it is said that quinine will prevent blood or fresh vege- tables from giving the guaiac test, which depends on oxidation. The leukocytes, which resemble amebae so closely, are affected in the same way as ameba?. With i part of quinine in 4000 of blood they lose their ameboid movements, become spheric, die, and soon disintegrate. In the intact animal, a strong solution prevents the emigration of leukocytes and their gathering to form pus at the site of inflammation. And while, in man, such closes as can be administered do not show this pronounced effect, still there is some effect upon the leukocytes, for their number may be reduced to one-half or one-fourth the normal (2000 to 4000 per cubic millimeter instead of 8000), the polynuclears being reduced out of proportion to the lymphocytes. Roth (1913) found a primary slight increase in the lymphocytes, which after several hours changed to a decrease. In a dog an intravenous dose markedly contracted the spleen and caused a decided decrease in the white cells, especially of the polynuclears. He thought the primary rise in man might be due to squeezing out the splenic leukocytes by its contraction. These are notably of the lympho- cyte type. Locally, the inorganic salts are distinctly irritant to raw sur- faces and mucous membranes, as when its solutions are used in the rectum or hypodermatically. After a hypodermatic of the hydro- chloride of quinine and urea there soon ensues a pronounced local anesthesia which lasts for some hours. Quinine is said to stimu- late the growth of hair, and is an ingredient of rum and quinine, eau de quinine, and other mixtures which are sold as hair-stimu- lants. CINCHONA 473 Alimentary Tract. It is intensely bitter, and, given before meals, acts as a bitter to promote appetite. Large doses irritate the stomach and may cause nausea and even vomiting. There is slight retardation in the activity of pepsin and trypsin, while the other digestive ferments are probably not affected. It is to be borne in mind that quinine sulphate, the alkaloidal salt almost universally employed, requires an acid medium for its solution; therefore it is- administered after meals. Quinine is said to retard the absorption of salts, and also probably of other substances (foods and medicines), from the stomach (Sollmann). Absorption. If the quinine salt goes into solution it is rapidly absorbed from the intestine and may appear in the urine in fifteen minutes. If the stomach is not acid, the quinine may not dis- solve. Circulation. In ordinary therapeutic doses there is probably a slight increase in the rate of the heart and a tendency to a rise in the blood-pressure from mild stimulation of the heart muscle and of the arterial muscles. The arterial action is a peripheral one, for on perfusing an isolated viscus, there is contraction of the arterioles, followed in a short time by their dilatation. In large doses there is direct depression of the muscles of the heart and of the arteries, with slow pulse (which occurs after atropine, so is due to muscular depression), and a fall in blood-pressure. From ordinary therapeutic doses the effect on the circulation is negligible. The blood we have already spoken of. Its coagulability is decreased and its white cells are lessened in number and probably also in activity. In bleeding experiments on dogs, de Sandro (1911) noted that dogs given quinine recovered their hemoglobin and red cells less readily than those without quinine. Cerebrum. It has the same tendency as the other antipy- retics, but not to so great a degree, to allay the pains of neuralgia and those associated with the onset of influenza and other acute illnesses. Large doses produce cinchonism, spoken of later. Medulla. Affected only in poisoning. Then, after a brief stimulation, the respiratory center is depressed, and death takes place from its paralysis. Spinal Cord. In the frog the reflexes are increased. In mammals there is probably no effect. Peripheral Nerves. After hypodermatic administration there is a slow and prolonged abolition of sensation at the site of injection. The Eye. In some persons there have been marked changes 474 PHARMACOLOGY AND THERAPEUTICS in the sight after a therapeutic dose. There are diminished acute- ness of vision, contraction of the field of vision, color-blindness, and dilated pupil. In the fundus there are seen irregular contractions of the retinal and choroidal arteries, edema and anemia of the retina, pallor of the optic discs, thrombosis of the central vein, and in some cases atrophy of the optic nerve, with more or less per- manent blindness, the patient sometimes appearing to see through a veil. The diminished vision is known as "quinine amblyopia." The blindness is known as "quinine amaurosis." DeSchweinitz reports a case of temporary blindness after 12 grains of quinine sulphate, though usually the doses have been large. According to this author the contracted field of vision does not regain its normal limits; but Parker (1912) reported the case of a man who took 240 grains (15 gm.) by mistake, was completely blind for a time, and had recovered full vision in three and one-third months. Weeks reports cases showing permanence of arterial contraction with paleness of optic discs and retinae. Ear. The deafness and ringing in the ears which are of such frequent occurrence seem to be due mostly to congestion, though arterial contraction and anemia of the middle ear and labyrinth are reported. Such congestion has been found in animals after large doses. If the quinine administration is continued, per- manent deafness may result either from degenerative changes in the spiral ganglia of the cochlea or from a chronic otitis media arising from the continued congestion. Muscle. Striped and cardiac muscles are stimulated at first, the muscles being more irritable and able to lift a greater load; but they are soon fatigued, and their total work amounts to less than normal. That the muscle itself is the part affected is proved because quinine has the same effect after curare. (Curare para- lyzes the motor nerve-endings to voluntary muscle.) Smooth muscle is not so surely affected, except perhaps the spleen and uterus, and perhaps that of the arteries. Immunity. In persons susceptible to quinine Boerner ob- tained a positive von Pirquet reaction in fifteen minutes from solutions of i : 10 to i : 1000. In other persons there was no reaction. Elimination. It appears very soon in the urine (fifteen to thirty minutes), and most of it is excreted in a few hours. Traces may be detected for three days or more. From 30 to go per cent, of it may be recovered from the urine unchanged, and some is changed to di-hydroxyl quinine. A small amount appears in other secretions. Koldewijn says that traces appear in the milk. Through irritation or circulatory changes of the skin there may Fig. 62. Purpuric and vesicular eruption from quinine (W. S. GoUheil in Archives of Diagnosis). CINCHONA 475 be various rashes, notably a scarlatiniform rash, eczema, urti- caria, and erythema with itching. So frequent are skin rashes from quinine that a rash of unusual type regularly elicits the physician's question, "Have you taken quinine?" Kidneys. Large doses of quinine irritate the kidneys and cause albuminuria or even hemoglobinuria or hematuria. After the use of quinine for long periods, uroerythrin may be a cause of red urine. Uterus. Uterine contractions seem to be favored, and the drug is employed in labor to increase the force of the contraction of the second stage. In the isolated guinea-pig uterus Lieb found that a solution of i : 100,000 caused an immediate increase in the rate and strength of the contractions, and that i : 25,000 caused tetanic spasm and rapid death of the organ. From doses of 8 to 15 grains (0.5-1 gm.) Maurer obtained a distinct ecbolic effect in nearly all cases within forty minutes. It is a common belief that quinine may produce abortion in a pregnant women, and I have seen several cases where abortion in the first three months followed, though it may not have been caused by, its use for cold or for malaria. There are also many cases of preg- nancy where abortion has not followed its use. Metabolism is affected by very small doses, even doses small enough to have no other effect. At first there is a slight increase in the nitrogenous content of the urine, probably due to increased leukocyte destruction; but soon there is a marked decrease, and this is especially noticeable in the urea and uric acid. The same amount of nitrogenous food may be absorbed, but less is con- sumed by the body, so there is a storing-up of proteins. Quinine has, then, just the opposite effect to fever, which is associated with excessive protein destruction. There is no evidence of incomplete oxidation of the nitrogenous products. Temperature. The normal oxidation processes are changed very little, if at all, the O 2 taken in, and the CO 2 given off, being about the same. Oxidation is usually taken as a criterion of the amount of heat generated, yet there is less heat generated after quinine, presumably owing to its lessening the destruction of proteins. Quinine lowers the temperature in fever almost en- tirely by lessening the production of heat; and as it lowers tem- perature after division of the spinal cord, it does not exert this action through the heat-regulating centers. Like all antipyretics, it acts best at about the time of a usual remission of temperature, and has but little effect in health. It is not so powerful a reducer of temperature as acetanilid, and in a continuous fever like typhoid has very little effect. As an anti- pyretic it has largely been supplanted by more effective drugs. 476 PHARMACOLOGY AND THERAPEUTICS Untoward Symptoms. Cinchonism, skin eruptions, gastric disturbances, diarrhea, and, rarely, hemoglobinuria. In cincho- nism there are fulness in the head (headache), ringing in the ears, deafness, dizziness, and mental dulness; and there may.be im- paired vision, muscular weakness with uncertain gait, and slow, rather weak pulse. The cerebral symptoms are attributed to circulatory changes. Sicard reports 15 cases of sciatic paralysis from the intragluteal injection in soldiers. In some people there is idiosyncrasy to very small doses, and in these susceptible people the addition of bromides lessens the tendency to cinchonism. Toxicology. The usual manifestation of overdosage is cinchonism (just described). Very large doses induce gastro- intestinal disturbances, mental sluggishness, disturbance of sight and hearing, slow, ineffective respiration, slow, weak heart, muscular weakness, and collapse. One ounce (30 grams) pro- duced only confusion and noises in the ears, but it may not have been absorbed. Quill reports unconsciousness and severe collapse five minutes after the taking of ^ ounce (15 gm.) in solution. Baer- mann reports death after two doses of 8 grains (0.5 gm.). Two drams (8 gm.) have also been reported as causing death. Harts- horn had a case with burning, swollen face, scarlatiniform rash, and fever. The author had a patient in whom the administration of quinine on different occasions was followed by chilliness, sweat- ing, vomiting, and diarrhea. The treatment is: for cinchonism, bromides; for collapse, the regular treatment for collapse. Therapeutics. Locally. i. Quinine and urea hydrochloride in solution has come into extensive use as a local anesthetic. Hertzler, Brewster, and Rodgers consider it suitable in all opera- tions which can ordinarily be done under cocaine. They use 0.25 per cent, in normal saline, and have determined that stronger solu- tions retard healing. Many operators use solutions of i to 3 per cent, strength. To lessen shock Crile uses it in major operations to anesthetize the field of operation in advance of cutting, and so abolish all afferent impulses. Quinine bisulphate, i : 3000 to i : 500, has also been used as a local anesthetic. 2. Both of these salts have been employed as disinfectants in gonorrheal urethritis, vaginitis, cystitis, and as wet dressings for infected wounds. 3. In amebic colitis, and for pin-worms, a solution of quinine bisulphate i : 2000 to i : 500, or quinine and urea hydrochloride, 0.5 per cent., may be employed as a colon irrigation. 4. In exophthalmic goiter Watson uses i to 4 c.c. of a 30 to 50 per cent, quinine and urea solution for injection into the thyroid, CINCHONA 477 repeating the dose every three or four days for eight to fifteen times. It produces connective-tissue proliferation with destruc- tion of thyroid cells, and is almost painless. 5. In hemorrhoids a similar solution is injected at the base of the pile, or 5-grain (0.3 gm.) suppositories inserted. 6. The quinine salts have frequently been added to hair tonics. Alimentary Tract. Its sole value by mouth is as a bitter, and for this the preferred preparation is the compound tincture of cinchona. It is not a true tonic, for it tends to inhibit the pro- teolytic enzymes, to irritate the stomach, and to retard absorption, and does not have any good effect on muscle at all. Systemically . It is employed to reduce the pains of influenza, the afternoon fever of tuberculosis, and the discomfort of a cold. In neuralgia and headache it is analgesic, and may also act by lessen- ing the nitrogenous waste products which are sometimes the cause of headache. It is not a very powerful antipyretic or analgesic. In the paroxysms of acroparesthesia Putman con- siders it almost specific. In bacterial infections, c. g., septicemia, it would seem to be harmful rather than helpful, for it depresses vitality and checks phagocytosis. For uterine effect it is employed in menorrhagia and uterine inertia. Among skin diseases, it has been recommended internally in pemphigus, exfoliative der- matitis, and pityriasis rubra. In pneumonia, Solis- Cohen uses 15 grains (i gm.) of quinine and urea hydrochloride hypodermatically, repeated every two or three hours for two, three, or four doses. The fever disappears by lysis instead of by crisis. In malaria it is practically specific. The asexual forms are, as a rule, vulnerable to quinine; the gametes or sexual forms are not, but in the human body die naturally in a few weeks. In tertian or quartan malaria, about two or three hours after a large dose of quinine, the parasites in the red cells can be seen to have lost their ameboid motions, and they soon become granular and die. The quinine acts most strongly on the forms just breaking into spores and on the free-swimming organisms; and as these are present in the blood about the time of the chill, the quinine, on account of its rapid absorption and rapid excretion, is best given just at this time. Fifteen grains (i gm.) may be administered just before, during, or after the chill, and because of possible develop- ment of new asexual forms from gametes, should be followed by 5 grains three times a clay for two or three months. In malarial regions quinine is taken in large quantities as a prophylactic. Craig recommends 10 grains (0.7 gm.) every fifth night. There is much evidence to show that it does reduce the number of cases 478 PHARMACOLOGY AND THERAPEUTICS in a malarial community, and does not seem to do any harm to the takers. In pernicious malaria the quinine and urea hydro- chloride in 10 per cent, solution has been employed up to 100 grains in a day, but recovery from this condition is rare in any case. Brewster reports the intravenous administration in per T nicious malaria of 100 grains in six hours without untoward effects. In Uackwater fever, which is believed by many to be a malarial manifestation, Cardamitis says that quinine does more harm than good. He cites 1347 cases treated by quinine, with 24.42 per cent, of deaths, and 1134 treated without quinine, with 7.32 per cent, of deaths. The Panama Canal Commission advises against its use during an attack of hemoglobinuria unless there are numerous malarial parasites in the blood. In amebic dysentery, Major Brooke believes 30 grains (2 gm.) a day to be as effective as ipecac. As a postoperative prophylactic against nausea, vomiting, gas-pains, backache, and thirst Bonnot recommends 10 grains (0.7 gm.) of the hydrochloride in 2 ounces (60 c.c.) of water by rectum every six hours for four to six doses. The effect is enhanced by the addition of sodium bromide. Administration. For its bitter effect, the cinchona prepara- tions are employed, diluted with water. For systemic effect, the quinine salts are preferred. These salts, because of their bitterness, are usually given in capsules or coated pills. The sulphate is the one in common use, and its absorption is more sure and more rapid if it is given in solution with a dilute mineral acid, as sulphuric, hydrochloric, phosphoric, or aromatic sulphuric. The hydrochloride, the di- hydrochloride, and the bisulphate are to be preferred, as they are soluble without the addition of acid. For hypodermatic and intravenous use the bimuriate of quinine and urea is employed. Quinine is thought to act better in malaria if given with arsenic and some aromatic, as ginger or capsicum, and this is especially the case in the estivo-autumnal variety, in chronic or relapsing malaria, and in "gamete carriers." For children, it may be given in the form of the comparatively tasteless (because insoluble) tannate, made into tablets with chocolate the so-called "quinine chocolates"; or it may be mixed with fluidextract of licorice (incompatible with acids), or with syrup of yerba santa, which has the peculiar property of lessening the appreciation of bitter taste. As it takes some time for the action on the taste-buds to develop, the yerba santa prob- ably lessens the bitterness solely by forming the insoluble tan- nate. ETHYLHYDROCUPREINE 479 Lascoff states that a mixture of quinine and acetylsalicylic acid, allowed to stand for some time, develops a poisonous substance resembling digitoxin in its action. The other alkaloids, quinidine, cinchonine, and cinchonidine, act in malaria like quinine, but in poisoning cause epileptiform convulsions. They have no advantages over quinine and are more expensive. ETHYLHYDROCUPREINE Ethylhydrocupreine has actions and uses similar to those of quinine, but because of a specific bactericidal effect upon all forms of the pneumococcus it has come into use in the treatment of pneumonia. In vitro a solution of as little as i : 10,000,000 may be inhibitory to the pneumococcus, and i : 500,000 is bactericidal. In serum this activity is reduced to one-fifth or one-tenth. In lobar pneumonia the method of Moore and Chesney at the Rockefeller Institute is to administer daily by mouth a beginning dose of "]\ grains (0.5 gm.) of the hydro- chloride, followed by 2\ grains (0.15 gm.) every three hours till a total of 22\ grains (1.5 gm.) have been given for the day. It is the consensus of opinion^that this amount should not be exceeded. It represents about 0.024 g 111 - P er kilo per twenty-four hours. They found that with this dosage "a specific pneumococcidal action appears in the blood within a few hours and can be main- tained more or less constant for several days." It has been noted that pneumococci not destroyed early may rapidly acquire complete resistance to the drug. The "pure alkaloid" may be given intramuscularly in solution in oil. Locally, in pneumococcus eye infections, as in ulcus cornea serpens, which is highly destructive to the sight, the drug has a decidedly curative effect in twenty-four to forty-eight hours. It is used in i per cent, solution applied for half a minute every hour following cleansing with boric acid solution. There is a primary pain followed soon by comparative analgesia. Toxicology. The poisonous symptoms are those of quinine, but amaurosis has occurred in so many instances from therapeutic doses that this is especially to be watched for. Adler reports one case after only two 4-grain (0.25 gm.) doses. At the Rockefeller Institute, after four 7^ -grain (0.5 gm.) closes at eight-hour inter- vals, a patient was unable to distinguish light for six days, and at the end of five months, as reported by Weeks, had slightly reduced fields of vision with color vision very indefinite, many of the retinal arteries narrowed and their walls irregularly thickened, and optic disks and retinae pale. 480 PHARMACOLOGY AND THERAPEUTICS ANTIRHEUMATIC ANTIPYRETICS SALICYLIC ACID Salicylic acid (acidum salicylicum, C 6 H 4 OH,COOH) is chemic- ally orthosalicylic acid, and is an organic acid which exists natur- ally in combination in the volatile oils of birch and wintergreen. It is generally prepared synthetically from phenol. The reputed superiority of salicylate made from the natural oils is not sub- stantiated by the experimental work of Eggleston and others. Engelhardt found phenol present in a number of samples of both the artificial and the natural oil. Salicylic acid has a biting taste, and is soluble in 460 parts of water and in 2.7 parts of alcohol. The salts of the alkali metals are readily soluble in water. Preparations and Doses. Salicylic acid; dose, y| grains (0.5 gm.); sodium salicylate and strontium salicylate; dose, 15 grains (i gm.). The salicylates of ammonium, quinine, bismuth, and physos- tigmine are official, but in the available dosage do not give a salicylic action. Microorganisms. In a solution of i in 500 salicylic acid is anti- septic, and will inhibit or retard the growth of bacteria, yeasts, and molds; and as in these dilutions it is not corrosive to living tissue, or poisonous to human beings, except in large amounts, it is safe for use in and about the body. But because it is not readily soluble in water, its use as an antiseptic is confined largely to the preservation of foods, the treatment of parasitic skin diseases, and the preparation of a mild antiseptic wash known as "boro-sal." Leach says that quantities sufficient to preserve milk affect the taste of the milk. It belongs to the phenol group of antiseptics, but does not possess the destructive properties and the penetrat- ing power of carbolic acid, and it retains its antiseptic power in fatty and alcoholic preparations. The alkaline salicylates, though less antiseptic than the acid itself, are freely soluble in water and are used in the preservation of foods. The Hygienic Laboratory recommends a i per cent, solution of sodium salicylate as a fly-poison. Enzymes. The action of these is inhibited or retarded, a i per cent, solution being sufficient to stop the ptyalin action on starch. Pepsin is somewhat lessened in its activity, and probably also the other digestive ferments. Very weak solutions seem to favor fer- ment action. Local Action. Besides its antiseptic action, it tends to stop local sweating, as of the hands or feet; to soften and facilitate the SALICYLIC ACID 481 removal of accumulations of horny epithelium, as of corns or warts, without causing inflammatory changes in the healthy underlying tissues; and in chronic skin diseases, such as eczema, to promote the growth of healthy skin. It is irritant to mucous membranes. Methyl salicylate and the volatile oils of wintergreen and birch are counterirritants. Alimentary Tract. Its taste is biting, and it is locally irritant. Its tendency is to retard gastric fermentation and the action of the digestive ferments. Whether or not it can reduce intestinal putrefaction is a question, for while Strasburger claims that the number of bacteria in the feces is distinctly reduced, other observers have been unable to detect any diminution in the indican of the urine. (See Salol.) By large quantities the pro- duction of bile is increased, but the use of the drug for this purpose in therapeutics has not been shown to have any value. The volatile oil salicylates have a typical carminative action, and in moderate dosage are well borne; the other salicylates are irritant and frequently produce nausea and even vomiting. Absorption is rapid from the stomach and duodenum. Systemically, it resembles acetanilid in its analgesic properties, but is much milder. It increases metabolism, yet is antipyretic by dilating the vessels and promoting sweating, and so increasing heat loss. Whether there is an effect on the heat-regulating center or not is not proved. Mandel found that it would prevent a rise of temperature from xanthine. Giglio found salicylate in the synovial fluid of many joints; and Fillippi and Nesti obtained it from the synovial fluid from the hip- joint of dogs one hour after its administration by mouth. It was present for from twenty-eight to fifty-four hours. They found it also in the joints of acute articular rheumatism, but only in the merest traces in a gonorrheal joint. Hanzlik and his co-workers find the percentage in joint fluids and blood practically the same, that after 200 grains (13 gm.) in both rheumatics and non-rheu- matics being about 0.025 P er cent. They found only the sodium salt and not any free salicylic acid. Dixon states that the joint pain and stiffness are removed by the injection into the joint of a salicylate. According to Falk and Tedesco (1909), it appears in all inflammatory exudates; and they recommend this as a diagnos- tic point in sputum examinations. They claim that the sputum of tuberculosis and pneumonia, being an exudate, gives the sali- cylic test, while the sputum of bronchitis and bronchiectasis, being a secretion, does not give the test. Bastedo and Johnson were unable to distinguish by this test, and found no salicylate in tuberculous sputum. 31 482 PHARMACOLOGY AND THERAPEUTICS Except for the dilatation of the skin arterioles, which is pro- nounced, the effect upon the circulation is usually negligible in therapeutics. The tendency of moderate doses is to stimulate slightly the heart muscle and the vasoconstrictor center; that of large doses is to depress them. In the blood the leukocytes tend to be increased in number. Metabolism. As shown by the rise of nitrogen, phosphorus, and sulphur in the urine, there is increased protein destruction. The excretion of urea and uric acid are increased, the rise in the latter being sometimes as much as 50 per cent. Fine and Chace and Denis have shown a marked reduction of the uric acid in the blood, Denis attributing this to a lowered threshold of the kidney for circulating urates. It does not produce an acidosis (Hanzlik). Excretion is by the kidneys, chiefly as salicyluric acid, a glycocoll compound which gives a violet-red color with ferric chloride. Traces are also found in the bile, milk, and sweat. The appearance in rheumatic and other exudates has been referred to above. In rheumatism there seems to be an increased destruc- tion. The kidneys may be irritated by large quantities, and Hanzlik and associates have shown that, both in rheumatics and non- rheumatics, albumin, leucocytes, and casts appear in the urine after full doses, the albuminuria ceasing when the salicyl is excreted. They found no effect on the phthalein excretion or on the blood nitrogen. But among drugs of this class salicylic acid is a comparatively safe one, for quite frequently 100 or 200 grains a day of sodium salicylate have been given without signs of kidney inflammation. Toxicology. The early signs of overdosage are: nausea, vom- iting, and sometimes diarrhea; or headache, ringing in the ears, and deafness; or mental excitement. As judged by these signs, Hanzlik (1913) found that for human adults the toxic amount of sodium salicylate is about 200 grains (13 gm.) , of methyl salicylate and aspirin about 120 grains (8 gm.), and of displosal, 100 grains (6.7 gm.). Salic ylism resembles cinchonism and is characterized by fulness in the head, headache, mental excitement with loquacity or a talkative delirium, or mental dulness and apathy, with ringing in the ears, deafness, disordered vision, and muscular weakness. The ear symptoms are not so common as from quinine, and arc due either to congestion or anemia or to de- generation of the nerve-elements of the cochlea. Scheyer reports a case of labyrinthitis with permanent impairment of the hearing. I he eye symptoms are also associated with circulatory changes in the retina or degenerative changes in retina or optic nerve. SALICYLIC ACID 483 In the salicylic intoxication the cerebral symptoms may resemble those from atropine, producing the so-called "salicylic jag." The patient is talkative and very cheerful, and may pass on to delirium with hallucinations, motor activity, and attempts to get out of bed. The cerebral excitement may be prevented, at least in part, by bromides. Very large doses produce weakness of the heart and depression of the respiratory and vasoconstrictor centers, with collapse. But the writer has frequently seen 20 grains of the sodium salic- ylate given every two hours, and occasionally 30 grains, without any noticeable effect on the heart's action or the blood-pressure. Occasionally, through idiosyncrasy, even small doses induce cardiac weakness. Seiler reports the death of a seven-year-old child after 75 grains (5 gm.), Gubler the death of an adult after 2\ drams (10 gm.), and Goodhart a death after 55 grains (3.6 gm.) given in proper therapeutic doses. Hanzlik found no especial tolerance for the salicylates in acute rheumatism. (Although phenol and salicylic acid are closely related chemically, neverthe- less they cannot be considered together pharmacologically or therapeutically.) Therapeutics. Locally, salicylic acid itself is employed: 1. As a surgical antiseptic, in the form of Thiersch's solution or boro-sal (acid salicylic, 2; acid boric, 8; in water, 1000). 2. In sweating of feet and hands, in alcoholic solution; and in bromidrosis (smelly feet), mixed with boric acid, and placed dry in the shoes. 3. In fungous skin diseases (ringworm, etc.) and chronic eczema, in ointment form. Lassar's paste (Pasta Zinci, N. F.) is composed of salicylic acid, 2 parts, zinc oxide and starch, of each, 24 parts, and petrolatum, a sufficient quantity to make 100 parts. 4. To remove corns and warts, in solution in flexible collodion, 15 grains (i gm.) to 2 drams (8 c.c.). It should not be applied beyond the corn, or it may cause the adjacent skin to peel. Internally, the sodium salicylate is employed: 1. In acute articular rheumatism and Us complications 10 to 20 grains (0.7-1.3 gm.) every two or three hours. That the salicylates give prompt relief is a very frequent experience, but there is some evidence that they do not diminish the length of the disease, the occurrence of endocarditis or the frequency of relapse. Denis suggests that their value may be due to the promotion of the excretion of toxins. The writer believes in their specificity. 2. In acute tonsillitis, pharyngitis, groining pains, sciatica, lumbago, muscular rheumatism, pleurisy, etc., all of which may have a true rheumatic origin. Seibert recommends it in chorea, 484 PHARMACOLOGY AND THERAPEUTICS but most men find it useless in this disease. Cockayne treated 355 cases with 60 to 300 grains (2-20 gm.) daily without influence on the course of the chorea. 3. In the indefinite muscular, joint, or neuritic pains, which are loosely spoken of as rheumatic. 4. In gouty attacks it is as valuable as atophan (Fine and Chace). In chronic gout and chronic rheumatism it is analgesic, but not curative. 5. In diabetes, von Noorden (1912) considers it the most valuable of the drugs used, except the nerve sedatives (codeine, etc.), but Hall could distinguish no desirable effect. (See also Acetyl-salicylic Acid and Salol.) Administration. Sodium salicylate is given in capsules or cachets with plenty of water, or in solution in wintergreen water or other flavored liquid. Its sweetish taste is unpleasant and nauseating to many. An alkaline bromide lessens the tendency to salicylism, and sodium bicarbonate lessens the irritation of the stomach, though it does not diminish the toxicity or the irritant action on the kidneys. There is nothing gained by enormous doses of sodium bicarbonate, as recommended by Lees. To avoid too great toxic effects the doses should be divided up and given at frequent intervals, and constipation assiduously avoided. Seibert (1911) has suggested the hypodermatic use, recom- mending the injection of to c.c. of a 20 per cent, solution for each 100 pounds of body weight. He repeats the dose every twelve hours, preceding it by an injection of a weak cocaine solution because of the pain. Heyn advocates rectal administration, the beginning dose being about 2 drams (8 gm.) with 4 to 6 ounces (120-180 c.c.) of water or starch-water. It appears in the urine in fifteen to thirty minutes, and is mostly absorbed in twelve hours. It has also been used intravenously in 20 per cent, solution in doses of 20 grains (1.3 gm.), but this solution causes inflammation or a slough if it leaks into the tissues, and may cause thrombosis in the veins, so the author prefers a 5 per cent, solution. In several instances it has been more effective than large doses by mouth. SALICYLIC ALLIES Acetyl-salicylic acid, or aspirin, C 6 Hi.O.COCH 3 .COOH, of slightly sour taste and acid reaction, is soluble in 125 parts of water and freely in alcohol. It gives no reaction with ferric chloride, unless previously decomposed by alkalies or boiling with water. On boiling with 10 per cent, sodium hydroxide solution it separates into its components. SALICYLIC ALLIES 485 In many instances it has proved less irritant to the stomach than either salicylic acid or sodium salicylate, but not infre- quently it causes hyperacidity with heartburn, or nausea or vomiting. The claim is made that it passes through the stomach unchanged, and is decomposed in the alkaline intestinal contents to form sodium salicylate and sodium acetate; but sodium car- bonate in a test-tube does not so decompose it. Theoretically, it should not be given with sodium bicarbonate or other alkali, lest it be decomposed in the stomach ; but in the author's experi- ence the bicarbonate lessens the nausea and heartburn which sometimes result from its use. Acetyl-salicylic acid has greatly replaced quinine in the affec- tions of the profession and the laity, and is prescribed or taken in 5 -grain (0.3 gm.) tablets or capsules every two or three hours for colds, sore throat, neuralgia, headache, and influenza. It is also used wherever a salicylate is indicated. Williamson (1902) found that it reduced the sugar in the urine in a number of cases of diabetes, but not in the severe cases, but Hall found that 60 grains (4 gm.) a day for twenty-seven days was without any effect. It is strongly diaphoretic. Toxicology. There are a number of reports of angioneurotic swelling of the face and throat, or general urticaria, with or with- out nausea, vomiting, dizziness, and collapse. These are due to idiosyncrasy, and have usually followed small doses, such as 15 grains (i gm.). Von Noorden (1912) says that in three of his cases acute nephritis followed the use of aspirin. When in long contact in solution quinine and acetyl-salicylic acid form quino- toxin, a substance possessing some of the actions of digitoxin. A death from this cause is reported. Novaspirin is the methyl-citric-acid ester of salicylic acid; diplosal is the salicylic-acid ester of salicylic acid; and diaspirin is succinyl disalicylic acid. It is claimed for all these that they pass through the stomach unchanged. Salol, or phenyl salicylate, CgELj.OH.COOCeHs, is in the form of crystals with a characteristic aromatic odor. It gives a violet color with ferric chloride. It is soluble in alcohol, but is insoluble in water and practically insoluble in gastric juice. In a test-tube alkalies produce the odor of phenol, and in the alkaline con- tents of the intestine it is decomposed and goes into solution as sodium salicylate and phenol. These products are rapidly ab- sorbed and are excreted in the urine as salicyluric acid and phenol sulphonates. Whether or not they have an antiseptic effect in the intestine is a moot question, most observers, with the exception of Herter, perhaps, having failed to note a diminution of the indican, or any other indication of diminished putrefaction. 486 PHARMACOLOGY AND THERAPEUTICS Indeed, phenol itself, judging from the work of Richards and Howland, is more prone to increase than to lessen the symptoms of auto-intoxication. Salol is sometimes carried through the in- testines without change, the odor being recognized in the feces. In its customary dose of 5 grains every three or four hours salol can have but little salicylic effect, and it is really a phenol drug rather than a salicylate. It is antipyretic and analgesic, however, and is frequently given with phenacetin for colds or influenza. In chronic colitis it is given in capsules with a few minims of castor oil, e. g., 5 grains (0.3 gm.) of salol and 5 min- ims (0.3 c.c.) of castor oil. In diabetes, Teschemacher (1901) noted a decided lessening of the sugar in 6 out of 9 cases. He gave 15 grains (i gm.) four times a day. As shown in experimental infections, the products in their excretion tend to render the urine antiseptic ; hence it is employed in infections of the urinary tract. Salophen is salicylic-acetanilid. Dose, 15 grains (i gm.). Saliphen is salicyl-para-phenetidin. Malakin is salicyliden-para-phenetidin. Mesotan is methyl-oxymethyl ester of salicylic acid, with the properties of a volatile oil. It is more irritant than methyl salicyl- ate, so is used diluted with an equal quantity of olive oil. Spirosal is monoglycol ester of salicylic acid, has also the prop- erties of a volatile oil, and is used in alcoholic or oily solution. Salicin is a glucoside obtained from willow and poplar barks, It is bitter and is not nauseating. In either the stomach or the duodenum it splits up to form salicyl alcohol and other close relatives of salicylic acid. (See Glucosides, Part I.) Its use 'is confined to the milder rheumatic manifestations, or to conditions of the stomach which prevent ordinary salicylic medication. Dose, 20 grains (1.3 gm.). Administration. The volatile oil types of salicylate are applied locally over the inflamed parts either by rubbing or on a compress. Internally they are given in capsules. Aspirin, salicin, salol, etc., are best given in capsules, but may be employed in tablet form. COLCHICUM Though it bears no relation to salicylic acid, colchicum, because of its use in gout, may properly be mentioned here. Both the seed and the corm of Colchicum aulumnale (fam. Liliacecc], a crocus-like plant, are official, the seed being required by the United States Pharmucopceiu to contain not less than 0.45 per cent, of the alkaloid colchicine, and the corm not less than 0.35 per cent. PHENYL-CINCHONINIC ACID 487 Preparations and Doses. (a) Colchicum seed, dose, 3 grains (0.2 gm.). Fluidextract, dose, 3 minims (0.2 c.c.). Tincture, 10 per cent., dose, 30 minims (2 c.c.). (b) Colchicum corm, dose, 4 grains (0.25 gm.). Extract (1.25 to 1.55 per cent, of colchicine), dose, i grain (0.06 gm.). (c) Colchicine, dose T ^ grain (0.0005 g 111 -)- The Wine of Colchicum Root, N. F., 40 per cent., and the Wine of Colchicum Seed, N. F., 10 per cent., are also employed. Pharmacology. Colchicum is a gastro-intestinal irritant, the larger therapeutic doses sometimes causing nausea, vomiting, and diarrhea. In poisoning there is intense gastro-intestinal irrita- tion, with vomiting, pain, and bloody stools; and there are irrita- tion of the kidneys (a remote local effect), collapse, and, some- times, an ascending paralysis, beginning in the legs. Death takes place from paralysis of respiration. It has resulted from J grain (0.003 g 111 -) f colchicine in a case of gout with nephritis. Diar- rhea calls for stoppage of the drug. There are no constant effects upon the uric-acid excretion in gout or in health, and there is nothing in the pharmacology of colchicum that explains its use in gout. Yet it seems to have great power in the acute attack to relieve the pain and swelling of the joints and to shorten the attack. In the words of von Noorden, "Colchicum accelerates the critical outpouring of uric acid that accompanies gouty seizures, but is inert in the intervals between the attacks, and in chronic and atypical gout." But Fine and Chace, Hanzlik, and others find that any value that the drug may have in gout is entirely unrelated to uric acid excretion. PHENYL-CINCHONINIC ACID Phenyl-cinchoninic acid, phenyl-quinoline-carboxylic acid, marketed under the proprietary name atophan, is official; dose, 8 grains (0.5 gm.). It is insoluble in water and alcohol and has a biting bitter taste. There is abundant evidence that this sub- stance in both normal and gouty subjects acts on the kidneys to increase the amount of urine and the excretion of all the ele- ments of the urine, but especially the uric acid. Fine and Chace found that it brought the uric acid of the blood to a percentage away below normal. McLester, after the large dose of 45 grains (3 gm.), noted that in three hours the uric acid of the blood was halved and the amount of urine trebled, in the next three hours the blood uric acid was again halved, but the total urine was small, 488 PHARMACOLOGY AND THERAPEUTICS and in the next three hours there was no change in the blood uric acid, both the uric acid in the blood and the excretion of urine having dropped to a low point. He concludes that atophan stimulates the kidneys to a marked degree, and that the excessive activity is followed by a period of fatigue and comparative in- activity. Brugsch, Folin and Denis, and others believe that the drug does not mobilize deposited urates, while Smith and Hawk consider that a rather high and long-continued excretion in cases of gout must be explained by urate mobilization. Daniels found that lithium citrate alone had no influence on the excretion of urine, but that when it was given in doses of 20 to 30 grains (1.3-2 gm.) a day to a person already getting atophan the uric acid elimination was increased 55 per cent. She figured that the lithium salt induced mobilization and brought the uric acid into the blood to be excreted. In any case it is recommended that alkalies and plenty of water be administered during the atophan treatment. Occasional untoward effects are gastric irritation, abdominal pain, diarrhea, purpura, urticaria, a scarlatiniform rash, and collapse. Cimicifuga, black snakeroot, is a bitter rhizome of the north- eastern United States, sometimes employed in gout and rheuma- tism. The dose of the fluidextract is 15 minims (i c.c.); of the extract, 4 grains (0.25 gm.). Piperazine, diethylene-diamine, is hygroscopic and very sol- uble in water. It is alkaline, forms salts with acids, and is incompatible w r ith alkaloidal salts, metallic salts, tannic acid, acetanilid, and acet-phenetidin. On the finding that its salt with uric acid was readily soluble, this drug was brought forward as a remedy in gout and the uric-acid diathesis; but its value is ques- tionable, for in the urine it is usually found in combination with the mineral acids rather than with uric acid. Starling reports it, however, as promoting the excretion of uric acid by the tubule cells, as shown in kidney experiments. Hanzlik states that equally worthless are piperazine, lycetol, lysidin, piperidine, quinic acid, quinidine, sidonal, urol, and urosin. DISINFECTANTS AND ANTISEPTICS A disinfectant is an agent that has the power to destroy microbic life, i. e., it is a germicide. An antiseptic is an agent that tends to retard the growth of microorganisms. A deodorant or deodorizer is an agent that will destroy or over- come a foul odor. It may or may not be disinfectant. Examples of such are: (i) For general use, chlorinated lime, cologne water, charcoal, the smoke of burning paper, burning straw, or burn- DISINFECTANTS AND ANTISEPTICS 489 ing coffee; (2) for bad breath, antiseptic solution, N. F. (contain- ing boric acid, thymol, eucalyptol, methyl salicylate, oil of thyme, sodium salicylate, sodium benzoate, alcohol, and water), or hydrogen dioxide; (3) for fetid breath, creosote; (4) in foul ulcers, potassium permanganate, hydrogen dioxide, or formal- dehyd. A preservative is an antiseptic agent used to prevent microbic changes (fermentation, putrefaction) in organic material, such as food, medicines, etc. Preservatives are so extensively employed in butter, milk, soups, vegetables, meat, etc., that it is possible to ingest a large quantity of one preservative or small doses of each of several preservatives at a single meal. Many of them retard decomposition without checking the activity of pathogenic germs. Sterilization is any process by which a substance is made germ- free. It usually implies destruction of germs by heat at 100 C. (212 F.) or higher. Pasteurization is a form of partial steriliza- tion at 1 60 F. for half an hour. It is used for milk. The ideal antiseptic or disinfectant for use about the body is one with a maximum action on microorganisms and a minimum action on the body tissues. Of blood disinfectants, quinine in malaria and salvarsan in syphilis would seem most nearly to approach this ideal; though their destructive effect is limited to certain organisms only. The germicidal value of many disinfectants is seriously inter- fered with by organic matter, especially blood-serum, so that the germicide that is strongest in the test-tube may be the weakest when in contact with the body tissues. Moreover, many ger- micides are decidedly more destructive to human tissues than to germs, so that their use may result in a lowering of the local resist- ance of the patient. (See Lambert's report on Iodine, page 499.) Tests with Albuminous Fluids. On mixing hydrocele fluid with an equal quantity of an antiseptic solution of sodium aurate, argyrol, and protargol (Verhoeff, 1906), and of collargol, albargin, ichthargan, argentamine, largin, and argonin (Derby, 1909), the germicidal effects were inhibited. With the same method, Verhoeff and Ellis (1907) found that lysol, i per cent., creolin, i per cent., listerine, 100 per cent., and liquor antisepticus, X. F., 100 per cent., failed to kill Staphylococcus aureus in two hours. The last-named authors also demonstrated that neither acetozone i : 1000, alphozone i : 1000, nor zinc sulphocarbolate, i per cent., mixed with solution of albumin, was successful in sterilizing typhoid culture in twenty-four hours; and that, mixed with albumin, alkalol, 100 per cent., borol, 50 per cent., alkathy- mol, ico per cent., glycothymoline, 100 per cent., zinc sulpho- 490 PHARMACOLOGY AND THERAPEUTICS carbolate, i per cent., and cuprol, 5 per cent., each failed to de- stroy Staphylococcus aureus in four hours. (See also under Silver.) Post and Nicoll (1910) made extensive tests, and reported the number of colonies in a loopful of test solution after different lengths of time. From their work the following table is compiled : SOLUTION" STREPTO- COCCUS GONO- coccus PNEUMO- coccus BACILLUS TYPHOSUS AFTER WHAT TIME IN MINUTES I. Silver preparations: Argyrol. 50 per cent Oo 3,000 00 o One 2,000 20O o Thirty. Argyrol, 10 pe r cent OO 2,000 OO o One II 7 Thirty. Protargol, 10 per cent 600 2OO <-- ^ i ,000 One. o o o Thirty. Silver nitrate, i per cent. . . . o o o One. Silver nitrate, i : 1000 o o <- ^20 t;oo One o o o Thirty. Silver nitrate, i : 5000 ^ I o 5 00 One. NH groups of the proteins into >NC1 groups, producing new substances which are known as chloramins and are antiseptic. Chlorinated lime, CaClo.Ca(OCl) 2 , is commonly known as "chloride of lime." It has been much employed in privies, sinks, cess-pools, etc., and for the purification of drinking-water. For the latter purpose a level teaspoonful of the powder is dis- solved in a pint of water, and of this one teaspoonful is mixed with two gallons of the water to be purified, i. e., i part in 2.000.000. In this dilution it gives no taste. Chlorinated lime deteriorates rapidly on exposure to air. FREE HALOGENS AND THEIR COMPOUNDS 495 Dakin and Dunham have found para-sulphon-di-chloramino- benzoic aoid to be the most suitable agent for the disinfection of drinking-water, a solution of i : 300,000 being able to sterilize a heavily contaminated water in about thirty minutes, and giving a barely perceptible taste. It keeps well if in tablet form. The Dakin-Carrel Treatment has become famous as a method for the continuous disinfection of wounds, the antiseptic employed being a solution of sodium hypochlorite (NaOCl) as obtained in Daufresne's modification of Dakin's solution. The formula of this solution as given by Carrel (Jour. Amer. Med. Assoc., December 9, 1916) is as follows: Preparation of Dakin's Solution. Daufresne's Technic. Dakin's solution is a solution of sodium hypochlorite for surgical use, the characteristics of which, established after numerous tests and a long practical experience, are as follows: (a) Complete Absence of Caustic Alkali. The absolute neces- sity for employing in the treatment of wounds a solution free from alkali hydroxide excludes the commercial Javelle water, Labar- raque's solution, and all the solutions prepared by any other procedure than the following : (b) Concentration. The concentration of sodium hypochlorite must be exactly between 0.45 and 0.50 per cent. Below 0.45 per cent, of hypochlorite the solution is not sufficiently active; above 0.50 per cent, it becomes irritating. Chemicals Required for the Preparation. Three chemical substances are indispensable to Dakin's solution: chlorinated lime, anhydrous sodium carbonate, and sodium bicarbonate. Among these three products the latter two are of a practically adequate constancy, but this is not the case with the first. Its content in active chlorine (decoloring chlorine) varies within wide limits, and it is absolutely indispensable to titrate it before using it. Titration of the Chlorinated Lime. There must be on hand for this special purpose: A 25 c.c. buret graduated in o.i c.c. A pipet gaged for 10 c.c. A decinormal solution of sodium thiosulphate (hyposulphite). The material for the dosage thus provided, a sample of the provision of chlorinated lime on hand, is taken up either with a special sound or in small quantities from the mass which then are carefully mixed. Weigh out 20 gm. of this average sample, mix it as completely as possible with i liter of ordinary water, and leave it in contact for a few hours, agitating it from time to time. Filter. Measure exactly with the gaged pipet 10 c.c. of the clear 496 PHARMACOLOGY AND THERAPEUTICS fluid; add to it 20 c.c. of a i : 10 solution of potassium iodid and 2 c.c. of acetic or hydrochloric acid. Drop, a drop at a.time, into this mixture a decinormal solution of sodium thiosulphate until decoloration is complete. The number of cubic centimeters of the hypochlorite solution required for complete decoloration, multiplied by 1.775, gives the weight of the active chlorine contained in 100 gm. of the chlorin- ated lime. This figure being known, it is applied to the accompanying table, which will give the quantities of chlorinated lime, of sodium carbonate, and of sodium bicarbonate which are to be employed to prepare 10 liters of Dakin's solution: Titer of chlorin- Chlorinated Anhydrous sodium Sodium bicarbonate, ated lime. lime, gm. carbonate, gm. gm. 20 230 115 96 21 220 no 92 22 210 105 88 23 20O IOO 84 24 IQ2 96 80 25 184 92 76 26 177 89 72 27 170 85 70 28 164 82 68 29 159 80 66 3 154 77 64 31 148 74 62 32 . 144 72 60 33 HO 70 59 34 135 68 57 35 132 66 55 36 128 64 53 37 124 62 52 Example: If it required 16.6 c.c. of the decinormal solution of the sodium thiosulphate for complete decoloration, the titer of the chlorinated lime in active chlorine is: 16.6 X i-775 = 29.7 per cent. The quantities to be employed to prepare 10 liters of the solution will be in this case: Chlorinated lime 154 ^m. Dry sodium carbonate 77 gm. Sodium bicarbonate 62 gm. Of crystalline sodium carbonate 220 gm. may be used instead of the 80 gm. of dry carbonate. Preparation of Dakin's Solution. To prepare TO liters of the solution: 1. Weigh exactly the quantities of chlorinated lime, sodium carbonate, and sodium bicarbonate which have been determined in the course of the preceding trial. 2. Place in a 1 2-liter jar the chlorinated lime and 5 liters of FREE HALOGENS AND THEIR COMPOUNDS 497 ordinary water, agitate vigorously for a few minutes, and leave in contact for from six to twelve hours, over night, for instance. 3. At the same time dissolve, cold, in the five other liters of water the sodium carbonate and the bicarbonate. 4. Pour all at once the solution of the sodium salts into the jar containing the maceration of chlorinated lime, agitate vigorously for a few moments, and leave it quiet to permit the calcium carbonate to settle as it forms. At the end of half an hour, siphon the liquid and filter it through double paper to obtain an entirely limpid product, which must be protected from light. Titration of Dakin's Solution. It is wise precaution to verify, from time to time, the titer of the solution. This titration utilizes the same material and the same chemical substances as are used to determine the active chlorine in the chlorinated lime: Measure out 10 c.c. of the solution, add 20 c.c. of i : 10 solu- tion of potassium iodid, and 2 c.c. of acetic or hydrochloric acid. Drop, a drop at a time, into this mixture a decinormal solution of sodium thiosulphate until decoloration is complete. The number of cubic centimeters employed multiplied by 0.03725 will give the weight of the sodium hypochlorite contained in 100 c.c. of the solution. A solution is correct when, under the conditions given above, from 12 to 13 c.c. of decinormal thiosulphate are required to complete the decoloration: 13 X 0.03725 = 0.485 per cent, of NaOCl. The Test for the Alkalinity of Dakin's Solution. Pour into a glass about 20 c.c. of the fluid, and drop on the surface a few centigrams of phenolphthalein in powdered form. Dakin's solu- tion, correctly prepared, gives absolutely no change in tint. It is to be noted that the solution must be of reasonable freshness, exactly neutral, and absolutely of a concentration between 0.45 and 0.50 per cent. The tubes must be so placed that the liquid runs down and not up into the wound, and must be so arranged as to bring and keep the liquid in contact with every part of the wound surface. To insure continuous contact and to hold the tubes in place fluff gauze is stuffed between the tubes. The antiseptic is rapidly taken up by the tissues, so its renewal is secured by an instillation of the liquid every two hours. At no time is enough solution allowed to run in to more than fill the wound and saturate the packing. The method is neither one of drainage nor of irrigation, nor a continuous drip process, for no liquid flows except during the two-hourly instillations. The skin for 3 or 4 inches on all sides is protected by a covering of bandage gauze impregnated with sterile petrolatum or vaseline. As the solution can dissolve dead tissue, clots, etc., all vessels must be tied off, otherwise there may be secondary hemorrhage. 498 PHARMACOLOGY AND THERAPEUTICS Pain is an indication that the solution is not right, or if during the instillation, that the liquid is being allowed to run in under too much pressure. This liquid not only forms chloramins as described above of a disinfectant value 14 to 22 times that of phenol, but, in addition, through its hypertonicity induces a flow of lymph from the wound surfaces and so prevents any absorption of toxic products through the lymph-channels. In the Dakin-Carrel treatment the absence of lymphatic involvement is striking. Dichloramin-T. This is toluene parasulphondichloramin, an antiseptic prepared by Dakin to do away with the difficulties of the technic and the care required in the Dakin-Carrel treatment. It is employed in 7.5 per cent, solution in chlorinated eucalyptol and chlorinated liquid petrolatum. The oils are chlorinated so that they will not take up the chlorine of the antiseptic, and they liberate the antiseptic slowly and continuously for a period of eighteen to twenty-four hours. Dichloramin-T corresponds with the >NC1 substances formed when Dakin's solution is brought in contact with the exudate of wounds. It is non-irritant to the skin or in the wound, and, according to Dakin, is as effective a germicide as iodine without its destructive effect. Like Dakin's solution, dichloramin-T can dissolve dead tissue and clots, so all hemorrhage must be stopped by ligation. Chlorazene is a proprietary preparation of the sodium salt of toluene parasulphochloramin, a non-irritant germicide four times the strength of phenol and used in 2 per cent, solution. Bromine is a reddish-brown, corrosive liquid, the fumes from which are very irritating to the respiratory passages. Severe bronchitis and laryngitis have occurred from the breaking of a bottle of bromine or its use in the laboratory. For bromine burns the best antidote is phenol, which forms the comparatively harmless tribromphenol. Bromine water is employed as a gargle. Iodine is used in the form of the tincture of iodine (iodine, 7 per cent.; potassium iodide, 5 per cent.) in the treatment of ring-worm and other parasitic skin diseases. This tincture or an alcoholic solution free from potassium iodide has recently come into extensive use as a skin disinfectant preliminary to operation. It is highly convenient in preparing the skin for paracentesis and small cuts, and for major surgery. It does not injure the skin, and its staining soon disappears. Experiments have shown it to have an almost instantaneous destructive effect upon the Staphylococcus albus of the skin as well as on other bacteria. The work of Post and Nicoll (see Table), Kinnaman, and many others has established its positive disinfectant value METALS AND THEIR COMPOUNDS 499 in surgery. Kinnaman found that a i : 100 iodine solution de- stroyed the Bacillus tuberculosis in seven minutes, and Bacillus prodigiosus and anthrax bacillus with spores in ten minutes. Lambert found that among a number of antiseptics iodine was the only one to which animal cells were more resistant than staphylococci. Churchill's tincture (16.5 per cent, of iodine) is also employed, but such strong solutions are not necessary. E. McDonald recommends a 2 per cent, solution in carbon tetrachloride. The antiseptic iodine compounds are iodoform and certain iodine-containing compounds of the phenol group, viz., thymol iodide (aristol), europhen and losophan, which are cresol com- pounds, and iodol (tetra-iodo-pyrrhol) . These were designed to have the iodoform antiseptic effect without its disagreeable odor, but they do not act like iodoform, and are probably anti- septic because of their phenol affinities rather than because of their iodine constituent. Their antiseptic value cannot, there- fore, be judged by their iodine percentage. lodoform is a yellow, crystalline powder, insoluble in water, and with a disagreeable, persistent, and penetrating odor. It is not germicidal except in contact with raw tissues or wound secretions, where part of it is believed to change into iod-albumi- nates and di-iodo-di-acetylene. Locally it is irritant and may cause a dermatitis or a pustular rash. After absorption it may have simply the action of an iodide, or give poisonous symptoms which indicate the presence of unchanged iodoform in the blood, lodoform poisoning usually manifests itself in one of three forms, the prominent symptoms being (i) Vomiting; (2) cerebral excitement and delirium; or (3) cerebral depression with melan- cholia. In each case the outcome may be coma and collapse. The poisoning is usually due to the packing of large cavities with strong iodoform gauze. The symptoms of hyperthyroidism have been reported. In tuberculous sinuses and in the peritoneal cavity in tuberculous peritonitis, a mixture of iodoform, glycerin, and ether, incorrectly called "iodoform emulsion," seems to be of benefit; though the belief that iodoform exerts a specific effect upon the tubercle bacillus has no experimental support. It has also been thought to have a special value in infections by the Bacillus pyocyaneus. To remove the odor of iodoform from the hands Ricketts recommends vinegar. V. METALS AND THEIR COMPOUNDS These combine chemically with albumin to form precipitates of metallic albuminates, which make an impenetrable pellicle. 500 PHARMACOLOGY AND THERAPEUTICS Thus the metallic salts have little penetrating power, and are readily destroyed by the body fluids. Those most employed as antiseptics and disinfectants are: Of mercury mercuric chloride and mercurophen; also, slightly, in ointment form, ammoniated mercury and mercuric oxide. Of gold sodium aurate, reported by Verhoeff (1906) as of great efficacy and little toxicity. Of silver the nitrate, protargol, argyrol, etc. Of copper and iron the sulphates. Of zinc the sulphate and the chloride. Of aluminium the acetate, made fresh in solution. Of bismuth the subiodide, and perhaps slightly the subnitrate and other salts. The pharmacology of the metals is considered further on. VI. MISCELLANEOUS INORGANIC COMPOUNDS Potassium nitrate (niter or saltpeter), sodium chloride, sodium borate (borax), and boric acid are employed as food preservatives, as in corned beef, ham, butter, etc. Wiley says that the small quantities of salt in butter are not preservative. Boric acid, a crystalline solid, is soluble in 18 parts of water, 16 of alcohol, and 5 of glycerin, and volatilizes when its solution is boiled. It is soothing locally, and mildly antiseptic. Post and Nicoll (1907) obtained no essential germicidal effect in twenty hours from saturated aqueous solutions; but Bernstein (1910) has demonstrated that it has some power to check the growth of yeasts and harmless saprophytes, though only slight effect on typhoid and other pathogenic germs. It is more effective, therefore, as a preservative than as a disinfectant. About the body it possibly acts more by changing the reaction of the fluids than by directly retarding the microbic growths. Its solution is used extensively as a cleansing application to inflamed mucous membranes, as of the eye, nose, mouth, vagina, etc. ; its ointment, as an application to eczematous areas, fungous skin diseases, and burns; and the acid itself as a dusting- powder in the shoes in sweating of the feet. It is almost specific against thrush in the mouths of infants. With salicylic acid it forms the antiseptic wash "boro-sal" or Thiersch's solution, which consists of boric acid, 8 ; salicylic acid, 2 ; and water, to make 1000. For children it has a wide range of application. Boric acid and its alkaline salt, sodium borate or borax, are very widely em- ployed as food preservatives. Borax was recommended by Cowers in epilepsy in doses of 20 grains (1.3 gm.) three times a day. PHENOL COMPOUNDS 50 1 Toxicology. Boric acid has been the cause of a number of cases of poisoning, the symptoms being: gastro-enteritis with vomiting and diarrhea, a papular eruption on the skin, general edema, a gray line on the gums, and central depression leading to collapse. Best (1904) gathered from the literature 5 cases of severe poisoning and 5 deaths. Severe symptoms have re- sulted from irrigating the colon with boric-acid solution, from packing the vagina, the ankle-joint, etc., with the powder, from washing out the pleural cavity, a lumbar abscess, etc. Recovery is reported of an infant of eight weeks after 2 doses of 3 ounces (90 c.c.) of a saturated solution, part of which was vomited. The treatment is abundance of water and alkalies. The glycerite of boroglycerin, a thick liquid made of boric acid and glycerin, is used on vaginal tampons in chronic endome- tritis and pelvic inflammations. VII. PHENOL COMPOUNDS This group includes phenol, the sulphocarbolates, resorcinol, pyrogallol, benzoic acid, salicylic acid, salol, cinnamic acid, cresol, creosol, guaiacol, creosote, tar, oil of cade, many volatile oils, camphor, thymol, aristol (di-thymol di-iodide), europhen and losophan (iodine compounds of cresol), iodol (tetra-iodo- pyrrhol), naphthalene, beta-naphthol, trimethol, etc. The drugs of this group, when taken internally, tend to in- crease the ethereal sulphates of the urine, and in some cases may result in indicanuria. They are less affected than most anti- septics by organic matter. They are all antiseptic, antipyretic, and analgesic. Their toxic action manifests itself by depression of the respiratory and vasoconstrictor centers, coma, and collapse. Benzoic and cinnamic acids and their salts are similar to salicylic acid in their action, though less effective in rheumatism. They are used as food preservatives, and even in very minute quantities retard the activity of the digestive ferments (Sailer and Farr). The cinnamates have been employed in tuberculosis. Sodium benzoate is used in cystitis to acidify and disinfect the urine. Dakin states that in men amounts of i to i^ drams (4-10 gm.) daily for two or three days are practically all elimi- nated as hippuric acid. Balsam of Peru, which contains ben- zoates and cinnamates, is used externally in chronic skin diseases; and, in the form of "balsam gauze," is applied to ulcers or wounds as a stimulant of granulation. Benzoin, which is also a balsam containing benzoates and cinnamates, is very fragrant. It is employed for inhalation in whooping-cough, laryngitis, nasopharyngitis, bronchitis, and 502 5 :/-\ O a u o PHARMACOLOGY AND THERAPEUTICS a Creosol IK Sodium Phenol O Sulphonate (Ethereal Sul- phate) O 4 ' / \ w Sulpho a / \ 8 U ^nmVAc \ / (Inactive and passes unchanged) icarbolate ^ U <^ yCresol O u 5 a Phenacetin IPhloroglucin (not antiseptic) O O Salicylic Add O Benzoic O Acid U a u H I a Pyro- gallol >O Hydro- quinone >Resorci- nol I Pyro- catechin Phenol a u Benzol O U 3 a \/ Acetanilid 'Cinnamic Acid Thymol Eugenol 'Anisol O Thymol _, Iodide O Guaiacol Carbonate *U Trichlor- phenol Europhcn = Cresol iodide. Losophan = Tri-iodo cresol. (Tetra- iodo- pyrrhol) Beta- Naphtalin /Antinosine = Na salt. v Eudoxine = Bi salt. The Chemical Relationships of the Phenol Group of Disinfectants. Nosophen = Tetra-iodo-phenolphthalein< x - PHENOL COMPOUNDS 503 pneumonia, one teaspoonful of the compound tincture (benzoin, aloes, storax, and tolu) being added to boiling water in a pitcher or to water boiling in a croup-kettle, and the steam inhaled. Its tincture is also mixed with water and used as a lotion for the skin in ivy-poisoning, sunburn, and other forms of dermatitis. Creosote, which is an empyreumatic volatile oil obtained during the distillation of wood-tar, contains 70 to 80 per cent, of guaiacol with cresol and creosol. A few drops may be used with steam in the same conditions as the compound tincture of benzoin, or it may be dropped on the sponge of a zinc respi- rator. Because of its strong odor, it is employed as an inhalant in ozena, fetid bronchitis, tuberculosis, bronchiectasis, gangrene of lung, etc. Internally, its chief employment is in pulmonary tuberculosis or persistent bronchitis, in dose of 5 minims (0.3 c.c.). It is very irritant to many stomachs and disagreeable to the taste, but it can often be taken in milk or cod-liver oil, or with a strong tasting tincture, such as the compound tincture of gen- tian. In some cases of tuberculosis it has a good effect on appe- tite, fever, and night-sweats. It is excreted to some extent by the lungs, as noticed in the breath and sputum, but there is no evidence of any antiseptic value in tubercle tissue or in the bronchi. Creosote carbonate (the carbonic ester) is a liquid of less penetrating odor and less biting taste, and it may be odor- less and tasteless. Guaiacol, the chief constituent of creosote, is an oily liquid, and is used in the same way as creosote; dose, 5 minims (0.3 c.c.). It is also employed as a counterirritant in epididymitis and tuber- culous peritonitis. Guaiacol carbonate (the carbonic ester) is a solid, and is given in 5-grain (0.3 gm.) capsules. It is tasteless and odorless and is usually well borne by the stomach. Cresol is much more germicidal than phenol. Compound cresol solution (liquor cresolis compositus) consists of 50 per cent, of cresol in a solution of soft soap. It is used in i per cent, solu- tion in water. Proprietary remedies of similar nature are lysol and creolin. Fatal poisoning has several times resulted from confusion over the name lysol. At the Hygienic Laboratory the disinfecting value in inorganic solutions as compared with phenol was, for compound cresol solution, 3; for creolin, 3.25; for lysol, 2.12. In solutions of peptone and gelatin, the value for compound cresol solution was 1.87; for creolin, 2.52; and for lysol, 1.57. Resorcinol (resorcin), readily soluble in water and alcohol, is used in 10 per cent, solution as a scalp wash for dandruff, and in skin lotions as antiseptic and antipruritic. In the stomach it is antifermentative; dose, 5 grains (0.3 gm.). A number of 504 PHARMACOLOGY AND THERAPEUTICS cases of poisoning are reported, even from the application of an ointment. Pyrogallol turns brown on exposure to air. It is employed in fungous skin diseases. Tar and oil of cade are added to oint- ments for chronic eczema and ring-worm. The syrup of tar (syrupus picis liquidac) is used in bronchitis as an expectorant. Naphthalin and beta-naphthol have a questionable value as intestinal antiseptics; dose, 5 grains (0.3 gm.). Fatalities are reported from a dose of 1.75 gm. of naphthalin given for thread-worms, and from moth-balls eaten by children. Tri- methol (trimethyl-methoxy-phenol), a proprietary remedy pro- posed as an intestinal disinfectant, is given in capsule or tablet in doses of about 20 a day. It may be irritant to the stomach. For children a syrup is obtainable. The iodine phenol compounds are probably antiseptic rather in relation to their phenol constit- uent than to their iodine ; they were brought out as substitutes for iodoform. Thymol iodide (aristol) is much employed as an anti- septic dusting-powder. Volatile Oils. Eucalyptol is one of the strongest antiseptics in the volatile oil group, but, owing to its oily nature, cannot readily be employed as an antiseptic. Its chief use is as an inhalant in respiratory diseases, coryza, whooping-cough, bron- chitis, etc., either with steam or by respirator, or sprayed from an atomizer. A favorite spray consists of about 2 per cent, each of eucalyptol, camphor, and menthol, dissolved in liquid paraffin. An application for burns is gauze impregnated with paraffin containing eucalyptol and other aromatic disinfectants. Oil of cinnamon, oil of cloves, and cugenol are used by dentists. Antiseptic solution (liquor antisepticus, N. F.) has been shown to have very slight, if any, antiseptic power. Its chief use is as a pleasant mouth-wash, and it is an official substitute for a number of proprietaries incorrectly called antiseptic, and aptly dubbed by Sollmann the "psychic antiseptics." For in- gredients, see page 489. PHENOL, OR CARBOLIC ACID Phenol is made synthetically and is also obtained from coal-tar by fractional distillation. It is a crystalline substance, of faintly acid reaction, freely soluble in alcohol, glycerin, and the oils, and in 20 parts of water. The crystals, which consist of about 96 per cent, of pure phenol, melt on warming, and remain liquid on the addition of about 8 to 10 per cent, of water. The official "phenol liquefactum" is made by adding 10 parts of water to 90 parts of the crystals. This forms a stock solution which is easier to handle than the crystals regularly employed; but if water is PHENOL, OR CARBOLIC ACID 505 added to it, the phenol separates as an oily liquid, and does not go into solution again until about 20 times its weight of water has been added. In other words, one can make a solution of official phenol of 5 per cent, or 90 per cent, strength, but not of any strength between. If, however, the phenol is previously dis- solved in glycerin, it can be mixed in any proportion with water. Phenol precipitates albumin, gelatin, and collodion, and makes a violet color with ferric salts. Preparations. Phenol, 96 per cent, pure phenol in crystal form. Liquefied phenol (phenol liquefactum) a permanent liquid made by mixing 9 parts of phenol crystals with i of water. Ointment, 3 per cent, in white petrolatum. Phenol tends to separate out on long standing. Glycerite, a 20 per cent, solution in glycerin. Dobell's solution (liquor sodii boratis compositus, N. F.), which contains 0.3 per cent, of phenol and 1.5 per cent, each of sodium bicarbonate and borax, with glycerin and water. Pharmacologic Action. Microorganisms. Phenol exerts a powerful precipitating effect upon protoplasm. This precipitate is not due to chemic combination, but to change of solvent, i. e., the protoplasmic elements are insoluble in a solution of phenol. There is no chemic action, and the phenol can be washed out of the tissues by a solvent. Since it is not chemically combined, it has greater penetrating power than most of the disinfectants. Even very dilute solutions, i : 500, cause the prompt cessation of motion of protozoa, leukocytes, spermatozoa, and ciliated epithelium, the protoplasm of the cell becoming granular and the cell soon disintegrating. Bacteria, as they have a cell wall, are more resistant; yet even these are penetrated more readily by phenol than by most germicides. The susceptibility to the phenol varies greatly with the different kinds of bacteria, and the spores are so resistant that they require to be exposed to strong solutions for hours. Wilbert (1916) shows that a mixture of i per cent, of phenol and 9 per cent, of alcohol with water is distinctly more disinfectant than a i per cent, solution of phenol in water alone. A solution in oil has diminished antiseptic action; for the phenol has greater affinity for oil than for the water or solution of salts in the tissues, and consequently does not penetrate into the organism. A 5 per cent carbolic ointment made with lard will go rancid in spite of the antiseptic. Very dilute solutions tend to activate both unorganized and 506 PHARMACOLOGY AND THERAPEUTICS organized ferments; stronger solutions retard their activity, and especially diminish that of the unorganized ferments of the ali- mentary tract. Locally, phenol is somewhat anesthetic, tending to allay itching and pain. It is absorbed by the unbroken skin, but much more readily by mucous membranes, and it acts on the sensory nerve-endings to produce numbness, though not complete analgesia. There may also be tingling. This may occur from i to 5 per cent, solutions, as when the hands are kept wet with a solution in its surgical use. It thus may considerably lessen pain, but usually does not annul it. The tingling and numb- ness may last half an hour or more. Strong phenol produces a burn, the pain from which is sometimes not noticeable at first on account of the anesthetic action. The skin becomes white and cold from constriction of the vessels, and numb from paral- ysis of the ends of the sensory nerves; later it becomes red and very painful, and still later may dry up and peel off, or the superficial tissues may slough off and leave a painful, slowly heal- ing, ulcerated area. Both weak and strong solutions applied to a finger or toe as wet dressings have frequently resulted in gangrene, the carbolic slowly penetrating the tissues and causing their death, while the anesthetic effect prevents the warning of pain. After a few hours the finger is found to be white and dead, and it subse- quently turns black on the surface. It is sometimes necessary to amputate, but usually not. Strong phenol usually causes pain early, so that measures are taken to stop the action, hence gangrene is less likely than from weak solutions. When applied to a wound, phenol solutions coagulate the blood and protein matters and form a pellicle over the surface. This pellicle protects the germs, so that phenol may have an undesirable effect upon the body cells and no useful one on the bacteria. On mucous membranes there are the same anesthetic and corrosive actions as on the skin. Weak solutions in the stomach are somewhat anesthetic and may allay vomiting. Systemically, phenol resembles acetanilid in its action, but the antiseptic and collapse actions predominate, and the anti- pyretic action is less. At first the heart is stronger from direct stimulation of its muscle; later this is weakened. The vaso- constrictor and respiratory centers are also at first stimulated, then markedly depressed, and in fever the temperature is lowered. But collapse is readily produced, and because of this the drug is not employed for its systemic effect. We must understand these effects, however, because of the frequency of carbolic poisoning. Fig. 63 .-Carbolic-acid poisoning. Coagulation of crests of the folds of mucos-. in the stomach (MacCallum). PHENOL, OR CARBOLIC ACID 507 In a study of the effects of the products of intestinal putre- faction on muscle, F. S. Lee found that in a solution of phenol, i : 2000, a muscle did nearly twice as much work as before, while in solutions of i : 1000 the muscle readily became fatigued and did less work (Herter). Excretion is by the urine. The phenol passes out partly unchanged and partly oxidized to hydroquinone and pyrocat- echin in combination as ethereal sulphates and glycuronates. The urine may have a smoky or dusky appearance, or may change to brownish-black or greenish-black on exposure to the air. In poisoning, practically all the sulphates of the urine may be in the form of ethereal sulphates, the inorganic sulphates completely disappearing. Toxicology. Phenol is usually readily obtainable, and is a favorite drug for committing suicide. Darlington points out that, in New York city alone, as the result of an ordinance forbidding the sale of strong carbolic, the number of suicides fell from 343 in a year to 36. Its recognition is usually easy from the odor, the corroded tongue and mouth covered with white pellicle, and the empty bottle. A case of fatal poisoning occurred from a surgical dressing at St. Thomas' Hospital, London. The effects from a poisonous dose may be of three types: 1. After an overwhelming dose the victim becomes un- conscious almost immediately and dies in a few minutes from shock. 2. From good-sized but not immediately fatal doses of strong phenol the local corrosion is marked, and there is rapid absorption of a large quantity of the drug. The patient is found in collapse, perhaps unconscious, with muscular tremors and twitchings or rarely convulsions. Death may follow in a few hours from paralysis of the respiration, the patient never regaining consciousness. Or recovery may take place, with extensive corrosion of the mouth, pharynx, esophagus, and stomach. Perforation of the stomach may occur, or months later cicatricial contractions in any part of the burned area, as in the pharynx, esophagus, and stomach. The symptoms of poisoning by strong phenol are, then: corrosion of the alimentary tract, followed by collapse, coma, and perhaps convulsions. 3. Where weak solutions have been taken, there is no local corrosion, but there is a gradual onset of collapse from depres- sion of centers and heart muscle. There are cold, clammy skin, nausea, vomiting, weak shallow breathing, weak rapid pulse, mental depression and anxiety, or coma and prostration, fol- 508 PHARMACOLOGY AND THERAPEUTICS lowed by recovery or death. The sulphates are lacking in the urine, so that when barium chloride does not give a precipitate in the urine, it is a fair conclusion that the patient is poisoned with phenol. Phenol is the most frequent cause of ochronosis (Beddard). Treatment of Poisoning. i. Locally, to remove the phenol, the best application is alcohol. But a bland oil or fat (olive, cottonseed, or linseed oil, or lard or butter), or glycerin or vine- gar will serve. These have more solvent powers for carbolic than the liquids of the protoplasm, 'so tend not only to prevent penetration, but also to extract the carbolic from the tissues. For the stomach, whisky or a 20 per cent, solution of alcohol may be employed; but this must be washed out at. once, as the alcoholic solution of phenol is very readily absorbed, and alcohol does not prevent the systemic effects. Clarke and Brown have shown that lavage with water is an effective measure. It is- said that lime will form an insoluble compound, and that potas- sium permanganate will oxidize and destroy the phenol, but these substances can hardly be given in sufficient quantity. After thorough lavage with water or 3 per cent, sodium sulphate, demulcents, such as oils, milk, and white of egg, may be swallowed. The burns, ulcers, or cicatricial contractions must later on be treated like any other burns or ulcers or cicatrices. 2. Systemically. On account of the disappearance of the inorganic sulphates from the urine and their replacement by ethereal sulphates, it has been believed that the alkaline sul- phates would combine with the phenol to form non-toxic sulpho- carbolates (phenolsulphonates), and so lessen its activity and promote its excretion. (The phenolsuphonates are not formed in a test-tube or in the stomach, though they are slowly formed in the body.) On this theory sulphates have been given by mouth in carbolic poisoning, and sodium sulphate in i to 2 per cent, solution has been administered intravenously. Sollmann and Brown (1907) studied this matter very carefully by an extended series of experiments, and found that the combination takes place too slowly for any useful antidotal effect, whether the sulphates are given before, with, or after the phenol, and whether they are given by mouth or intravenously; therefore they are not chemic antidotes. A saline infusion may, however, be of great value in the treatment of collapse and to promote diu- resis; and it would be well to add i per cent, of sodium sulphate to this. The treatment is that for collapse. Therapeutics.- Locally, phenol is added to lotions to allay itching. Strong phenol is used as a powerful local antiseptic in clog-bite, carbuncles, small infected cavities, and other small MISCELLANEOUS ORGANIC COMPOUNDS 509 superficial wounds. Its continued action or penetration may be checked by alcohol. It is sometimes injected into cyst cavities to cause an inflammation and obliteration of the cyst (bursitis, hydrocele), and also into hemorrhoids. For ordinary antiseptic purposes, as washing a wound, disin- fecting excreta, towels, bedding, etc., solutions of i to 5 per cent, strength are employed for from one-half to two hours. They are more antiseptic and more penetrating than the ordinary solutions of bichloride of mercury, and they do no harm to fabrics or metal dishes. In the European war Chlumsky's Solution has been much employed. It consists of phenol, 30 parts; camphor, 60; alcohol, 10. Bacelli (1911) tabulates 94 cases of tetanus treated intraven- ously by increasing doses of 5 to 22^ grains (0.3-1.5 gm.), in twenty-four hours, in a 2 per cent, solution. He found that in 190 reported cases the mortality was only 17.36 per cent. The method would seem to be highly dangerous; but Bacelli thinks that patients with tetanus are exceptionally tolerant to phenol. VIZI. MISCELLANEOUS ORGANIC COMPOUNDS Ichthyol. and thiol are oily-looking sulphur compounds which are soluble in water and the oils, and not in alcohol. Ichthyol is obtained from a shale, and thiol is prepared synthetically. Their 3 to 5 per cent, solutions are applied externally as soothing lotions, as in bad sunburn. Their 50 per cent, solution is painted over infected areas to promote absorption of serous or fibrinous exudates. Ichthyol ointment, 10 to 50 per cent., is applied to lessen glandular or joint swellings and in erysipelas. It has been thought that it may favor the resistance of the tissues by inducing a local gathering of leukocytes. Vaginal tampons bearing a solution of 10 to 30 per cent, in glycerin are largely employed in cases of chronic endometritis and chronic pelvic inflammations. Ichthyol has an unpleasant odor, \vhile thiol is nearly odorless. Internally, ichthyol is employed in cases of intestinal putre- factive toxemia as an intestinal disinfectant, dose, 3 to 5 grains (0.2-0.3 S 111 -) m a capsule or enteric pill. It is slightly laxative. Ichthyol enters into "Bum Mixture." (See Hoffmann's Ano- dyne.) Methylene-blue (methyl-thionine chloride) is little used as an antiseptic. It turns the urine a bluish-green, a fact that has been made use of as a functional test for the kidneys. It has been injected into recurrent or inoperable carcinomata, but with- out any noteworthy effects. After its ingestion by mouth Brauer found large quantities of it in the bile. The ordinary 510 PHARMACOLOGY AND THERAPEUTICS commercial article usually contains zinc, and if taken internally may cause vomiting. The author saw a case of acute gastro- enteritis follow a capsule of methyl-blue, prescribed by the physician in mistake for methylene-blue. Formaldehyd (HCOH) is a gas, and its aqueous solution, containing not less than 37 per cent, by weight of absolute formaldehyd, is official under the name of "Liquor Formalde- hydi." This solution should be neutral or only faintly acid to litmus, showing the absence of formic or other acids. It is marketed under the name of "Formalin," and usually contains about 10 per cent, of methyl alcohol to facilitate solution and prevent polymerization. At ordinary temperature it gives off formaldehyd gas. On cooling the solution below 68 F., a white powder results. This is known as paraformaldehyd (paraform, trioxymethylene) , and is a polymeric form of formaldehyd. On gently heating, this is reconverted into gaseous formaldehyd. Formaldehyd is pungent and very irritating to eyes, nose, and throat. It is rendered inert by alkalies, especially ammonia ; it reduces Fehling's solution; it attacks metals (instruments); it hardens tissues, blood, and gelatin (blood on the hands be- comes darkened and difficult to wash off) . This last property has been made use of to harden gelatin capsules so that they would pass through the stomach into the intestine before dissolving (glutol capsules); but the degree of hardening is uncertain. It is employed as a hardening and fixing agent for anatomic and biologic specimens, and is used as an arterial injection for embalming the dead and for preserving cadavers for dissection. It may be employed for fixing blood-smears. An important property is that of preventing the coagulation of serum albumin by heat, as in urine. Formaldehyd is a powerful disinfectant. It is much employed as a preservative of foods. One part in 20,000 cannot be detected by its odor, yet will keep milk for several days. In i : 50,000 strength it retards the growth of the lactic acid bacillus, but has little effect on the colon or typhoid bacillus (Vaughan). Bur- nam (1912) found that a i : 20,000 solution retarded, but did not destroy, typhoid bacillus and streptococcus; but that a i : 1000 solution killed colon, typhoid, and pyocyaneus bacilli, streptococcus and Staphylococcus aureus in twenty-four hours. It is used as a preservative of cider, fruit-juices, and canned foods, and is employed as a valuable general disinfectant for sick-rooms. The gas may be generated (i) By warming the solution ; (2) by heating paraformaldehyd; (3) by adding one pound of fresh quicklime to a mixture of 6 ounces of aluminium sulphate and 8 ounces of formaldehyd solution, as advised by the New York MISCELLANEOUS ORGANIC COMPOUNDS 51! Health Department, this amount yielding enough gas to dis- infect a room containing 1000 cubic feet; (4) but the best method of all is to add compressed blocks of potassium permanganate to the formaldehyd solution in a large pail. The gas is given off with violent ebullition (formanganate disinf ector) . (5) Lawall pours a mixture of i| ounces (45 c.c.) of commercial sulphuric acid with i pint (480 c.c.) of formaldehyd solution over 9 ounces (270 gm.) of sodium dichromate crystals. This is cheaper than the permanganate method. The exposure to the gas should be from twelve to twenty-four hours. It has little penetrating power, so may fail to enter the cracks in the floor or penetrate a mattress. In the presence of moisture, as steam, it is more effective than when dry. If the temperature of the room is below 52 F., it may polymerize into paraform. It does not kill vermin. Doty and others report that bedbugs, roaches, mosquitos, or even rats, rabbits, and guinea-pigs were alive after many hours' exposure. The gas is immediately neutralized by ammonia gas. Formaldehyd is somewhat used for sterilizing absorbent cotton, sutures, and surgical dressings; but, on account of its action on metals, its irritating vapor, and its bad effect on the hands, is limited in its use as a surgical disinfectant. Locally, the solution of formaldehyd has been used in fungous skin diseases (favus, sycosis, ring-worm), to disinfect foul ulcers and cancers, to check local sweating, and to harden and dry up small growths, such as moles, condylomata, and even cancer. Daniel says that formalin rubbed into warts with a stick makes them come off without leaving a scar. In very weak solution it has been employed as an antiseptic to mucous membranes, as in catarrh of the nose, throat, or vagina usually with other mucous membrane antiseptics. Recently it has been recom- mended to leave a weak solution of formaldehyd in the pleural cavity after paracentesis for pleurisy with effusion. Poisoning. There are a number of reported cases of poisoning from its ingestion by mouth, with intense irritation of the esoph- agus and stomach, vomiting, diarrhea, coma, and collapse. The kidneys are also irritated, as shown by albuminuria, bloody urine, or suppression. The urine may contain albumin and formic acid. The chemic antidote for the stomach is ammonia, well diluted, and followed by demulcents, such as bland oils, mucilagin- ous drinks, starch water, milk, and white of eggs. Collapse is treated in the usual way. 4 XH 3 + 6HCOH = X(CH 2 ) 6 + 6H : O Ammonia Formaldehyd Hexamethyl- Water enamine 512 PHARMACOLOGY AND THERAPEUTICS Hexamethylenamine, N 4 (CH 2 ) 6 , known also as urotropine, cystogen, formin, etc., is an artificial alkaloid made by combining 6 molecules of HCOH with 4 of ammonia. It occurs in crystals which are soluble in 1.2 parts of water and in 10 parts of alcohol. It is incompatible with acids and salts of acid reaction, and with mercuric chloride. Hexamethylenamine has no local action. A 50 per cent, solution is non-irritant (Burnam). In the acid gastric juice formaldehyd is liberated and may be irritating. It is rapidly absorbed, has no essential systemic action, and appears in the urine in a few minutes. If the kidneys are diseased its excretion is greatly retarded, a fact which explains the "urotropin test" for kidney function. It has been found in the ear discharge in a case of middle-ear disease, and in the milk, bile, pancreatic juice, blood, saliva, synovial fluid, nasal and bronchial secretions, pleural effusions, and cerebrospinal fluid of human beings. It is not essentially diuretic, and has no power to dissolve uric-acid calculi. It came into use as a urinary disinfectant, its value depending on its ability to liberate formaldehyd. This it tends to do in acid fluids. Jordan (1911) gave 10 grains (0.7 gm.) three times a day, and found that when the urine was alkaline or of low acidity, there was no germicidal effect. When the urine was alkaline, he could obtain the effect by administering acid sodium phosphate to acidify the urine; and when the urine was acid, he could lessen the effect by administering potassium citrate. Sollmann (1908) found that in alkaline urine it developed antiseptic properties, i. e., formaldehyd in antiseptic amounts, only after one and a half hours. In ammoniacal urine formaldehyd cannot exist, as it has great chemic affinity for ammonia. When formaldehyd is present, the urine will reduce Fehling's solution. At Johns Hopkins Hospital hexamethylenamine was found to lessen greatly the number of typhoid bacilli in the urine of typhoid patients, though not to render the urine completely germ free. In pyelitis and in cystitis it is disinfectant, though in Bacillus coli infections and in gonorrhea it has sometimes failed completely to clear the urine. L'Esperance found formaldehyd present in the urine in 52 per cent, of cases taking hexamethylenamine. Burnam (1912) tested the urines of some of Howard A. Kelly's cases after they were given hexamethylenamine. Of 10 cases taking 5 to 10 grains (0.3-0.7 gm.) three times a day, only 2 showed formalde- hyd; some others gave the reaction when the dose was increased to 20 to 30 grains (1.3-2 gm.) every four or six hours; and some gave no reaction, even after a dose of 100 grains (6.7 gm.). He found it in some cases with alkaline urine, and failed to get it in MISCELLANEOUS ORGANIC COMPOUNDS 513 some with acid urine. In some patients the concentration in the urine reached as high as i : 5000. Levy and Strauss obtained similar results and found this strength antiseptic, but not germicidal, except to the typhoid bacillus. The use of hexamethylenamine in therapeutics depends solely on its power to liberate formaldehyd. Its appearance in a se- cretion does not, therefore, indicate its antiseptic value in that secretion, for when it does not liberate formaldehyd its antiseptic effect is very slight. Burnam (1912) tested the secretions other than urine in cer- tain cases of Dr. Howard A. Kelly. The following are his results from Hehner's test, which reacts very delicately to both hexa- methylenamine and formaldehyd. (The urine was the only secretion that was positive with Burnam's test, which reacts with formaldehyd in amounts above i : 150,000, but not with hexamethylenamine.) 1. The Bile. In 10 cases of biliary fistula, 60 grains (4 gm.) a day gave only a faint test, though bile containing as much as i : 50,000 gives a sharp reaction. 2. The Saliva. Only faint traces. 3. Sputum. In three cases of bronchitis, absolutely none of the drug present. 4. Cerebrospinal Fluid. In one case getting 15 grains (i gm.) every three hours for twenty-four hours, 4 c.c. of the spinal fluid showed mere traces. In all these fluids the drug, either hexamethylenamine or formaldehyd, was not present in amounts above i : 150,000, and therefore was absolutely without antiseptic value. Hanzlik (1910) showed that there was no formaldehyd set free in the saliva, and Fullerton points out that Sollmann's demonstration of the time required for the development of formaldehyd in alkaline liquids would forbid its formation in any free-running secretion. It is to be noted that formaldehyd in the urine may lessen the heat test for albumin and the test for indican, and may give Fehling's reaction. Untoward Effects. In acid urine it sometimes so increases the acidity as to make the urine irritating, or sets free enough for- maldehyd to do this; and marked vesical pain, frequent burning micturition, bloody urine, and defoliation of the bladder mucous membrane have been reported. The kidneys are also irritated at times, though Richardson (1899) showed that in the presence of an existing nephritis there was no increase in albumin or casts. Coleman (1903) reported the following untoward sequelae: irri- tation of stomach, diarrhea, and abdominal pain; irritation of kidneys and bladder, with hematuria and hemoglobinuria ; head- 33 514 PHARMACOLOGY AND THERAPEUTICS ache, ringing in cars; and a skin rash like that of measles. Crowe reports that of 95 cases getting an average dosage of 75 grains (5 gm.) a day, 7 developed painful micturition and hematuria. He has noted also skin rashes, acute catarrh of mucous membranes, and gastric irritation. Frothingham (1909) reported that very large doses could be given to guinea-pigs without toxicity, though their stomachs were prone to become ulcerated and to bleed. He sometimes got necrosis at the site of a hypodermatic injection of the drug. Burnam says that a 50 per cent, solution is not irritant locally. Therapeutics and Administration. From the above it is seen that there is no question of the frequent value of hexamethylena- mine as a disinfectant in the urinary tract. For this purpose it is .given in amounts of 5 to 20 grains (0.3-1.3 gm.) three times a day with large quantities of water to favor elimination by the kidneys. If the urine is alkaline, it may be acidified by acid sodium phosphate, but this must not be given at the same hour as the drug, as they are chemically incompatible. As proved by an overwhelming amount of experimental data, outside the urinary tract hexamethylenamine has no therapeutic value whatever. Even in the urinary tract the drug rarely produces enough formaldehyd to render the urine com- pletely destructive to bacteria. THERAPEUTIC CLASSIFICATION OF DISINFECTANTS I. GENERAL DISINFECTANTS AND DEODORIZERS (a) Used in dry form for water-closets, sinks, and cess-pools, copperas (ferrous sulphate), naphthalin (tar balls), lime, and chlorinated lime are preferred because cheap. (b) Used in solution for utensils, excreta, bedding, etc., from the sick-room. For basins, chambers, bed-pans, etc., a solution of mercuric bichloride, zinc chloride, or phenol is employed. The zinc chloride is odorless, an obvious advantage over carbolic, whose universally recognized odor suggests unpleasant sick- room experience. In full strength, Platt's Chlorides, a proprie- tary, failed to kill the typhoid bacillus in ten minutes (Hygienic Bulletin Xo. 82). The bichloride destroys metallic utensils. The urine, feces, or sputum may be received in, and mixed with, a 3 per cent, solution of carbolic, a i : 5000 solution of mercuric bichloride, a i per cent, solution of zinc chloride, or one-quarter its bulk of quicklime. The mixture should be allowed to stand for half an hour. (c) Used as gas for rooms and contents, bedding, clothes, etc., formaldehyd, sulphur dioxide, free chlorine, the creosols of DISINFECTANTS FOR SURGICAL SUPPLIES 515 smoke (burning sugar, coffee, brown paper, etc.). It is difficult to find a gaseous disinfectant that will penetrate through bed- clothes and mattresses, and into the cracks of a wall or floor. J. S. Billings says that "terminal disinfection no longer holds a prominent place in the control of infectious diseases, for the reason that by the time the infective agent has disappeared from the person of the patient, it has long since disappeared from the premises and surroundings." II. PRESERVATIVES 1. Pharmaceutic alcohol, glycerin, sugar, benzoin, aromatic oils, boric acid. 2. Foods boric acid, borax, saltpeter (KNO 3 ), salicylic acid, sodium benzoate, formaklehyd, sodium chloride (butter, ham, fish, corned beef), smoke (smoked beef and ham), sugar, vinegar. 3. Anatomic material formaldehyd, acetic acid, arsenic, alcohol, glycerin, potassium bichromate. 4. Antitoxins, vaccines glycerin, trichlorphenol, phenol, tri- kresol. Alcohol is the most useful preservative for vegetable drugs in solution; thus tinctures and fluid extracts keep well, while aqueous solutions, such as infusions, do not. A saturated solution of sugar is antiseptic, as seen in jams and medicinal syrups; syrups less than saturated will ferment or mold. Glycerin is a much-used preservative of vegetable extracts. To preserve meat, borax and saltpeter are used, or the meat is salted or smoked (as ham, corned beef, smoked beef, etc.) ; through exposure to smoke it absorbs cre- osols and other wood-tar constituents. Boric acid, sodium benzo- ate, salicylic acid, and formaldehyd are added to various canned and preserved foods and to milk, cream, and butter. Boric acid will also retard the common fungus growth in solutions of chem- icals, such as cocaine. A too much used preservative of milk is formaldehyd, which, in amounts sufficient to keep milk for a week, cannot be detected by its odor. Lard may be kept from becoming rancid for a time by the presence of benzoin, as in benzoinated lard. Butter is believed to keep better when it is salted. Chem- ically preserved foods (embalmed foods) are usually less readily digested than normally, as their tissues are hardened, and also the preservatives interfere with the activity of the digestive ferments. III. DISINFECTANTS FOR SURGICAL SUPPLIES For utensils, surgical instruments, and dressings the best of all disinfectants is live, superheated steam at 220 to 225 F. The 516 PHARMACOLOGY AND THERAPEUTICS next best is dry heat. Instruments can be boiled with water, or placed in 5 per cent, phenol or 70 per cent, alcohol, or a mixture of phenol and alcohol. Catgut is sterilized by boiling with cumol at 330 F. (165 C.). Dressings, absorbent cotton, etc., may be sterilized by dry heat or formaldehyd. IV. DISINFECTANTS FOR LOCAL USE ABOUT THE BODY 1. Skin. (a) For the patient's skin, preliminary to operation. Scrubbing with soft soap and application of tincture of iodine. (b) For the surgeon's hands. Chlorine, generated by rubbing the hands with chlorinated lime and washing soda; potassium permanganate, i : 5000, followed by oxalic acid to remove the brown stains; tincture of iodine; alcohol; 3 per cent, phenol; and mercuric bichloride i : 2000. It is of no use to dash the hands into an antiseptic solution, then think them disinfected. The bichlo- ride of mercury, for example, requires many minutes for its action. (c) For the obstetrician's hands. A half per cent, solution of lysol or of the official compound solution of cresol. Both are rather soapy and serve as lubricants in vaginal examinations. Their slipperiness interferes somewhat in the handling of instru- ments. All antiseptics for the hands and skin are preceded by thorough scrubbing with green soap and hot water. This acts by removing the loose epithelium and bacteria, and is probably of quite as much value as most of the antiseptics in freeing the skin from germ life. In open wounds there are very few antiseptics that do not harm the tissues of the host more than they do those of the bacteria. (d) In skin diseases. The organic substances, tar, oil of cade, naphthalin, balsam of Peru, benzoin, resorcinol, salicylic acid, pyrogallol, ichthyol, formaldehyd; and the inorganic sub- stances, mercuric chloride, ammoniated mercury, mercurial oint- ment, boric acid, sulphur, iodine and its compounds. 2. In eye boric acid, silver salts, copper sulphate, mercuric oxide ointment. 3. In nose camphor, menthol, oil of eucalyptus, boric acid, the silver salts, peroxide of hydrogen. 4. In mouth and throat boric acid, the silver salts, hydrogen dioxide, mercuric chloride, ferric chloride, glycerin, iodine. 5. In urethra and bladder the silver salts, potassium per- manganate, zinc sulphate. 6. In vagina compound solution of cresol, creolin, lysol, phenol, ichthyol, mercuric chloride, boroglycerin. THE HEAVY METALS 517 7. In rectum boric acid, silver salts, quinine bisulphate, cal- cium permanganate. 8. In larynx and bronchi by inhalation oil of eucalyptus, camphor, menthol, creosote, benzoin. 9. In open wounds iodoform and the phenol iodine com- pounds, mercuric chloride, phenol, potassium permanganate, balsam of Peru (gauze), ichthyol, aluminium acetate, bismuth subiodide, zinc sulphate (in red wash), boric and salicylic acids (Thiersch's solution), hydrogen dioxide. As a temporary ap- plication to war wounds, Keilty and Packer recommend an oint- ment made of 70 per cent, of castor oil with wax and spermaceti, and the addition of 10 per cent, of thymol and tricresol. V. DISINFECTANTS TO BE GIVEN BY MOUTH For the stomach sodium salicylate, 10 grains (0.7 gm.); resor- cinol, 10 grains (0.7 gm.); sodium sulphocarbolate, 10 grains (0.7 gm.); creosote, 5 minims (0.3 c.c.); aromatic oils, 5 minims (0.3 c.c.). For the intestines acetyl-salicylic acid, salol, naphthalin, beta-naphthol, trimethol, or ichthyol, in dose of 5 grains (0.3 gm.) several times a day. After absorption to have a remote local effect in their excre- tion. (a) Urinary tract certain of the volatile oil series (turpentine, balsam of copaiba, oil of sandalwood, cubebs, buchu, uva-ursi), hexamethylenamine (urotropin), benzoates, salol. (b) Respiratory tract volatile oil series (turpentine, terpin hydrate, cubebs, tar, creosote). (c) In other secretions or body fluids no known drug. Hexa- methylenamine, formerly employed, has been proven worthless. THE HEAVY METALS The heavy metals, though differing markedly in some of their details of action and in their therapeutic uses, have certain phar- macologic actions in common. Their salts tend to precipitate proteins, forming metallic albuminates of variable composition. The salts which are most readily dissociable into ions act most rapidly and tend to be irritant. They may even be caustic, caus- ing death of tissue. The soluble salts, through precipitation of the proteins of the cells, tend to be astringent. The organic prep- arations and double salts tend to dissociate less easily and have less local action. The salts of inorganic acids tend to be especially astringent from the setting free of the acid. The absorption of most of the salts is slow, and their excretion 518 PHARMACOLOGY AND THERAPEUTICS also very slow, and chronic poisoning by some of the metals may follow the repeated ingestion for many days of very minute quantities. They are mostly excreted by the kidneys and the gastro-intestinal tract; and in the poisoning these organs tend to be inflamed. The nervous system is also sensitive to the metals, peripheral neuritis, excitability, and scleroses in the brain or cord being sometimes manifestations of metallic poisoning. MERCURY There are many official salts and preparations of mercury (hydrargyrum), and their actions and uses are so distinct that they may well be considered separately according to their ther- apeutic uses. The therapeutic classes are: (i) The disinfectants. (2) The antisyphilitics. (3) The cathartics. (4) Those with special uses. I. The Disinfectants (a) Mercuric chloride, hydrargyri chloridum corrosivum, HgClo, known also as bichloride of mercury or corrosive sublimate, is soluble in 13 parts of water and 3 of alcohol. The U. S. Pharmacopoeia has introduced a bichloride tablet, Toxitabella hydrargyri chloridi corrosivi, which contains mercuric chloride about 7^ grains (0.45-0.55 gm.) and an equal amount of sodium chloride. It must be of angular shape (not discoid), must bear the word "poison" and skull and cross-bones, and must be colored blue, preferably with sodium indigotindisulphonate. The solution in water takes place slowly, but is hastened by the addition of some sodium or ammonium chloride. These chlorides, however, prevent the ready dissociation of the bichlo- ride into ions, and reduce the antiseptic power about half (Wolf). In Paul and Krony's experiments the number of an- thrax colonies obtained after six minutes' exposure of the spores to bichloride, i : 60, was 8, while when the bichloride was mixed with an equal amount of sodium chloride, they obtained 32 colonies, and with four times as much sodium chloride, 382 colonies. These chlorides retard correspondingly the precipitation of al- bumin. Mercuric chloride has many incompatibles, such as alkaloids, alkalies, lime-water, and soap. A large basin of bi- chloride antiseptic solution will be destroyed by a very small amount of green soap. It is also decomposed by carbonates, silicates, and sulphates, such as occur in the natural waters; so that in making its solutions, distilled water is preferable. A solution of i : 1,000,000 will kill protozoa, a solution of i : 10.000 will prevent the growth of molds and bacteria. It ig. 64. Destruction of tubular epithelium caused by poisoning with mercury bichloride (MacCallurn) . THE ANTISYPHILITICS 519 takes some time for their destruction, however, and it is absurd to suppose an instrument or the hands to be sterilized by a moment- ary dipping or rinsing of them in the solution. The spores of bacteria are much more resistant than the germs themselves. The bichloride acts by forming a chemical precipitate with the proteins of the protoplasm; as a consequence, it has little penetrat- ing power and is quickly rendered practically useless by albumin- ous fluids. It may coagulate an albuminous envelope about bacteria without killing them. Locally, its solutions are astringent and irritating, and, if strong, are corrosive to the tissues. Even very weak solutions, if much used, cause roughening and discoloration of the skin, and in the form of a continuous wet dressing may produce a derma- titis or a pustular rash. In i : 4000 to i : 1000 aqueous solution mercuric chloride has been one of the most used antiseptics for the hands of the surgeon or obstetrician, for the skin preliminary to operation, for infected wounds, for excreta, and in i : 10,000 solution as an irrigation in any accessible body cavity, as throat, vagina, uterus, bladder, etc. It is also used in fungus and bacterial skin diseases and for pubic lice. Harrington's solution, as used at the Mayo Clinic, is mercuric chloride, 0.8 gm.; hydrochloric acid, 60 gm.; distilled water, 300 gm.; alcohol, 640 gm.; i. e., i : 1250 by weight. (6) The other mercurial antiseptics are less employed. The ointment of mercury in two strengths, viz., mercurial ointment (unguentum hydrargyri), 50 per cent., and blue ointment (un- gu en turn hydrargyri dilutum), 33 per cent., and the ointment of ammoniated mercury (white precipitate ointment) are employed in fungous and bacterial skin diseases ; the ointment of the nitrate of mercury (citrine ointment) is used expecially for ring-worm. The ointment of the yellow oxide is preferred about the eye, as in blepharitis, conjunctivitis, and keratitis. Schamberg, Kolmer, and Raiziss (1917) have brought for- ward mercurophen (sodium oxymercury orthonitrophenolate) as a salt which, against Staphylococcus aureus, has in aqueous solution 50 times the disinfectant power of bichloride, and in ascitic fluid 200 times the power of bichloride. II. The Antisyphilitics As local applications to venereal sores, mercuric chloride, calomel, and the ointments of mercury and ammoniated mercury are employed. Mercurial ointment (unguentum hydrargyri) contains 50 per cent., and the diluted mercurial ointment (un- 520 PHARMACOLOGY AND THERAPEUTICS guentum hydrargyri dilutum), 30 per cent, of mercury. Black wash (lotio nigra, N. F.) is calomel, 4 grains (0.25 gm.), to lime- water, i ounce (30 c.c.); yellow wash (lotio flava, N. F.) is bichlo- ride, 1 1 grain (0.09 gm.), to lime-water, i ounce (30 c.c.). For the systemic action mercury is administered by inunction, by mouth, and by hypodermatic or intravenous injection. For inunction the mercurial ointment is regularly employed, but it is dirty and tends to irritate the skin, and its absorption is uncertain. Ten to 30 grains are rubbed well into the softer parts of the skin every day or two, a new area being chosen for each successive inunction, on account of irritation. The favorite sites are the inner surfaces of the thighs and arms, and the chest, back, and abdomen. Oleate of mercury and white precipitate ointment are occasionally used instead of mercurial ointment. Weil and Elliott have shown that the mercury, ammoniated mercury (white precipitate), and calomel ointments will mercurialize a patient more readily than an ointment made from the non- volatile salts such as the salicylate and the oxides. By mouth, the favorites are the biniodide, T ^ grain (0.004 gm.), and the protoiodide, \ grain (0.015 g 111 -), an d for children the mercury with chalk, i grain (0.06 gm.). The bichloride, dose, -% grain (0.002 gm,), is sometimes given in a mixture with potassium iodide, with which, however, it changes to the biniodide. For deep intramuscular injection the insoluble mercuric salicylate and the soluble bichloride, biniodide, and benzoate are the favorites. The former is insoluble in water or oil, and is used in 10 to 30 per cent, admixture with liquid paraffin or olive oil. According to Lascoff, it makes the best mixture if half per cent, of lanolin is added. The dose is \ to \\ grains (0.03-0.1 gm.), injected into the buttock once a week, or every five days, or in urgent cases every second day. More or less soreness, as of a bruise, may follow the injection for a day or two, and occasionally headache, languor, nausea, and diarrhea. The benzoate, dose i grain (0.06 gm.), and the bichloride and biniodide, dose y 1 ^ to i grain (0.006-0.012 gm.), are more readily absorbed, so must be administered every second day. The bichloride is irritating, and also destroys the needles. The advantages of the hypoder- matic method are : the exact dosage, the cleanliness, and the close supervision of the patient which are gained by the necessarily frequent visits. In comparing mercury with salvarsan, Schamberg and Kolmer found that in the test-tube salvarsan was more destructive to animal parasites and mercury more destructive to vegetable organisms. The intravenous route is not much employed because of the THE CATHARTICS 521 danger of thrombosis or phlebitis. The dose recommended is grain (o.oi gm.) of the bichloride in 2\ drams (10 c.c.) of distilled water, or \ to i^ grains (0.03-0.1 gm.) of the benzoate in i per cent, normal saline. To avoid thrombosis Nixon mixes the 10 c.c. of bichloride solution with 10 c.c. of blood drawn into the syringe, and injects the mixture. Mercurialized human or horse serum is also employed, ^ or ^ grain (0.0012-0.0024 gm.) of the bichloride being added to about i ounce (30 c.c.) of serum. For cerebrospinal syphilis, tabes, paresis, etc., the intraspinal injection of mercurialized human or horse serum may be employed in amounts representing -^ grain (0.0012 gm.) of mercuric bichloride. It may give the same sequelae as intraspinal salvar- sanized serum (see Salvarsan). III. The Cathartics. (See under Cathartics.) IV. Those with Special Uses, Other Than Those Mentioned Mercury subsulphate (turpeth mineral), as an emetic in croup. Dose, 2 grains (0.13 gm.) for a child of six. Calomel, in croupous laryngitis; 5 to 20 grains volatilized on a tin plate or in a teaspoon, and inhaled not often employed at the present time. Calomel may be of value at the beginning of a course of diuresis. If ^ is absorbed, it tends to irritate kidney cells, but, as a matter of fact, most of it fails of absorption and passes out by the rectum. It is probable that much of the value of calomel in inducing diuresis is due to the relief of the splanchnic circulation through purging. In malaria, Barlow uses bichloride intravenously, the dose being | grain (0.015 S m -) m t ounce (20 c.c.) of saline solution. He claims it to be especially useful as an adjunct to quinine, in the refractory cases. The use of mercury succinimide, ^ grain (0.0012 gm.) every second clay for 30 injections, has been recommended in tuber- culosis, but has not proved curative. Systemic Action of Mercury Salts. After absorption mercury becomes generally distributed throughout the body, but is espe- cially stored up in the liver. In its therapeutic use it has .little direct action on any of the tissues ; but an improvement in the blood and nutritional state is believed to follow repeated small doses. Elimination. It is eliminated by the salivary glands, stomach, liver, kidneys, skin, colon, and rectum. It appears in the urine in three to twenty-four hours after ingestion, and in the feces after twenty-four hours (Lambert and Patterson). After sub- cutaneous injections for syphilis, Mironowitsch found more mercury in the sweat than in the urine. The major portion 522 PHARMACOLOGY AND THERAPEUTICS passes through the walls of the colon and upper rectum and may cause considerable irritation or actual colitis. Koldewijn applied mercurial ointment to cows, and was unable to find mercury in the milk; but Haas found that -% grain (0.0005 g 111 -) of mercuric chloride given three times a day to the mothers of syphilitic infants had a slight but positive remedial effect on the nursing child. It is said that mercury has been detected in the tissues six months after its administration has been stopped. Kidneys. Even after cathartic doses of a mercurial the metal has been found in the urine. Mercuric chloride has a special de- structive action upon the epithelium of the convoluted tubules, and has been employed to produce experimental tubular nephritis. In acute poisoning there may be a violent exudative nephritis or ne- phrosis; in subacute or chronic poisoning there may be a diffuse nephritis, the destructive effects in the tubules being followed by changes in the glomeruli and increase of connective tissue. Foster reports a case of bichloride poisoning that died after forty-one days with the kidney lesion almost strictly confined to the tubu- lar epithelium. The non-protein nitrogen rose to 238 mg. per 100 c.c. of blood, but there was no chloride or water retention. Calomel is frequently employed to aid other diuretics; but it probably acts by catharsis to relieve the kidneys, rather than by direct irritation of the kidney cells. Toxicology of Mercury. i. The mildest form of poisoning has for its prominent feature "mercurial stomatitis," or, as it is commonly called, "salivation." This is a not uncommon result of mercury salts administered as remedies, even a grain or two of calomel being sufficient in some cases to produce it. It is much more readily produced in nephritis than when the kidneys are unimpaired. In several instances the author has seen salivation in nephritis from two or three compound cathartic pills (each of which contains one grain of calomel). The symptoms of "salivation" are: profuse flow of saliva, metallic taste, very foul breath, coated swollen tongue, soreness or ulceration of the gums or inside of the mouth, soreness of the tooth-sockets (test patient by having him hit teeth together) , and loosening of the teeth. The profuse salivation may go on to inflammation of the salivary glands and necrosis of parts of the mouth and jaw. In addition, the patient feels ill and there may be headache, lassitude, muscular weakness, and diarrhea; occasion- ally there is constipation. As a prophylactic during the adminis- tration of mercury salts, and as treatment for mercurial stomatitis, a mouth-wash of a saturated solution of potassium chlorate with a little tincture of myrrh is recommended. 2. Severe acute poisoning is usually due to the bichloride, THE CATHARTICS 523 either from swallowing the tablets or a solution (often with suicidal intent) , or from the retention of strong solutions used as uterine or vaginal douches. From mouth doses the dominant lesion is nephritis; from vaginal douches it is generally colitis. Taken by mouth, bichloride gives a strongly metallic and astrin- gent taste. If the swallowed liquid is strong encugh there is local corrosion of mouth, esophagus, and stomach, followed by ab- dominal pain and vomiting. There may be copious serous or bloody stools, albuminous or bloody urine, or suppression of the urine, delirium, coma, collapse and death, or slow recovery. Postmortem examination shows the local corrosion of the upper part of the alimentary tract, and also acute colitis, acute proctitis, and acute nephritis. In the enterocolitis there may be extensive necrosis; in the nephritis there are fatty degeneration and necrosis of the cells of the convoluted tubules. Pericarditis is reported. There is occasionally a period of a day or two before the onset of the symptoms. In a patient that died ten days after taking 225 grains (15 gm.), Rosenbloom found most of the mercury in the liver, but much also in the large and small intestines, heart, kidneys, blood and muscles, and in the stomach and intestinal contents. If the patient does not die quickly, he may be ill for days or weeks, with marked salivation, inflammatory and gangrenous lesions of the pharynx, cheeks, and hard palate, spongy and broken-down gums, loss of the teeth, gastritis, colitis, and nephri- tis. He may eventually recover, or may die of uremia or colitis or general prostration. Arterial pressure may be high until col- lapse sets in. The leucocytes are regularly high (Vogel). Lewis and Rivers report acidosis. Treatment. Recovery has taken place after nine days of anuria, a fact which indicates the value of vigorous and persistent treatme'nt. At the outset, after bichloride is swallowed, white of egg or milk should be given to form non-corrosive albuminates; and these should promptly be removed from the stomach by lavage or vomiting to prevent absorption. Bland oils and other demulcents may then be given to soothe damaged membranes. The sys- temic treatment is eliminant. As the mouth, colon, and kidney symptoms develop, these require vigorous treatment. Potassium chlorate and myrrh make a favorite mouth-wash, and if the mouth is foul, peroxide of hydrogen. The Lambert- Patter son Treatment. Perhaps the most highly successful form of treatment is that of S. W. Lambert and H. S. Patterson, of St. Luke's Hospital, New York. They advise immediate administration of the whites of several eggs, followed 524 PHARMACOLOGY AND THERAPEUTICS by lavage. On admission to the hospital they give another thorough lavage and introduce through the tube a pint of milk, following this in one hour by another lavage if the nausea and vomiting continue. As soon as the stomach permits they begin the following routine: (i) Hourly liquid by mouth, 8 ounces (240 c.c.) of milk alternating with 8 ounces (240 c.c.) of a mixture of potassium bitartrate and sugar, each i dram (4 gm.), lactose 4 drams (15 gm.), lemon juice, one ounce (30 c.c.), with boiling water, i pint (480 c.c.). (2) A continuous rectal drip of a solution of potassium acetate, 3j (4 gm.) to Oj (480 c.c.). (3) Lavage of the stomach twice daily. (4) Irrigation of the colon twice daily. (5) A daily hot-pack sweat. The treatment is continued until there is no mercury in the urine on two successive days. In some of the cases received late this stage has not been reached for as much as three weeks. In a number of cases treated by this type of alkali-water therapy, even after anuria for several days the urine had returned to normal in three or four weeks, and the kidneys were apparently permanently restored. Macnider has shown that alkalies seemed to give the best pro- tection against the development of tubular nephritis in experi- mental uranium poisoning. A case reported by H. C. Wood illustrates a possible danger from copious water ingestion if the anuria is not overcome. The patient passed only 3! ounces of urine in seven days and on the four subsequent days 4, 9, n, and 14 ounces, and on the twelfth day died of pulmonary edema. Biirmeister recommends the substitution of new blood for the mercury-containing blood by repeated copious venesections and transfusions. Wilms uses calcium sulphide intravenously, i grain (0.06 gm.) in i ounce (30 c.c.) of tap-water filtered hot for each grain of mercury salt ingested. He also gives i grain (0.06 gm.) every hour by mouth. Sodium phosphite has been proposed, but it has a reducing value only in the stomach. Hall's antidote, consisting of potassium iodide, quinine hydro- chloride and water, has been shown by Barbour to be valueless. Decapsulation of the kidneys has overcome the anuria in some cases. 3. Chronic Poisoning. This is seen among makers of mirrors, barometers, thermometers, and felt for felt hats, the hides being impregnated with mercury. It also occasionally results from the mercury treatment of syphilis. The writer saw a case in a man who had used cinnabar (mercuric sulphide) in an Indian make-up. Besides the salivation, the poisoning shows the usual effects of the heavy metals on the nutrition, the alimentary tract, the ner- vous system, and the blood. These effects are: loss of appetite, nausea, and other derangements of digestion, constipation or LEAD 525 diarrhea, colic, anemia, loss of flesh and strength, and aching in bones and joints. There may be a general cachexia. There is no line on the gums, as in lead-poisoning. The effect on the nervous system may be pronounced. There are: a tremor of the hands and lips or the whole body, irritability of temper, fear, hallucina- tions, loss of memory, mental weakness, loss of will-power, and perhaps a peripheral neuritis (Starr says rare, if occurs at all). The diagnosis is confirmed by finding mercury in the urine or feces. The treatment is removal of the patient from exposure to the mercury, potassium iodide and free water-alkali therapy to promote elimination, and care for the nervous condition, the mal- nutrition, the anemia, and the salivation. Oliver thinks iodide is useless. During the treatment of syphilis a sore throat or mouth due to mercury may sometimes be attributed to the disease, and may persist until the mercury is stopped. Busch says that mer- cury is contraindicated in Addison's disease. LEAD The lead (plumbum) salts are not much employed in medicine. Preparations. (a) For External Use. The acetate and sub- acetate are antiseptic and astringent and are soothing to wounds and bruises. Liquor plumbi subacetatis (Goulard's extract) con- tains about 25 per cent, of lead subacetate. Liquor plumbi subacetatis dilutus (lead-water) is a 4 per cent, solution of the liquor. It is used as a wet dressing for wounds and bruises, and as a soothing application in skin diseases, sunburn, ivy poison, and eczema. Lead and opium wash (Lotio Plumbi et Opii, N. F.) contains lead acetate, 26 grains (1.75 gm.), tincture of opium, 52 minims (3.5 c.c.), and water to make 3^ ounces (100 c.c.). Lead oleate is a sticky, insoluble mass, which is used as the mechanical basis of plasters. It is known as "lead plaster." From the prolonged application of plasters it has caused poison- ing. Lead sulphate is present as a sediment in liquor alumini aceta- tis (Burow's solution) , when this is made of lead acetate and alum. It should be filtered off, as it has caused poisoning. (b) For internal use the only salt employed is the acetate, dose, 2 grains (0.13 gm.). Its only use is to overcome intractable diarrhea, as from tuberculous enteritis or colitis, and to induce a temporary obstipation, as in operations about the anus or rectum. Pills of lead and opium, N . F., contain i grain (0.06 gm.) each of lead acetate and powdered opium. 526 PHARMACOLOGY AND THERAPEUTICS Toxicology. Though lead has but little use in therapeutics, it is of importance to physicians because of the frequency of chronic lead -poisoning or plumbism. This occurs very commonly among painters and plumbers and other workers in lead (type, lead pipe, shot, pottery glazing, enamelware, etc.), and is one of the diseases often met with in clinics and hospitals. It may even result from hair-washes containing lead acetate, from water that has stood in lead pipes, from canned food with lead in the solder of the cans, from wall-paper, or from the prolonged application of plasters (with lead plaster base) to the skin. Gottheil reports a case of death from the sediment (lead sulphate) in Burow's solution made with lead acetate and alum. Stewart reports 64 cases in children from eating buns colored with chrome yellow. The symptoms are: Anemia and wasting, foul breath, bad taste in the mouth, loss of appetite, especially in the morning, gastric and intestinal disturbances, pains in the joints and bones, and spots before the eyes. Sailer and Speese found almost com- plete absence of gastric juice in 10 out of 12 subjects. Chronic nephritis is very common, and the arterial pressure tends to be high. Blackfan gives the symptoms in children as change in dis- position, peevishness, restlessness at night, appetite poor, breath foul, hemorrhage from gums, pain in epigastrium, constipation, and pain in legs. In children the paralysis usually affects the legs rather than the arms. Sixteen of Stewart's 64 cases had convulsions. In rabbits, Charteris found that lead car- bonate produced a marked anemia, with degeneration of both the leukoblastic and the erythroblastic elements of the bone- marrow. In addition to these symptoms there are usually certain mani- festations which are characteristic of lead, and determine the type of the complaint to the physician, viz. : i. Colic. Lead colic, painter's colic true colic with marked constipation. The patient is relieved by pressure upon the abdomen and will often be found lying prone upon a pillow or bolster. Mosse found that the injection of lead acetate into ani- mals caused degenerative changes in the sympathetic ganglia of the abdomen, and it has generally been believed that the con- stipation is due to irritation of the splanchnic inhibitory nerves of the intestine. But both the constipation and the colic are prob- ably due to an irregular irritation of the vagus nerves, the motor nerves of the small intestines, for Oliver found that in animals dead from lead-poisoning the small intestines were contracted tightly at irregular intervals, and Hertz noted by the .r-rays that the retardation occurs in the small intestine, which is unusual in LEAD 527 constipation. It is presumably a spastic constipation. In the small intestine in rabbits and cats Hirschfelder found irregular constrictions which were checked by atropine and nicotine. The intestinal arteries were strongly contracted. Vaquez (1904) and Pal (1905) found the* colic associated with a crisis of general arterial hypertension. Its severity can be lessened by atropine, nitrites, opium, or cathartics, the establishment of coordinated peristalsis apparently aiding in overcoming the spasms. Colic is the most frequently observed of the striking manifestations. It is sometimes followed by a soreness in the abdomen which per- sists for weeks. 2. Palsy. The usual lesion is a motor neuritis of the musculo- spiral nerve below the origin of the branch which goes to the supi- nator longus. This causes paralysis of the extensors of the fore- arm, with the exception of the supinator longus, and shows in the characteristic "wrist-drop." The first paralysis may show in the extensor indicis and the extensor minimi digiti, the extensor meta- carpi pollicis usually escaping. The intrinsic muscles of the hand undergo considerable atrophy. The paralyzed muscles show the reaction of degeneration. There is no pain. Though this is the usual lesion, the motor neuritis may show in other regions also. Indeed, it is prone to appear in the limb most used. In left- handed workers it may appear first in the left arm. In children it is usual in the legs. Starr says that colic precedes the palsy in over 90 per cent, of the paralytic cases. There may also be a general peripheral neuritis (sensory and motor) similar to that from alcohol, with pain or great sensitiveness to pressure, ataxia, foot-drop, etc. It may be so pronounced as superficially to resemble locomotor ataxia, lateral sclerosis, or anterior poliomyelitis. And there may be an optic neuritis, causing temporary or permanent blindness, laryngeal paralysis, or involvement of any of the cranial nerves. Gowers says that a lateral tremor of the fingers is peculiar to lead. In poisoned cats, Goadby and Legg have found minute hemorrhages in the nerves. 3. Encephalopathy. This is a rare manifestation, and is said to be more frequent in negroes than in whites. It may give many different symptoms. Intense headache, vertigo, mental depression, and insomnia are the most common. But it may go on to violent delirium, with convulsions or apoplexy, or may develop into dementia paralytica. Kehrer says that lead menin- gitis should be distinguished from lead encephalopathy, in the latter the lesion being a degeneration of the vasa vasorum of the brain vessels. Moleen reports a lymphocytosis in the spinal fluid. 528 PHARMACOLOGY AND THERAPEUTICS In addition to these striking results, -the continued absorp- tion of lead is believed to be a cause of arteriosclerosis, cirrhosis of the liver, chronic interstitial nephritis, and gouty attacks (by checking the elimination of uric acid). In female workers in lead it has frequently brought on abortion by causing the death of the fetus. The offspring of male workers in lead are often defi- cient in size and vitality, and similar results have been obtained in experiments on rabbits and fowls. Both diachylon plaster and lead acetate pills have been taken to produce abortion. After death from lead there is a striking rapidity of decom- position with putrefactive odor. The largest amount of lead is found in the liver. Diagnosis. In a painter, plumber, or other worker in lead, anemia, poor nutrition, backache, tremor, weakened grip, a bad taste in the mouth, and loss of appetite for breakfast are always suspicious symptoms; and it is highly advantageous for the pa- tient if the diagnosis is made at this stage. In one not known to be working in lead, the cause may not be suspected until the characteristic colic or palsy makes its appearance. Hayhurst reports that a 5 per cent, solution of sodium sulphide applied to the skin usually shows brown or black on hands, wrists, and fore- arms. In a well-marked case there are three things to be looked for, viz., lead in feces or urine, degenerated red cells, and a lead line on the gums. Lead is frequently but not always found in the feces and sometimes in the urine. Degenerative stippling or polychromatophilia in the red cells was found by Oliver in 60 per cent, of cases. It is probably a rather late manifestation, for Rambousek found it in only one of seven animals experi- mentally poisoned with lead acetate, and in painters Harris, of the Division of Industrial Hygiene, rarely found it in the early stages. Liebermann reports a lessened fragility of the red cells. The lead line on the gums is usual, especially if the teeth are not in good condition. It is made by a bluish patch just within the margin of each gum, and is usually more prominent on the lower gums. Occasionally there are bluish-black patches on the in sides of the cheeks and lower lip. If the teeth are absent there is no lead line. Treatment. As prophylactic measures, lemonade containing sulphuric acid, keeping the fingers out of the mouth and washing the hands before eating, and proper ventilation to remove the dust of lead salts have proved extremely efficient in Germany and England. Potassium iodide is the usual remedy, but in experimental animals Oliver found that it did not increase the elimination of COPPER 529 lead. It may be that potassium iodide acts to overcome the high arterial tension, rather than to promote elimination. Gowers states that it actually increases the toxic action by increasing the solubility of the metal. Oliver recommends milk in large quantities, with the addition of sulphur to form the unabsorbable lead sulphide, and attention to the bowels. The use of sulphates tc form lead sulphate in the alimentary tract has been recom- mended on the mistaken idea that this salt is not absorbed. For colic, cathartics are indicated, also atropine, warm baths, heat to the abdomen, and, in some cases, opiates. For the neuritis or palsy and for the meningitis the usual treatment for such conditions is called for. For the encephalopathy, an ice-bag to the head, amyl nitrite, and lumbar puncture may be employed. COPPER Copper (cuprum) and its salts have a peculiarly deleterious action upon the lower forms of plant life, a mere trace in water, as from dragging bags of copper sulphate through the water, being found sufficient to keep it free from algal growth without injuring the higher plant life or the animal life. Even contami- nated water left in a copper vessel will after a time be found aseptic. But Clark and Gage warn against the assumption that the water will be freed from bacteria in any reasonable length of time, and they find that vessels made of other metals will be just as effective as copper. Pennington and associates claim that i part of copper sulphate in 2,000,000 will kill typhoid bacilli in ten hours; but Clark and Gage find that even i in 100,000 kills them only occasionally, and that copper sulphate, to be safe, must be present in as much as i part in 1000. The salt regularly employed in medicine is the sulphate, or blue-stone. It is locally astringent, irritating, and even caustic. Its taste is harsh and strongly metallic, and when it is swallowed it irritates the stomach and causes vomiting. Uses. Sticks made of copper sulphate are used as an astrin- gent and caustic for exuberant granulations and granulated eyelids. A solution of 5 to 15 grains in an ounce is used locally in conjunctivitis, urethritis, and vaginitis. Ten grains (0.7 gm.) in solution have been used as an emetic, but if it is not promptly vomited it may injure the stomach. It is recommended in dose of | to i grain (0.015-0.06 gm.) in actinomycosis and sporotrichosis. Claims made for copper salts as remedies for tuberculosis have not been substantiated. Toxicology. Acute poisoning is that of an irritant, and is usually checked by the prompt vomiting of the drug. Chronic 530 PHARMACOLOGY AND THERAPEUTICS poisoning occurs especially in brass workers, the symptoms resembling those of poisoning by other metals. Even the minute amounts used to color canned vegetables may be deleterious. ZINC The zinc (zincum) salts fall into two distinct classes, viz., those which are irritant locally, and those which are soothing locally. The irritant salts are the sulphate and the chloride. Their action resembles that of copper sulphate. The sulphate is em- ployed in i to 5 per cent, solution in urethritis, vaginitis, and conjunctivitis. To produce vomiting the dose is 30 grains (2 gm.) . The chloride is also caustic, but its chief use is in i per cent, solution as an odorless disinfectant. The soothing salts are the stearate, which is a light, fluffy, rather greasy, white powder, and the oxide and carbonate, which are heavy white powders. They are insoluble in water and very slightly astringent, and are of value as soothing protectives to inflamed surfaces. They may be employed in lotion or oint- ment form, or as dusting-powders in chafed or inflamed skin, as in eczema or dermatitis. They are rarely used internally, as they tend to form the irritant chloride. Zinc ointment, a 20 per cent, admixture with benzoinated lard, is very widely employed, either by itself or as a vehicle for other drugs in the treatment of the skin. Calamine, a natural impure carbonate of zinc, is red from the presence of iron, and sometimes slightly gritty. The official precipitated carbonate of zinc, which is white, is a pure form. Calamine lotion (un- official) is a mixture of zinc oxide, calamine, glycerin, lime-water, and rose-water. The oxide and the sulphate in 2-grain (0.15 gm.) doses were at one time employed in epilepsy, chorea, whooping-cough, and other spasmodic nervous affections, but are scarcely used internally at present. Zinc chills (spelter chills, brass chills, brass shakes, brazier's chills, brass founder's ague) occur where zinc is volatilized and usually after work is over, probably because sweating stops. Their appearance is favored by indulgence in alcohol. After a period of lassitude, dull headache, oppression in the chest and sometimes nausea, the chill comes on with muscular pains, the temperature rising as high as 103 F. The chill subsides with the onset of profuse sweating, zinc being eliminated in urine and feces. Swelling of the spleen and albumin in the urine are reported, but, as a rule, the shakes are looked upon merely as an inconvenience and are not often reported to a doctor (U. S. Bureau of Mines, Bulletin 73). BISMUTH 531 BISMUTH The bismuth (bismuthum) salts commonly employed are the subcarbonate and the subnitrate, which are white, and the sub- gallate, which is yellow. Dose, 30 grains (2 gm.). The sub- nitrate is crystalline, the subcarbonate and the subgallate are amorphous. They are insoluble in water, are very slightly as- tringent, and resemble in their action the soothing salts of zinc. But their chief use is in the alimentary tract, where they do not form irritant compounds. The milk of bismuth (magma bis- muthi), dose, 5j (4 c.c.), is also official. They act in a purely mechanical manner as protectives and demulcents to the mucous membrane of both stomach and bowels. It has been ascertained that if given before irritant emetics, they can prevent vomiting. The author has in a number of instances given bismuth subnitrate with a test-breakfast, and has usually at the end of the hour found a much lessened secre- tion or acidity. In a few cases the gastric secretion was not changed by the bismuth. It is noteworthy that at the end of the test-breakfast hour the bismuth salt was uniformly mixed with the extracted stomach contents, and that it had changed from a heavy powder to a flocculent substance that settled slowly with the food. Several hours after its administration to dogs the author found the bismuth subnitrate in this same flocculent state, and coating the mucous membrane very uniformly as far as the ileocecal valve. In the colon the bismuth salt becomes black from the formation of the sulphide or from reduction, and renders the stools black. As the sulphide forms hard crystals, it sometimes acts as an irritant. The bismuth salts have come into very extensive use in #-ray work, their opacity to the rays making it easy to obtain pictures of the whole alimentary tract. The subcarbonate, the oxide, and the oxychloride are employed for this purpose by mouth or rectum, in amounts of 2 to 4 ounces (60-1 20 gm.), mixed with zoolak, buttermilk, thick soup, etc. The subnitrate is no longer employed in these large amounts, as a number of cases of bismuth and nitrite poisoning have occurred from its use. Boehme showed that bismuth subnitrate, when mixed with human feces, liberated nitrites. In one x-ray case of the author's two very large bismuth balls formed in the colon and had to be broken up in the rectum before they could be extracted. Toxicology. From the local application to extensive burns, from the injection into tuberculous sinuses, and from the use of it for x-ray pictures, bismuth has been the cause of poisoning. 532 PHARMACOLOGY AND THERAPEUTICS Its symptoms resemble largely those of poisoning by the other heavy metals, and are: salivation and stomatitis, with a black, violet, or blue-gray line on the gums, nausea, vomiting, diarrhea, signs of kidney and colon irritation, convulsions, and collapse. Baehr and Mayer found considerable amounts of bismuth in liver, spleen, kidneys, and large intestine, and Rosenbloom found it in the urine. Davis and Kaufmann (1910) report a black line on the gums in 6 out of 25 cases in which bismuth had been injected into tuberculous sinuses or joints. One fatal case occurred from less than one ounce of the 33 per cent, paste. For such poisoning Beck, who was the originator of the bis- muth treatment for sinuses, recommends to flood the sinus or cavity with warm olive oil and let it remain for twenty- four hours, and to wash the sinus with olive oil daily thereafter until the symptoms have subsided. He advises that the gums should be watched for the blue or black line, which is the first sign of poisoning. Therapeutics. Beck's method of treatment of chronic sinuses or tuberculous cavities is to inject, not oftener than once a week, a 33 per cent, paste of bismuth subnitrate with vaseline. He advises against it in acute cases, or when fresh surfaces have been opened up by probing or cutting. Internally, the insoluble bismuth salts are used: (i) To check nausea, vomiting, and gastric irritation, as in ulcer, marked hyperchlorhydria, and gastric intolerance. (2) To check intestinal irritation, either that of fermentative diarrhea or that from in- flammation of small intestine or colon. The soluble bismuth salts, such as the citrate, have no value in medicine unless the bismuth is precipitated from them in the alimentary tract. Of the "milk of bismuth," a white suspension, Hulse (1910) reports that in 21 infants with gastro-enteritis it passed through the alimentary tract unchanged and without effect; while inside of twenty-four hours bismuth subnitrate resulted in diminished blood and mucus and fewer stools, and showed by the dark color of the stools that it had undergone change. CERIUM The official salt of cerium (cerium) is the oxalate, Ce 2 (C 2 O.i) 2 .- ioHoO, an inert powder, insoluble in water. The commercial article is very impure. Its action is practically that of the in- soluble bismuth salts in allaying gastric and intestinal irrita- tion, but its therapeutic use is mostly to check nausea and vomit- ing. Baehr and Wessler (1909) found it non-poisonous to dogs even in closes of 50 grams (if oz.). They noted also that its SILVER (ARGENTUM) 533 action was mechanical as a protective to the gastric mucous membrane, and that it would check the vomiting from stomach irritants; but that it had no influence on the vomiting brought about by apomorphine, which is a central emetic. They found the usual dose entirely too small for protective purposes, and recommend doses of 30 to 60 grains (2-4 gm.). A mixture of cerium oxalate, 5 grains (0.3 gm.), and sodium bicarbonate, 10 grains (0.7 gm.), has frequently been employed in refractory cases of nausea and vomiting, as in pregnancy. It may be given with water, or added to a glass of milk and the milk fed in small quantities at a time. SILVER (ARGENTUM) The official salt employed is silver nitrate, a crystalline salt which is decomposed by oxidizable organic matter and light, and is soluble in less than its own weight of water. "Lunar caustic" is silver nitrate toughened by the addition of hydro- chloric acid to make a small amount of silver chloride (horn silver) , and molded into sticks. Silver nitrate is antiseptic and very irritant locally. It coagulates protein, so is astringent, and may readily destroy the soft tissues, so is caustic. It has little penetrating power, and its action may be checked very promptly by sodium chloride, which changes it to the inert silver chloride. Wildbolz (1907), by reduction with the Finsen light, found that i : 1000 to i : 100 solutions penetrated to the subepithelial tissue of a dog's urethra, while i to 3 per cent, solutions of protargol had less penetrating power. In 2 per cent, solution silver nitrate is used as a prophylactic against gonorrheal ophthalmia in the newborn (Crede's method). In 0.5 to 5 per cent, solution it is employed in nose and throat, or for cracked nipples or canker sores or ulcers, and in o.i to i per cent, solution for the conjunctiva, vagina, urethra, bladder, or rectum in various infections. The lunar caustic is employed to destroy exuberant granu- lations, to remove small neoplasms, warts, condylomata, etc., and to stimulate the surface of a sluggish ulcer or sore. To re- move a wart the pointed caustic stick is moistened and bored down into the central artery of the wart. The wart turns black and may be removed in a few days. In the stomach, the nitrate has been employed in hyper- chlorhydria and chronic gastritis; but as it is immediately rendered inert by hydrochloric acid or sodium chloride, it is useless unless preceded by thorough lavage. If it is employed 534 PHARMACOLOGY AND THERAPEUTICS at all, the best method is to administer it in i : 500 solution through the lavage tube, and then, after two or three minutes, to remove it by thorough lavage. If it is desired to give silver nitrate in pills, kaolin and petrolatum should be employed in their manufacture, for extracts, glucose, glycerin, and other organic excipients will render the nitrate inert. In the bowel, it has much local employment in colitis and proctitis. Rogers found that in aqueous solution i : 10,000 killed the dysentery bacillus in five minutes, but that in the pres- ence of organic matter and salts it failed to kill in a strength of i : 100. Not infrequently it increases the irritation instead of curing it. The nitrate makes a black stain on exposure to light, to remove which the skin may be washed with solution of potassium cyanide, or covered with tincture of iodine and washed off with solution of sodium hyposulphite. A number of organic silver compounds are also to be had, the most used of which are argyrol (silver vitellin) and protargol (silver protein). Colloidal silver, collargol, is also employed by mouth in dose of 45 grains (3 gm.), by inunction with a 15 per cent, ointment, and intravenously for septic conditions in doses of 2 drams (8 c.c.) of a 2 per cent, solution. Dunger has shown that an intravenous of collargol suspension caused a prompt destruction of 40 to 80 per cent, of the circulating leuco- cytes, but stimulated the bone-marrow so that in twelve hours the leucocyte count was restored. These preparations are not essentially astringent, and are not precipitated by albumin and chlorides. As argyrol and collargol are non-irritant, and pro- targol only slightly irritant, they have come into very extensive use to replace silver nitrate. Comparative studies of the relative antiseptic values of the silver preparations show that the only one with pronounced germicidal effect in aqueous solution is the silver nitrate; but that albuminous substances, as in serum and the tissues, quickly destroy its antiseptic power. In Rogers experiments with the dysentery bacillus, albargin (silver gela- tose) gave the best results in the presence of organic matter and salts. Marshall and Neave have shown that the percentage of silver does not indicate the antiseptic value. Derby (1906) tested a staphylococcus on a mixture of hydro- cele fluid and bovine serum. With an equal volume of 2 per cent, silver nitrate he could still obtain a growth after thirty to forty minutes; with an equal volume of 8 per cent, protargol, a growth after sixty minutes; and with 50 per cent, argyrol, an abundant growth after three and one-half hours. Bayard Clark and Wylie (1911) report an extensive series ALUMINIUM (ALUMINUM) 535 of comparative bacteriologic studies, from which we take the following as examples: ORGANISM SOLUTION NUMBER OF COLONIES FROM ONE LOOPFUL TAKEN AFTER S minutes 15 minutes 30 minutes Streptococcus. . . Gonococcus 2 per cent, silver nitrate . . i per cent, silver nitrate . . 10 per cent, protargol O 6 25 O 4 IS o O 30 70 80 O 5 20 O O 8 o 25 50 100 O o 20 o o o IS 10 IS 30 per cent, argyrol 10 per cent, argyrol 2.5 per cent, collargol i : 5000 silver nitrate . . i : 1000 silver nitrate 10 per cent, protargol 30 per cent, argyrol 2.5 per cent, collargol .... These might be compared with the table given under Disin- fectants, page 490. Untoward effects of silver are: (i) argyria, a bluish staining of the skin which is permanent. It may appear in spots (the "spotted boy" of the circus). It usually was the result of the now obsolete treatment of epilepsy and other nervous diseases with silver nitrate. It is reported from the use of collargol. (2) There is also at times from the local use in the eye a con- junctival argyria. According to Theobold, this is more common from the organic compounds than from the nitrate. Collargol and argyrol solutions are employed for injection into the ureters to^obtain #-ray pictures of the ureter and kidney pelvis. ALUMINIUM (ALUMINUM) Alum (alumen, aluminis) of the Pharmacopoeia is potas- sium alum, the double sulphate of aluminium and potassium, KAl(SO 4 ) 2 .i2H 2 O, or ammonium alum, NH 4 Al(SO 4 )2.i2H 2 O. It is soluble in about 9 parts of water and insoluble in alcohol. Its taste is sour, and it is decidedly astringent by coagulation of the proteins of the superficial cells, but it is not very irritant. It is a constituent of some baking-powders, but is, without much doubt, harmful to digestion. It is employed, usually in 5 per cent, solution, as a gargle or spray in relaxed sore throat, as a vaginal douche, and as a wash for the skin to stop local sweating of the hands and feet or the 536 PHARMACOLOGY AND THERAPEUTICS night-sweats of tuberculosis. The crystals may be used to shrink canker sores in the mouth, or to check hemorrhage from scratches or small cuts. The powdered alum has been used in 6o-grain (4 gm.) dose as an emetic, but is not at all reliable. Burnt alum (alumen exsiccatum) is alum with the water of crystallization driven off by heat. It has a great affinity for water, is powerfully astringent, and is slightly caustic. Its chief employment is as an application to sluggish ulcers. The solution of aluminium subacetate, N. F., is made by acting on calcium acetate with aluminium sulphate in solution, the in- soluble calcium sulphate being removed by nitration. The solu- tion of aluminium acetate, N. F. (Burow's solution) is prepared by mixing solutions of alum, 12.6 gm., and lead acetate, 15 gm., and adding water enough to make 100 c.c. The precipitate of lead sulphate is filtered off, as poisoning has occurred from failure to remove this. Either formula makes a slightly astringent, slightly antiseptic liquid, the chief use of which is as a wet dressing for infected wounds. Koll (1912) reports great success with it also in 42 cases of colon bacillus infection of the urinary tract. A 25 per cent, solution of aluminium chloride may be applied every two or three days for sweating of hands, feet, or axillae. It is irritant and may cause a dermatitis. IRON There are many official preparations of iron (ferrum), but a knowledge of only seven or eight will give a good equipment for iron therapy. (Those made in our laboratory were the syrup of ferrous iodide, the solution of ferric chloride, the tincture of ferric chloride, the liquor ferri et ammonii acetatis, Blaud's pills of ferrous carbonate, and the arsenic antidote of ferric hydroxide with magnesia.) There are four main uses in medicine for preparations of iron, as follows: 1 . Disinfectant. Ferrous sulphate (copperas) , for sinks, water- closets, cess-pools, etc. It is cheap, but not very effective. 2. Astringent. The ferrous and ferric salts of the mineral acids, especially the sulphates, the subsulphates, and the chlo- rides, precipitate protein, are strongly astringent, and coagulate the blood. They are also irritant. A mixture of equal parts of the tincture of ferric chloride, glycerin, and water is a favorite application in sore throat; it is astringent and irritant; it may attack the teeth. The use of these astringent preparations in nose-bleed and other small hemorrhages (the styptic action) results in a dirty coagulum and irritation of the tissues, and it IRON 537 has practically been abandoned. Liquor ferri chloridi, liquor jerri subsulphatis (Monsel's solution), and liquor ferri tersulphatis are official. 3. Arsenic Antidote. The freshly precipitated ferric hydrox- ide changes the active arsenows preparations into the compara- tively inactive and insoluble arsem'c compounds of iron. Arny gives the reaction with arsenous acid as: 3As 2 O 3 -f 2Fe(OH) 3 = 2Fe(AsO 2 ) 3 + 3H 2 O. Ferric hydroxide as an antidote may be administered in large quantity, after which it must be washed out of the stomach without delay to remove the arsenic compound formed. Ferri hydroxidum cum magnesii oxido is made with a mixture of magnesium oxide and water, and may be given freely. MgO + H 2 = Mg(OH) 2 Fe 2 (S0 4 ) 3 + 3Mg(OH) 2 = 2 Fe(OH) 3 + 3 MgSO 4 It is not necessary to wash out the magnesium sulphate. Ferric hydroxide may also be made by precipitating the solu- tion of ferric sulphate or ferric chloride with ammonia water, filtering, and washing the precipitate with water to remove the ammonium sulphate. 4. Hematinic, tending to increase the hemoglobin content of the blood. The hematinics may be separated into six varieties: (a) Metallic Iron (Ferrum Reductum; Reduced Iron}. Dose, i grain (0.06 gm.). It is a fine, grayish-black powder, made by reducing ferric oxide with hydrogen. It consists of not less than 90 per cent, pure iron, and requires acid in the stomach for its solution. (b) The Inorganic Ferrous Salts. They are: The carbonate in the saccharated carbonate, massa ferri carbonatis (Vallet's mass), and pilula ferri carbonatis (Blaud's pills); the iodide in pills of ferrous iodide and syrup of ferrous iodide, dose, 15 minims (i c.c.); the sulphate, dose, 3 grains (0.2 gm.); the dried sulphate, dose, 2 grains (0.13 gm.) ; the latter in pills of aloes and iron, each containing i grain (0.06 gm.). (c) The Inorganic Ferric Salts. These are the chloride, dose of the tincture, 5 minims (0.3 c.c.) ; and the phosphate, dose, 4 grains (0.25 gm.). The elixir and the syrup of the phosphates of iron, quinine, and strychnine, dose, 2 drams (8 c.c.), are no longer pharmacopceial. These mineral salts are astringent, irritat- ing to the stomach, and constipating. In liquid form they tend to blacken the teeth and to injure the enamel. To protect the teeth the dose should be well diluted, taken through a tube, and followed by rinsing the mouth. The tincture of the chloride contains free acid and is especially destructive to the teeth. 538 PHARMACOLOGY AXD THERAPEUTICS (d) The Salts of Organic Acids. These are the ferric acetate, citrate, and tartrate. U. S. P. preparations are: Liquor ferri et ammonii acetatis (Basham's mixture), dose, 2 drams (8 c.c.); and the soluble double alkaline salt, iron and ammonium citrate. The iron and ammonium tartrate, and iron and potassium tartrate, dose, 4 grains (0.25 gm.), the citrate of iron and quinine, dose, 4 grains (0.25 gm.), containing ^ grain of quinine, and the citrate of iron and strychnine, containing i per cent, of strych- nine, dose, 2 grains (0.13 gm.), are no longer pharmacopceial. The salts of this group do not readily dissociate, so they do not readily precipitate proteins. Hence they are less irritant, less astringent, and less constipating than the salts of the mineral acids. Their solutions do not corrode the enamel of the teeth. The citrate in 5 per cent, solution has been used hypoderm- atically in dose of i grain (0.26 gm.) with reported rapid effects. (e) Artificial Protein (or Organic) Compounds. Albuminates, peptonates, etc. Ovoferrin is a liquid purporting to be made from the white of egg; ferratin, a preparation claimed incorrectly to be the natural iron compound of the pig's liver. (/) True "organic" or "masked" iron, sometimes spoken of as food iron, as in hemoglobin or yolk of egg. Absorption. To prevent irritation of the stomach, iron prep- arations are regularly administered after meals, and mostly form the ferrous chloride or albuminate in the stomach. On passing to the duodenum, the chloride or sulphate probably changes to the carbonate. After a meal containing an added iron salt, granules of iron are found in the epithelium and leukocytes of the duodenal mucous membrane and in no other portion of the alimentary tract (Macallum). But after an iron-nuclein compound, Cloetta found it also in the membrane much further down the small intes- tine. It enters the blood probably either as the albuminate or carbonate. There seems to be no essential difference in absorb- ability between the inorganic and organic forms of iron. The spleen does not exert any constant or important influence on the iron metabolism. Even in the absence of the spleen a sufficient supply of iron results in normal blood conditions. A medicinal dose of an iron salt is 3 to 5 grains, but, as has been shown by severing the intestine above the cecum, almost all of this passes through the alimentary tract unabsorbed. Some of it forms the sulphide, and this may give a dark or blackish color to the feces. Iron that is absorbed but does not enter into hemo- globin or some other natural organic compound is a foreign sub- stance and is poisonous. The Absorbed Iron. This passes into the portal blood and perhaps slightly into the lymph, and is soon found deposited in IRON 539 the spleen and mesenteric lymph-nodes and slightly in the liver cells and the cells of the convoluted tubules of the kidney. Later it is found in greatest abundance in the bone-marrow and liver, and still later appears in the epithelium of the colon and rectum, where it is excreted into the feces. Of the iron excreted by normal persons under normal conditions, about nine-tenths is excreted in the feces, and one-tenth in the urine. Practically all the medici- nal iron is excreted in the feces. A portion of the iron of the liver is synthetized into organic compounds (ferratin, etc.), ready for conversion into hemoglobin, and the rest is doled out for excre- tion. There is no increase in the amount of iron in the bile. Effect on Blood. Normally, the whole adult human body contains from 40 to 55 grains of iron, enough to make a 2-inch nail. The ordinary diet contains -^ to i grain (5 to ib mg.) of iron per day, this minute amount being sufficient to maintain the iron equilibrium of the- body. During the growing period more iron is necessary. In human milk, between the third and twelfth days of lactation, Cameron found 21 mg. of iron in 100 c.c. ; while in mixed cows' milk Bunge found 3.5 mg., and Van Slyke only i mg. in 100 c.c. Krasnogorsky found the iron of milk more readily absorbed than that of egg-yolk or spinach. For over a month Charteris (1903) gave normal rabbits a daily hypodermatic of \ to i grain (0.03-0.06 gm.) of an albu- minate of iron. They maintained health and gained weight. There was no essential change in the bone-marrow except a slight increase in the density and vascularity of the leukoblastic elements. But healthy mice fed on cheese and iron regularly contained more iron in their tissues than control mice fed on cheese alone, and healthy goats fed on milk and iron more than goats fed on milk alone. Therefore, in health, though the ad- ministration of iron results in some accumulation of iron either free in the blood or stored up in the liver, spleen, etc., it is not fol- lowed in adults by any notable increase in either the hemoglobin or the red cells, and the iron is in a sense a foreign body; that is, it does not go to form blood, and there is no plethora established. But after bleeding, animals have been shown to utilize iron that was given them, and in many human cases with hemoglobin below normal its administration seems to be followed by a greater in- crease in both the hemoglobin and the red cells than conies from the food alone. In these cases it is possible that "under the stimulus of iron the blood-forming organs become active in the synthesis of hemoglobin" (von Noorden). Kleinschmidt found that growing dogs had a much greater power than adults to utilize iron given with the food. Hemoglobin itself, as in raw blood or uncooked meat, is con- 540 PHARMACOLOGY AND THERAPEUTICS verted by the gastric juice to acid hematin, and when taken by man is believed to be mostly unabsorbed. It has been ascertained that i c.c. of blood by mouth will give a test in the feces. How- ever, Halliburton's experiments with raw blood on rats fed on an otherwise iron-poor diet, showed a slight increase in the red blood- corpuscles and hemoglobin of the blood, and the presence of absorbed iron in the cells of the duodenal mucous membrane. In cooked blood, as in cooked meat, the hemoglobin is changed and is absorbed more readily, but even then not readily. Toxicology. In excessive amounts iron may produce nausea, vomiting, constipation, and headache. Dixon says that if it is administered intravenously it is as toxic as arsenic. In very large quantities the irritant inorganic salts may cause great irritation of stomach and bowels, with collapse. There is no satisfactory evidence that excess of iron has any power to increase a hemor- rhagic tendency or to bring on plethora. Therapeutics. The therapeutic classification given above indicates its uses. As a hematinic it may be employed in all con- ditions with diminished hemoglobin. Its most prompt effects are seen in chlorosis, but good results may also follow its use in the secondary anemias. It is best given in conjunction with appe- tizers, tonics, laxatives, etc., according to need. In nephritis the anemia is often treated with iron, especially Basham's mixture, but there is no satisfactory evidence of any direct effect upon the kidneys or upon the excretion of albumin. It has been employed also in functional albuminuria, and there is a traditional belief that it will cure this condition. The citrate has been used hypo- dermatically, in 5 or 10 per cent, solution, in dose of i grain (0.06 gm.) daily. It is readily absorbed. MANGANESE Though found in the tissues in minute quantity, manganese is not essential to life, and does not form an integral part of any protein molecule. Bertrand and Megreccann claim that man- ganese acts as a catalytic agent for iron, an almost infinitesimal amount causing an increased absorption and utilization by the tissues. In anemia it is sometimes given with iron, e. g., in the form of a peptonate or albuminate. Manganese dioxide, dose, 2 grains (0.013 gm.), and potassium permanganate, dose, i grain (0.06 gm.), are official and have a reputation as emmenagogues. Potassium permanganate, through its oxidizing powers, is locally antidotal to morphine, and in i : 10.000 to i : 1000 aqueous solution has considerable value as an antiseptic and deodorizer. In India it has been found useful locally in snake-bite, and it is recommended by von Adelung in ARSENIC (ARSENUM) 541 ivy-poisoning. Calcium permanganate, a less irritating compound, is used by Rogers for colon irrigations in amebic dysentery. He uses 15 grains (i gm.) to a pint (480 c.c.). Chronic poisoning occurs in workers in zinc mines, manganese grinding mills, and among those making potassium permanganate. Great muscular weakness, a coarse intention tremor, muffled speech, and depressed cerebration are the most striking features. In some cases there is pronounced hysteria. The treatment consists of hydrotherapy, electricity, and physical exercises. ARSENIC (ARSENUM) Arsenic is widely distributed in nature and can be detected in many of our commonly used chemicals and even in certain chemic drugs. It is said to appear in the fruit of trees sprayed with Paris green, and in other plants grown in the soil where Paris green has been used. Preparations and Doses. (a) Those of Arsenous Acid. Arsenic trioxide, arsenous acid, white arsenic, As 2 O 3 , is an anhy- dride which occurs as a practically odorless and tasteless white powder, made either from the glassy variety, soluble in 30 parts of water, or from the porcelain or crystalline variety, soluble in 100 parts of water. Both dissolve in 5 parts of glycerin and are sparingly soluble in alcohol. Dose, -^ grain (0.002 gm.). Solution of arsenous acid, liquor acidi arsenosi, i per cent., is acid with hydrochloric acid. Dose, 3 minims (0.2 c.c.). Fowler's solution, liquor potassii arsenitis, KAsO 2 .HAsO 2 .H 2 O, i per cent., contains the compound tincture of lavender to give it distinctive odor, taste, and color as a preventive against accidents. Dose, 3 minims (0.2 c.c.). This is the favorite liquid preparation. It is incompatible with acids, and tends to oxidize and deteriorate. Arsenous iodide, AsI 3 ; dose, ^ grain (0.005 g 111 -)- Donovan's solution, liquor arseni et hydrargyri iodidi, contains 1 per cent, each of arsenous iodide and mercuric iodide. Dose, 2 minims (0.12 c.c.). (b) Those of Arsenic Acid. Sodium arsenate, Na 2 HAsO 4 ,- 7H 2 O; close, T V grain (0.005 gm-)- Dried sodium arsenate, sodii arsenas exsiccatus, is sodium arsenate deprived of its water of crystallization by heat. As this water constitutes about two-fifths of the arsenate, the drying nearly doubles the strength. Dose, $ grain (0.003 gm.). Solution of sodium arsenate, i per cent, of the dried salt; dose, 3 minims (0.2 c.c.). (c) Besides the official preparations, there are a number of organic compounds that are in use: 542 PHARMACOLOGY AND THERAPEUTICS Sodium arsanilate (sodium aminophenyl arsonate) is employed in the form of atoxyl, C 6 H 4 (NH 2 ).(AsC).OH.ONa) + 3 H 2 O, con- taining 3 molecules of water of crystallization and 26 per cent, of arsenic; and soamin, C 6 H 4 (NH 2 ).(AsO.OH.ONa) + 5H 2 O, which contains 5 molecules of water of crystallization and 2 2 per cent, of arsenic. They are white powders, soluble in 5 or 6 parts of water, and decomposed by acids. Because of the acidity of the gastric juice, they are given hypodermatically. Dose, to 3 grains (0.02-0.2 gm.) every second day. Arsacetin is sodium acetyl arsanilate, C 6 H 4 (NHCH 3 CO).- (AsO.OH.ONa), soluble in 10 parts of cold water and 3 parts of hot water. It can be sterilized in the autoclave at 130 C. for one hour without decomposition. The claim is made that it is not split up by acids. The hypodermatic dose is 3 grains (0.2 gm.) two or three times a week. By mouth the dose is f grain (0.05 gm.) three or four times a day. Arsenophenylglycin, As 2 (COOH.CH 2 .N.H.C 6 H 4 ) 2 , has a hypo- dermatic dose of 12 grains (0.8 gm.). Sodium cacodylate, sodium dimethyl arsenate, (CH 3 ) 2 AsO.- ONa + 3H 2 O, is readily soluble in water. It liberates arsenic quite slowly, hence is less toxic and less active than the inorganic salts. Dose, i grain (0.06 gm.) hypodermatically, or 3 grains (0.2 gm.) by mouth daily. A hypodermic of 4 to 6 grains (0.25-0.35 gm.), repeated in four days, was recommended by John B. Murphy in syphilis. Recently doses of i to 7^ grains (0.06-0.5 gm.) intravenously have been used in pernicious anemia, leukemia, and Hodgkin's disease. A number of other compounds of caco- dylic acid have also been employed, as those of iron, mercury, quinine, lithium, etc. Owing to the formation of cacodyl oxide, the cacodylates are prone to give a garlicky odor to the breath, especially when administered by mouth. Saharsan, Ehrlich's "606," is diamino-dihydroxy-arseno- benzol dihydrochloride, (C 6 H 3 As.OH.NH 2 HC]) 2 . It is a bright yellow powder, of strongly acid reaction, and completely but slowly soluble in 10 parts of water. It is used somewhat hypoder- matically, but preferably intravenously. Before use it must be freshly made into a sterile solution of slightly alkaline or neutral reaction. It is very readily oxidized, so is kept in vacuo, or in ampules filled with an indifferent gas. The maximum dose is 10 grains (0.6 gm.), which for intravenous use is dissolved in 300 c.c. of normal saline to which 23 drops of 15 per cent, sodium hydroxide solution arc added. Diarsenol, a recent substitute for salvarsan, made in Canada, is claimed to be the dihydrochloride of dioxydiamidoarsenobenzol, and is administered in the same way as salvarsan. ARSENIC (ARSENUM) 543 Neo-salvarsan, soluble in water and of neutral reaction, and therefore available by simple solution, may be administered with much greater ease. It is sodium-diamino-dihydroxy-arseno- benzol-methanal sulphoxylate mixed with half its weight of inert substance. Its dose is if times that of salvarsan. It de- teriorates very quickly, so must be kept in vacuo. Sodium- salvarsan, a similarly soluble compound, is recommended highly by Wechselmann and by Dreyfus. Pharmacology. Microorganisms. Arsenic is added to em- balming mixtures to prevent rapid decomposition. It is more destructive, however, to highly organized life than to bacteria. Local. Arsenic is irritant. It does not precipitate protoplasm and does not form an albuminate, but slowly acts on the tissues to produce inflammation. An arsenic paste, for example, causes pain, redness, and swelling, with fatty degeneration of the epithe- lium and inflammation of the tissues beneath. The inflammatory reaction may be so intense that destruction of tissue follows, with sloughing and the formation of an ulcer. The drug is, therefore, a slowly acting and very painful caustic, which destroys tissue, not by precipitating protoplasm, but by inducing an acute inflam- matory reaction. In its use to destroy the nerves of teeth the destruction of the nerve depends upon inflammation and swell- ing in the opening of the root of the tooth, so that the circulation of the nerve is cut off. Alimentary Tract. Nausea, vomiting, diarrhea, and colic are commonly seen from the use of arsenic. These effects seem- to be produced after absorption, for they occur late, and even when .the drug is administered hypodermatically. Experimentally, after large hypodermatic injections, there is edema of the intestine from increased permeability of the capillaries, with degeneration and exfoliation of the intestinal epithelium. Arsenic-eaters claim that it helps the appetite. Absorption takes place from the stomach with fair rapidity when the preparation is in solution. The power of absorption may be rendered less by repeated doses. (See Tolerance.) Circulation. Large therapeutic doses tend after a few days to produce edema of the skin and alimentary tract, as shown by puffiness about the eyes and other parts of the body, or by general edema, nausea, vomiting, or diarrhea. This is due to increased transudation of serum, from heightened permeability of the sub- cutaneous and submucous capillaries. In some cases petechial (capillary) hemorrhages are seen. The effect upon the blood-pressure is ordinarily negative. In severe poisoning the blood-pressure falls from loss of serum by transudation, the heart remaining good. 544 PHARMACOLOGY AND THERAPEUTICS In chronic poisoning there may be fatty degeneration of the heart and arteries. Blood. It is upon the blood or blood-making organs that arsenic seems to exert its most valuable therapeutic effects. The normal bone-marrow consists essentially of erythroblastic and leukoblastic elements and fat cells. When arsenic is administered for long periods to young growing animals, the bone-marrow be- comes more vascular, with increase in the leukocytic elements, decrease in the fat, and little if any change in the erythrocytic elements (Charteris, 1903). There is no change in either the number of red cells or the percentage of hemoglobin in the blood. Besredka, from sublethal doses in rabbits, noted a temporary diminuticn of the leukocytes in the blood, followed by a poly- morphonuclear leukocytosis. In the Manchester epidemic, in which over 3000 cases of arsenic poisoning occurred from arsenic in beer, the cases which came to postmortem showed these changes. But some of the most pronounced cases showed extensive degeneration of the marrow-cells and profound anemia; and this corresponded with Charteris' findings that "from repeated doses large enough to cause cachexia and emaciation in rabbits, the bone-marrow under- goes hyaline degeneration, and this is accompanied by decrease in the red cells and hemoglobin." The tendency of arsenic is, therefore, to increase the leuko- blastic elements of the bone-marrow and the leukocytes in the blood ; but in severe chronic poisoning, to induce degeneration of the marrow-cells, wasting, and profound anemia. In pernicious anemia there is an increase in the erythroblastic elements of bone-marrow, associated with increased destruction of red blood-corpuscles (hemolysis) ; in leukemia, there is an in- crease in the leukoblastic elements. In both of these conditions arsenic is employed, at times with benefit, and it may be that it acts on some yet undiscovered toxin or parasite. It scarcely seems to be curative, however, for its effects do not last. In chronic malaria, also, there is a destruction of red cells which may be more or less checked by arsenic. Kidneys and Suprarenals. Brown and Pearce (1915) tested 60 arsenic compounds and found that all in toxic amounts caused congestion and hemorrhage in the suprarenals, alterations in the lipoid content, cellular degenerations and necroses, and reduc- tion in chromaffin. In the kidneys they obtained varying effects according to the compound used. Arsenous acid produced a vascular nephritis, arsacetin a tubular nephritis, while salvarsan and neosalvarsan produced a vascular nephritis with some tubular ARSENIC (ARSENUM) 545 changes, and atoxyl and arsenophenyl-glycin a tubular nephritis with some vascular changes. Metabolism. Long-continued administration lessens the ac- tivity of the liver, so that it forms less glycogen and has less power of oxidation. This shows in the urine by increased amounts of uric acid and ammonia, and the presence of leucin, tyrosin, and sarcolactic acid, the total nitrogen of the urine not being much changed. There may be a swollen liver and jaundice. After a fatal dose arsenic is usually found most abundantly in the liver. Considerable doses not only cause degenerative changes in the bone-marrow, but have a strong tendency to produce fatty degeneration in the liver, kidneys, heart, arteries, capillaries, the epithelium of the lungs and alimentary tract, and striated muscle and skin (dermis and epidermis) . Bone. In growing animals of poor nutrition it tends to bring about an increase in the density of bone, the cancellous portion being encroached upon by the increasing thickness of the hard bone. This may be due to the increased vascularity of the bone- marrow. In adults there is probably no effect on bone. Epithelium. That it promotes the nutrition of the skin and epithelial tissues is a general belief, as indicated by the sale of arsenic complexion tonics, by the frequent administration of Fowler's solution to horses to improve their appearance, and by the use of arsenic in chronic skin diseases. Thomas Oliver gave a dog with short, stubby hair i grain a day, and the hair became sleek and long (Allbutt's System of Medicine). Excretion. It is excreted in the urine and to some extent in the feces. Traces may appear in the gastric juice, the bron- chial mucus, the sweat, and the milk. It is reported as appearing in the stomach after administration by rectum (KandikofT) or hypodermatically. Its elimination is very slow, and traces may be recovered two or three weeks after its administration has ceased. Tolerance. Among the mountaineers of Styria, Hungary, and certain parts of the Punjab there are a number of persons known as "arsenic-eaters." They live to old age and have no symptoms attributable to arsenic except perhaps catarrh of the upper respiratory passages. Knapp and Buchner saw a man who had had the habit for thirty-six years take 2.6 grains (0.175 gm.) of orpiment (arsenic sulphide). Knapp administered 7 grains (0.45 gm.) of arsenic trioxide to one of the arsenic-eaters of Graz without any effect. Maclagan saw a man take 6 grains (0.4 gm.). It is taken about once or twice a week, and is said to act somewhat like an intoxicant, increasing combativeness, 35 546 PHARMACOLOGY AND THERAPEUTICS stimulating the sexual appetite, and giving a feeling of strength and general well-being. Besredka injected sublethal doses in rabbits, and found that the leukocytes usually contained arsenic, but not in the cases that proved fatal. He thought the leukocytes important in preventing the poisoning. Housmann (1903) found that in arsenic-habituated dogs the mucous membranes of the alimentary tract were very little penetrable. Later, Cloetta had a dog which in two years had become habituated to a daily dose of 2.6 grams of arsenic trioxide by mouth. He found that all of this but 0.13 per cent., i. e., about -^ grain (0.003 g 111 -) a day, passed out with the feces. On administering hypodermatically one-six- tieth the usual daily amount the dog died in six hours. This showed that the mucous membrane of the alimentary tract had become resistant to absorption. Jcachimoglu (1916) thinks this due to an acquired resistance of the mucous membrane to injury by the arsenic. Cushny states, however, that in the arsenic- eaters a large amount of arsenic is found in the urine. A search for antibodies in these eaters has proved negative and there is no true immunity conferred. Christison was of the opinion that habit tended to increase the activity of the inorganic poisons in the blood rather than to diminish it. Toxicology. The arsenows compounds are about twice as toxic as the arsemc. Acute poisoning is generally due to Paris- green (aceto-arsenite fcf copper), or white arsenic, taken with suicidal intent. The symptoms come on slowly. There is the gradual onset, in fifteen minutes to half an hour, of burning in the esophagus, pain in the abdomen, nausea, vomiting, and cramps, followed by violent diarrhea with rice-water or bloody stools, excessive thirst, suppression of the urine, prostration, and low blood-pressure from great transudation of serum. The rice- water stools are composed of serum containing rolled-up flakes of mucus and epithelial debris. In fatal cases the patient either (i) Grows rapidly weaker and dies in from six to twenty-four hours, or (2) after partial recovery from the acute symptoms passes slowly into a condition of collapse, with death in a few days. In the latter case the skin is said to exhale an odor of garlic (arseniuretted hydrogen) . At postmortem there is fatty degeneration of liver, kidneys, heart, etc., as mentioned above, and the poison is found in nuclein combination, chiefly in the liver, but also in the other organs subject to degeneration, viz., kidneys, spleen, lungs, nervous system, blood, and the walls of the stomach and intestines. In experimental animals Dutcher and Steel found the most arsenic in muscle, liver, and kidney. Oliver reports that his ARSENIC (ARSENUM) 547 dog on i grain of arsenic a day eventually died from chronic poisoning, but that no arsenic was found in his liver or bones. After acute poisoning, recovery from the acute symptoms may be followed by the manifestations of chronic arsenic poisoning. In experimental work arsenous acid is given to produce acute vascular nephritis, through its effect upon the capillaries of the glomeruli. Nephritis may occur in acute or subacute poisoning in man. (See Kidneys and Suprarenals above.) The treatment is thorough lavage of the stomach, bearing in mind that the insoluble arsenic preparations may cling closely to the inflamed stomach wall and corrode it, and so be washed off with difficulty. Freshly prepared ferric hydroxide, as in the U. S. P. preparation "ferri hydroxidum cum magnesii oxido," is the chemic antidote. It oxidizes the arsenows to an arsem'c compound, and forms the iron arsena/c. (See Iron.) This is not only not readily absorbable, but when absorbed is less readily ionized, and is therefore less poisonous. It must be removed by lavage. The treatment of the bowels presents difficulties, for if measures are taken to check the diarrhea, some of the arsenic may be retained in the bowel and absorbed. Probably a large dose of a saline cathartic, followed, after its elimination, by large doses of bismuth subnitrate and mucilaginous drinks or olive oil, will be best both for stomach and bowels. A hot-water bottle or atropine may relieve the abdomi- nal cramps. Opium, bismuth, and chalk mixture may be em- ployed, if deemed necessary, for the diarrhea, but they must not be used too early. Large doses of sodium bicarbonate are said to lessen the tendency to fatty degeneration. Further treatment is that for collapse, bearing in mind that the primary collapse is largely due to loss of fluid from the blood. A saline infusion may be of value, but transfusion promises better. Chronic or cumulative arsenic poisoning may be produced from the gradual absorption of very minute quantities, as from the dyes in stockings and the coloring-matter of wall-paper, carpets, cur- tains, artificial flowers, etc. Morse reports poisoning in an infant from the blue silk lining of its basket. The famous epidemic of 1900, in which over 3000 cases of poisoning were discovered in Eng- land and Wales, occurred from minute quantities (i to f of a grain of arsenic trioxide per gallon) in a cheap beer. The arsenic was traced back to the sulphuric acid which was used in the manu- facture of the glucose employed in the preparation of this par- ticular brand of beer. Starr reports that of 42 samples of furs examined in New York, n were heavily loaded with arsenic. Cases of poisoning are reported from the therapeutic use of the drug in chorea, pernicious anemia, etc. 548 PHARMACOLOGY AND THERAPEUTICS The onset may be very insidious, and the stomach and bowel symptoms, though regularly present, may not be of startling character. The patients look chronically ill, and have loss of appetite, nausea, diarrhea or constipation, abdominal cramps, puffiness under the eyes, anemia, headache, irritability of tem- per, insomnia, debility, and emaciation. In addition there may be: (i) Swelling of the liver with or without jaundice, associated with fatty degeneration, and rarely followed by atrophy. (2) General edema. (3) Various skin eruptions. (4) A dark pig- mentation of the skin, known as arsenic melanosis, with kera- tosis of palms and soles, falling of the hair and nails, and other trophic manifestations. (5) Peripheral neuritis, with paralysis or ataxia, pain, etc., resembling that from alcohol. (6) Cold in the head and hoarse voice. From the arsenic treatment of chorea, G. M. Swift has seen the following: hemorrhage from stomach, hemorrhage from kid- neys, conjunctivitis, neuritis, serious anemia, and tedious gastro- intestinal inflammation with albumin in the urine. Similar re- ports have come from others from the use of arsenic in chorea, pernicious anemia, etc. Oliver reports brown pigmentation in children treated for chorea. Heffter asserts that in cases of chronic poisoning arsenic is always to be found in the hair. Death has occurred from i grain of arsenic trioxide (Kun- kel) and from \ ounce of Fowler's solution administered in a period of four days (Taylor). In the medicinal use of arsenic, the first indications of cumu- lative poisoning are usually puffiness under the eyes, nausea, diarrhea, abdominal cramps, headache, and coryza. The treatment of chronic poisoning is stoppage of the drug or removal of the patient from the arsenic-bearing substances, and attention to the general health. Potassium iodide is often given, but Oliver says that iodide increases the pigmenta- tion of the skin, and does not promote the elimination of the drug. Therapeutics. Locally. Arsenic trioxide is employed in the form of a paste as a caustic for lupus and superficial epithe- liomata; it is very slow in action and very painful. It is used by dentists to destroy the nerves of teeth by setting up in them an inflammatory reaction. Internally, arsenic preparations are used: (i) In diseases of the blood or blood-making organs, as chlorosis, pernicious anemia, leukemia, Hodgkin's disease, chronic malaria. (2) In certain bone and joint diseases of obscure origin, as chronic rheumatism, rheumatoid arthritis, osteitis deformans, osteo- malacia, and rickets. (3) In nervous conditions, as chorea, ARSENIC (ARSENUM) 549 hay-fever, and spasmodic asthma. Swift says it does more harm than good in chorea. (4) In chronic non-parasitic skin diseases (not in acute inflammatory skin diseases). (5) In any run-down conditions with anemia and poor nutrition. Von Noorden and others have found arsenic preparations useless in diabetes, though Salkowski reported that in animals poisoned by arsenic no artificial diabetes could be produced by puncture of the fourth ventricle or by curare. Arkin and Korper (1916) state that arsenic has no specific action in tuberculosis. The organic preparations have been employed in trypano- somiasis, Vincent's angina, relapsing fever, syphilis, leprosy, pellagra, malaria, splenic anemia, leukemia, etc., with varying results. It is claimed that arseno-phenyl-glycin is the best in trypanosomiasis (Wendelstadt, Roehl). Atoxyl has a very strong tendency to produce optic nerve atrophy and permanent blindness. Administration. Arsenic tri oxide is generally used with iron or strychnine in pills or as an elixir. Fowler's solution is mostly employed by itself in doses by drops, one drop from a bottle lip or standard dropper being practically one minim. Through some fallacy it has become customary to begin with a small dose, say three drops three times a day, and to increase the dose each day by a drop or t\vo until the patient shows the first signs of cumu- lative poisoning. But the harmful metabolic effects of the drug contraindicate such a method of administration; and there are numerous instances of neuritis and other toxic manifestations which bear witness to the inadvisability of giving this drug to its physiologic limit. Salvarsan and Neosalvarsan. In syphilis these are the remedies of choice, the dose being regularly followed by a prompt subsidence of any acute manifestations of the disease. Yet in most cases they are not completely curative and must be alternated or combined with the mercury treatment. Not only do they act in the primary and secondary stages, but according to Fordyce "in all the active manifestations of late syphilis the therapeutic effect is almost as intense as in the early contagious period." Xeosalvarsan is more easily administered and less irritating to the veins, but it is less efficient than salvarsan. Fox states that while the symptomatic value of neosalvarsan is only slightly less than that of salvarsan, its total value, estimated serologically, is considerably less. Adler has shown that after intravenous doses of salvarsan, arsenic is present in the blood usually for thirty-six to forty-eight hours and occasionally for many days, and Stiihmer's experiments demonstrate that the greater part of the salvarsan becomes stored in lungs, liver, and 550 PHARMACOLOGY AND THERAPEUTICS spleen, and that from these depots it is doled out again to the blood. The arsenic is excreted by the kidneys and intestines. These drugs are regularly administered intravenously, the dose of neosalvarsan being one and one-half times that of salvar- san. The subcutaneous and intramuscular routes have prac- tically been abandoned for salvarsan because of its destructive action on the tissues; but for neosalvarsan they are still employed, and there are a number of reports from army surgeons in Europe of excellent immediate therapeutic effects thus obtained. In cerebrospinal syphilis, and to a less extent in locomotor ataxia and general paresis, additional clinical improvement has followed the intraspinous use of salvarsanized serum. This method, introduced by Robertson of Edinburgh, has been brought into general clinical use by Swift, Ellis, and Draper. These investigators all now advocate fortifying by a minute amount of added salvarsan. The method given by Draper is as follows: At weekly intervals 0.3-0.6 gm. of salvarsan is given intra- venously, and followed forty minutes later by the withdrawal of about 50 c.c. of blood. This is centrifuged, and the serum after heating at 56 C. for thirty minutes is introduced into the spinal canal the same day. The dose is 20 to 25 c.c. of 100 per cent, serum or 30 c.c. of 50 per cent, serum. Salvarsan up to 0.0005 gm. maybe added in vitro before the injection, or may be added to serum obtained from blood withdrawn before the intravenous administration of the drug. Though several authors have claimed that quite as much arsenic reaches the spinal canal after simple intravenous administration, the researches of Camp, Hall, and others would suggest that this is not the case. In 17 cases Camp administered 0.6 gm. of salvarsan intravenously, and on testing the spinal fluid fifteen minutes to forty hours later found arsenic present in only one case. Hall at twenty-four hours found arsenic present in the spinal fluid in 2 cases and absent in 4, and after neosalvarsan found arsenic absent at one and a half, six, and twenty-four hours. On the other hand, it is to be noted that the arsenic readily disappears from the spinal fluid, for after intraspinal injections of 3 mg. of neosalvarsan in simple solution only 4 out of 7 spinal fluids showed arsenic at ten hours, and only i out of 10 at twenty-four hours (Hall). The method of adminis- tering neosalvarsan intraspinally in simple solution mixed with cerebrospinal fluid is not approved, as it has been the cause of a number of deaths and of paralysis of the lower limbs, probably because the amount employed has been too large or the dilution insufficient. Untoward Effects. i. Locally, there may be a cellulitis from leakage of the drug into the tissues, or phlebitis and thrombosis of ARSENIC (ARSENUM) 551 the vein. 2. From the intravenous use, the immediate effects, those that occur during or within a few minutes of the injection, are of anaphylactic nature and do not occur at the first injection. They are a choking feeling or oppression about the chest with slight dyspnea, fulness in the head, flushing of the face, cyanosis and restlessness, followed sometimes an hour or more later by a chill, with fever and vomiting, and an urticarial rash or a generalized erythema. Occasionally during the injection there is a severe pain in the lumbar region. Draper reports anaphylaxis in 55 per cent, of all cases, and always with the later doses. His theory is that the drug with the patient's serum forms a new protein to which the patient is sensitized by the first dose. The late effects, those which occur after twenty-four hours, are: a feeling of weight in the stomach, nausea, vomiting and diarrhea, with fever, headache, restlessness, and insomnia. Rarely there may be a severe illness with rapid, weak pulse, fe- ver, jaundice, urobilinuria, albuminuria, suppression of the urine, or an arsenical neuritis. In kidney cases uremia has resulted. Fuchs reports a seven-day heart-block. A number of deaths have been reported, almost all being due to collapse in heart cases, or to nephritis, hemorrhagic encephalitis, or myelitis. Severe symptoms have been overcome by an intensive alkali- water therapy (Woodyat, Eberly). The Jarisch-Herxheimer reaction is an intensification of the symptoms or the rash, presumably from a liberation of a large amount of the spirochetal endotoxins. 3. From the intraspinal use numbness of the feet, severe pains in the legs, temporary paraplegia, and severe headache are not uncommon; hemiplegia and paralysis of the arms have also been reported. Contraindications and Cautions. The contraindications are: Severe disease of the gastro-intestinal tract, kidneys, heart, and arteries not due to syphilis, any acute febrile disease, even a severe cold in the head, hemorrhage as after abortion, chronic alcoholism, and lead-poisoning. Yak ym off found the toxicity in mice increased threefold if they were given a preliminary minute infection with the colon bacillus. In some cases salvarsan shows a selective action on the optic nerve, or on the auditory nerve, causing vestibular disturbance, so in diseases of the eye and ear it must be used with judgment, as it has in many instances caused a permanent blindness or deafness. In syphilitic myocarditis or aortitis the beginning close should be probably not over 0.15 gm., as fatalities have occurred after full dosage. Wechselmann finds its use immediately following intensive mercury treatment especially dangerous to the kidneys, 552 PHARMACOLOGY AND THERAPEUTICS but Fordyce says this is not the experience of most observers. In any case it should not be administered at less than five-day intervals. In infants the drug must be used with caution, as the liberated endotoxins may produce disastrous effects. Use in Non-syphilitic Cases. Salvarsan has been employed for intensive arsenic treatment in pernicious anemia, leukemia, Banti's disease, splenic anemia, and kala-azar. It has also been employed in relapsing fever, frambesia, leprosy, amebic dysentery, refractory malaria, filariasis, trichiniasis, and many other condi- tions, with some good results and many failures. The author and others have obtained apparent cures of chyluric filariasis. It has been reported a cure in experimental trypanosomiasis. ANTIMONY The only official salt is the double tartrate of antimony and potassium, or tartar emetic, K(SbO).C 4 H 4 O 6 . It is soluble in 12 parts of water and insoluble in alcohol. Preparations and Doses. Antimony and potassium tartrate. Dose, T V grain (0.006 gm.). This enters into: Compound syrup of squill, or Coxe's hive syrup, 0.2 per cent., with senega and squill. Dose, 30 minims (2 c.c.). Compound licorice mixture, 0.024 P er cent. Dose, i dram (4 c.c.), and The unofficial wine of antimony, 0.4 per cent. Dose, 15 min- ims (i c.c.). Pharmacologic Action. Locally it is irritant and was for- merly used as a pustulant. Systemically it resembles arsenic, but is absorbed with greater difficulty and has a nauseant effect, as a consequence of which it tends to fluidify and promote the flow of mucus in the respiratory tract. It was formerly employed in dose of | to 2 grains (0.03-0.12 gm.) as an emetic, but its chief use now is in colds in which the respiratory mucus is thick and tenacious. It has recently been extensively employed intravenously in trypanosomiasis (internal and external), Leishmaniosis, oriental sore, and kala-azar with specific effect. To prevent hemolysis Caronia advises solutions of not over i per cent, with normal saline. The dose is f grain (0.04 gm.) increased to 3 grains (0.2 gm.), and administered at intervals of two or three days. Rogers (1917) recommends the same treatment in per- sistent malaria. It maybe given by mouth in the form of anti- mony lithium tartrate in dose- of TO to 2 grains (0.1-0.13 gm.) in 3 pints (1500 c.c.) of water daily (Camac). Chronic poisoning has been observed in typesetters, and is PHOSPHORUS 553 usually mistaken for plumbism. The symptoms are: anemia, poor nutrition, constipation, ready fatigue, nervousness, in- somnia, dizziness, headache, and pain in the muscles or nerves. The blood-pressure tends to be low, and the blood to show di- minished leukocytes and eosinophilia. The antimony may be found in the stools. The treatment is the same as that for chronic lead-poisoning. The Hygienic Laboratory has called attention to the presence of antimony in certain rubber nipples for babies, and E. W. Miller (1916) found that foods took up antimony from cheap enamelware. For example, fresh milk dissolved out 3 mg., a helping of spinach, 10 mg., and cranberry, cider, and grape-juice, 3 to 14 mg. PHOSPHORUS Phosphorus is insoluble in water, but soluble in ether, chloro- form, and the oils. It is readily oxidized to phosphorous acid, which is an inert compound. It resembles arsenic in its action, but is less irritant locally, and has a greater tendency to produce fatty degenerations. Charteris (1903), in his studies on the bone-marrow, administered it subcutaneously to rabbits. In the early stages the marrow showed hyperemia and an increase in the leukoblastic tissue ; after prolonged administration the marrow was markedly degenerated. In growing animals the growth of bone has been decidedly promoted, the cancellous portion giving way to the development of hard bone. In adult animals Char- teris found no change in the bones. Toxicology. Acute poisoning somewhat resembles that from arsenic. After a latent period, which may be several hours, there are burning in the stomach, abdominal pain, and vomiting. At first the liver is swollen, but it soon undergoes a rapid atrophy of the type of acute yellow atrophy. Jaundice usually comes on in twenty-four hours. There are leucin, tyrosin, and other incompletely oxidized bodies in the urine. The local antidote is an oxidizing agent, such as peroxide of hydrogen or potassium permanganate. Scoville says that old turpentine oil changes the phosphorus into a non- toxic turpentine-phosphorous acid. Other oils should not be employed unless promptly washed from the stomach. Chronic poisoning is to be seen among the makers of matches, Its chief manifestation is "fossy jaw," a condition of necrosis of the jaw bones which is incurable, and often necessitates extensive curetage of the parts to check the horrible cadaverous odor. It may even require removal of the entire maxilla. Char- teris laid bare the periosteum of the lower jaw of rabbits, and 554 PHARMACOLOGY AND THERAPEUTICS repeatedly exposed them to phosphorus fumes, but could not get necrosis. Therapeutics. Phosphorus has been used in dose of y^ grain (0.0006 gm.) in the treatment of rickets and osteomalacia. It is given in the form of a pill, an elixir, or a i per cent, solution in olive oil. It is probably mostly inert. Tlie hypo phosphites (Na 2 P0 2 , CaPO 2 , etc.) have been much employed as nerve tonics. The belief that they furnish phos- phorus to the nerve tissues is negatived by the fact that they pass unchanged through the system, and can be almost entirely recovered from the urine as hypophosphites. The compound syrup of the hypophosphites contains the hypophosphites of cal- cium, potassium, and sodium; dose, 2 drams (8 c.c.). The Glycero phosphates. Calcium glycerophosphate, CaPO 4 .- C 3 H 5 (OH) 2 , is soluble in 50 parts of water at 25 F. ( 4 C.) and more soluble at lower temperatures; the sodium salt, Na 2 PO 4 .- C 3 H 5 (OH) 2 , is very soluble in water and is deliquescent. Dose of each, 4 grains (0.24 gm.) They are esters of phosphoric acid, and their administration results in an increase in the urinary phosphates. They are at the present time much in use as general "nerve tonics," and have largely replaced the useless hypophos- phites. But there is no satisfactory evidence that they increase the phosphorus in the nervous tissues, or that in exhaustion the nervous tissues are lacking in phosphorus; and there is abundant evidence that the body can get its needed phosphorus quite as well from the inorganic phosphates; at least this is the case in hens and ducks, which give out a large amount of phosphorus in their eggs in the form of lecithin. Fingerling tried to enrich the milk of goats by the administration of phosphorus compounds. He found that, even when the food was deficient in phosphorus, the organic phosphorus compounds exerted no more favorable influence than the inorganic ones. Marshall (1915) corroborates this finding. Lecithin (see page 32) is a glycerophosphoric acid, substituted by two fatty acid radicals, and combined with choline. It contains about 4 per cent, of phosphorus, and probably sets free phosphoric acid. It occurs in most animal and plant cells, but especially in the brain and nerves, yolk of egg, fish-eggs, blood- plasma, and bile. An ordinary mixed diet may furnish as much as i to 2 drams (4-8 gm.) per day (von Noorden). It is broken up by the pancreatic juice into glycerophosphoric acid, fatty acids, and choline (Dixon). When used in the emulsification of fats it promotes their absorption. It is "a very important material for building up the compli- cated phosphorized nuclein substances of the cell and cell THE IODIDES 555 nucleus" (Hammarsten) . Its administration in large amounts in anemia tends to increase the hemoglobin and red cells and to improve the nutrition. Nerking, by the injection of a lecithin- saline solution in rabbits, was able to cut short or abolish anes- thesia and narcosis. He looked upon this as evidence in favor of the Meyer-Overton theory of narcosis. When eggs are available it hardly seems of advantage to prescribe the commercial lecithin in doses of 5 to 10 grains (0.3-0. 7 gm.). THE IODIDES Preparations and Doses. Iodine (iodum), J grain (0.006 gm.). Sodium iodide, potassium iodide, 10 grains (0.7 gm.); diluted hydriodic acid, 10 per cent., i dram (4 c.c.). Tincture of iodine, 7 per cent, iodine and 5 per cent, potas- sium iodide, with alcohol. Compound solution of iodine (Lugol's solution), an aqueous solution of 5 per cent, of iodine and 10 per cent, of potassium iodide. lodoform, CHI 3 , 4 grains (0.25 gm.). Iodipin, sajodin, and iodival are iodized fats. lodalbin and iodocasein are iodized albumins. According to Leathes (1911) iodipin can be absorbed and stored up as fat without giving up its iodine to the tissues. McLean found that iodine derivatives of fats and fatty acids are held in part by the lipoids of the cells. The iodized albumins are better borne by the stomach than the alkaline salts, but have no other differences in action. The dose of iodipin is i dram (4 c.c.) in emulsion, that of sajodin, iodival, and iodocasein is 10 grains (0.7 gm.). Pharmacologic Action. Externally. For the external action of iodine see Counterirritants and Disinfectants. Internally. The alkaline iodides are freely soluble in water and have a disagreeable bitter taste and a salt action. Locally they are irritant, so require proper dilution before their admin- istration. They have always been considered valuable remedies, but their mode of action has been the subject of much surmise, It is generally understood that they promote the flow of saliva and respiratory mucus, that they increase the activity of the thyroid gland, and that they tend to lessen the viscosity of the blood. Mueller and Inada hold that the viscosity is lessened, but Determunn says not. Adam thought that ordinary doses were too small to cause decreased viscosity, though large amounts would do so. Jorns and also Boveri find that small doses for long periods lessen the viscosity. 556 PHARMACOLOGY AND THERAPEUTICS Absorption and excretion are rapid, iodine being recoverable from the saliva and urine a few minutes after their ingestion. Hanzlik (1912) found that with sodium iodide in i to 10 per cent, solution there was a rapid initial absorption of 50 to 75 per cent, of the total, and then a marked inhibition of absorp- tion due to a local effect on the absorbing epithelium. He found also that the application to the mucous membrane of 0.2 to i per cent, sodium chloride prevented absorption of the iodide. Unlike many salts, they do not remain in the body, but are excreted rapidly by the kidneys. Seventy-five per cent, of the dose appears in the urine inside of twenty-four hours. The remainder may remain in organic combination in the body. In fatty combination they are held by the lipoids of the cells for a longer time. The excretion is much retarded in chronic passive congestion of the kidneys and interstitial nephritis. Iodine is not found in the cerebrospinal fluid, even after very large doses by mouth. Because of its excretion in the saliva, it may produce a very unpleasant metallic taste in the mouth, with coated tongue. To avoid this it is recommended to gargle with a solution of sodium bicarbonate during the iodide administration. Action on the Thyroid Gland. (See next article on Thyroid Gland.) Marine and Lenhart (1909) found that iodine given in any form was taken up by the thyroids, whether these were normal, colloid, or hyperplastic ; that the subjects with hyperplastic glands lost weight for one or two weeks, then rapidly gained; and that iodine hastened the tendency of all active hyperplasias to revert to colloid. Many of the experiments have suggested that much of the benefit of iodides in a number of conditions may be due to in- creased thyroid activity. Circulation. In normal persons or laboratory animals iodides have no measurable effect upon the blood-pressure, but in those with high arterial tension they have a tendency to lower it. This effect is probably due both to the lessening of the viscosity of the blood and to the increase in thyroid activity. Their value in arteriosclerosis may possibly be due to improved blood-flow in the va^a vasorum, owing to diminished viscosity of the blood. From sodium iodide Macht found a stimulating effect on the heart and arteries, and from potassium iodide a depressing effect. Respiratory Organs. There is increased fluidity of mucus in the nose, throat, and bronchi. This is considered by Hender- son and Taylor (1910) to be a reflex effect. In tuberculosis, iodides are believed to be harmful, because of their tendency THE IODIDES 557 to interfere with connective-tissue formation and to soften the caseous matter; for this promotes the spread of the disease. In cases with doubtful physical signs of tuberculosis it is a common custom to administer iodides to "bring out the rales." But the author's clinical experience coincides with that of others in finding this a dangerous practice, and the experiments of Sorel (1909) give additional proof that tuberculosis is a contra- indication to iodide. Sorel infected guinea-pigs with the tubercle bacillus, then administered potassium iodide to a certain number of them. The iodide pigs died of tuberculosis some weeks earlier on the average than those which did not get the iodide. It has been reported also that weak doses of iodide in the tuber- culous will give a reaction similar to that of fair doses of tuber- culin, a reaction which may help to establish a diagnosis, but is not without danger. Iodide is said also to give such a reaction in lepers. A positive luetin reaction can be obtained in those taking iodide. In asthma associated with chronic bronchitis and emphysema the action of iodides is probably an expectorant one. Theory of Action in Syphilis and Tuberculosis. Necrotic tissues in syphilis (gumma) and tuberculosis (caseous areas) take up more iodine than other tissues, and Jobling and Petersen find that both in the blood and the necrotic material iodine combines with and renders inert the antitrypsin which is the normal pre- ventive of the resolution of necrotic tissue. As a result the caseous matter is subjected to attacks by the tryptic ferments and is digested and absorbed, the contained bacteria being set free. In the case of syphilis iodides are valuable because the gummata are absorbed and the contained bacteria are rendered accessible to germicidal agents such as mercury or salvarsan. In the case of tuberculosis of the lungs iodides are prone to be harmful, for as the cheesy matter is absorbed tubercle bacilli are set free and may spread the infection or be expectorated; further- more, arteries in the caseous areas, having lost their support, may rupture and cause hemorrhage. Untoward Actions. Besides the local irritation of the stom- ach, the most frequent undesirable effects are those upon the skin and mucous membranes. i. Skin. The skin lesion usually shows as irregularly scat- tered pimples, the chief sites of which are the face, shoulders, neck, and back. It has been thought that the skin affection was due to elimination of the drug by the sebaceous glands, and its decomposition by the fatty acids of the sebaceous secretion. But many investigators have failed to find either free iodine or iodide in the sebaceous secretion, and the dermatopathologists 558 PHARMACOLOGY AND THERAPEUTICS agree that the changes begin in the papillary layer and not in the glands (Stelvvagon) . Other skin lesions than acne may make their appearance, as urticaria or a vesicular or bullous or hemorrhagic-bullous or purpuric eruption, or disseminated, bright or dusky red, and painful nodules. A few cases of carbuncle formation with serious destruction of the subdermal tissues are reported, even resulting in death. The serious eruptions usually occur in patients with much lowered vitality, and especially in those with chronic nephritis. 2. Mucous Membranes. The mucous membranes chiefly irritated are the conjunctivas and those of nose, throat, bronchi, and stomach. A not unusual effect is that of a severe cold in the head, with watery, injected eyes, headache, and general malaise; there may be, in addition, nausea, salivation, and tender teeth and gums. The patients think they have influenza. A number of cases of edema of the glottis have been reported, also purpuric eruptions on the mucous membranes, and inflammation and swelling of the parotid glands. It has been ascertained by extensive clinical experience that the minor eruptions are more frequent from the smaller doses of 5 or 10 grains, and that they sometimes disappear when the dose is increased. Prophylactic measures against the lesions of skin and mucous membranes are great cleanliness of skin and mouth, alkalies, and arsenic. Some think that the sodium iodide is less irritating than the other salts. Iodide Fever. In a case of plumbism, Oliver reports a tem- perature of 101.8 F., and albumin in the urine from 5 -grain doses of potassium iodide. In a case of chronic rheumatism of the author's (1912) 10 grains of potassium iodide three times a day caused swelling and intense burning of the face and hands, fever, and eventually delirium. It was learned that the same phenomena had followed iodide the previous year. Konried reports two cases of iodide fever, one of them being from the local use of an ointment. Longcope suggests that there may be a sensitization of the patient by the formation of a new protein out of the drug and the patient's serum. Chronic iodism is a state in which there are anemia and emacia- tion, nervousness, tachycardia, and loss of sexual power. Much iodide, even without any poisonous symptoms, tends to lower the body tone and to depress the spirits. Therapeutics. Iodides are believed to be more or less spe- cific in tertiary syphilis and actinomycosis. They do not pre- vent the development of experimental syphilis. According Fig. 65. Dermatitis medicamentosa of pustulobullous type, following inges- tion of potassium iodide. Principally upon the face, with some pustular lesions on the neck and shoulders. Subsided upon withdrawal of the drug, and recurred on experimental readministration (Stelwagon). Fig. 66. Dermatitis medicamentosa of a bullous type, from the ingestion of potassium iodide in a woman aged fifty. Face, neck, forearms, and hands in- volved, and the seat of considerable edematous swelling and variously sized blebs. In some parts blebs became confluent, broke, and uncovered a superficially ex- coriated surface, as shown in cut. Recovery without any scarring or other trace. Patient had a weak heart (Stelwagon). THE IODIDES 559 to Jonathan Hutchinson, "Over the tertiary manifestations of syphilis, the gumma, whether of skin, cellular tissue, coats of arteries, cerebral meninges, or periosteum, potassium iodide exercises almost as definite an influence as mercury over the earlier ones." Fordyce says that iodide has no effect on the early lesions of syphilis, and only a negligible one in rendering the Wassermann reaction negative. It has, however, a profound and physiologic effect on the later lesions. Iodides are also employed in: 1 . The asthma of emphysema and chronic bronchitis. 2. Arteriosclerosis and some other conditions with chronic connective- tissue production; not in cirrhosis of the liver or chronic nephritis (unless for arterial hypertension). 3. Aneurysm of the aorta. 4. Cases with arterial tension, from whatever cause. 5. Chronic rheumatism or rheumatoid affections. 6. Poisoning by the heavy metals. Oliver believes them of little or no use in promoting the excretion of metallic poisons, and Cowers states that they increase the poisoning by promoting the solubility of the metal. 7. Colloid goiter Schondroff calls attention to the good results that have been obtained from iodides and from sea plants containing iodine. It is generally thought that they should not be used in hyper- thyroidism. Krehl advises strongly against their use, as he has seen latent hyperthyroidism change under small doses of iodide into a permanently intractable active form. But Marine and Lenhart (1909) point out that in the hyperplastic glands small doses tend to hasten the change to colloid, which may be desir- able. They advise very small doses. There are a number of reports of the development of exophthalmic goiter as the result of iodine medication. Contraindications. The chief of these is pulmonary tuber- culosis. Administration. Potassium or sodium iodide may be given in milk ("best way of all" Dock), or in saturated aqueous solution, or in dilute solution flavored with compound syrup of sarsaparilla or syrup of orange-peel. Of the saturated solu- tion of potassium iodide in water, i minim is practically a drop, as dropped from a bottle mouth or standard dropper, and it contains i grain. In syphilis this is often begun by three doses a day of 10 to 15 drops (0.7-1 c.c.), this dose being increased one drop each day until 45 or 60 grains (3 to 4 gm.) of the drug are being taken three times a day. For convenience, compressed tablets may be employed, but they should be dissolved before 560 PHARMACOLOGY AND THERAPEUTICS swallowing, or taken with a large draught of water. Klemperer and others have used sodium iodide intravenously in doses of i| to 2\ drams (5-10 grn.) two or three times a week. THYROID GLAND Desiccated thyroid glands (thyroideum siccum) are the dried thyroids of various domestic animals, and are required by the Pharmacopoeia to contain between 0.17 and 0.23 per cent, of iodine. They are administered in tablet or capsule form; dose, i to 5 grains (0.06-0.3 gm.) one to three times a day. The commercial article regularly contains iodine, and yields by special treatment various principles, such as thyroiodin and thyreo- globulin. Kendall has isolated a number of chemical principles, each of which has a special physiologic activity. The alpha- iodine compound most closely represents thyroid activity. Iodine Content. Most thyroid glands contain iodine. In the dried glands of adult human beings Vincent found 0.3 to 0.9 per cent. ; in the dried glands of seven dogs Seidell obtained 0.036 to 0.271 per cent.; and in ten sheep's thyroids dried, Simp- son and Hunter obtained 0.048 to 0.383 per cent. But in the thyroids of many children and those of certain individuals of various species, as the ox, horse, pig, sheep, etc., iodine has been present in mere traces or totally absent. Yet these animals seem to get along as well as those with iodine-containing thyroids, and cannot be distinguished from them ; and after thyroidectomy they show just as severe symptoms as those with even a high percentage of iodine in their thyroids. It is evident, therefore, as Vincent says, that thyroid gland free from iodine seems to meet the needs of the body apparently as well as that contain- ing iodine. But the experiments of Baumann, Roos, Hunt, and many others point out the ability of the gland to take iodine given by mouth into organic combination, and Hunt and Seidell have shown that there is a parallelism between the iodine content of thyroid and its physiologic activity. In their experiments, 46 dogs were used. On two successive days, 1.5 to 2 gm. of potas- sium iodide, or i to 1.3 gm. of iodoform (CHI 3 ), were adminis- tered by mouth, and on the third day the dog was killed. The thyroids of the iodoform dogs averaged 0.3 per cent, of iodine, and of the iodide dogs, 0.148 per cent. ; while those of the controls ranged between 0.106 and 0.129 per cent. These thyroids were then tested on rats and mice, and were found to decrease the resistance of rats and mice to poisoning by morphine and of rats to poisoning by acetonitril, practically in proportion to the percentage of iodine present. THYROID GLAND 561 From the many experiments with thyroid the numeric indi- cator of the activity of the preparation would seem to be the percentage of iodine. And this has led to the belief, on the part of some investigators, that commercial thyroid is merely a special form in which iodine may be administered in organic combina- tion. That this is true in some cases is indicated by the resem- blance of the effects to those of other iodine preparations; but in thyroid absence, as in myxedema or cretinism or after thy- roidectomy, no other iodine preparation is of any avail. Pharmacology. Protein Metabolism. Roos (1899) found that thyroid rich in iodine caused a marked increase in nitrogen excretion; that thyroid poor in iodine caused scarcely any in- crease, and that iodine-free thyroid had no effect at all on the nitrogen. Oswald found the same to be true of thyreoglobulin, the presence or absence of iodine determining the increase or otherwise of nitrogen metabolism. Schondroff, after a series of experiments of long duration, came to the same conclu- sion. In 4 patients with dementia praecox, Ross noted an in- creased output of total nitrogen, creatinin, and indolacetic acid. It may therefore be taken as established that commercial thyroid, which regularly contains iodine, increases protein loss. Fat Metabolism. As long ago as 1894 thyroid was recom- mended in obesity. Stuve, in tests with healthy men, found the consumption of oxygen increased about 20 per cent., and Thiele and Nehring obtained similar results. In myxedema Magnus- Levy recorded an increase of 80 per cent. These figures indicate a loss of fat out of proportion to the loss of protein. Marine and Williams (1908) found in a dog that in eighteen days n gm. of dried sheep's thyroid containing 0.0292 per cent, of iodine caused no loss of weight; while in another dog, in the same time, ii gm. of a preparation containing 0.1092 per cent, of iodine caused a loss in weight of 454 gm. There are many clinical reports pointing to the value of thyroid in obesity, but it must be remembered that, with the reduction of fat, there is also excessive protein destruction, and this is a serious feature in any reduction cure. Bone. Many surgeons have attested to the power of thy- roid to promote union in delayed fractures, and Bircher (1910) has found that it promotes the growth of bone in normal animals. Relation to Adrenals. Cretins have large adrenals (Carlson), and Cannon has shown that thyroid activity may be, at least in some measure, dependent upon the epinephrine supply. Cannon has further shown that thyreoglobulin or stimulation of the thy- roid gland augments the activity of the adrenals. Toxicology. An intravenous dose causes a slowing of the 36 562 PHARMACOLOGY AND THERAPEUTICS pulse and a fall in blood-pressure. As this is prevented by atropine or by cutting the vagi, it must be due to stimulation of the vagus center. When the drug is given in full dosage for long periods to dogs, cats, horses, sheep, etc., and especially when given to monkeys and man, it produces a regular group of effects. There are anemia, emaciation and muscular weakness, excessive sweat- ing, a tendency to fever, headache, nervousness, tremor of face and limbs, various pains and tingling or pricking sensations or paralyses, increased heart-rate, and sometimes exophthalmos and dilatation of the pupil. Similar effects are to be seen in exophthalmic goiter, and some of them suggest stimulation of the sympathetic nervous system. In monkeys Edmunds found that death occurred from asthenia. Therapeutics. (i) In Myxedema and Cretinism. In these conditions the effects are most striking. In myxedema the mentality and the physical characteristics are restored; in cre- tinism the patient may be changed from a maldeveloped and hopelessly idiotic child to a well-developed and more intelligent one. Complete change to normal is not obtained. (2) After Thyroidectomy to prevent the usual train of symp- toms. It is effective if the parathyroids have not been removed. (3) In Hypothyroidism, as after some partial thyroidectomies, and in the late stages of exophthalmic goiter where reversion to colloid has taken place. It is believed that there are many cases of hypothyroidism, with ill-dsfined symptoms, in which thyroid may be of benefit; but the distinguishing features of this condition have not been satisfactorily determined. (4) In Colloid Goiter. (5) In Obesity. (6) In Rheumatoid Arthritis. (7) In Infantile Wasting. (8) In Osteomalacia, Rickets, and Delayed Union of Fractures. It is contraindicated in the hyperplasia stage of exophthalmic goiter, as it increases the symptoms. (For recent reviews on thyroid, see books on Internal Secretions by Swale Vincent and Biedl.) ANTITHYROID PREPARATIONS There are several preparations on the market designed to overcome thyroid hyperactivity. The best known are: Beebe's serum, a serum obtained from animals after inocula- tion with the proteins from human thyroids. Antithyroidin (Moebius) the blood-serum obtained from sheep whose thyroid glands had been removed at least six weeks before. It is preserved with 0.5 per cent, of phenol, and is given by mouth in dose of 8 to 15 minims (0.5-1 c.c.) three times a day. EXPECTORANTS 563 Thyreoidectin, consisting of gelatin capsules each containing 5 grains (0.3 gm.) of a powder prepared from the dried blood of thyroidectomized animals. Dose, one or two capsules three times a day. Any therapeutic value from these preparations is very doubtful. EXPECTORANTS Expectorants are remedies which facilitate the expulsion of mucus from the respiratory organs. They do this largely by increasing the fluidity or the rate of the secretion. Most of them act reflexly from an irritant (nauseant) action in the stom- ach. Henderson and Taylor (1910) believed this to be the case with ammonium compounds, antimony, ipecac, and senega. Coleman holds that ammonium chloride fluidifies by increasing the water in the bronchi, which it carries out as the medium of its own excretion (see Ammonium Chloride) . We have considered the ammonium salts, iodide, antimony, and pilocarpine. Others in common use are: Ipecac, i grain (0.06 gm.); senega, 15 grains (i gm.), and aspidosperma (quebracho), 30 grains (2 gm.). Que- bracho and its alkaloids, quebrachine and aspidospermine, have a peripheral action of the nicotine- curare type, and stimulate the respiratory center, hence have been employed in emphysema and asthma. In a test-tube the alkalies liquefy mucus, but when given by mouth probably have no effect in the bronchi. Certain bronchial antiseptics have been mentioned under Antiseptics. Whether or not they act as true expectorants is a question; and whether they are eliminated in the bronchial mucus in sufficient quantity to stimulate the mucous membrane or to act as antiseptics has not been proved. They are: Certain volatile oil drugs, as oil of turpentine, terebene, pine needle oil, tar, creosote, camphor, cubebs, and garlic, dose, 5 minims (0.3 c.c.) or 5 grains (0.3 gm.); also terpin hydrate, dose, 5 grains (0.3 gm.), benzoic acid, benzoin, balsam of Tolu, and balsam of Peru. The syrup of tar, syrupus picis liquids, has a dose of i dram (4 c.c.). In some cases bronchial activity is promoted by the tonic action of such a drug as strychnine. Favorite expectorant mixtures are: i. The compound licorice mixture, brown mixture (not Brown's Mixture), which contains extract of licorice and spirit of nitrous ether, each 3 parts, paregoric 12 parts, and antimony and potassium tartrate 0.024 part in 100, with syrup, acacia, and water. Dose, i dram (4 c.c.). It is not a very effective ex- pectorant. 564 PHARMACOLOGY AND THERAPEUTICS 2. The compound syrup of squill (Coxe's hive syrup), which contains 8 parts each of the fluidextracts of squill and senega, and 0.2 part of tartar emetic per 100. Dose, \ dram (2 c.c.) every two or three hours. 3. Mistura pectoralis, N. F. (Stokes' mixture), containing ammonium carbonate, 8 grains (0.5 gm.), the fluidextracts of senega and squill, each, 15 minims (i c.c.), paregoric, 75 minims (5 c.c.) in each ounce (30 c.c.), with syrup of Tolu. Dose, i dram (4 c.c.) every two or three hours. Therapeutics. To promote the flow of mucus and lessen congestion in the respiratory tract, particularly in the dry stages of bronchial, nasal, or laryngeal inflammation. IPECACUANHA Ipecac (ipecacuanha) is the root of Cephaelis Ipecacuanha from Brazil, and of the Carthagena ipecac, Cephaelis acuminata (Fam. Rubiaceoi), and it is required to yield on assay not less than 2 per cent, of alkaloid. It contains 3 alkaloids emetine, the important one, and cephaeline and psychotrine. Preparations and Doses. The expectorant dose is: Ipecac, i grain (0.06 gm.). Fluidextract, i minim (0.06 c.c.). Syrup, 7 per cent, of fluidextract (acid with acetic acid), 15 minims (i c.c.). Powder of ipecac and opium (Dover's powder), 10 per cent, each of ipecac and opium, 10 grains (0.6 gm.). The emetic dose is 15 grains (i gm.). The dose in amebic colitis is 30 grains (2 gm.), decreased about 3 grains (0.2 gm.) daily, and given at bedtime and in enteric pills to prevent vomiting; Morgan recommends that a liquid ipecac preparation be given through a duodenal tube. Emetine hydrochloride, freely soluble in water and alcohol, is used subcutaneously in doses of ^ grain (0.02 gm.) one to three times a day. It should not be continued beyond ten days, but with intervals of a few days may be repeated for a second, third, or fourth period of a week or ten days. Pharmacologic Action of Emetine. Microorganisms. Eme- tine in solutions of i : 100,000 is destructive to both pathogenic and non-pathogenic ameba?. In strong solutions up to 5 per cent. Kolmer and Smith found its bactericidal value 5 times that of phenol. Skin, Mucous Membranes, and Alimentary Tract. The drug is irritant locally. Applied to the skin it has a pustulant action, and in solutions of i : 500 causes marked irritation of mucous IPECACUANHA 565 membranes. Chauffard set up a violent irritation of the in- testines by an irrigation with i : 10,000. Lyons, 1915, took ^ grain (0.03 gm.) by mouth, and quickly developed nausea, followed in one hour by vomiting, and an hour later by loose stools accompanied by griping. In oral administration nausea and vomiting come on almost at once, yet may be prevented by the previous administration of a large dose, i dram (4 gm.), of bismuth subnitrate or cerium oxalate. Much larger doses than can be borne by mouth must be given subcutaneously or even intravenously before the development of nausea, vomiting, or diarrhea. These effects would, therefore, seem to be essentially local. But Eggleston and Hatcher have found that in animals with stomachs removed emetine intravenously caused symptoms of nausea and the movements of vomiting, therefore there must be a certain central action as well. After subcutaneous doses Foulkrod found emetine in the stomach, but Lyons failed to find it in the intestines. Circulation. There is a weakening of the heart muscle with slowing and dilatation similar to that from chloroform and not influenced by atropine or cutting the vagi. Death may result from auricular and ventricular fibrillation. In the frog and turtle heart-block has been observed. From therapeutic doses there is a very short and slight rise in arterial pressure followed by a sharp fall and a quick return to its former level. From toxic doses there is a progressive slowing and weakening of the heart and fall in pressure, with collapse. Pellini and Wallace obtained no change or a slight contraction of the arteries; but Evans, Middleton, and Smith say that there is a transient vasoconstric- tion followed by definite vasodilation. Sollmann observed a vasomotor paralyzing action. Howell has noted a deficiency in fibrinogen in the bloccl as the result of which clotting is retarded and the clot is not retractile. Respiratory. There is some depression from subcutaneous doses, but from intravenous the respiratory center is stimulated and the rate and depth of respiration increased (Pellini and Wal- lace). From toxic amounts there is a decided tendency to pulmonary congestion or to hemorrhagic pneumonic consolida- tion, with or without hemoptysis. Kidneys. There is no effect except in poisoning, \vhen there may be nephritis with albuminuria and chloride and nitrogen retention. Toxicology. There are many reports of ill effects from the human use of the drug. From ^ grain (0.03 gm.) daily by hypo- dermic for four days Levy and Rowntree report severe diarrhea, abdominal pain, tenesmus, and toxic delirium, with recovery, in 566 PHARMACOLOGY AND THERAPEUTICS a woman of 95 pounds, and death in a man from 29 grains (2 gm.) given subcutaneously in the course of twenty days. They caused death of a dog by hemorrhagic gastro-enteritis from grain (o.oi gm.) subcutaneously daily for three days. Spehl and Colard gave 22 grains (1.44 gm.) in eighteen days, when there developed a flaccid paralysis, especially of the neck muscles, fol- lowed by difficulty in swallowing, mastication and speech, with edema of the face, kidney retention, and rapid weak heart. The symptoms subsided after stoppage of the drug. Johnson and Murphy, 1917, had two deaths of men after the subcutaneous use of a total of 23! and 25 grains. These amounts tally with Dalimier's estimation from animal experiments that the toxic dose for a i2o-pound adult is about 27 grains (1.8 gm.) whether it is given in a short period or during two or three weeks. Harrison reports a death from the wine of ipecac. From many reported cases a summary of the toxic effects from subcutaneous doses shows that besides the pronounced gastro- intestinal irritation there may be acute renal insufficiency, general edema, hemoptysis, flaccid paralysis, peripheral neuritis, delirium, coma, and failure of the heart. There is a consensus of opinion that intravenous doses are exceedingly dangerous, and that if used intravenously at all the drug should be well diluted and very slowly administered. Therapeutics. Ipecac is employed (i) as an expectorant in dry bronchitis, laryngitis, and rhinitis, (2) as a nauseant or emetic in non-diphtheritic croup, (3) as a diaphoretic in the form of Dover's powder at the onset of a cold (see Diaphoretics), and (4) in amebic dysentery to supplement the subcutaneous injections of emetine. Emetine has its greatest usefulness in the treatment of amebic dysentery, in which it apparently attacks the organisms in the intestinal wall. It does not destroy the encysted forms found in the ameba-carriers. It is to be borne in mind that by prolonged use emetine itself may result in diarrhea or dysentery. In pyorrhea alveolaris it may produce improvement by destruction of the Entameba buccalis, but it fails to cure because the ameba is not the cause of the pyorrhea (U. S. Public Health Reports, 1916). It has been recommended in chronic non-amebic follicular enter- itis, sprue, and some other diseases. Chauffard employed it in tuberculous hemoptysis, but neither clinical results nor its pharmacologic action justify its use for any internal hemorrhage, and because of its causing pulmonary congestion Zepf and others believe it contraindicated in hemoptysis. ERGOT 567 EMMENAGOGUES These are remedies which tend to bring on the menstrual flow. They are: 1 . Local measures, as hot or mustard foot- or sitz-baths, hot- water bottle or counterirritant drugs (turpentine, mustard) to lower abdomen, hot vaginal douches. 2. Strong purgatives, as aloes, jalap, castor oil. 3. Genito-urinary irritants, as cantharis. 4. Drugs which stimulate the uterine muscle, as ergot, hydrastis, quinine, and caulophyllum (blue cohosh). Pilcher found prompt contraction of uterine strips from caulophyllum. 5. Measures to improve the general health, as iron, cod-liver oil, strychnine; in heart disease, digitalis; in tuberculosis, dry cool air. In early pregnancy any of these measures except those of the first and last groups may result in abortion, so an emmenagogue is also an abortifacient. Such substances as corn-smut, cotton- root bark, viburnum, valerian, and the strong volatile oils (rue, tansy, pennyroyal, etc.) have been shown to be without stimulat- ing action. Lieb states that "the uterine colic which results from irritant cathartics or (so-called) emmenagogue oils is not due to direct stimulation of the uterus, but is purely reflex." Many volatile oils tend rather to overcome uterine colic. ERGOT Ergot (ergota) is a fungus which replaces the grain of rye. It rapidly deteriorates and should not be more than one year old. Our supply comes from Europe. Constituents. Though a vast amount of study was given to ergot for many years, its chemistry remained in a state of great confusion until Dale and his associates published their admirable studies in 1909 and 1910. We now recognize three very active alkaloids, ergotoxine, beta-iminazolylethylamine, and para-hydroxy-phenylethylamine, and two others, ergotine and isoamylamine. In addition there may be choline, and there are ergotinic acid, various saponins, and 20 to 35 per cent, of fat. A rare constituent, but one with a powerful depressant action on the circulation, is acetylcholine. Ergotoxine is a hydrated ergotine. It is almost insoluble in water, but is soluble in alcohol. Its phosphate, which is soluble in water, is employed. Para-hydroxy-phenylethylamine (tyramine), readily soluble in water, is closely related to certain amines found in unpurified cod-liver oil as the result of the putrefaction of the cod-livers. 568 PHARMACOLOGY AND THERAPEUTICS It also bears a somewhat close chemical relation to epinephrine. It may be formed by the prolonged trypsin digestion of egg- albumin (Langestein, 1902), and was obtained by the action of a culture of human feces on broth to which tyrosin was added (Barger and Walpole, 1909); hence it is probably a product of intestinal putrefaction in some human cases. It has also been prepared synthetically. Preparations and Doses. Ergot, 30 grains (2 gin.). Fluidextract (acetic), 30 minims (2 c.c.). Extract, 4 grains (0.25 gm.) The alkaloids also may be employed ergotoxine phosphate in dose of --$ grain (0.0012 gm.), and tyramine in dose of \ grain (0.03 gm.) hypodermatically. They are not irritant. A very efficient artificial mixture containing the three important al- kaloids in proper proportions to give a pronounced ergot action is to be had. Standardization. Up to the present no chemic assay has proved satisfactory. For the biologic assay three chief meth- ods have been employed, viz., the blood-pressure method, which estimates the para-hydroxy-phenylethylamine, the uterine method which estimates the beta-iminazolylethylamine, and the cockscomb method, which estimates the ergotine. The first is not good, the pressor effect giving no indication of the con- tractile power of the drug upon the uterus. The uterine method is satisfactory, but is expensive and tedious. Edmunds and Hale and a number of others recommend the cockscomb method, finding it in very close agreement with the uterine method and much simpler. It is based on the development of a purple hue in the comb of a rooster from an injection of ergot. The standard is considered to be 0.75 c.c. of fluidextract per kilo, equivalent to 1.87 mg. of ergotoxine phosphate. Deterioration. Ergot rapidly deteriorates unless kept from the air, and a number of investigators report that ergot and ergot preparations are useless if more than a year old. Yet this is not found to be the case in clinical experience, which corresponds more nearly with the experimental work of Haskell and Eckler (1912). They tested separately, and then mixed together, a large number of fluidextracts made in the different years. Those one and two years old gave a reaction in the standard amount, i. e.j 0.75 c.c. per kilo. Those three years old required i c.c. for the reaction, and those four years old 1.5 c.c., and those five years old 1.75 c.c. Pharmacologic Action. The active principles of ergot stimu- late the ends of certain sympathetic nerves or their myoneural ERGOT 569 junctions. In large amounts ergotoxine paralyzes the same endings. Local. Ergot is irritant to mucous membranes and raw tissues. It has practically no constricting action on mucous membranes, but when injected hypo- dermatically produces a moderate con- striction of the arteries at the point of injection. In some cases it has caused local gangrene. Alimentary Tract. Preparations of ergot are irritant locally and may cause nausea, or, in poisoning, a violent gastro- enteritis. The alkaloids are not irritant. The therapeutic doses of ergot stimulate the ends of the splanchnic (inhibitory) nerves, and cause decreased intestinal peristalsis. Very large doses cause par- alysis of the same sympathetic nerve- endings, and result in increased peristalsis and activity of the bowels. This effect is not obtainable in therapeutics. In test- ing roosters it is usual for their bowels to move. Circulation. (a) Ergotoxine. In- jected intravenously in a dog in dose of ^5 grain (i mg.) per kilo there is a prompt rise in arterial pressure with considerable slowing and weakening of the heart. A second injection makes a smaller rise in pressure or no change. An injection of epinephrine at this time causes dilatation of the arteries, the so-called "vasomotor reversal" of Dale. The ergotoxine at first stimulates and then paralyzes the myoneural junctions of the vasoconstrictor nerves, but leaves the vasodilator nerves untouched. (b) Para-hydroxyphenylethylamine (ty- -p\g. ramine) intravenously results in a prompt and marked rise in arterial pressure. This effect differs from that of epinephrine in its slower development, its four or five times as great duration, and its production (at least this is a claim put forward) by mouth and subcutaneous doses. The constriction of the arteries at the site of a hypoder- matic injection is less than that from epinephrine, but it lasts 67. Ergotized rye (Maisch). 570 PHARMACOLOGY AND THERAPEUTICS longer and may result in local gangrene. Tests on human arterial pressure have been made by several observers. In a patient of Hoyt's with myocarditis, 40 mg. subcutaneously produced a rise of pressure from 85 to 130 mm. in five minutes, and the pressure had returned to its former level in nineteen minutes. By mouth Hoyt found that doses of 5 and 10 mg. three times a day, and Clark that a dose of 100 mg. repeated in forty minutes, had no effect. (c) Beta-iminazolylethylamine intravenously in dose of ^-$ grain (o.i mg.) per kilo produces an immediate and prolonged fall in blood-pressure due to an as yet unexplained peripheral action. It occurs after destruction of the central nervous sys- tem, but perfusion of isolated arteries results in contraction. The heart is slowed, but its output per minute is increased. (d) The Whole Drug. Though the action of the active prin- ciples is, therefore, well known, the effect of preparations of ergot itself upon the circulation is problematic. For, given intrave- nously, ergot may induce a fall in pressure, as Sollmann and Brown (1905) found in 350 experiments on 38 animals; or it may cause a striking rise in pressure. The fall in pressure may be due to beta-iminazolylethylamine, to acetylcholine, or to the saponin bodies. In therapeutics, it is hardly possible to give enough ergot to obtain a rise in pressure, but a hypodermatic or intravenous of ^tyramine is a practical method of raising the arte- rial tension in emergency. Respiration. After the intravenous injection of o.ooi gm. per kilo of ergotoxine, the respiratory center is depressed, as shown by slow and shallow breathing or Cheyne-Stokes respira- tion (Wiggers). From broncho-constriction owing to direct stimulation of bronchial muscle (Jackson), an intravenous of beta-iminazoylethylamine in an unanesthetized animal may cause asthma. Uterus. Though the other principles stimulate the uterus, the very pronounced action of ergot is due in large measure to beta-iminazolylethylamine. With a solution of i : 600,000 Lieb obtained powerful contraction with temporary tetany. The uterine constriction is promoted to a slight degree through a central action, but essentially through stimulation of the uterine muscle. In the early stages of pregnancy the increase may be seen in the strengthening of the normal intermittent contrac- tions which take place at this time; and there is a prevalent belief both in the profession and among the laity that in the early months of pregnancy ergot is abortifacient. But experiments with pregnant animals have not shown it to possess this power to any great degree; and in pregnant women, it has very fre- ERGOT 571 quently failed to have the slightest effect. It is of considerable interest that in some cases of ergotism pregnancy has gone on to term without interruption. In labor, moderate doses tend to increase the strength of the normal intermittent contractions, while large doses (i dram 4 gm.) produce a continuous or tetanic contraction of the uterus. This makes ergot of value after labor to promote the normal postpartum uterine contraction; but it should not be adminis- tered until the uterus is empty, lest the organ go into tetanic contraction and compress the contents without expelling them. The drug usually takes thirty to sixty minutes to act when given by mouth. The stoppage of uterine hemornhage is essentially due to the uterine contraction, and is not to any great degree, if at all, attributable to contraction of the uterine arteries. Toxicology. Acute poisoning is usually the result of large doses taken to produce abortion. The symptoms are (i) those of gastro-enteritis, with nausea, vomiting, diarrhea, and abdominal pain, and (2) various nervous manifestations, such as itching, tingling, hyperesthesia, and anesthesia of the skin, mental depression, convulsions, coma, and collapse. The treat- ment is symptomatic for gastro-enteritis and collapse. In a fatal case Rosenbloom and Schildecker found ergotinine in stomach, intestines, liver, and kidneys. Chronic Poisoning or Ergotism. This is not seen in this country, though it has been in the past common enough in Europe from the consumption of bread made from ergot-infected rye. The ergotism manifests itself either by gangrene or by certain pronounced nervous symptoms. The gangrene is caused by persistent contraction of the arteries in some particular part of the body, chiefly the fingers, toes, ears, and tip of the nose. But there may be sloughing in any part of the body surface, or ulcer of the stomach, or even gangrene of the lung or of the uterus. The small arteries of the part are found to contain hyaline plugs, as in any case of dry gangrene. The nervous type shows in gastro- intestinal disturbances, itching of the skin, headache, dizziness, disordered vision, temporary or permanent blindness, drowsiness, mental depression, and clonic or epileptiform convulsions which may leave permanent contractures in hands, feet, arms, legs, or trunk. These manifestations are thought to be due to spasm in the arteries of the central nervous system; the permanent effects are due to softening from the shutting off of the arteries. Fuchs has pointed out that ergot is a cause of endemic tetany. Therapeutics. The main employment of ergot is (i) To prevent postpartum hemorrhage, which it does by inducing uterine 572 PHARMACOLOGY AND THERAPEUTICS contraction rather than by narrowing the vessels; (2) to check menorrhagia, and (3) to overcome subinwlulion of the uterus. Though it has been used for hemorrhage from stomach, lungs, kidneys, etc., there is no indication that a therapeutic dose pro- duces constriction of the arteries in these regions. In any dose whatever it does not constrict the pulmonary arteries. It has been employed to raise blood-pressure, but for this purpose, as we have seen, the active principles are to be used, and not ergot itself. Thus tyramine might be employed in shock or collapse. To obtain arterial constriction, Wiggers used -^ grain (o.ooi gm.) of ergotoxine phosphate per kilo in dogs. He advised that the dose should not be repeated, as the paralysis of the nerve-endings might come on. On empiric grounds ergot has been proposed for a great many different conditions; for example, it is spoken highly of in diabetes insipidus, enuresis nocturna, and delirium tremens. The author found it useless in diabetes mellitus and the night- sweats of tuberculosis. Ransom speaks highly of it in delirium tremens. (See Alcohol.) Ergotoxine is employed in physiologic experimentation to paralyze sympathetic nerve-endings, especially the vasocon- strictors. HYDRASTIS Hydrastis, or goldenseal, is the dried rhizome and roots of Hydrastis canadensis (Fam. RanunculacecE) , yielding, when assayed, not less than 2.5 per cent, of hydrastine. It is a small herb of the eastern United States. Constituents. Three alkaloids: hydrastine, 2.5 per cent.; berberine, 3 to 4 per cent., and a little canadine; in addition, some resinous material. Preparations. Hydrastis, 30 grains (2 gm.). Fluidextract (2 per cent, hydrastine), 30 minims (2 c.c.). Glycerite (1.2 per cent, hydrastine), 30 minims (2 c.c.). Tincture (0.4 per cent, hydrastine), i dram (4 c.c.). Hydrastine and hydrastine hydro- chloride, ^ grain (o.oi gm.). The hydrochloride is freely soluble in water and alcohol. Pharmacologic Action. Local. It has a slightly astringent action, and in some sections is employed as a stimulant of mucous membranes in chronic catarrhal conditions, as of nose, throat, urethra, and vagina. Alimentary Tract. It has a bitter effect upon appetite. Through a central action it increases the motor and secretory activity of the stomach and promotes intestinal peristalsis. Large doses cause vomiting and diarrhea. HYDRASTININE HYDROCHLORIDE 573 Nervous System. On the medulla and cord, hydrastine acts mildly like strychnine, stimulating slightly the respiratory, vagus, and vasoconstrictor centers and increasing reflex irritability. Very large doses cause tonic and clonic convulsions, incoordina- tion, and depression of the medullary centers. Eye. Locally applied, it first contracts then dilates the pupil. Circulation. Lieb says that after a momentary and negligible rise small doses produce a slight but persistent fall in arterial pressure. The heart rate is practically unchanged. In poisoning, the centers are depressed, and the heart becomes slow and feeble from direct action on the cardiac muscle. At the same time the muscles in the arterioles become depressed and the vessels dilate; hence blood-pressure is very low. It differs materially from strychnine, as this tendency to depress the heart is manifested before convulsions come on. Respiratory. Ordinarily, the respiratory center is stimulated ; but in poisoning it is depressed, and death takes place from as- phyxia brought on by paralysis of the respiratory center or by the convulsions. Muscle. Muscular tissue of all kinds (except perhaps the uterus) is primarily stimulated, then depressed. Uterus. Hydrastis resembles ergot in its tendency to in- crease the normal contraction of the uterus, but it is much less powerful in bringing about contraction of the postpartum uterus. In menorrhagia or metrorrhagia from fibroids, subinvolution, or relaxed uterus, it may arrest hemorrhage. The uterine effect is due to both the hydrastine and the berberine. Elimination. Hydrastine is excreted in the urine as such, no hydrastinine being formed in the body. Slight amounts also appear in the saliva and feces. Therapeutics. Hydrastis has been much employed locally in chronic catarrh of nose, throat, urethra, and vagina. Owing to the large amounts of bitter alkaloids, it is a powerful bitter. It is also employed in postpartum hemorrhage, subinvolution, menorrhagia, and metrorrhagia, whether caused by fibroids or not. HYDRASTININE HYDROCHLORIDE This salt (hydrastinine hydrochloridum) , CnHnNOz-HCl, is the hydrochloride of an artificial alkaloid formed by the oxidation of hydrastine. Dose, \ grain (0.03 gm.). It is freely soluble in water and alcohol. Hydrastinine has a local constricting effect on arteries, and has the same action on centers as hydrastine; but it has little if any effect in depressing the heart and other muscles. It induces a rise in blood-pressure through stimulation 574 PHARMACOLOGY AND THERAPEUTICS of the vasoconstrictor center. It causes rapid dilatation of the pupil, the effect wearing off inside of twenty-four hours. It is for its action on the uterus, however, that hydrastinine is employed, as it tends to stop hemorrhage by stimulating the uterus itself. It is not so good as ergot in postpartum hemorrhage, but is largely employed in subinvolution, in late hemorrhage fol- lowing parturition, and in profuse menstruation, whether caused by fibroids or not. A 10 per cent, solution has been employed locally on cotton in hemorrhage from nose, mouth, rectum, and uterus. Cotarnine hydrochloride, stypticin, is oxymethyl-hydrastinine ; dose, \ grain (0.03 gm.). It is prepared from narcotine, and has an action practically like that of hydrastinine, but with a hydras- tine tendency to depress the heart muscles, and a mild narcotic action. Its uses are those of hydrastinine. CARBON MONOXIDE This gas (CO) becomes of interest from the frequency of its poisoning. Most of the cases result from illuminating-gas, which contains 6 to 10 per cent., and is frequently inhaled with suicidal intent. But some come from defective flues of furnaces, coal stoves, charcoal fires, blast furnaces, and the "after-damp" of mines and old wells. The gas has great affinity for hemoglobin, and prevents the formation of oxyhemoglobin unless oxygen is present in very great excess. But the compound is not a very stable one and usually, if respiration is good and oxygen plentiful, splits up so that all the carbon monoxide will be exhaled by the lungs in from one to three hours. The monoxide does not oxidize to carbon dioxide in the body. Except for its affinity for hemoglobin the gas is physiologically harmless. The action of the gas is asphyxial, the exclusion of oxygen from the tissues, particularly the central nervous system, being the cause of the symptoms. Haldane found that when mice were placed in oxygen under two atmospheres pressure, so that the plasma would carry enough oxygen to maintain life, carbon monoxide had no toxic effect; but that when the oxygen pressure was removed by exposing the mice to the air, poisoning followed. The toxic symptoms are, therefore, due to an interference with the oxygen-carrying power of the blood. The blood of a man at rest may become nearly one-third saturated without his realizing that anything is wrong (Henderson) ; and in a few hours he is as lit for vigorous exertion as before. Haldane observed that death occurs when about 80 per cent, of the hemoglobin is disabled, and that the best remedy is the inhalation of pure oxygen. CARBON MONOXIDE 575 The symptoms are those of stimulation of the cerebrum and medullary centers, followed by their depression. At first there are headache, dizziness, mental excitement or delirium, slow pulse from stimulation of the vagus center, raised arterial pres- sure from stimulation of the vasoconstrictor center, dyspnea from stimulation of the respiratory center, and nausea and vomiting from stimulation of the vomiting center. These may be fol- lowed by mental dulness or coma, prostration, rapid weak pulse, lowered blood-pressure, slow and shallow or Cheyne-Stokes respiration, fever, loss of control of the sphincters, and convul- sions, usually of cerebral (epileptiform) type. The heart con- tinues to beat after respiration has ceased. In the late stages there is sometimes great spasticity or muscular rigidity, so that the patient seems as "stiff as a board." Spiller and others find this associated with bilateral softening of the inner segments of the lenticular nuclei, the softening being due to changes in the minute supplying arteries. Henderson noted a marked acidosis, but obtained no amelioration of the symptoms after large intra- venous infusions of 3 per cent, sodium bicarbonate. A striking characteristic of the poisoning is a subsidence of the acute symptoms, followed by apparent recovery, and then some hours or days later the appearance of serious disturbances of the nervous system, showing in loss of vision, mental derange- ment, peripheral neuritis, paralyses, epileptiform convulsions, or collapse and death. There may be permanent cardiac weakness. Acute poisoning is divided by McCombs (1912), who has seen 1000 cases, into three stages, viz.: 1. Before the patient loses consciousness. It is the stage of stimulation. 2. After the patient loses consciousness, respiration still per- sisting. This is the stage of depression. In this stage or later, cherry-red spots over the cheek-bones, neck, trunk, and thighs may make their appearance, and there may be petechiae. 3. Patient unconscious, no spontaneous respiration. The heart is rapid, weak, intermittent. Chronic poisoning occurs from the leakage of gas tubes, gas-heated irons, or other continued exposure. It shows in nausea, headache, dizziness, mental depression, lassitude, anemia, loss of appetite and of flesh and strength, and gastric dis- turbances. It may give any of the symptoms of the first stage of acute poisoning. McCombs, \vho has studied the men of gas companies, reports polycythemia as quite common, and calls attention to the fact that there are many men who have been much exposed to the gas for many years without any special sign of ill health. 576 PHARMACOLOGY AND THERAPEUTICS Treatment. i. Of first importance in the mild poisoning is fresh air, and in the severe degrees, oxygen, under pressure, if possible. 2. Artificial respiration when required, deep breathing being essential to the elimination of the gas. 3. Maintenance of body warmth. 4. For the nausea of the mild type effervescing drinks, and for the headache a carminative, such as aromatic spirit of am- monia. 5. Transfusion of blood after a preliminary blood-letting, with manipulation of the heart and artificial respiration, is the method recommended by Crile and Lenhart, who experi- mented on 1 6 dogs, giving carbon monoxide until respiration ceased. Yandell Henderson (1916) says that neither blood-letting nor transfusion can be of use, as the symptoms are not due to retained gas. He found that within one or two hours after the patient had been removed to fresh air the amount of carbon monoxide in the blood was far below the harmful percentage. The damage to the nerve-centers results from lack of oxygen, and has already been done when the patient is rescued. BENZINE AND GASOLINE The benzine of the Pharmacopoeia has a specific gravity of 0.638-0.660 at 25 C. and is known commercially as petroleum ether. Commercial benzine has a specific gravity of about 0.746 and commercial gasoline of 0.699 to 0.713. All are spoken of by the producers as "naphtha." Mixtures of commercial benzine and air, containing 2.4 to 4.9 per cent., are explosive. Benzine does not dissolve phenol, but benzene (benzol) does. Benzine and gasoline are absorbed fairly well through the lungs and with difficulty from the stomach. They are eliminated mostly by the lungs and slightly by the kidneys. In acute poisoning the most notable effect is great congestion with exten- sive hemorrhages, or edema of the lungs causing suffocative dyspnea and frothy expectoration of thin bloody liquid. There are also congestion of brain, liver, and kidneys, and a cherry red color to the blood resembling that in carbon monoxide poisoning. The treatment is lung ventilation, oxygen, and transfusion of blood. Burgh reported the death in four hours of an eighteen- months-old child after swallowing a little more than an ounce of benzine. Jaffe reports the death of a child twenty-one months old from a mere sip, and complete absence of symptoms in adults from as much as if ounces (50 c.c.). Chronic BENZOL 577 is believed to result from inhalation of the gas by workers in the distilleries. It leads to connective-tissue changes in lungs, liver and kidneys, and perhaps of other organs. BENZOL Benzol (benzene, C 6 H 6 ) is a colorless, inflammable liquid, in- soluble in water, soluble in 4 parts of alcohol, and freely miscible with the oils. It is a solvent for phenol, a property by which it can be differentiated from benzine. Sellings (1910) reported 7 cases of purpura haemorrhagica in tin workers who used a benzol preparation as a substitute for solder. Santesson (1897) and also McClure (1916) reported series of cases of aplastic anemia from the use of benzol as a solvent for rubber. Following Sellings work v. Koranyi applied benzol to the treatment of leukemia. In experimental work on rabbits by Sellings and others, there has been noted a primary rise in the leukocyte count followed by an irregular fall, after which there may be a secondary rise and a secondary fall, and finally a return to normal when the drug is stopped. The blood-forming tissues, the bone-marrow, spleen, lymph-nodes, and lymph-follicles are rendered aplastic, and may become atrophic. The result is an aplastic anemia with diminu- tion in the number of blcod-platelets and white cells, the poly- nuclear count being relatively more affected than the mono- nuclear. The liver and kidneys show fatty changes, and in some animals there are hemorrhages into the wall of the stomach and intestines and into the lungs. After stopping the benzol, Sellings found complete regeneration of the aplastic organs in ten to twenty-one days. The red blood-cells may be increased primarily, but they soon show the effects of the bone-marrow aplasia in a progressive anemia, with hemoglobin index about i and pratical absence of nucleated red cells. Musser and Krumbhaar in 6 rabbits could not produce purpura, though they obtained the characteristic anemia and leukopenia. With the use of benzol there is an increase in the phenols of the urine. Benzol is not a cure for leukemia, but may be looked upon as a symptomatic remedy. There are wide differences in individual tolerance to the drug, so that the dose is uncertain. The begin- ning dose, however, may be put at 8 minims (0.5 c.c.) three times a day, and this amount is rapidly increased to double. It may be given after meals in milk, or in capsules with equal parts of olive oil. Mixed with olive oil it has also been used subcutaneously and by rectum, but it is irritant. Winslow and Edwards (1917) gave it intravenously to dogs and rabbits, with 37 578 PHARMACOLOGY AND THERAPEUTICS immediate agitation, convulsions, and if the dose were large enough, death. The lethal dose for 2 dogs weighing 25 and 29 pounds was 45 minims (3 c.c.). In man it must not be employed intravenously. If the leukocytes show a rapid fall in number, the benzol should be stopped no matter how high the count, for this is an indication of severe aplasia. The author had one case (demonstrated by Dr. J. H. Larkin at the New York Pathological Society) with over 1,000,000 white cells per cubic millimeter. The benzol, 45 minims (3 c.c.) daily, was stopped when the leuko- cytes fell rapidly to about 200,000, but rapid progress downward continued, and when the count reached 10,000 the patient died. The bone-marrow was very red, and showed crowded myelocytes with much new connective tissue, new vessels, and hemorrhages. Billings and others have noted basophilic granular degeneration of the lymphocytes. In the two fatal poisoning cases of Sellings series the leukocytes fell to 480 and 140 per cubic millimeter. From the use of the drug in leukemia Neumann reports a drop of white cells to 200. Other untoward effects from its medicinal use are heart-burn, flatulence, nausea, vomiting, diarrhea, bronchial irritation, minute hemorrhages of skin and mucous membranes (purpura haemorrhagica) , albuminuria, ringing in the ears, and dizziness. In addition to lymphoid and myeloid leukemia, benzol has been recommended in pseudoleukemia and polycythemia. Ki- ralyfi reports no effect in Banti's disease, and the most marked effect in lymphoid leukemia. Others have noted the best effects in myeloid leukemia, and Sellings found experimentally that the myeloid tissues were most affected. In the severe aplastic anemia of benzol poisoning McClure obtained recovery in one case by repeated transfusions of blood to the number of five. OXYGEN Oxygen gas (oxygenium) is marketed under compression in steel containers. It is regularly used by inhalation, but has also been employed subcutaneously, intravenously, and intra- abdominally. For inhalation it is passed through water or alcohol in a bottle, and conveyed to the patient by tubing terminating either in a nose-piece to be inserted into the nostril, or in a funnel to be held before the face. It tends to dry the membranes, so if continued for any length of time should be accompanied by the steam from a croup kettle. Action. The inhalation of oxygen in health has no effect on metabolism, or on the character, frequency, or depth of res- piration, but it regularly reduces the rate of the heart and tends to raise arterial pressure. !$, "**' A '^'* : .< \.?|.'.V* ;. . % .'-Lv-V-^^ Fig. 68. Bone-marrow of rabbit after long treatment with benzol. Practically all the blood-forming elements are destroyed (MacCallum). OXYGEN 579 Kraus reports that in cardiac failure the amount of oxygen taken up by the blood and of CO 2 given off is practically un- changed. Leonard Hill says that breathing pure oxygen has little effect on the capillary oxygen tension, and Zuntz and Schumberg produced experimental polypnea and found that the greatly in- creased amount of oyxgen taken into the lungs caused no altera- tion in the quantity of oxygen taken into the blood. Yet Starling says that the normal oxygen in the blood and plasma is about 15.6 per cent., and that on breathing pure oxygen for a short time the percentage rises to 19.9 per cent. In cases of cyanosis, however, where the oxygen tension of the alveolar air is low and the CO 2 tension in the blood is high, the ability of the blood to take up oxygen is diminished; yet administered oxygen tends to drive out the carbon dioxide. Peabody observed that in pneu- monia the oxygen-carrying power of the blood falls as the disease progresses. Bence found that in cases of cyanosis, oxygen reduced the viscosity of the blood and so favored the circulation; and Stewart noted that, in a case of emphysema, chronic bronchitis, and recur- ring cyanosis, it increased the blood-flow in the hands from 30 to 70 per cent., though it brought about no especial changes in the respiratory movements. Hill and Flack have noted that after hard boxing-bouts of men not in good training, the inhalation of oxygen reduced the pulse-rate almost to normal, abolished the shallow, hurried breathing, and prevented the stiffness of the muscles which otherwise would have followed on the next day. It has been used in other athletic exercises with similar results, and in mountain-climbing the inhalation of oxygen has proved preventive of "mountain-sickness," which overcomes those not inured to hard work at high altitudes. Karstner (1916) determined that atmospheres containing 80 to 90 per cent, of oxygen produce in rabbits in twenty- four to forty-eight hours congestion, edema, epithelial degeneration and desquamation, fibrin formation, and finally a fibrinous bronchopneumonia probably of irritative origin. There were no undesirable effects except the local ones in the lungs. It is possible that the local irritation is due in part to the low humidity of the artificial atmosphere. Karstner and Ash (1917) found that atmospheres with up to 60 per cent, of oxygen produced no pathologic changes. Therapeutics. The net results of the researches give us the impression that while oxygen inhalation has little measurable effect in normal persons, it may have a distinct value in cases of oxygen want, i. e., those cases in which the oxygen tension of the alveolar air is low, or there is hindered passage of oxygen through 580 PHARMACOLOGY AND THERAPEUTICS the alveolar walls, so that the oxygen tension in the blood is below normal. Add to this also the effect of increased oxidation in lessening acidosis, and the revival value of fresh oxygen to the diseased alveolar and capillary tissues, and it would seem that oxygen is a good therapeutic agent in gas-poisoning, pneumonia, edema of the lungs, severe bronchial asthma, heart failure, collapse in general anesthesia, and possibly uremia. Undoubtedly its best effect is seen in conditions with cyanosis. In the night dysp- nea of heart cases most striking effects are reported by Macken- zie, who uses a hat box over the head with a hole for the neck, and directs a stream of oxygen into this for fifteen or thirty minutes at bedtime. Haldane says that in carbon monoxide poisoning pure oxygen rapidly drives out the poisonous gas. Pure oxygen should not be used continuously for more than half an hour, but it may be employed continuously to enrich the air which the patient breathes. PART III PRESCRIPTION WRITING FOR three obvious reasons the writing of prescriptions is the dread of the young medical practitioner. The reasons are: (i) His fear that he may not express his desires correctly; (2) his distrust in his ability to make satisfactory combinations or palatable mixtures; and (3) his anxiety lest a faulty construction should make him the subject of the pharmacist's criticisms. A prescription (pr4 grain of extract of nux vomica, and Blaud's pill, 5 grains one after eating. Miscellaneous. Take belladonna plaster and spread it upon surgeon's adhesive plaster over a circular area 2 inches in INCOMPATIBILITY 603 diameter. (In this case it would be better to write the directions to the pharmacist in English.) Criticize the following as to (i) Completeness; (2) order and correctness of names of ingredients; (3) correctness of amounts; (4) safety of dosage; (5) directions. 1. 1$ Spirit! ammon. aromat 5i 2. Rx Mixt. creta 3ii Tr. opii Sii Subnitrate bismuthum 5ii As directed. INCOMPATIBILITY Incompatibility between two substances may be said to exist when their admixture brings about physical or chemical change other than simple solution. Such a change (i) may be desired in a prescription, (2) may make little, if any, difference, or (3) may be undesirable. A chemic reaction may result in a pre- cipitate, may show merely in an alteration of color, or may make no visible change at all. But the physician should know in what form his remedies are when the patient takes them. "Incompatibility" is a bugaboo raised for the alarm of the prospective prescription writer, and it is an unnecessary alarm. For, though a great many incompatibles for almost any active chemical may be found in the laboratory, yet but few of these are ever likely to be encountered in a prescription; and of those few, the result not infrequently makes no practical change in the medicinal value, or is deliberately desired. The following are those most likely to be encountered in the practical use of drugs : I. Incompatibility Depending on Change of Solvent. (a) Precipitate When Added to Aqueous Liquids. Substances in alcoholic solution and insoluble in water; as in spirits, fluid- extracts, and tinctures, especially resinous ones, like tincture of cannabis, benzoin, myrrh. (b) Precipitate When Added to Alcoholic Liquids. Substances in aqueous solution and insoluble in alcohol; as solutions of many salts (sodium sulphate, ammonium chloride) , ichthyol, and mucil- age of acacia. Mere insolubility, as of oils or bismuth subnitrate in water, makes these really incompatible with the solvent; but such are considered under the head of "solubility." II. Chemic Incompatibility. Rule i: Acids and salts of acid reaction are incompatible with alkalies and salts of alkaline reaction and the halogen salts, as hydrochloric acid or potassium bitartrate with sodium bicarbonate or magnesia. Rule 2 : Highly oxidized substances, like chromium trioxide (chromic acid), potassium permanganate, and potassium chlorate 604 PHARMACOLOGY AND THERAPEUTICS are decomposed by organic matter. Potassium permanganate in solution turns brown; dry potassium permanganate or chromic acid may take fire or explode. Potassium chlorate, when rubbed with sulphur, hypophosphites, ammonium chloride, tannic acid or other organic substance, will explode violently. Rule 3: Silver nitrate is incompatible with organic material and turns to black oxide or black metallic silver. With chlorides or hydrochloric acid it forms the insoluble silver chloride. Rule 4: Mild mer curous chloride (calomel) is incompatible with sodium carbonate and lime-water. With the latter it makes a black precipitate of mercurous hydroxide, and forms "black wash," sometimes employed as an application to venereal sores. Calomel is insoluble in water or alcohol, comparatively inert chemically, and bland to tissues. Rule 5: Corrosive mercuric chloride (corrosive sublimate) is incompatible with iodides, many metallic salts, alkaloidal salts, tannic acid, lime-water, and albumin. With excess of lime-water it makes a yellow precipitate of mercuric oxide, and forms "yellow wash," employed as an application to venereal sores. When the mercury salt is in excess, the precipitate is red oxychloride. With soap, as on the surgeon's hands, its antiseptic power is destroyed. With potassium iodide it forms mercuric biniodide 2 KI -+- HgCl 2 = 2 HC1 + Hglo. The iodide is of a brilliant scarlet and dissolves in excess of the potassium iodide. These two salts are often prescribed together to form the biniodide. In albumin, as in white of egg or milk, we have the antidote when the drug is swallowed. Rule 6: Lead acetate decomposes alum and other sulphates and the iodides, and tends to precipitate many organic substances, e. g., glucosides, from their solution. The admixture with alum makes Burow's solution. The precipitate of lead sulphate should be filtered off. The pre- cipitate with the iodide is lead iodide of a brilliant yellow. Rule 7: Ferric salts (a) make "ink" with tannic acid; (b) make blue to reddish or purple colors with compounds of the phenol group, such as phenol, resorcin, salicylates, etc.; (c) make a red color with acetates, and (d] form a dirty-brown pre- cipitate with alkalies or alkaline salts. Rule 8: Tannic acid is incompatible with alkaloidal salts r dry potassium chlorate (explodes), metallic salts, gelatin, and albumin. With ferric salts it makes "ink." For salts of alka- loids and antimony it is the local antidote. It occurs in many vegetable drugs, and preparations of these INCOMPATIBILITY 605 may not only precipitate alkaloidal salts, but may change the gelatin coating of a pill or a gelatin capsule to a tough, leathery, insoluble substance. Alcohol, as in tinctures, may prevent the precipitation of alkaloidal salts by tannic acid. Rule 9: Chloral hydrate decomposes to chloroform under the influence of strong alkalies; and when mixed with camphor, menthol, thymol, and similar substances, undergoes a physical change to a liquid. Rule 10: Alkaloidal salts are incompatible with (a) Alkalies the precipitate is the pure alkaloid. (b) Tannic acid the precipitate is the insoluble tannate. (c) Iodine, iodides and bromides the precipitate is the iodide or bromide. (d) Mercuric bichloride the precipitate is an insoluble double salt. Quinine in addition is especially precipitated by salicylates and benzoates. All these precipitates are more soluble in alcohol than water, so may not show in tinctures and other alcoholic liquids. Rule 1 1 : Glucosides are incompatible for the most part with lead acetate and tannic acid, and are decomposed by the mineral acids. INDEX ABBREVIATIONS in prescription writing, 597 special, in prescription writing, 599 A. B. C. mixture, 102 Abortifacients, 567 Abrin, 27 Abrus precatorius, 27 Absinthe, 320 cordial, 320 Absolute alcohol, 316 Absorption, to promote, counterirritants for, 78 Acacia, 28, 29 Accelerator system, 150 depression, 151 stimulation, 150, 151 Acetanilid, 462 excretion, 468 untoward effects, 468 Acetanilid-salicylic acid, 462 Acetanilidum, 462 Acetates, 89 Acetic acid, 89 diluted, 89 glacial, 89 Aceto-arsenite of copper, 546 Acetonuria in anesthesia, 304 Acet-phenetidin, excretion, 468 untoward effects, 468 Acet-phenetidinum, 462 Acetum, 160 definition, 40 Acetyl-salicylic acid, 484 poisoning from, 485 Acid, acetanilid-salicylic, 462 acetic, 89 diluted, 89 acetyl-salicylic, 484 aconitic, 231 agaric, 412 arsenic, 541 arsenous, 541 solution of, 541 benzoic, 501 boric, as preservative, 500 poisoning from, 501 caffeotannic, 264 camphoric, 412 dose, 412 Acid, carbolic, 504. See also Phenol. burns from, alcohol as preventive, 354 t cinnamic, 501 citric, 88, 90 effect of, on clotting of blood, 89 in typhoid fever, 89 crotonic, 136 di-ethyl barbituric, 365 ergotinic, 567 filicic, amorphus, for tape-worms, 119 formic, 89 in rheumatism, 89 glacial acetic, 89 gymnemic, 109 hydriodic, diluted, 555 hydrochloric, therapeutics, 87 hydrocyanic, 426 diluted, 426 preparations, 426 therapeutics, 427 lactic, 89 for tuberculous ulcers of throat, 89 in diabetes, 90 malic, 90 nitric, 86 dilute, therapeutics, 88 for warts or nevi, 87 therapeutics, 87 nitrohydrochloric, 86 dilute, therapeutics, 88 diluted, 86 oxalic, 90 poisoning from, 90 para - sulphondi - chloramino- benzoic, 495 phenyl-cinchoninic, 487 in gout, 487, 488 phenyl-quinoline-carboxylic, 487 phosphoric, dilute, therapeutics, 88 phosphorous, 553 salicylic, 480 absorption, 481 administration, 484 as surgical antiseptic, 483 dose, 480 excretion, 482 hypodermatic use, 484 in bromidrosis, 483 607 6o8 INDEX Acid, salicylic, in chorea, 483 in corns, 483 in diabetes, 484 in gout, 484 in pain, 484 in rheumatism, 483 in skin diseases, 483 in sweating of feet and hands, 483 in warts, 483 intravenous administration, 484 pharmacologic action, 480-482 poisoning from, 482 preparations and doses, 480 rectal administration, 484 therapeutics, 483 toxicology, 482 succinyl disalicylic, 485 sulphuric, action of, 78 aromatic, 86 in night-sweats of tuberculosis, 88 sulphurous, 493 tannic, 29, 114 and alkaloids, incompatibility, 22 of coffee, 264 of tea, 265 therapeutics, 115 tartaric, 88, 90 trichloracetic, 89 trichlorethyl-glycuronic, 361 uric, 252 valerianic, 394 waters, 147 Acidol, 88 Acidosis in anesthesia, 304 sodium bicarbonate in, 95 Acids, caustic, 78 fruit, 90 inorganic, 86 action, 86 poisoning from, treatment, 87 therapeutics, 87 toxicology, 86 organic, 88 plant, and their salts, 20 Acidum aceticum, 89 citricum, 88 formicum, 89 lacticum, 89 nitrohydrochloricum, 86 salicylicum, 480 sulphuricum aromaticum, 86 tannicum, 114 tartaricum, 88 Acne, calcium sulphide in, 124 potassa sulphurata in, 1 24 Aconine, 231 Aconite, 231 absorption of, 232 administration, 236 constituents, 231 excretion, 235 fluidcxtract, dose, 231 Aconite in fevers, 236 in pain, 235 in reducing high arterial pressure in chronic interstitial nephritis, 233 in trifacial neuralgia, 236 pharmacologic action, 232-235 poisoning from, 235 treatment, 235 preparations and doses, 23 1 Squibb's test for, 232 therapeutics, 235 tincture, dose, 231 toxicology, 235 Aconitic acid, 231 Aconitine, 231 dose, 232 Aconitum, 231 napellus, 231 Acrinyl isothiocyanate, 26 Acroparesthesia, paroxysms of, quinine in, 477 Actinomycosis, copper sulphate in, 529 iodides in, 558 Active constituents of drugs, 19, 20 principles, 44 Adalin, 366 Addison's disease, epinephrine in, 205 Adenin, 252 Adeps, 30 lanae hydrosus, 32 Adjectives, Latin, 589 Administration, 52, 62 by hypodermatoclysis, 55 by inunction, 55 by mouth, 53 by rectum, 55 by skin, 55 by veins, 55 channel of, dose and, 51 frequency of, dose and, 52 hypodermatic, 53 advantages, 54 disadvantages, 54 intracutaneous, 54 intramuscular, 53, 54 intravenous, 55 methods, 53 subcutaneously, 53 superficial, 54 through lungs by inhalation, 55 time of, 56 dose and, 52 Adonidin, 161 Adonis vernalis, 160 Adrenaline, 196. See also Epinephrine. Adrenals, relation of thyroid gland to, 561 Adverbs, Latin, 590 /Ether, 284 /Ethylis carbamas, 366 chloridum, 312 Agar to give bulk and soft consistency to feces, 125 INDEX 609 Agar-agar to give bulk and soft consist- ency to feces, 125 Agaric acid, 412 deadly, 443 fly, 442, 443 Agaricin, 41 2 dose, 412 in excessive sweating, 412 Agaricus campestris, 443 Age, dose and, 48 Ague, brass founder's, 530 Air, superheated, 450 Albargin, 534 Albolene, liquid, 33, 125 solid, 33 ' Albuminuria, functional, iron in, 540 Alcohol, 316 absolute, 316 absorption, 323 as anhidrotic, 354 as antiseptic, 353 as cooling lotion, 353 as hypnotic, 354 as narcotic or sedative, 354 as preservative, 515 as preventive of carbolic acid burns, 354 contraindications, 355 dehydrated, 316 denatured, 316 deodorized, 316 diluted, 316 elimination, 341 ethyl, 316 fecundity and, 352 food value, 331-336 grain-, 316 heredity and, 352 in convalescence, 354 in diabetes, 343 in fever, 354 in gout, 343 in insomnia, 354 in shock, 354 in trigeminal neuralgia, 354 medicinal quantities, effects of. 352 methyl, 355 blindness from, 355, 356 poisoning from, 355 narcosis, stages, 331 pathologic effects on organs, 350 pharmacologic action, 321-343 poisoning from, 344 after-effects, 345 treatment, 345 preparations, 316 resistance to disease and, 352 salicyl, 25 stupor from, 344 therapeutics, 353 to furnish food and stimulation, 354 to harden skin, 354 39 Alcohol to prevent or check a cold, 354 tolerance, 343 toxicology, 344 wood, 355 Alcoholic liquids, 40 Alcoholism, acute, 344 treatment, 345 chronic, Korsakoff's psychosis in, 347 treatment, 347 cure of, 349 Lambert's treatment, 349 Ales, 317 Alimentary tract, effect of sodium bi- carbonate on, 94 Alkalies and alkaloids, incompatibility, 22 caustic, 78, 91 mild, 91 Alkaline saline waters, 147 waters, 147 Alkaloidal salts, 21 differences in physiologic actions, 24 solubility of, 21 Alkaloids, 20 and alkalies, incompatibility, 22 and bromides, incompatibility, 22 and iodides, incompatibility, 22 and iodine, incompatibility, 22 and mercuric chloride, incompatibility, 22 and tannic acid, incompatibility, 22 artificial, 23 incompatibles, 22 nomenclature, 21 occurrence, 22 opium, 373 isoquinoline, 373 phenanthrene, 373 physical character, 22 pure, 21 solubility of, 21 solubility of, 21 taste of, 22 Allyl isothiocyanate, 26 sulphocarbamide, 80 Almond, bitter, oil of, 25, 426 spirit of, 426 oil, 30 water, bitter, 426 Aloes, 133 dose, 133 pills of, 133 preparations, 133 tincture of, 133 Aloin, 26, 133 Aloinum, 133 Alum, 535 burnt, 536 waters, 147 Alumen, 535 exsiccatum, 536 Aluminis, 535 6io INDEX Aluminium, 535 acetate, solution of, 536 as antiseptic and disinfectant, 500 chloride in sweating of hands, feet, and axillae, 536 Aluminum, 535 Alypine, 423 Amanita muscaria, 442, 443 phalloides, 27, 442, 443 toxin, 27 verna, 443 Amaroids, 26 Amaurosis, quinine, 474 Amblyopia, quinine, 474 tobacco, 435 Amebic colitis, quinine in, 476 dysentery, calcium permanganate in, S4i emetine in, 566 ipecac in, 566 quinine in, 478 American hellebore, 236 Aminopurins, 252 Ammonia, absorption of, 219 effects after, 222 administration, 222 aromatic spirit, 218 as antacid carminative, 223 as counterirritant, 222 as expectorant, 223 as reflex circulatory stimulant, 222 respiratory stimulant, 222 chloride of, 223 contraindication, 223 elimination of, 222 liniment, 218 liver in disposal of, 220 muriate of, 223 pharmacologic action, 218-222 poisoning from, 222 treatment, 222 preparations, 218 therapeutics, 222 toxicology, 222 water, 218 stronger, 218 Ammoniated mercury, ointment of, as antiseptic, 519 tincture of valerian, 107 Ammonium, 218 acetate, 224 solution of, 224 alum, 535 benzoate, 225 bromide, 225 carbonate, 218 chloride, 223 absorption of, 223 action of, 223 excretion of, 224 in acute pharyngitis, 224 in bronchitis, 224 Ammonium chloride in laryngitis, 224 pharmacologic action, 223, 224 therapeutics, 224 preparations, 218 salicylate, 225 valerate, 225 Amorphous filicic acid for tape-worms, 119 Amygdala amara, 426 Amygdalin, 25 Amyl nitrite, 239 dose, 239 effect, 242 in angina pectoris, 245 in chloroform collapse, 245 Amylene hydrate, 366 Amylis nitris, 239 Amylum, 28 Analgesia, spinal, with cocaine, 414, 421 Analgesic antipyretics, 462 administration, 470 in pain, 470 pharmacologic action, 463-468 therapeutics, 469 to overcome fever, 470 toxicology, 468, 469 Anaphylactic shock, epinephrine to check, 205 Anaphylaxis, atropine in, 408 Anatomic material, preservatives for, 515 Anemia, cholesterol in, 32 iron in, 540 lecithin in, 555 pernicious, cholesterol in, 32 sodium cacodylate in, 542 transfusion of blood in, 226 Anesthesia, acetonuria in, 304 acidosis in, 304 atropine as preliminary to, 408 Bier's vein, 422 by intratracheal insufflation, 307 by pharyngeal insufflation. 309 chloroform, 292, 300 advantages, 300 collapse in, amyl nitrite in, 245 camphor in, 309 treatment, 309 contraindications, 304 dangers, 301-304 delayed poisoning from, 302 intravenous, 307 phagocytic activity of leukocytes after, 305 preventive measures in, 304 cocaine hydrochloride, 420 collapse in, oxygen in, 580 treatment, 309 colonic, 306 cyanosis in, treatment, 309 effect, on immunity, 305 on infections, 305 Epsom salt, 313 INDEX Anesthesia, ether, 292 administration, general remarks, 305 of sodium bicarbonate, 299 after-effects, 297 chloretone as preliminary to, 364 collapse in, 296 saline infusion in, 309 treatment, 309 conjunctivitis after, 298 danger-signs, 296 distention of stomach and intestines for, 297 first stage, 294 fourth stage, 296 having stomach empty, 299 helpful measures in, 298 indications, 299 injection of atropine sulphate in, 299 intravenous, 307 kidneys after, 298 nausea after, 297 pain in back after, 297 phagocytic activity of leukocytes after, 305 postoperative gastric or intestinal paralysis after, 298 preliminary administration of seda- tive drugs, 298 anesthetization with chloroform, 298 with nitrous oxide or ethyl chloride, 298 feeding with carbohydrates and water, 299 preventive measures in, 298 reassuring patient, 299 recovery from, 297 respiratory troubles after, 298 second stage, 295 sore tongue after, 298 third stage, 295 thirst after, 297 untoward sequels, 298 vomiting after, 297 warming vapor, 299 ethyl bromide, 313 chloride, 312 false, 297 Gwathmey's oil-ether colonic method, 306 intravenous, 307 Bier's, 425 local, 425 paraldehyd for, 307 with chloroform, 307 with cocaine, 422 with ether, 307 laughing-gas, 310 local, epinephrine to prolong, 205 magnesium sulphate, 313 morphine as preliminary to, 387 nitrogen monoxide, 310 Anesthesia, nitrous oxide, 310 objects, 292 pulse in, 309 rectal, 306 Schleich's infiltration, 425 scopolamine-morphine, 409 scopolamine-narcophin, 409 spinal, in strychnine poisoning, 279 with cocaine, 414, 415, 421 with stovaine and strychnine, 41 e therapeutics, 310 untoward symptoms, treatment, 309 Anesthesin, 424 A/iesthetics, general, 284 Aneurysm, gelatin in, 71 of aorta, digitalis in, 195 Angina pectoris, amyl nitrite in, 245 Hoffmann's anodyne in, 288 Angioneurotic edema, calcium in, 100 Anhidrotics, 411 Animal charcoal, 109 purified, 109 experimentation, 58 Ankylostoma americana, treatment, 117 Anoci-association, Crile's, 249, 250 Anodyne, Hoffmann's, dose, 284 in angina pectoris, 288 in dyspnea, 288 in hysteria, 288 in spasm, 288 therapeutics, 288 Antacids, 91 as antemetics, 112 not of alkaline reaction, 101 of alkaline reaction, 91 Antagonists, 57 Antemetics, 112 Anthelmintics, 115 Anthracene derivatives, 131 action on bowel, 132 therapeutics, 132 Anti-bitters, 109 Anti-diarrheics, 146 Antiformin, 494 Antihysterics, 393 Anti-malarial antipyretics, 470 Antimony, 552 and potassium tartrate, 552 in kala-azar, 552 in Leishmaniosis, 552 in malaria, 552 in oriental sore, 552 in trypanosomiasis, 552 pharmacologic action, 552 poisoning, 552 preparations and doses, 552 wine of, 552 Antiphlogistine, 76 Antipyretic drugs, 461 Antipyretics, 461 analgesic, 462 administration, 470 6l2 INDEX Antipyretics, analgesic, in pain, 470 pharmacologic action, 463-468 therapeutics, 469 to overcome fever, 470 toxicology, 468, 469 anti-malarial, 470 antirheumatic, 480 Antipyrina, 462 Antipyrine, 24, 462 excretion, 468 in chorea, 469 in diabetes, 469 in nasal hemorrhage, 469 in tuberculous laryngitis, 469 in whooping-cough, 469 pharmacologic action, 463-468 poisoning from, 468, 469 salicylate, 462 therapeutics, 469 untoward effects, 468 Antirheumatic antipyretics, 480 Antiseptic iodine compounds, 499 solution, 504 Antiseptics, 488 classification, 491 psychic, 504 tests for value, 489 Antispasmodics, 393 Antisyphilitics, mercury preparations, Antithyroid preparations, 562 Antithyroidin, 562 Antitoxins, preservatives for, 515 Anuria, glucose in, 70 Anus, diseases of, cocaine in, 421 itching of, epinephrine, in, 205 Aorta, aneurysm of, digitalis in, 195 Aortic insufficiency, digitalis in, 193 stenosis, digitalis in, 194 Aortitis, digitalis in, 195 Aperient, 122 Apocodeine, 388 as cathartic, 124 Apocynein, 160 Apocynin, 160 Apocynum, 160 Apolysin, 463 Apomorphine, 23 hydrochloride, in Apothecaries' system, prescriptions of, weights and measures, 43 exact equivalents, 44 Appalache tea, 253 Appetite gastric juice, 107 juice, 324 Apple, bitter, dose, 13? cider, 318 Apple-brandy, 319 Aqua, 39 ammonia;, 218 fortior, 218 Aqua amygdalae amarse, 426 Aqueous liquids, 39 Arabinose, 28 Areas, Head's, 74 Argentum, 533 Argyria, 535 conjunctival, 535 Argyrol, 534 Arhythmia from digitalis, 166 phasic, from digitalis, 166, 176 sinus, digitalis in, 189 from digitalis, 166 Aristol, 490, 504 Aromatic bitters, 108, 109 elixir, 106, 320 spirit of ammonia, 218 sulphuric acid, 86 Aromatics, 102 for prescription, 585 pharmacologic action, 102-104 Arrowroot starch, 28 Arsacetin, 542 Arsenic, 541 absorption, 543 acid, 541 administration, 549 excretion, 545 melanosis, 548 organic compounds, 541 pharmacologic action, 543-546 poisoning, acute, 546 iron as antidote, 537, 547 treatment, 547 chronic, 547 treatment, 548 cumulative, 547 preparations and doses, 541 therapeutics, 548 tolerance, 545 toxicology, 546 trioxide, 541 white, 541 Arsenical waters, 147 Arsenic-eaters, 545 Arseniureted hydrogen, 546 Arsenophenylglycin, 542 Arsenous acid, 541 solution of, 541 iodide, 541 Arsenum, 541 Arterial dilators, 239 pressure, 154 high, digitalis in, IQI in chronic interstitial nephritis, aconite for reducing, 233 increased, from digitalis, 1 70 raising, mechanical measures for, 225 regulators of, 155 Arteries, blood in, decrease of, causes, 149 increase of, causes, 149 changes in caliber, 152 INDEX 6i3 Arteries, conditions of, influence, on use- fulness of digitalis, 192 connective-tissue changes in, from epinephrine, 201 contraction of, 153 coronary, constriction of, from digi- talis, 176 cutaneous, action of digitalis on cir- culation through, 180 dilatation of, 153 measures for increasing volume of blood, in, 225 peripheral, contraction of, from digi- talis, 178 pulmonary, action of digitalis on cir- culation through, 180 systemic, action of digitalis on circula- tion through, 178 Arterioles as regulators of arterial pres- sure, 155 cutaneous, caliber, 154 Arteriosclerosis, digitalis in, 195 from smoking, 435 Arthritis, dry, vaseline in, 33 magnesium sulphate in, 315 rheumatoid, liquid petrolatum in, 33 thyroid gland in, 562 Artificial alkaloids, 23 emulsion, 40 leech, 248 respiration in strychnine poisoning, 2/9 Asagraea officinalis, 237 Ascaris lumbricoides, remedies for, 116 Aspergillus oryzae, 85 Aspidium, oleoresin of, for tape-worms, iiQ , poisoning from, 119 Aspidosperma as expectorant, 563 Aspidospermine as expectorant, 563 Aspirin, 484 poisoning from, 485 Assay processes, 44 Assayed drugs, 44 Asthma, anterior lobe extract of pituitary gland in, 211 bronchial, calcium in, 100 epinephrine in, 202 oxygen in, 580 potassium nitrate in, 240 powders, 245 spasmodic, lobelia in, 428 sparteine suphate in, 428 stramonium in, 408 tobacco in, 430 Astringents, 113 metallic, 113 vegetable, 114 Ataxia, locomotor, salvarsan in, 550 Atophan, 487 Atoxyl, 542 Atropa belladonna, 394 Atrophy, pigment, in morphinism, 386 Atropine, 395 absorption, 397 administration, 406 and morphine in hypodermatic use, 389 as preliminary to general anesthesia, 408 elimination, 404 in anaphylaxis, 408 in diabetes, 398 in diseases of eye, 407 in exophthalmic goiter, 408 in hyperthyroidism, 408 in obstipation, 407 in pain, 403 in serum sickness, 408 in spasmodic nervous conditions, 407 pharmacologic action, 396-405 poisoning from, 405 treatment, 406 solubility of, 21 sulphate, 396 injection, in ether anesthesia, 299 solubility of, 21 therapeutics, 406 to check excessive vagus action, 408 to depress sensory nerve-endings, 407 to diminish secretion, 406 to relax overcontracted smooth muscle, 406 to stimulate respiration, 408 tolerance, 405 toxicology, 405 Auricular fibrillation, digitalis in, 190, 194 _ from digitalis, 170 flutter, digitalis in, 189 from digitalis, 170 Auriculoventricular bundle, action of digitalis on circulation through, 171 Axilla, sweating of, aluminium chloride in, 536 Axillary sup, 231 BACK, pain in, after ether anesthesia, 297 Bacterial infections, quinine in, 477 Baking soda, 92 Balsam gauze, 501 of Peru, 501 Balsams, 36 Barbaloin, 133 Barium, 212 action of, 212 poisoning from, 212 Barnes' medicine dropper, 584 Basham's mixture, 224, 225, 538 Bath, bed-, 461 cold, 461 electric, 445 foot-, mustard, 77 614 INDEX Bath, hot-air, 445 Nauheim, as circulatory stimulant, 157 Russian, 444 tub-, 461 Turkish, 444 vapor, 445 Beck's treatment of chronic sinuses, 532 Bed-bath, 461 Beebe's serum, 562 Beer, 317 lager, 317 Beeswax, 32 Belladonna, 394, 395 administration, 406 constituents, 395 dose, 395 elimination, 404 extracts, 396 fluidextracts, 396 group, 394 pharmacologic action, 396-405 preparations and doses, 395 leaves, tincture, 396 liniment, 396 occurrence, 394 ointment, 396 pharmacologic action, 396-405 plaster, 396 poisoning from, 405 treatment, 406 therapeutics, 406 to depress sensory nerve-endings, 407 to diminish secretion, 406 tolerance, 405 toxicology, 405 Benedictine, 320 Benzaconine, 231 Benzaldehyde, 106 Benzene, 577 Benzin, 33 Benzine, 576 poisoning, 571 Benzinum purificatum, 33 Benzoic acid, 501 Benzoin, 501 compound tincture of, 133 Benzol, 577 in leukemia, 577, 578 in lymphoid leukemia, 578 in myeloid leukemia, 578 in polycythemia, 578 in pseudoleukemia, 578 poisoning, 577, 578 Benzosulphinide, 68 Benzoyl ester of pseudo-tropine chloride, 423 Benzoyl - tetramethyl-diamino-ethyl-iso- propylic alcohol chloride, 423 Berherine, 572 Bernard's experiment with strychnine, Beta-eucaine chloride, 423 lactate, 423 Beta-iminazolylethylamine, 567 effect on circulation, 570 Beta-naphthol, 504 Beverages, caffeine, 264 Bhang, 392 Bichloride of mercury as disinfectant, Si8 dose, 520 in malaria, 521 Bier's intravenous local anesthesia, 425 vein anesthesia, 422 Bile, 126 salts, 126 Biliousness, calomel in, 131 Bismuth, 531 as antiseptic and disinfectant, 500 in gastric irritation, 532 in intestinal irritation, 532 in nausea, 532 in vomiting, 532 milk of, 531, 532 poisoning, 531 subcarbonate, 531 subgallate, 531 subnitrate, 531 with vaseline in chronic sinuses and tuberculous cavities, 532 therapeutics, 532 treatment for sinuses, 532 Bismuthum, 531 Bites, dog-, caustics for, 79 Bitter almond, oil of, 25, 426 spirit of, 426 water, 426 apple, dose, 137 principles, 26 Bitters, 107 anti-, 109 aromatic, 108, 109 simple, 108 Black snakeroot, 488 tea, 265 wash, 520 Blackwater fever, quinine in, 478 Bladder, catheterization of, in strychnine poisoning, 279 disinfectants, 516 Blaud's pills, 537 Bleeding from nose, counterirritants for, 7 8 Blindness from methyl alcohol, 355, 356 Blister, fly-, 77 Blistering, 72, 73 Blood, capillary flow of, alterations in, 149 clotting of, effect of citric acid on, 89 coagulation of, effect of calcium on, 99 effect of iron on, 539 in arteries, decrease of, causes, 149 increase of, causes, 149 INDEX 615 Blood in heart, output of, influences affecting, 149 transfusion of, 225 conditions indicating, 226 in anemia, 226 in carbon monoxide poisoning, 576 in collapse, 226 in hemophilia, 227 in hemorrhage, 226 in infectious conditions, 227 in malnutrition, 227 in prostration, 227 in protracted weakness, 227 in sepsis, 227 in shock, 226 and collapse, 251 Lindemann's method, 226 Satterlee and Hooker's method, 226 volume of, in arteries, measures for increasing, 225 measures for decreasing, 245 Blood-letting, 245, 247 Blood-pressure, remedies which lower, 231 Blood-supply of brain, 154 of heart, 154 Blood-vessels, 152 Blue ointment as antiseptic, 519 pill, 131 Body heat, methods of raising, 444 Bone-black, 109 Borax as preservative, 500 in epilepsy, 500 Boric acid as preservative, 500 poisoning from, 501 Boroglycerin, glycerite of, 501 Boro-sal, 480, 500 Bowel splint, 375, 376 Brain, blood-supply, 154 wet, 348, 350 Brandy, 319 apple-, 319 French, 319 milk-punch, 320 pear-, 319 Brass founder's ague, 530 shakes, 530 Brazier's chills, 530 Breathing, Cheyne-Stokes, 377 British gum, 29 Brom-di-ethyl-acetyl-carbamide, 366 Bromides, 367 absorption, 368 and alkaloids, incompatibility, 22 dose, 367 elimination, 369 in cardiac excitability, 371 in convulsions, 371 in nervous affections, 371 in pain, 371 in strychnine poisoning, 279 in vomiting, 371 Bromides, pharmacologic action, 368- 370 poisoning from, acute, 370 chronic, 370 treatment, 371 rash from, 369, 370 therapeutics, 371 to lessen nervous irritability, 371 sexual hyperesthesia, 371 to quiet reflexes, 371 toxicology, 370 Bromidrosis, salicylic acid in, 483 Bromine, 498 waters, 147, 498 Bromipin, 372 in epilepsy, 372 Bromism, 370 Bromoform, 372 in whooping-cough, 372 poisoning from, 372 Bromural, 366 Bronchi disinfectants, 517 Bronchial asthma, calcium in, 100 epinephrine in, 202, 205 oxygen in, 580 potassium nitrate in, 240 muscles, action of strychnine on, 276 Bronchitis, ammonium chloride in, 224 chronic, cod-liver oil in, 72 Broom, 428 Brown mixture, 563 Brucine, 268 Buckthorn, 133 Bum mixture, 288 Bundle, auriculoventricular, action of digitalis on circulation through, 171 Burns, carbolic acid, alcohol as prevent- ive, 354 Burnt alum, 536 Burow's solution, 525, 536 Butter, 30 cocoa-, 30, 267 Butyl chloral hydrate, 363 in trifacial neuralgia, 363 CACAO-BUTTER, 30, 267 Cade, oil of, 35, 504 Caffeina, 253 citrata, 253 effervescens, 253 Caffeine, 252, 253 absorption, 254 administration, 263 allies, 263 as emergency heart stimulant, 262 as stimulant, 262 as tonic, 262 beverages, 264 citrated, 253 diuresis, 258, 260, 261 diuretic action, 456 6i6 INDEX Caffeine, dose, 253 effervescent citrated, 253 excretion, 258 group, 252 in collapse, 262 in dropsy, 262 in night dyspnea of heart cases, 262 pharmacologic action, 254-261 poisoning from, 261 treatment, 261, 262 preparations and doses, 253 sodio-benzoate, 253 sod io-salicy late, 253 strychnine and, comparison of action, 275 therapeutics, 262 toxicology, 261 Caffeol, 264 Caff eon, 264 Caffeotannic acid, 264 Calabar bean, 436 Calabarine, 436 Calamine, 530 lotion, 530 Calcii carbonas praxipitatus, 97 Calcium, 97 absorption, 98 carbonate, 97 chloride, 97 in pleural effusion, 100 effect in intestines, 100 on coagulation of blood, 99 glycerophosphate, 554 hydroxide, 97 in angioneurotic edema, 100 in bronchial asthma, 100 in chilblains, 100 in clotting of milk by rennet, 99 in diabetes, 100 in edema, 100 in hay-fever, 100 in hemorrhage, 100 in nervous diseases, 100 in serum-sickness, 100 in tetany, 98, 100 in transudation, 100 lactate, 97 permanganate, 541 pharmacologic action, 97-100 poisoning, 100 preparations, 97 sulphide in acne, 124 in mercury poisoning, 524 therapeutics, 100 Calculus, ureteral, papaverine in, 390 Calisaya, 470 Calomel, 129 administration, 130 diuretic action, 457, 521 in biliousness, 131 in croupous laryngitis, 521 in sluggish liver, 131 Calomel in venereal sores, 519 therapeutics, 131 Camphor, 107, 213 absorption of, 214 administration, 217 as anti-diarrheic, 217 as antipyretic, 217 as carminative, 217 as cooling application, 217 as counterirritant, 217 as stimulant and antiseptic to mucous membranes, 217 chloral-, 213, 217, 359 elimination of, 216 in chloroform collapse, 309 in colds, 217 in collapse, 217 in diarrhea, 217 in fever, 217 in hysteric conditions, 217 in nervous instability, 217 in pneumonia, 217 in shock, 217 liniment, 213 local uses, 217 menthol-, 213, 217 monobromated, 213 pharmacologic action, 213-216 poisoning from, 216 preparations and doses, 213 spirit of, dose, 213 therapeutics, 217 toxicology, 216 water, dose, 213 Camphora, 213 monobromata, 213 Camphorated oil, 213 tincture of opium, dose, 373 Camphoric acid, 412 dose, 412 Canadine, 572 Cane-sugar, 27, 69 in leucorrhea, 69 Cannabinine, 392 Cannabinol, 392 Cannabis, 392 constituents, 392 extract, dose, 392 fluidextract, dose, 392 pharmacologic action, 392 preparations and doses, 392 saliva, 392 therapeutics, 393 Cantharides, 77 Cantharis, 77 vesicatoria, 77 Capillary flow of blood, alterations in. 149 Carbo animalis, 109 ligni, IOQ Carbohydrates and water, preliminary feeding with, in ether anesthesia, 299 INDEX 617 Carbolic acid, 504. See also Phenol. burns, alcohol as preventive, 354 Carbon dioxide in collapse, 252 in shock, 252 therapeutics, 79 monoxide, 574 poisoning from, 574 acute, 575 chronic, 575 oxygen in, 580 transfusion of blood in, 576 treatment, 576 Cardamom, compound tincture, 107 Cardiac depressants, 231 excitability, bromides in, 371 insufficiency, edema of, diuretics in, 456 muscle, action of digitalis on circula- tion through, 1 66 Carica papaya, 85 Carminatives, 102 as antemetics, 112 as anthelmintics, 105 as anti-asthmatics, 105 as anticolics, 104 as antihysterics, 105 as antirheumatics, 105 as antiseptics, 105 and anesthetics, 105 as bronchial stimulants, 105 as correctives, 105 as counterirritants, 105 as diuretics, 105 as emmenagogues, 105 as odors and flavors, 104 as stimulants in chronic skin diseases, 105 to growth of hair, 105 to mucous membranes of nose and throat, 105 as urinary antiseptics, 105 compound tinctures, 107 doses, 107 elimination of, 104 elixirs, 106 fluidextracts, 107 in leprosy, 105 in tympanites, 105 pharmacologic action, 102-104 poisoning from, 104 preparations, 106 simple aromatic tinctures, 107 spirits, 106 therapeutics, 104 tinctures, compound, 107 simple aromatic, 107 toxicology, 104 volatile oils of, 106 waters, 106 Cascara sagrada, 133 Castile soap, 30, 31, 127 Castor oil, 30, 127 Castor oil, administration, 128 therapeutics, 128 Castor-lax, 128 Cataplasma, definition, 42 kaolini, 76, in Cathartic enema, 143 as softening agent, 143 to soften feces, 144 measures, 122 apocodeine, 124 cereals, 123 drugs, 124 exercises, 122 fixed oils, 127 foods, 123 fruits, 124 glycerin, 127 habit formation, 122 massage, 123 mechanical agents to give bulk and soft consistency to feces, 124 physostigmine salicylate, 124 pituitary extract, 124 response to desire to defecate, 122 salads, 123 soaps, 127 vegetables, 123 water, 124 mercurials, 129 pills, compound, 131, 133, 137 vegetable, 137 Cathartics, 119 acting by selective affinity, 124 cramp from, 121 griping from, 121 saline, 137 doses, 138 in constipation, objections, 143 Moreau's loop and, 141 pharmacologic action, 139-142 preparations, 138 therapeutics, 142 time to give, 56 Catheterization of bladder in strychnine poisoning, 279 Caustic acids, 78 alkalies, 78, 91 lunar, 533 metallic salts, 78 Caustics, 78 therapeutics, 79 toxicology, 79 Cauterize, 79 Cautions, 63 Cecum as factor in defecation, 120 Cells, effect of drugs on, 57 Cellulitis, magnesium sulphate in, 315 Central emetic, in nervous stimulants, 252 system, remedies acting on, 252 which depress, 282 sedatives as antemetics, 112 6i8 INDEX Cephaeline, 564 Cephaelis acuminata, 564 ipecacuanha, 564 Cera alba, 32 flava, 32 Cerate, definition, 42 Ceratum, definition, 42 Cereals as cathartic measure, 123 Cerebral circulation, adequate, main- tenance of, 155 congestion, counterirritants for, 78 depression from hypnotic drugs, 358 Cerebrospinal fluid, effect of pituitary extract on, 210 syphilis, neosalvarsan in, 550 salvarsan in, 550 Cerium, 532 in nausea, 532 in vomiting, 532 oxalate, 532 Cetaceum, 32 Cetyl palmitate, 32 Cevadilline, 237 Cevadine, 236 pharmacologic action, 237 Chalk, drop-, 97 mixture, 97 powder, compound, 97 precipitated, 97 prepared, 97 Chalybeate waters, 147 Chamomillin, 26 Charcoal, 109 animal, 109 purified, 109 wood-, 109, no Charta, definition, 42 sinapis, 77 Chartreuse, 320 Chemic incompatibility. 603 percentage liquid, 38 Chemical relationships ot phenol group of disinfectants, 502 Chemistry, pharmaceutic, 18 Chenopodium, oil of, for hookworms, 117 for pin-worms, 1 1 8 for round-worms, 118 for tape-wo r ms, 118 for whip- worms, 1 1 8 poisoning from, 118 Cherry, wild, fluidextract of, 426 infusion of, 426 syrup of, 426 Cherry-gum, 29 Chewing-tobacco, 429 Cheyne-Stokes' respiration, 377 Chilblains, calcium in, 100 Children, doses for, 48 Chills, brazier's, 530 spelter, 530 zinc, 530 Chloral hydrate, 245, 358 Chloral hydrate, absorption, 359 administration, 363 as circulatory depressant, 363 as hypnotic, 362 as motor depressant, 363 cautions, 363 contraindications, 363 elimination, 361 in obstetrics, 363 in pain, 363 in strychnine poisoning, 279 in toothache, 362 pharmacologic action, 359-362 poisoning from, acute, 362 chronic, 362 therapeutics, 362 toxicology, 362 untoward effects, 362 Chloralamide, 363 Chloral-camphor, 213, 217, 359 Chloralformamidum, 363 Chloralism, 362 Chloralum hydratum, 358 Chloramins, 494 Chlorazene, 498 Chlorbutanol, 363, 424 Chloretone, 363, 424 as preliminary to ether anesthesia, 364 in seasickness, 364 Chloride of ammonia, 223 of lime, 494 Chlorinated lime, 494 Chlorine, 494 water, 494 Chloroform, 289 and epinephrine, simultaneous use, effects, 204 anesthesia, 292, 300 advantages, 300 camphor in, 309 collapse in, amyl nitrite in, 245 treatment, 309 contraindications, 304 dangers, 301-304 delayed poisoning from, 302 intravenous, 307 phagocytic activity of leukocytes after, 305 preventive measures in, 304 as antemetic, 292 as antihysteric, 292 as carminative, 292 as rubefacient, 292 dose, 289 elimination, 291 for tape- worms, 119 habit, 292 in colic, 292 in flatulence, 292 in pain, 202 in toothache, 292 INDEX 6lQ Chloroform in vomiting, 292 inhalations in strychnine poisoning, 279 liniment, 213, 289 pharmacologic action, 289-292 poisoning, delayed, 302 preliminary administration, in ether anesthesia, 298 preparations and doses, 289 spirit, dose, 289 therapeutics, 292 water, dose, 289 Chloroform-acetone, 363 Chloroformum, 289 Chlorosis, iron in, 540 Chlumsky's solution, 509 Chocolate, 253, 264, 267 Cholagogue, 122 Cholera drops, Sun, 213 kaolin in, no mixture, Sun, 146 purified animal charcoal in, no saline infusion in, 230 Cholesterol, 32 in anemia, 32 in pernicious anemia, 32 Choline, 567 Chorea, antipyrine in, 469 magnesium sulphate in, 315 salicylic acid in, 483 Chrome holes, 79 Chromium trioxide, 79 Chrysarobin, 26, 81 in psoriasis, 81 Churchill's tincture of iodine, 499 Cider, apple, 318 pear, 318 Cimicifuga, 488 in gout, 488 in rheumatism, 488 Cinchona, 470 administration, 478 compound tincture of, 109 dose, 470 constituents, 470 fluidextract, dose, 470 pharmacologic action, 471-476 preparations and doses, 470 rubra, 470 tincture, dose, 470 Cinchonidine, 470 sulphate, 471 Cinchonine, 470 sulphate, 471 Cinchonism, 476 Cinnaldehyde, 106 Cinnamic acid, 501 Cinnamomum camphora, 213 Cinnamon, oil of, 504 Cinnamyl-cocaine, 412 Circulation, cerebral, adequate, main- tenance of, 155 Circulation, coronary, 151 adequate maintenance of, 155 physiology of, 148 pulmonary, 155 remedies whose chief action is upon, 148 Circulatory organs, functions, 148 stimulants, 157 Citrate of iron and quinine, 538 and strychnine, 538 dose, 269 Citra'ted caffeine, 253 effervescent, 253 Citrates, 90 Citric acid, 88, 90 effect of, on clotting of blood, 89 in typhoid fever, 89 Citrine ointment as antiseptic, 519 Citrophen, 463 Clark's rule for dosage, 48 Clay poultice, 76 Clitocybe illudens, 443 Clotting of blood, effect of citric acid on, 89 of milk by rennet, calcium in, 99 Cloves, oil of, 504 Coagulation of blood, effect of calcium on, 99 of citric acid on, 89 Coca, 412 wine of, therapeutics, 420 Cocaine, 412 as diagnostic agent in tic, 421 excretion, 418 habit, 420 treatment, 420 hydrochloride, 412 as anesthetic, 420 in collapse from narcotic drugs, 422 in diseases of anus, 421 of esophagus, 421 of nose, 420 of stomach, 421 of throat, 421 in itching of vulva, 421 in spasm of urethra, 421 in vaginismus, 421 intravenous anesthesia with, 422 pharmacologic action, 413-419 poisoning, 419 Magnan's sign in, 419 treatment, 419 spinal anesthesia with, 414, 415, 421 substitutes, 422 therapeutics, 420 toxicology, 419 untoward effects, 418 Cocktail, 320 Cocoa, 30, 268 nibs, 267 Cocoa-butter, 30, 267 Cocoanut oil, 30 62O INDEX Codeine, 373, 388 dose, 373 in cough, 388 in diabetes, 387, 388 in pain, 388 phosphate, 373 sulphate, 373 Cod-liver oil, 30, 71 in chronic bronchitis, 72 in malnutrition, 72 in poor nutrition, 72 in rickets, 72 in spasmophilia, 72 in tuberculosis, 72 preparations and doses, 72 therapeutics, 72 Coffee, 253, 264 habit, 266 pharmacologic action, 265,266 tolerance, 266 Cognac, 319 Colchicine, dose, 487 Colchicum, 486 autumnale, 486 in gout, 487 pharmacologic action, 487 poisoning from, 487 preparations and doses, 487 Cold, 76, 461 as preservatives, 492 bath, 461 quinine in, 477 Cold-pack, 461 Colds, camphor in, 217 Colic, chloroform in, 292 lead, 526 painter's, 526 Colitis, amebic, quinine in, 476 silver nitrate in, 534 Collapse, 248 caffeine in, 262 camphor in, 217 carbon dioxide in, 252 counterirritants for, 78 epinephrine in, 206, 251 from narcotic drugs, cocaine in, 422 in anesthesia, oxygen in, 580 treatment, 309 in chloroform anesthesia, amyl nitrite in, 245 camphor in, 309 treatment, 309 in ether anesthesia, 296 saline infusion in, 309 treatment, 309 massage of heart in, 251 mechanical measures in, 225, 251 mild and transitory, 250 moderate degree, 250 pituitary' extract in, 251 respiratory paralysis and, 249 saline infusion in, 230 Collapse, severe, 250 stimulants in, 251 symptoms, 250 transfusion of blood in, 226, 251 treatment, 250 prophylactic, 250 Collargol, 534 Collodion, definition, 41 Collodium, definition, 41 Colloid goiter, iodides in, 559 thyroid gland in, 562 Colloidal silver, 534 Colocynth, compound extract of, 133, 137 dose, 137 dose, 137 Cologne spirit, 316 Colon as factor in defecation, 120 irrigations of saline solution, 145 Colonic anesthesia, 306 Colors for prescription, 586 Coma, 282 Compensation of heart, 156 failure, 156, 157 digitalis in, 194 threatened failure, 157 Compound cathartic pills, 131, 133, 137 chalk powder, 97 cresol solution, 503 extract of colocynth, 133, 137 dose, 137 jalap powder, dose, 137 laxative pills, dose, 269 licorice mixture, 563 powder, 552 morphine powder, 374 pharmaceutic preparations, 39 rhubarb pills, 133 solution of iodine, 555 spirit of ether, dose, 284 of juniper, 319 of orange, 320 syrup of hypophosphites, 554 dose, 269 of squill, 1 60, 552 as expectorant, 564 tincture of benzoin, 133 of cardamom, 107 of cinchona, 109 dose, 470 of gambir, 114 of gentian, 109 of lavender, 107 Compressed tablets, 587 definition, 41 Confectio, definition, 42 Confection, definition, 42 Congestion, cerebral, counterirritants for, 78 counterirritants for, 78 Conium, 427 fluidextract, 427 INDEX 621 Conjunctions, Latin, 591 Conjunctival argyria, 535 Conjunctivitis after ether anesthesia, 298 copper sulphate in, 529 zinc sulphate in, 530 Connective-tissue changes in heart and arteries from epinephrine, 201 Constipation, 119 chronic, hormonal in, 85 saline cathartics in, objections, 143 Contraction of peripheral arteries from digitalis, 178 Contraindications, 63 Convalescence, alcohol in, 354 Convallamarin, 160 Convallaria, 160, 184 majalis, 160 Convallarin, 160 Convulsions, bromides in, 371 magnesium sulphate in, 315 Convulsive center, action of digitalis on, 183 reflexes, 272 f rom strychnine, 272 Coordinated reflexes, 272 Copper, 529 aceto-arsenite of, 546 as antiseptic and disinfectant, 500 poisoning, 529 therapeutics, 529 Copperas as disinfectant, 536 Cordials, 320 Cornea, ulcer of, ethylhydrocupreine in, 479 Corns, salicylic acid for, 483 Cornstarch, 28 Coronary arteries, constriction, from digitalis, 176 circulation, 151 adequate, maintenance of, 155 Corrosive sublimate as disinfectant, 518 Cotarnine, 23 hyclrochioride, 574 Cottonseed oil, 30 Cough, codeine in, 388 lactucarium lozenges in, 393 morphine in, 378, 387 papaverine in, 390 strychnine in, 276 Counterirritants, 72 as antemetics, 112 cautions, 78 measures, 75 mode of action, 73 therapeutics of, 78 Counterirritation, 72 Cowling's rule for dosage, 49, 595 Coxe's hive syrup, 552 as expectorant, 564 Cramp from cathartics, 121 Cream of tartar, 101, 102 dose, 138 Crede's method of prophylaxis against gonorrheal ophthalmia, 533 Creme de menthe, 320 Cr ernes, 320 Creolin, 503 Creosote, 35, 503 carbonate, 503 Cresol, 503 solution, compound, 503 Creta praeparata, 97 Cretinism, thyroid gland in, 562 Crile's anoci-association, 249, 250 pneumatic suit in shock, 225, 251 Croton oil, 30, 136 dose, 137 Crotonic acid, 136 Croup, mercury subsulphate in, 521 Croupous laryngitis, calomel in, 521 Crude drugs, 19 Crystalline gratus strophanthin, 161 elimination, 183 Cumulative poison, 47 Cupping, dry-, 76, 247 wet-, 247 Cuprum, 529 Curare, 427 Curarine, 427 Cutaneous arteries, action of digitalis on circulation through, 180 arterioles, caliber, 154 Cyanides, 426 pharmacologic action, 426 poisoning from, 426 treatment, 427 preparations, 426 Cyanosis in anesthesia, treatment, 309 oxygen in, 580 Cycloplegic, definition, 403 Cymarin, 160 Cystogen, 512 D AKIN-CARREL treatment, 495 Dakin's solution, preparation, 495, 496 Daufresne's technic, 495 test for alkalinity, 497 titration, 497 Dale's vasomotor reversal, 569 Dating prescription, 582 Datura stramonium, 394 Daufresne's technic for preparation of Dakin's solution, 495 Dawson's solution for saline infusion, 227 Deadly agaric, 443 nightshade, 394 Deafness from smoking, 435 Death's-head fungus, 442, 443 Decapsulation of kidneys in mercury poisoning, 524 Decoction, definition, 40 Decoctum, definition, 40 622 INDEX Defecate, response to desire to, as cathartic measure, 122 Defecation, mechanical factors of, 120 cecum and colon, 120 small intestine, 120 Degeneration, fatty, of heart, digitalis in, 192 Dehydrated alcohol, 316 Delayed chloroform poisoning, 302 Delirium tremens, 348 ergot in, 348, 572 hyoscine in, 409 lumbar puncture in, 349 magnesium sulphate in, 315 treatment, 348 Delphinium, 236 Demulcents, 67 Denatured alcohol, 316 Deodorant, 488 Deodorized alcohol, 316 opium, 373 Deodorizer, 488 Deodorizers used as gas, 514 in dry form, 514 in solution, 514 Deoxidizers, 493 Depressants, cardiac, 231 Depression. 57 Desiccated hypophysis, 207 thyroid glands, 560 Dextrin, 29 Dextro-glucose, 69 Dextro-hyoscyamine, 395 Dextrose, 69 diuretic action, 455 Diabetes, alcohol in, 343 antipyrine in, 469 atropine in, 398 calcium in, 100 codeine in, 387, 388 glycerin in, 31 insipidus, ergot in, 572 pituitary extract in, 210 lactic acid in, 90 morphine in, 387 opium in, 387 salicylic acid in, 484 sodium bicarbonate in, 95 Di-acetyl morphine, 390 Diacetyltannin, 115 Diamino-dihydroxy-arsenobenzol dihy- drochloride, 542 Diaphoresis, 443 character of sweat in, 447 in chronic rheumatism, 450 in nephritis, 448 in sickness, 448 in uremia, 448 measures to produce, 443, 444 relation of, to nitrogenous excretion, 447 Diaphoretics, 443 Diaphoretics, administration, 449 therapeutics, 449 to assist kidneys, 449 to hasten outbreak of rash, 450 to lessen congestion of internal eye, 449 of middle and internal ear, 449 edema and promote absorption of dropsical effusions, 449 obesity, 449 to lower temperature, 449 to overcome chill or cold, 449 Diarrhea, camphor in, 217 kaolin in, no mixture, Squibb's, 213 remedies for, 146 Diarsenol, 542 Diaspirin, 485 Diastase, 84 Dibothriocephalus latus, remedies for, 119 Dichloramin-T, 498 Diet, salt-free, prolonged, results of, 93 Dietetic measures, 18 Di-ethyl barbituric acid, 365 malonyl urea, 365 morphine chloride, 424 Diethylene-diamine, 488 Diffusion, 228 Digalen, 158 dose, 158 Digestive ferments, 81 Digifolin, 159 Digipuratum, 158 Digitalein, 158 Digitalin, 158 dose, 158 Digitalis, 157 absorption of, 164 action of, on nutrition of heart, 177 on recuperative power of heart, 1 77 allies, 159 elimination, 183 arhythmia from, 166 auricular fibrillation from, 170 change in electrocardiograms from, 177 complete heart-block from, 172 constituents, 157 constriction of coronary arteries from, 176 contraction of peripheral arteries from, 178 diuresis, 181 doses, 158 elimination of, 183 fluiclextract of, dose, 159 group, i 60 heart-block from, 172 in aneurysm of aorta, 195 in aortic insufficiency, 193 stenosis, 194 in aortitis, 195 in arteriosclerosis, 195 INDEX 623 Digitalis in auricular fibrillation, 100, 194 flutter, 189 in dilatation of heart, 192 in dropsy, 181, 182 in edema, 181, 182 in failure of compensation of heart, 194 in fatty degeneration of heart, 192 in heart-block, 189 in high arterial pressure, 191 in infectious diseases,- 195 in mitral insufficiency, 193 stenosis, 194 in muscular inability of heart asso- ciated with valvular lesion, 192 in myocarditis, 192 in normal rhythm of heart, 191 in paroxysmal tachycardia, 189 in pneumonia, 166, 195 in premature contractions of heart, 189 in pulsus alternans, 189 in sinus arhythmia, 189 in venous engorgement, 181 in water-retention, 182 incipient heart-block from, 172 increased arterial pressure from, 179 indications, 194 influence of conditions of arteries on usefulness of, 192 of heart on usefulness of, 192 infusion of, dose, 158, 159 local action, 162 partial heart-block from, 172 permanency of preparations, 161 persistence of effect, 187 pharmacologic action, 162-184 phasic arhythmia from, 176 poisoning from, 184 cumulative, 186 overwhelming dose, 184 single large dose by mouth, 185 symptoms, 186 treatment, 188 preparations and doses, 158 standardization and permanency, 161 pulsus alternans from, 176 purpurea, 157 retention of urine from, 181 series, 160 slowing of heart from, 165 standardization and permanency of preparations, 161 suppression of urine from, 181 therapeutics, 188 summary, 195 tincture of, dose, 158, 159 toxicology, 184 use as determined by rhythm and rate of heart, IQI value of, 183 Digitalosmin, 158 Digitonin, 20, 158 Digitoxin, 158 dose, 158 Dihydrpxyphthalophenone, 134 Dilatation of arteries, 153 of heart, 156 digitalis in, 192 of veins, 154 Dilators, arterial, 239 Dilute nitric acid, therapeutics, 88 nitrohydrochloric acid, therapeutics, 88 phosphoric acid, therapeutics, 88 Diluted acetic acid, 89 alcohol, 316 hydriodic acid, 555 nitrohydrochloric acid, 86 Dimazon ointment, 80 Dimethyl xanthines, 252 Di-methyl-amino-benzoyl pentanol chlo- ride, 423 Dimethyl - dimethyl - amino - pyrazolon, 462 Dimethyl-ethyl carbinol, 366 Dionine, 391, 424 Diphtheria, kaolin in, no Diplosal, 485 Dipropaesin, 424 Dipsomania, 346 Direct local action, 52 Disease, nature of, dose and, 51 resistance to, alcohol and, 352 Disinfectants, 488 bladder, 516 bronchi, 517 classification, 491 therapeutic, 514 eye, 516 for dressings, 515 for local use about body, 516 for obstetrician's hands, 516 for skin, 516 for surgeon's hands, 516 for surgical instruments, 515 supplies, 515 for utensils, 515 in skin diseases, 516 intestinal, 517 larynx, 517 mouth, 516 nose, 516 open wounds, 517 rectum, 517 respiratory, 517 stomach, 517 tests for value, 489 therapeutic classification, 514 throat, 516 to be given by mouth, 517 urethra, 516 urinary tract, 517 624 INDEX Disinfectants used as gas, 514 in dry form, 514 in solution, 514 vagina, 516 Disinfection of wounds, Dakin-Carrel treatment, 495 terminal, 515 Dispensatory, 47 Distilled liquors, 318 from fermented saccharine fruit- juices, 319 from malt liquors, 318 medicinal dose, 321 Diuresis, 450 caffeine, 258, 260, 261 digitalis, 181 in acute nephritis, 460 in chronic nephritis, 460 production of, 453 by caffeine, 456 by calomel, 457 by dextrose, 455 by increasing blood-flow through kidneys, 453 by inorganic salts, 455 by lowering osmotic pressure of blood, 454 by measures which decrease tubular absorption, 456 which increase glomerular fluid, 453 tubular secretion, 456 by organic salts, 455 by theobromine, 456 by theocine, 456 by theophylline, 456 by urea, 455 by water, 455 secretion threshold in, 457 therapeutic production, 453 therapeutics, 459 to cause removal of dropsy and edema, 459 to promote elimination of toxins, 459 Diuretics, 450 in edema of cardiac insufficiency, 456 in nephritis, 456 therapeutics, 459 to cause removal of dropsy and edema, 459 to promote elimination of toxins, 459 Diuretin, 264 Dobell's solution, 505 Dogbane, 160 Dog-bites, caustics for, 79 Donovan's solution, 541 Dormiol, 366 Dosage, 47 Clark's rule, 48 Cowling's rule for, 49, 595 for children, 48 Fried's rule for, 49 Dosage, Young's rule for, 49 Dose, age and, 48 body weight and, 48 channel of administration and, 51 factors which modify, 48 for children, 48 form of remedy and, 51 frequency of administration and, 52 idiosyncrasy and, 50 maximum, 47 minimum, 47 nature of disease and, 51 object of medication and, 51 occupation and, 50 prevous habits and, 50 race and, 50 repeated, 47 sex and, 50 single, 47 susceptibility and, 50 temperature and, 50 therapeutic, 47 time of administration and, 52 toleration and, 50 toxic, 47 weight and, 48 Dover's powder, dose, 373, 564 in cold, 449 Draper's method of intraspinous use of salvarsan, 550 Drastics, 135 cautions, 136 doses, 137 pharmacologic action, 135 poisoning from, 135 preparations, 137 therapeutics, 136 uses, 135 Dressings, disinfectants for, 515 Drink, Imperial, 88 Drinkers, periodic, 346 steady, 346 Drip-sheet, 461 Drop-chalk, 97 Drops, 584 Dropsy, caffeine in, 262 digitalis in, 181, 182 elaterin in, 136 Drugs, active constituents, 19 administration of, 52. See also Admin- istration. as cathartic measures, 124 assayed, 44 crude, 19 effect of, on cells, 57 how much to learn about, 61 irritant, time to give, 56 organic, constituents of, 19 active, 19, 20 inert, 19 selective, 56 sites and modes of action, 56 INDEX 625 Drugs, useful, book of, 47 varieties, 19 Drunkenness, 344 after-effects, 345 treatment, 345 Dry-cupping, 76, 247 Dry wine, 318 Dwarf tape- worms, remedies for, 119 Dwarfism, anterior lobe extract in, 211 Dysentery, amebic, calcium permangan- ate in, 541 emetine in, 566 ipecac in, 566 quinine in, 478 kaolin in, no purified animal charcoal in, no Dyspnea, Hoffmann's anodyne in, 288 Dystrophia adiposo-genitalis, anterior lobe extract in, 211 EARLY-BIRD mixture, poisoning from, 119 Earth, fullers', no Eau de Javelle, 494 Ecgonine, 412, 413 Eclampsia, veratrum in, 238 Edema, angioneurotic, calcium in, 100 calcium in, 100 digitalis in, 181, 182 of cardiac insufficiency, diuretics in, 456 of lungs, acute paroxysmal, morphine in, 387 oxygen in, 580 relation of, to salt retention, 93 Effervescent citrated caffeine, 253 salt, granular definition, 42 Effervescing mineral waters, 146 potassium citrate, dose, 138 sodium phosphate, dose, 138 Egg-albumin tannate, 115 Egg-nog, 320 Ehrlich's "606," 542 Elaterin, 26, 136 dose, 137 in dropsy, 136 Electric bath, 445 Electrocardiograms, change in, from digitalis, 177 Eleopten, 35 Elixir, aromatic, 106, 320 aromaticum, 106, 320 definition, 40 glycyrrhizae, 106, 320 of phosphates of iron, quinine, and strychnine, 537 dose, 269 Elixirs, 319 official, 320 pharmaceutic, 320 Emetics, ni central, IIT 40 Emetics, reflex, in therapeutics, 112 Emetine, 564 hydrochloride, 564 in amebic dysentery, 566 in pyorrhea alveolaris, 566 pharmacologic action, 564, 565 Emmenagogues, 567 Emodins, 131 Emollients, 67 Empiric therapeutics, 58 Emplastrum, definition, 42 Empyreumatic oils, 34, 35 Emulsin, 25, 27 Emulsion, artificial, 40 definition, 40 natural, 40 Emulsum, definition, 40 Encephalopathy, lead, 527 Enema, 55, 143 cathartic, 143 as softening agent, 143 to soften feces, 144 evacuating, 144 nutritive, 144 of salt solution, 230 to induce expulsion of gas, 144 Engorgement, venous, digitalis in, 181 Enteric pills, 36, 586 ; Entoloma sinuatum, 443 Enuresis nocturna, ergot in, 572 Enzymes, 27 Epididymitis, magnesium sulphate in, 3.IS Epilepsy, borax in, 500 bromipin in, 372 Epinephrine, 196 absorption of, 198 and chloroform, simultaneous use, effects, 204 connective-tissue changes in heart and arteries from, 201 dangers, 206 elimination of, 204 hydrochloride, solution of, dose, 197 hypodermic injection, 205 in Addison's disease, 205 in anterior poliomyelitis, 205 in bronchial asthma, 202, 205 in collapse, 206, 251 in hay-fever, 205 in hemorrhage, 205 in infantile paralysis, 205 in itching of vulva, 205 in nose-bleed, 205 in postpartum hemorrhage, 205 in shock, 206, 251 increased force of heart from, 200 intramuscular injection of, effects of, 199 intravenous administration, 206 dangers, 206 626 INDEX Epinephrine, intravenous injection, ef- fects, 199 local use, dangers, 206 metabolism of, 204 pharmacologic action, 197-204 poisoning from, 204 preparations and doses, 197 slowing of heart from, 200 subcutaneous injection, effects, 199 therapeutics, 205 to check anaphylactic shock, 205 to prevent local hemorrhage, 205 to prolong local anesthesia, 205 to shrink mucous membrane, 205 toxicology, 204 vasoconstriction from, 199 Epispastic, 72 Epistaxis, counterirritants for, 78 Epsom salt as anesthetic, 313 intraspinal method, 314 intravenous use, 314 Meltzer's theory, 314 dose, 138 in arthritis, 315 in cellulitis, 315 in chorea, 315 in convulsions, 315 in delirium tremens, 315 in epididymitis, 315 in erysipelas, 315 in pain, 315 in spasmophilia, 315 in tetanus, 314 Ergot, 567 constituents, 567 deterioration, 568 dose, 568 extract, dose, 568 fluidextract, dose, 568 in delirium tremens, 348, 572 in diabetes insipidus, 572 in enuresis nocturna, 572 in menorrhagia, 572 in subinvolution of uterus, 572 pharmacologic action, 568-570 poisoning, 571 chronic, 571 preparations and doses, 568 standardization, 568 therapeutic?, 571 to prevent postpartum hemorrhage, 57i toxicology, 571 Ergota, 567 Ergotine, 567 Ergotinic acid, 567 Ergotism, 571 gangrene in, 571 nervous type, 571 F.rgotoxine, 567 effect on circulation, 569 phosphate, dose, 568 Eriodictyon, 109, 425 Erysipelas, magnesium sulphate in, 315 Erythrol tetranitrate, 240 effect, 242 Erythroxylon coca, 412 truxillense, 412 Escharotics, 78 Eseridine, 436 Eserine, 436 Esophagus, diseases of, cocaine in, 421 Essences of plants, 34 Essential oils, 34 Ether, 284 absorption, 285 anesthesia, 292 administration, general remarks, 305 of sodium bicarbonate, 299 after-effects, 297 chloretone as preliminary to, 364 collapse in, 296 saline infusion in, 309 treatment, 309 conjunctivitis after, 298 danger-signs, 296 distention of stomach and intestines after, 297 first stage, 294 fourth stage, 296 having stomach empty, 299 helpful measures in, 298 indications, 299 injection of atropine sulphate in, 299 intravenous, 307 kidneys after, 298 nausea after, 297 pain in back after, 297 phagocytic activity of leukocytes after, 305 postoperative gastric or intestinal paralysis after, 298 preliminary administration of seda- tive drugs, 298 anesthetization with chloroform, 298 with nitrous oxide or ethyl chloride, 298 feeding with carbohydrates and water, 299 preventive measures in, 298 reassuring patient, 299 recovery from, 297 respiratory troubles after, 298 second stage, 295 sore tongue after, 298 third stage, 295 thirst after, 297 untoward sequels, 298 vomiting after, 297 warming vapor, 299 compound spirit, dose, 284 dose, 284 elimination, 287 INDEX 627 Ether habit, 288 inhalations in strychnine poisoning, .279 nitrous, spirit of, 240 petroleum, 576 pharmacologic action, 285-288 preparations and doses, 284 rash, 288 spirit of, dose, 284 therapeutics, 288 Ethyl alcohol, 316 bromide anesthesia, 313 chloride, 312 anesthesia, 312 preliminary anesthetization with, in ether anesthesia, 298 spray, 425 ester of para-amido-benzoic acid, 424 oxide, 284 Ethylated compounds, 364 Ethylhydrocupreine, 479 hydrochloride, 471 in pneumonia, 479 in ulcus cornea; serpens, 479 poisoning from, 479 Ethyl-morphine hydrochloride, 391 Eucaine, 423 Eucalyptol, 106, 504 Eugenol, 106, 504 Euonymus, 136 dose, 137 Euquinine, 471 Europhen, 499 Evacuating enema, 144 Exalgine, 462 Excipient, 586 Exercise as cathartic measure, 122 Exophthalmic goiter, atropine in, 408 pituitary extract in, 210 quinine in, 476 Expectant treatment, 61 Expectorants, 563 Experimentation, animal, 58 Extract, definition, 41 Extraction, 37 Extractive, 38 Extractum, definition, 41 malti, 72 Eye, diseases of, atropine in, 407 disinfectants, 516 FALSE anesthesia, 297 Fat allies, 32 sweating and, 446 Fats, 29 Fatty degeneration of heart, digitalis in, 192 Feces, impacted, cathartic enema to soften, 144 mechanical agents to give bulk and soft consistency to, 124 Feces, mechanical agents to give bulk and soft consistency to, agar, 125 agar-agar, 125 liquid petrolatum, 125 phenolphthalein-agar, 125 psyllium seeds, 125 regulin, 125 sulphur, 124 lotum, 125 praecipitatum, 125 whole flaxseed, 125 Fecundity, alcohol and, 352 Feet, sweating of, aluminium chloride in, 536. salicylic acid in, 483 Ferments, 27 digestive, 81 Ferratin, 538 Ferri hydroxidum cum magnesii oxido, 537 Ferric acetate, 538 citrate, 538 hydroxide, 537 salts, inorganic, 537 tartrate, 538 Ferrous salts, inorganic, 537 sulphate, 493 as disinfectant, 536 Ferruginous waters, 147 Ferrum, 536 reductum, 537 Fever, aconite in, 236 alcohol in, 354 camphor in, 217 iodide, 558 Fibrillation, auricular, digitalis in, 190, 194 from digitalis, 1-70 ventricular, from digitalis, 171 Fibrolysin, So therapeutics, 80 Field mushroom, 443 Filicic acid, amorphus, for tape-worms, 119 Filtration, 228 Fischer's solution, 96 in nephritis, 96 Fixed oils, 29 as cathartics, 127 Flatulence, chloroform in, 292 wood-charcoal in, no Flavors for prescription, 585 Flaxseed, whole, to increase bulk of feces, 125 Flowers of sulphur as laxative, 125 Fluidextract, definition, 40 Fluidextractum, definition, 40 Flutter, auricular, digitalis in, 189 from digitalis, 170 Fly agaric, 442, 443 Spanish, 77 628 INDEX Fly-blister, 77 Food as cathartic measure, 123 iron, 538 preservatives, 500, 515 value of alcohol, 331-336 Foot-bath, mustard, 77 Formaldehyde, 510 poisoning from, 511 therapeutics, 511 Formaldehyde- tannin, 115 Formalin, 510 Formic acid, 89 in rheumatism, 89 Formin, 512 Formulary, National, 46 Fortified wines, 318 Fossy jaw, 553 Fowler's solution, 541 Foxglove, 157 Fractures, delayed union, thyroid gland in, 562 Frangula, 133 Fraxinus ornus, 28 French brandy, 319 Fried's rule for dosage, 49 Fruit acids, 90 Fruits as cathartic measure, 124 Fullers' earth, no Functional albuminuria, iron in, 540 Fungi, poisonous, 443 Fungus, death's-head, 442, 443 Furfurol, 429, 430 GAMBIR, compound tincture of, 114 Gamboge, dose, 137 Gangrene from phenol, 506 in ergotism, 571 Ganja, 392 Gas, expulsion of, enema for, 144 illuminating-, poisoning from, 574 oxygen, 578 Gas-poisoning, oxygen in, 580 Gasoline, 576 poisoning, 576 Gastric irritation, bismuth in, 532 juice, appetite, 107, 324 psychic, 107, 324 paralysis, postoperative, after ether anesthesia, 298 ulcer, scarlet red in, 80 Gastritis, chronic, silver nitrate in, 533 Gauze, balsam, 501 Gelatin, 70 glycerinated, 71 in aneurysm, 71 in hemorrhage, 71 in shock, 71 Gelatinum, 70 Gelatose, silver, 534 Gelsemium, 428 fluidextract, 428 Gelsemium, tincture, 428 General protoplasm poisons, 56 Gentian, compound tincture of, 109 Germicides, 488 Gin, 319 Glacial acetic acid, 89 Gland, suprarenal, dried, dose of, 197 thyroid, 560 Glassfuls, 585 Glauber's salt, dose, 138 Glaucoma, pilocarpine hydrochloride in, 442 Glomerulus of kidney, functions, 451, 452 Glonoin, 239 spirit of, 240 Glucose, 24-26, 28, 69 as diuretic, 70 as food, 70 as prophylactic against shock, 70 in delayed chloroform poisoning, 303 therapeutics, 70 Glucosides, 24 Glucosum, 28, 69 Gluside, 68 Glutol capsules, 510 Glycerin, 30, 31 action and uses, 31 and rose-water, 31 as cathartic, 127 in diabetes, 31 suppositories, 31 Glycerinated gelatin, 71 Glycerinum, 31, 127 Glycerite, definition, 41 of boroglycerin, 501 Glycerites, 31 Glyceritum, definition, 41 Glycerophosphates, 554 Glyceryl, 29 trinitrate, 239 Glyco-heroine, 391 Glycosides, 24 Glycyrrhizin, 20 Goiter, colloid, iodides in, 559 thyroid gland in, 562 exophthalmic, atropine in, 408 pituitary extract in, 210 quinine in, 476 Gold as antiseptic and disinfectant, 500 Goldenseal, 572 Gonorrheal ophthalmia, Cr6d6's method of prophylaxis against, 533 Goulard's extract, 525 Gout, alcohol in, 343 cimicifuga in, 488 colchicum in, 487 lithium in, 92 phenyl-cinchoninic acid in, 487, 488 salicylic acid in, 484 Grain-alcohol, 316 Granatum for tape- worms, 119 INDEX 629 Granatum, poisoning from, 119 Granular effervescent salt, definition, 42 Granulated opium, 373 Green soap, 31 tincture of, 31 tea, 265 Griping from cathartics, 121 Guaiacol, 503 carbonate, 503 Guanin, 252 Guarana, 253 Guaza, 392 Gum arabic, 29 British, 29 cherry-, 29 resin, 36, 40 Gums, 27, 28 lead line on, 528 Gwathmey's oil-ether colonic method of anesthesia, 306 Gymnemic acid, 109 HABIT, chloroform, 292 cocaine, 420 treatment, 420 coffee, 266 ether, 288 formation as cathartic measure, 122 hasheesh, 392 heroine, 391 kola, 266 morphine, 384 paraldehyd, 367 tea, 266 tobacco, 432 Habits, previous, dose and, 50 Hall's antidote in mercury poisoning, 524 Halogens, free, 494 compounds, 494 Hands, obstetrician's, disinfectants for, Si6 surgeon's, disinfectants for, 516 sweating of, aluminium chloride in, 536 salicylic acid in, 483 Hard soap, 31 Harrington's solution, 519 Hasheesh habit, 392 Hashish, 392 Hay-fever, calcium in, 100 epinephrine in, 205 Headache from smoking, 435 quinine in, 477 Head's areas, 74 Heart, action of, influences affecting, 150 remedies affecting, directly, 150 indirectly, 150 blood in, output of, influences affect- ing, 149 blood-supply, 154 compensation, 156 failure of, 156, 157 Heart compensation, failure of, digitalis in, 194 threatened failure, 157 conditions of, influence, on usefulness of digitalis, 192 connective-tissue changes in, from epinephrine, 201 contractility, 152 action of digitalis on, 167 depressants, 231 dilatation of, 156 digitalis in, 192 failure, oxygen in, 580 increased force, from epinephrine, 200 irritability of, from digitalis, 168 irritable, of soldiers, 435 massage of, in shock and collapse, 251 muscle, action of digitalis on circula- tion through, 1 66 muscular inability, associated with valvular lesion, 192 nutrition of, action of digitalis on, 177 optimum rate, 152 overexcitability of, from digitalis, 169 overirritability of, from digitalis, 169 premature contractions; digitalis in, 189 rate, 152 recuperative power, action of digitalis on, 177 resistance, 151 rest force, 157 rhythm of, coupled, from digitalis, 176 influences affecting, 152 nodal, from digitalis, 170 normal. 165 digitalis in, 191 reversed, from digitalis, 171 slowing of, from digitalis, 165 from epinephrine, 200 tobacco, 435 tonicity of, action of digitalis on, 166, 167 working force, 157 Heart-beats, premature, from digitalis, 169 Heart-block, complete, from digitalis, 172 digitalis in, 189 from digitalis, 172 incipient, from digitalis, 172 partial, from digitalis, 172 Heat, 75 as disinfectant, 492 body, methods of raising, /\/\<\ Heat-regulating centers, 463 action of digitalis on, 183 Heavy liquid petrolatum, 33 metals, 517 oxide of magnesium, 96 wine, 318 Hedonal, 366 INDEX Hellebore, American, 236 Helleboreln, muscular effects, 184 Hemlock, poison, 427 Hemophilia, transfusion of blood in, 227 Hemophysis, sodium chloride as prophy- lactic against, 94 Hemorrhage, calcium in, 100 epinephrine in, 205 gelatin in, 71 local, epinephrine to prevent, 205 mechanical measures in, 225 nasal, antipyrine in, 469 counterirritants for, 78 postpartum, diluted acetic acid in, 89 epinephrine in, 205 ergot to prevent, 571 saline infusion in, 230 transfusion of blood in, 226 Hemorrhoids, quinine in, 477 Henbane, 394 Heredity, alcohol and, 352 Heroine, 390 glyco-, 391 habit, 391 Hexamethylenamine, 24, 512 administration, 514 therapeutics, 514 untoward effects, 513 Hexamethylenamine-tannin, 115 Highball, 320 Hirudin, 247, 248 Hirudo, 247 Hodgkin's disease, sodium cacodylate in, 542 Hoffmann's anodyne, dose, 284 in angina pectoris, 288 in dyspnea, 288 in hysteria, 288 in spasm, 288 therapeutics, 288 Hog-back kidney, 351 Holocaine, 424 Homatropine, 23 hydrobromide, 411 Honey, definition, 41 Hooker and Satterlee's method of blood transfusion, 226 Hookworms, treatment, 117 Hops, 393 Hormonal, 85 in chronic constipation, 85 in tympanites, 85 Horn silver, 533 Horrors, 348 Hot-air bath, 445 Hot-pack, 444 Humulus, 393 lupulus, 393 Hydragogue, 122 Hydra rgyri chloridum corrosivum as disinfectant, 518 mite, 129 Hydrargyrum cum creta, 131 Hydrastine, 572 dose, 572 elimination, 573 hydrochloride, dose, 572 Hydrastininae hydrochloridum, 573 Hydrastinine, 24 hydrochloride, 573 therapeutics, 574 Hydrastis, 114, 572 canadensis, 572 constituents, 572 dose, 572 elimination, 573 fluidextract, dose, 572 glycerite, dose, 572 pharmacologic action, 572, 573 preparations, 572 therapeutics, 573 tincture, dose, 572 Kydrated chloral, 358 Hydremic plethora, 454 Hydriodic acid, diluted, 555 Hydrochloric acid, therapeutics, 87 Hydrocyanic acid, 426 diluted, 426 preparations, 426 therapeutics, 427 Hydrotherapeutic measures, 18 Hygienic measures, 17 Hymenolepis nana, 116 remedies for, 119 Hyoscine, 395, 409 as anaphrodisiac, 409 as general anesthetic, 409 as mydriatic and cycloplegic, 409 as narcotic, 409 hydrobromide, 396 in delirium tremens, 409 in insomnia, 409 therapeutics, 409 Hyoscyamine, 395, 408 hydrobromide, 396 sulphate, 396 Hyoscyamus, 394, 395 dose, 395 niger, 394 therapeutics, 408 tincture, 396 Hyperchlorhydria, silver nitrate in, 533 Hyperisotonic solutions, 228 Hyperthyroidism, atropine in, 408 iodides in, 559 pancreatin in, 83 pituitary extract in, 210 Hypertonic solutions, 228 Hypcrtrophied tissue, trichloracetic acid for, 89 Hypnotic measures, 357, 358 Hypnotics, 356 ethylated, 364 which do not abolish pain, 358 INDEX 631 Hypnotics which may be used to abolish pain, 367 Hypochlorites, 494 Hypodermatic administration, 53 advantages, 54 disadvantages, 54 Hypodermatoclysis, administration by, 55 Hypodermic administration of salicylic acid, 484 injection of epinephrine, 205 tablets, 53, 587 Hypodermoclysis, saline infusion by, 230 Hypoisotonic solutions, 228 Hypophosphites, compound syrup of, 554 dose, 269 of phosphorus, 554 Hypophysis, desiccated, 207 sicca, 207 Hypothyroidism, thyroid gland in, 562 Hypotonic solutions, 228 Hypoxanthine, 252 Hysteria, Hoffmann's anodyne in, 288 Hysteric conditions, camphor in, 217 ICHTHYOL, 509 as intestinal disinfectant, 509 Idiosyncrasy, dose and, 50 Ilex cassine, 253 Illuminating-gas, poisoning from, 574 Immunity, effect of anesthesia on, 305 quinine, 474 Imperial drink, 88 Incompatibility, 58, 603 chemic, 603 depending on change of solvent, 603 Incompatibles, alkaloids, 22 Indian tobacco, 428 Indication, definition, 63 Inebriety, 345 Inertia, uterine, pituitary extract in, 210 quinine in, 477 Infantile paralysis, epinephrine in, 205 wasting, thyroid gland in, 562 Infantilism, pancreatic, pancreatin in, 82 pituitary, anterior lobe extract in, 211 Infections, effect of anesthesia on, 305 Infectious conditions, transfusion of blood in, 227 diseases, digitalis in, 195 Infiltration anesthesia, Schleich's, 425 Inflammation, counterirritants for, 78 Influenza, quinine in, 477 Infusion, definition, 40 intravenous, 55 of wild cherry, 426 Infusum, definition, 40 Ingluvin, 85 in nausea and vomiting of pregnancy, 85 Inhalation, administration through lungs by, 55 Inorganic acids, 86 action, 86 poisoning from, treatment, 8; therapeutics, 87 toxicology, 86 Insomnia, alcohol in, 354 hyoscine in, 409 Instruments, surgical, disinfectants for, 5i5 Insufflation, intratracheal, anesthesia by, 37 pharyngeal, anesthesia by, 309 Intestinal disinfectants, 517 infections, purified animal charcoal in, no irritation, bismuth in, 532 paralysis, pituitary extract in, 210 peristalsis, morphine in, 387 postoperative, after ether anesthesia, 298 worms, anthelmintics for, 115 Intestines, distention of, after ether anesthesia, 297 effect of calcium in, 100 small, as factor in defecation, 120 Intoxicants, 316 Intracutaneous administration, 54 Intramuscular administration, 53, 54 injection of epinephrine, effects, 199 Intratracheal insufflation, anesthesia by, 307 Intravenous administration of epineph- rine, 206 dangers, 206 of ouabain, 196 of salicylic acid, 484 of strophanthin, 196 anesthesia, 307 Bier's, 425 paraldehyd for, 307 with chloroform, 307 with cocaine, 422 with ether, 307 infusion, 55 of salt solution, 227 injection, 55 of epinephrine, effects, 199 local anesthesia, 425 medication, 55 Inunction, administration by, 55 Invertase, 27 lodalbin, 555 Iodide fever, 558 Iodides, 555 absorption, 556 administration, 559 and alkaloids, incompatibility, 22 contraindications, 559 excretion, 556 in actinomycosis, 558 632 INDEX Iodides in colloid goiter, 559 in hyperthyroidism, 559 in syphilis, 558 theory of action, 557 in tuberculosis, theory of action, 557 pharmacologic action, 555-557 preparations and doses, 555 therapeutics, 558 untoward actions, 557 Iodine, 498, 555 absorption, 556 and alkaloids, incompatibility, 22 Churchill's tincture, 499 compound solution, 555 compounds, antiseptic, 499 content of thyroid gland, 556, 560 excretion, 556 pharmacologic action, 555-557 phenol compounds, 504 therapeutics, 558 tincture of, 498, 555 untoward actions, 557 waters, 147 lodipin, 555 lodism, chronic, 558 lodival, 555 lodocasein, 555 lodoform, 499, 555 emulsion, 499 poisoning, 499 lodol, 499 lodum, 555 Ipecac, 564 and opium, powder of, dose, 373 as diaphoretic, 566 as emetic, 566 as expectorant, 566 as nauseant, 566 dose, 564 fluidextract, dose, 564 in amebic dysentery, 566 poisoning, 565 preparations and doses, 564 syrup, dose, 564 therapeutics, 566 toxicology, 565 Ipecacuanha, 564 Irish whiskey, 319 Iron, 536 absorption, 538 and ammonium citrate, 538 tartrate, 538 and potassium tartrate, 538 and quinine, citrate of, 538 and strychnine, citrate of, 538 artificial organic compounds, 538 as antidote in arsenic poisoning, 537, 547 as antiseptic and disinfectant, 500 as astringent, 536 as disinfectant, 536 as hematinic, 537, 540 Iron carbonate, 537 chloride, 537 effect on blood, 539 food, 538 in anemia, 540 in chlorosis, 540 in functional albuminuria, 540 iodide, 537 masked, 538 metallic, 537 organic, 538 phosphate, 537 poisoning, 540 reduced, 537 salts of organic acids, 538 sulphate, 537 dried, 537 therapeutics, 540 toxicology, 540 Irritable heart of soldiers, 435 Irritant drugs, time to give, 56 Irritants, 126 Irritation, 57 Isoamylamine, 567 Iso-nitroso-antipyrine, 462 Isophysostigmine, 436 Isopilocarpine, 439 Isopral, 366 Isoquinoline opium alkaloids, 373 Isotonic solutions, 228 Itching of vulva, cocaine in, 421 epinephrine in, 205 Ivy-poisoning, potassium permanganate in, 54i JABORANDI, 439 Jaborine, 438 Jalap powder, compound, dose, 137 resin of, dose, 137 Jarisch-Herxheimer reaction, 551 Jasmine, yellow, 428 Jaw, fossy, 553 Jervine, 236 pseudo-, 237 Jimson-weed, 394 Juice, definition, 40 Juniper, compound spirit of, 319 Junket, 84 KALA-AZAR, antimony in, 552 Kamala for tape- worms, 119 poisoning from, 119 Kaolin, 1 10 in cholera, no in diarrhea, no in diphtheria, 1 10 in dysentery, no Keratin, 36 for coating pills, 586 Kerosene oil, 33 INDEX 633 Kidneys, action of digitalis on, 180 after ether anesthesia, 298 decapsulation of, in mercury poison- ing, 524 functions of, 450, 451 glomerulus of, functions, 451, 452 hog-back, 351 tubules of, functions, 451, 452 Knock-out drops, 363 Kola, 253 habit, 266 Kolliker's schema to show reflex arc, 273 Korsakoff 's psychosis, 347 Kroenig and Gauss method of producing twilight sleep, 410 LABARRAQUE'S solution, 494 Labor, pituitary extract in, untoward effects, 211 Lactalbumin, 84 Lactarius torminosus, 443 Lactase, 27 Lactic acid, 89 for tuberculous ulcers of throat, 89 in diabetes, 90 Lactophenin, 463 Lactophosphate of lime, syrup of, 97 Lactuca virosa, 393 Lactucarium, 393 lozenges in cough, 393 syrup, 393 tincture, 393 Lager beer, 317 Lambert-Patterson treatment of mer- cury poisoning, 523 Lambert's treatment of alcoholism, 349 of morphinism, 386 Lanolin, 32 Lard, 30 Larkspur, 236 Laryngitis, ammonium chloride in, 224 croupous, calomel in, 521 tuberculous, antipyrine in, 469 Larynx disinfectants, 517 Lassar's paste, 483 Latin adjectives, 589 adverbs, 590 conjunctions, 591 in prescription writing, 587 nouns, 588 prepositions, 590 verbs, 590 Laudanum, 373 Laughing-gas, 310 anesthesia, 310 Laurocerasus, 426 Lavender, compound tincture of, 107 Laxative measures, 122 pills, compound, dose, 269 Laxatives, sulphur sublimatum, 125 Lazy man prescription, 595 Lead, 525 acetate, 525 and opium pills, 525 wash, 373, 525 colic, 526 encephalopathy, 527 line on gums, 528 oleate, 525 palsy, 527 plaster, 525 poisoning, 526 diagnosis, 528 treatment, 528 wrist-drop in, 527 preparations, 525 subacetate, 525 sulphate, 525 toxicology, 526 ' Lead' water, 525 Lecithin, 32, 554 in anemia, 555 Leech, 247 artificial, 248 Leishmaniosis, antimony in, 552 Lemonade, 88 Lemon-juice, 40 Leprosy, carminatives in, 105 Leptandra, 136 dose, 137 Leucorrhea, cane-sugar in, 69 Leukemia, benzol in, 577, 578 lymphoid, benzol in, 578 myeloid, benzol in 578 sodium cacodylate in, 542 Leukocytes, phagocytic activity, after chloroform or ether anesthesia, 305 Leukomains, 23 Levant wormseed, 116 Levo-hyoscyamine, 395, 408 Levulose, 28 in testing functional power of liver, 28 Licorice, 20 mixture, compound, 563 powder, compound, 552 Light liquid petrolatum, 33 wine, 318 Lily-of-the-valley, 160 Lime, chloride of, 494 chlorinated, 404 lactophosphate of, syrup of, 97 Lime-water, 97 Limonis succus, 40 Lindemann's method of blood transfu- sion, 226 Line, lead, on gums, 528 Liniment, ammonia, 218 chloroform, 213 definition, 41 of soft soap, 31 soap, 213 Linimentum, definition, 41 saponis mollis, 31 634 INDEX Linseed oil, 30 Lipoids, 32 Liquefied phenol, 505 Liqueurs, 320 Liquid albolene, 33, 125 extracts of malt, 317 paraffin, 33, 125 petrolatum, 33, 125 heavy, 33 in rheumatoid arthritis, 33 light, 33 prescriptions, 583 measures, 584 vaseline, 33, 125 Liquids, administration, 585 alcoholic, 40 aqueous, 39 miscellaneous, 40 percentage, 38 chemic, 38 pharmaceutic, 38 strength of, 38 Liquor acidi arsenosi, 541 ammonii acetatis, 224 antisepticus, 504 arseni et hydrargyri iodidi, 541 calcis, 97 cresolis compositus, 503 definition, 40 ferri chloridi, 537 et ammonii acetatis, 224, 538 subsulphatis, 537 formaldehydi, 510 hydrogenii dioxidi, 492 hypophysis, 207 magnesii citratis, dose, 138 plumbi subacetatis, 525 dilutus, 525 potassii arsenitis, 541 sodii boratis compositus, 505 chloridi physiologicus, 227 Liquors, distilled, 318 from fermented saccharine fruit- juices, 319 from malt liquors, 319 medicinal dose, 321 malt, 316 Lithia waters, 147 Lithium, 92 carbonate, 92 citrate, 101, 102 in gout, 92 poisoning, 93 Liver, functional power of, levulose in testing, 28 in disposal of ammonia, 220 sluggish, calomel in, 131 Lobar pneumonia, ethylhydrocupreine in, 479 Lobelia, 428 fluidextract, 428 in spasmodic asthma, 428 Lobelia tincture, 428 Lobeline, 428 Local action, direct, 52 remote, 52 Locke's solution for saline infusion, 227 Loco disease, 212 Loco-weed, 212 Locomotor ataxia, salvarsan in, 550 Losophan, 499 Lotio flava, 520 nigra, 520 plumbi et opii, 373 Lotion, definition, 41 plumbi et opii, 525 Lugol's solution, 555 Lumbar puncture in delirium tremens, 349 Luminal, 365 Lunar caustic, 533 Lungs, administration through, by in- halation, 55 edema of, acute paroxysmal, morphine in, 387 oxygen in, 580 Lupulin, 393 fluidextract of, 393 Lymphoid leukemia, benzol in, 578 Lysol, 503 MADEIRA wine, 318 Mad- weed, 212 Magendie's solution, 374 Magma bismuthi, 531 magnesiae, 96 dose, 138 Magnan's sign in cocaine poisoning, 419 Magnesia, milk of, 96 dose, 139 Magnesii carbonas, 96 oxidum, 96 ponderosum, 96 Magnesium, 96 carbonate, 96 dose, 138 citrate, dose, 138 heavy oxide of, 96 hydroxide, 96 dose, 138 oxide, 96 dose, 138 peroxide, 96 sulphate, 313 as anesthetic, 313 intraspinal method, 314 intravenous use, 314 Meltzer's theory, 314 dose, 138 in arthritis, 315 in cellulitis, 315 in chorea, 315 in convulsions, 315 INDEX Magnesium sulphate in delirium tre- mens, 315 in epididymitis, 315 in erysipelas, 315 in pain, 315 in sciatica, 315 in spasmophilia, 315 in tetanus, 314 poisoning by, 143 Malakin, 463, 486 Malaria, antinomy in, 552 bichloride of mercury in, 521 quinine in, 477 Malates, 90 Male-fern for tape- worms, 119 Malic acid, 90 Malnutrition, cod-liver oil in, 72 transfusion of blood in, 227 Malt, extract of, 72, 85 liquid extracts, 317 liquors, 316 Maltase, 27 Manganese, 540 dioxide, 540 poisoning, 541 Manna, 28 Mannite, 28 Mannitol hexanitrate, effect, 242 Maranta, 28 Masked iron, 538 Mass, definition, 41 Massa, definition, 41 ferri carbonatis, 537 hydrargyri, 131 Massage as cathartic measure, 123 of heart in shock and collapse, 251 Mate, 253 Materia medica, 18 Maximum dose, 47 Measures and weights, 43 apothecaries', 43 exact equivalents, 44 metric, 43 Mechanical applications, 68 measures, 18 Medicine-droppers, 584 Medinal, 365 Mel, definition, 41 Melanosis, arsenic, 548 Meltzer's plan of treatment with mag- nesium sulphate in tetanus, 315 theory of anesthetic action of mag- nesium sulphate, 314 Menopause, premature anterior lobe extract of pituitary gland in, 211 Menorrhagia, ergot in, 572 quinine in, 477 Menstruum, 37 Menthol, 106 Menthol-camphor, 213, 217 Mercurial ointment, 520 as antiseptic, 519 Mercurial stomatitis, 522 Mercurialized serum, intraspinal injec- tion, 521 Mercurials, cathartic, 129 Mercuric chloride and alkaloids, incom- patibility, 22 as disinfectant, 500, 518 in venereal sores, 519 Mercurophen as antiseptic, 519 as disinfectant, 500 Mercury, 518 administration, by intramuscular in- jection, 520 by inunction, 520 by mouth, 520 intravenous route, 521 ammoniated, ointment of, as anti- septic, 519 as antiseptic and disinfectant, 500 as disinfectant, 518 bichloride of, as disinfectant, 518 dose, 520 in malaria, 521 biniodide, dose, 520 elimination, 521 in syphilis, 519 nitrate of, ointment, as antiseptic, 5i9 oleate of, 520 pill, 131 poisoning, 522 protoiodide, dose, 520 subsulphate in croup, 521 succinimide in tuberculosis, 521 systemic action, 521 toxicology, 522 with chalk, 131 dose, 520 Mesotan, 486 Metallic astringents, 113 iron, 537 salts, caustic, 78 Metals and their compounds as anti- septics and disinfectants, 499 heavy, 517 Methyl alcohol, 355 blindness from, 355, 356 poisoning from, 355 salicylate, 106 Methyl-acetanilid, 462 Methylene-blue as antiseptic, 509 Methyl-ouabaln, 160 Methyl-oxymethyl ester of salicylic acid, 486 Methyloxypurins, 252 Methyl - para - amido - meta - oxybenzoic ester, 424 Methyl-propyl-carbinol-urethane, 366 Methyl-thionine chloride, 509 Metric prescriptions, 581 system, 43 Meyer-Overton theory of narcosis, 282 6 3 6 INDEX Milk, clotting of, by rennet, calcium in, 99 of bismuth, 531,532 of magnesia, 96 dose, 138 peptonizing, pancreatin for, 83 secretion of, effect of pituitary extract on, 209 sugar of, 28, 69 Milk-punch, 320 brandy, 320 Mindererus, spirit of, 224 Mineral oil, Russian, 125 oils, 33 waters, 146 effervescing, 146 non-effervescent, 146 non-thermal, 146 sparkling, 146 still, 146 thermal, 146 Minimum dose, 47 Mistura cretae, 97 definition, 40 pectoralis, 160 as expectorant, 564 Mitral insufficiency, digitalis in, 193 stenosis, digitalis in, 194 Mixture, definition, 40 Monkshood, 231 Monobromated camphor, 213 Monobrom-valeryl-urea, 366 Monoglycol ester of salicylic acid, 486 Monohydrated sodium carbonate, 92 Monsel's solution, 537 Moore and Roaf theory of narcosis, 282 Moreau's loop, saline cathartics and, 141 Morning tonic, 345 Morphine, 374 absorption, 376 and atropine in hypodermatic use, 389 as preliminary to general anesthesia, 387 contraindications or cautions, 387 di-acetyl, 390 dose, 374 excretion, 381 habit, 384 hydrochloride, 374 in acute paroxysmal edema of lungs, 387 in cough, 387 in diabetes, 387 in intestinal peristalsis, 387 in pain, 379, 387 in vomiting, 387 pharmacologic action, 374 383 poisoning, 383, 384 chronic-, 384 treatment, 383 powder, compound, 374 sulphate, 374 Morphine, susceptibility, 382 therapeutics, 386 to induce sweating, 387 tolerance, 382 toxicology, 383 untoward effects, 382 Morphine-stupor, 410 Morphinism, 384 Lambert's treatment, 386 Petty's treatment, 386 pigment atrophy in, 386 Stokes' treatment, 386 treatment, 385 Mountain-sickness, oxygen as preven- tive, 579 Mouth, administration by, 53 disinfectants, 516 Mucilage, 29 definition, 40 Mucilago, 40 Mucous membranes, effect of sodium bicarbonate on, 94 Muriate of ammonia, 223 Muscarine, 442 poisoning, 442 Muscle, cardiac, action of digitalis on circulation through, 166 Muscles, bronchial, action of strychnine on, 276 Muscular inability of heart associated with valvular lesion, digitalis in, 192 bone, action of strychnine on, 274 Mushroom, field, 443 poisoning, 442 treatment, 443 Musk, 394 dose, 394 tincture, dose, 394 Mustard, 77 foot-bath, 77 oil of, volatile, 26 paste, 77 Mutual helpers, 57 Mydriatic, definition, 403 Myeloid leukemia, benzol in, 578 Myocarditis, digitalis in, 192 Myricyl palmitate, 32 Myrosin, 25-27 Myrrh, 114 Myxedema, thyroid gland in, 562 NAME of patient on prescription, 582 Naphtha, 576 wood, 355 Naphthalin, 504 Narcophin, 374 Narcosis, 282 alcohol, stages o., 331 Meyer-Overton theory, 282 Moore and Roaf theory, 282 theories, 282 INDEX 637 Narcosis, Verworn's theory, 283 Narcotic poisoning, strychnine in, 280 Narcotics, 282 Narcotine, 373 Nasal hemorrhage, antipyrine in, 469 Nataloin, 133 National Formulary, 46 Pharmacopceial Convention, 46 Natural emulsion, 40 Nauheim bath as circulatory stimulant, 157 Nausea after ether anesthesia, 297 and vomiting of pregnancy, ingluvin in, 85 treatment, 112 bismuth in, 532 cerium in, 532 Necator americana, treatment, 117 Neosalvarsan, 543, 549 contraindications and cautions, 551 in cerebrospinal syphilis, 550 in syphilis, 549 therapeutics, 549 untoward effects, 550 Nephritis, acute, diuresis in, 460 chronic, diuresis in, 460 interstitial, aconite in reducing high arterial pressure in, 233 diaphoresis in, 448 diuretics in, 456 Fischer's solution in, 96 Nervous affections, bromides in, 371 diseases, atropine in, 407 calcium in, 100 strychnine in, 280 instability, camphor in, 217 irritability, bromides in, 371 stimulants, central, 252 peripheral, 436 system, central, remedies acting on, 252 which depress, 282 effect of digitalis on, 183 peripheral drugs affecting, 394 Neuralgia, quinine in, 477 trifacial, aconite in, 236 butyl chloral hydrate in, 363 veratrum in, 238 trigeminal, alcohol in, 354 Neuromuscular junction, receptive sub- stance at, 153 Neutral principles, 24 Nevi, nitric acid for, 87 trichloracetic acid for, 89 Nicoll and Post's bacteria table, 490, 491 Nicotiana Rustica, 429 tabacum, 429 Nicotine, 429 pharmacologic action, 430, 431 poisoning, acute, 431 treatment, 431 Nightshade, deadly, 394 Night-sweats of tuberculosis, sulphuric acid in, 88 Niter, 240 as preservative, 500 sweet spirit of, 240 Nitrates, 239 Nitric acid, 86 dilute, therapeutics, 88 for warts or nevi, 87 therapeutics, 87 Nitrites, 239 administration, 245 excretion, 244 pharmacologic action, 240-244 poisoning from, 244 preparations and doses, 239 therapeutics, 244 toxicology, 244 Nitrogen monoxide, 310 anesthesia, 310 Nitrogenous excretion, relation of dia- phoresis to, 447 ' Nitroglycerin, 239 effect, 242 Nitrohydrochloric acid, 86 diluted, 86 therapeutics, 88 Nitrous ether, spirit of, 240 oxide, 310 anesthesia, 310 preliminary anesthetization with, in ether anesthesia, 298 Nodal rhythm of heart from digitalis, 1 70 Node, sinus, action of digitalis on circula- tion through, 165 Nomenclature of alkaloids, 21 of pharmaceutic preparations, 30 Nose, diseases of, cocaine in, 420 disinfectants, 516 Nose-bleed, counterirritants for, 78 epinephrine in, 205 Nouns, Latin, 588 Novaspirin, 485 Novocaine, 423 Nutrients, 68 Nutrition, poor, cod-liver oil in, 72 Nutritive enema, 144 Nux vomica, 268 constituents, 268 preparations and doses, 268 OBESITY, diaphoretics to lessen, 449 thyroid gland in, 562 Obstetrician's hands, disinfectants for, Si6 . Obstetrics, scopolamine-morphine anes- thesia in, 410 Obstipation, atropine in, 407 Occupation, dose and, 50 Official preparations, 45 Oil, almond, 30 6 3 8 INDEX Oil, camphorated, 213 castor, 30, 127 administration, 128 therapeutics, 128 cocoanut, 30 cod-liver, 30, 71 in chronic bronchitis, 72 in malnutrition, 72 in poor nutrition, 72 in rickets, 72 in spasmophilia, 72 in tuberculosis, 72 preparations and doses, 72 therapeutics, 72 cottonseed, 30 croton, 30, 136 dose, 137 kerosene, 33 linseed, 30 of bitter almond, 25, 426 of cade, 35, 504 of chenopodium for hookworms, 117 for pin- worms, 118 for round-worms, 118 for tape-worms, 118 for whip-worms, 118 poisoning from, 118 of cinnamon, 504 of cloves, 504 of mustard, volatile, 26 of tar, 35 of turpentine for tape- worms, 119 olive, 30, 127 peanut, 30 Russian mineral, 125 Oil-ether colonic method of anesthesia, 306 Oils, empyreumatic, 34, 35 essential, 34 fixed, 29 as cathartics, 127 mineral, 33 volatile, 34 as antiseptics, 504 occurrence, 34 Ointment, blue, as antiseptic, 519 citrine, as antiseptic, 519 definition, 42 dima/on, 80 mercurial, 520 of ammoniated mercury as antiseptic, SIQ of nitrate of mercury as antiseptic, 519 of yellow oxide as antiseptic, 519 phenol, 505 white precipitate, 520 as antiseptic, 519 zinc, 530 Ointments, 32 Oleate, definition, 42 of mercury, 520 Oleatum, definition, 42 Olein, 29, 30 Oleoresin, definition, 40 of aspidium for tape-worms, 119 Oleoresina, definition, 41 Oleoresins, 36 Oleum cadinum, 35 lini, 30 morrhuae, 30, 71 olivse, 127 picis liquidae, 35 ricini, 30, 127 theobromatis, 30 tiglii, 30 dose, 137 Olive oil, 30, 127 Operative measures, 18 Ophthalmia, gonorrheal, Cred6's method of prophylaxis against, 533 Opii pulvis, 373 Opium, 372 absorption, 376 alkaloids, 373 isoquinoline, 373 phenanthrene, 373 and ipecac, powder of, dose, 373 camphorated tincture, dose, 373 contraindications or cautions, 387 deodorized, 373 tincture, dose, 373 extract, dose, 373 granulated, 373 granulatum, 373 in diabetes, 387 in intestinal peristalsis, 387 in pain, 379, 387 in vomiting, 387 pharmacologic action, 374-383 poisoning, 383 chronic, 384 pin-point pupils in, 380 powdered, 372 preparations and doses, 373 therapeutics, 386 tincture, 373 Optimum rate of heart, 152 Optochin, 471 Orange, compound spirit of, 320 Orexine hydrochloride, 109 tannate, 109 Organic acids, 88 drugs, constituents, 19 active, 19, 20 inert, 19 Oriental sore, antimony in, 552 Orthoform, 424 therapeutics, 424 Osmosis, 228 Osteomalacia, phosphorus in, 554 thyroid gland in, 562 Ouabaln, 161 elimination of, 183 intravenous use, 196 INDEX 639 Overton-Meyer theory of narcosis, 282 Ovoferrin, 538 Oxalic acid, 90 poisoning from, 90 Ox-gall, dried, 127 extract of, 127 fresh, 126 Oxidases, 27 Oxidizers, 492 Oxygen, 578 as preventive of mountain-sickness, 579 gas, 578 in bronchial asthma, 580 in carbon monoxide poisoning, 580 in collapse in anesthesia, 580 in cyanosis, 580 in edema of lungs, 580 in gas-poisoning, 580 in heart failure, 580 in pneumonia, 580 in uremia, 580 inhalation of, in strychnine poisoning, 279 pharmacologic action, 578 therapeutics, 579 Oxygenium, 578 Oxymethyl-hydrastinine, 574 Oxyntin, 88 Oxypurins, 252 Oxyuris vermicularis, remedies for, 116 Oxyxanthine, 252 PACK, cold-, 461 hot-, 444 Pain, aconite in, 235 analgesic antipyretics in, 470 atropine in, 403 bromides in, 371 chloral hydrate in, 363 chloroform in, 292 codeine in, 388 counterirritants for, 78 in back after ether anesthesia, 297 magnesium sulphate in, 315 morphine in, 379, 387 salicylic acid in, 484 Pains, referred, 73 Painter's colic, 526 Palmitin, 29 Palsy, lead, 527 Pancreatic infantilism, pancreatin in, 82 juice, effect of pituitary extract on flow Of, 2IO Pancreatin, 82 for peptonizing milk, 83 in chronic pancreatitis, 82, 83 in hyperthyroidism, 83 in pancreatic infantilism, 82 Pancreatinum, 82 Pancreatitis, chronic, pancreatin in, 82, 83 Pantopon, 374 Papain, 85 Papaver somniferum, 372 Papaverine, 373, 389 elimination, 389 hydrochloride, 389 in cough, 390 in pyloric spasm, 390 in spasm, 390 in ureteral stone, 390 in vomiting, 390 poisoning from, 389 sulphate, 389 therapeutics, 390 toxicity, 389 Paper, definition, 42 Para - amido - benzoic-acid - propyl ester, 424 Para - amino - benzoyl - diethyl - amino- ethanol chloride, 423 Para-diethoxyl-ethenyl-diphenyl-amidin chloride, 424 Paraffin, 33 liquid, 33, 125 Paraffinum, 33 Paraform, 510 Paraformaldehyd, 510 Paraguay tea, 253 Para-hydroxy-phenylethylamine, 567 effect on circulation, 569 Paraldehyd, 366 for intravenous anesthesia, 307 habit, 367 in strychnine poisoning, 279 poisoning from, 367 Paralysis, 57 gastric or intestinal postoperative, after ether anesthesia, 298 infantile, epinephrine in, 205 intestinal, pituitary extract in, 210 lead, 527 respiratory, collapse and, 249 strychnine in, 280 Sunday-morning, 345 Para-sulphondi-chloramino-benzoicacid, 495 Paregoric, dose, 373 Paresis, general, salvarsan in, 550 Paris-green, 546 Paroxysmal tachycardia, digitalis in, 189 from digitalis, 170 Paroxysms of acroparesthesia, quinine in, 477 Pasta zinci, 483 Paste, Lassar's, 483 mustard, 77 Pasteurization, 489, 492 Patterson-Lambert treatment of mercury poisoning, 523 Peanut oil, 30 640 INDEX Pear brandy, 319 cider, 318 Pelletierine for tape- worms, 119 Pepo for tape- worms, 119 Pepsin, 27, 81, Pepsinum, 81 Peptonizing milk, pancreatin for, 83 Percentage liquids, 38 chemic, 38 pharmaceutic, 38 strength of liquids, 38 Perhydrol, 96 Periodic drinkers, 346 Peripheral arteries, contraction, from digitalis, 178 nervous stimulants, 436 system, drugs affecting, 394 resistance, influences affecting, 149 Peristalsis, intestinal, morphine in, 387 Pernicious anemia, cholesterol in, 32 sodium cacodylate in, 542 Peroxide of hydrogen, 492 Peruvian bark, 470 Petrolatum, 33 album, 33 liquid, 33, 125 heavy, 33 in rheumatoid arthritis, 33 light, 33 white, 33 Petroleum benzin, 33 ether, 576 Petty's treatment of morphinism, 386 Pharmaceutic chemistry, 18 elixirs, 320 measures, 18 percentage liquid, 38 preparations, 37 compound, 39 definitions of kinds in common use, 39 nomenclature, 39 simple, 39 Pharmacist, 18 Pharmacodynamics, 18 Pharmacognocist, 18 Pharmacognosy, 18 Pharmacologic action, 62 ,63-65 Pharmacologist, 18 Pharmacology, 18 Pharmacopoeia, 45 definition, 45 United States, 45 Pharmacy, 18 Pharyngeal insufflation, anesthesia by, 39 Pharyngitis, acute, ammonium chloride in, 224 Phasic arhythmia from digitalis, 166, 176 Phen-acetamide, 462 Phenacetin, 462 Phenanthrene opium alkaloids, 373 Phenol, 504 as anesthetic, 425 as antiseptic, 508 compounds, 501 iodine, 504 excretion, 507 for infected cavities, 79, 508 gangrene from, 506 glycerite, 505 in tetanus, 509 liquefactum, 504, 505 liquefied, 505 ointment, 505 pharmacologic action, 505-507 poisoning from, 507 treatment, 508 preparations, 505 therapeutics, 508 toxicology, 507 Phenolphthalein as laxative, 134 Phenolphthalein-agar to give bulk and soft consistency to feces, 125 Phenolsulphonates, non-toxic, 508 Phenyl salicylate, 485 Phenyl-cinchoninic acid, 487 in gout, 487, 488 Phenyl-dimethyl-pyrazolon, 462 Phenyl-quinoline-carboxylic acid, 487 Phlebotomy, 245 , Phlorhizin, 26 Phloridzin, 26 Phlorizin, 26 Phosphoric acid, dilute, therapeutics, 88 Phosphorous acid, 553 Phosphorus, 553 hypophosphites of, 554 in osteomalacia, 554 in rickets, 554 poisoning, acute, 553 chronic, 553 therapeutics, 554 toxicology, 553 Phthalem test, 135 Physical measures, 18 Physiologic limit of drug, 48 Physiology of circulation, 148 Physostigma, 436 constituents, 436 dose, 436 excretion, 438 extract, dose, 436 . pharmacologic action, 436-438 poisoning from, 438 preparations and doses, 436 therapeutics, 438 tincture, dose, 436 toxicology, 438 venenosum, 436 Physostigmine, 436 as cathartic, 438 pharmacologic action, 436-438 salicylate as cathartic, 124 INDEX 641 Physostigmine salicylate, dose, 436 Pick-me-up, 345 Picraconitine, 231 Pigment atrophy in morphinism, 386 Pill, blue, 131 compound cathartic, 131 definition, 41 mercury, 131 Pills, Blaud's, 537 compound cathartic, 133 rhubarb, 133 enteric, 36, 586 of aloes, 133 of lead and opium, 525 Pilocarpidine, 439 Pilocarpine, 439 as diaphoretic, 442 elimination, 441 hydrochloride, dose, 439 in glaucoma, 442 nitrate, dose, 439 pharmacologic action, 439-441 poisoning from, 441 treatment, 441 therapeutics, 441 toxicology, 441 Pilocarpus, 439 as diaphoretic, 442 constituents, 439 dose, 439 elimination, 441 fluidextract, dose, 439 jaborandi, 439 microphyllus, 439 pharmacologic action, 439-441 poisoning from, 441 treatment, 441 preparations and doses, 439 therapeutics, 441 toxicology, 441 Pilula antiperiodica, 471 sine aloe, 471 definition, 41 ferri carbonatis, 537 Pilulae catharticae compositae, 137 vegetabiles, 137 Pink-root for round- worms, 117 Pin-point pupils in opium poisoning, 380 Pin-worms, quinine in, 476 remedies for, 116 Pinus palustris, 35 Piperazine, 488 Pituitary extract, 207 as cathartic, 124 effect of, on cerebrospinal fluid, 210 on flow of pancreatic juice, 210 of saliva, 210 on secretion of milk, 209 from anterior lobe, effects and uses, 211 in asthma, 211 in dwarfism, 211 41 Pituitary extract from anterior lobe in dystrophia adiposo-geni- talis, an in pituitary infantilism, 211 in premature menopause, 211 from whole gland, 211 in collapse, 251 in diabetes insipidus, 210 in exophthalmic goiter, 210 in hyperthyroidism, 210 in intestinal paralysis, 210 in labor, untoward effects, 211 in shock, 210, 251 in tympanites, 210 in uterine inertia, 210 pharmacologic action, 207-210 therapeutics, 210 toxicology, 210 gland, anterior lobe, 211 whole gland, 211 infantilism, anterior lobe extract in, 211 Placebo, 61 Plant acids and their salts, 20 Plants, essences of, 34 Plaster, definition, 42 lead, 525 Pleistopon, 374 Plethora, hydremic, 454 Pleural effusion, calcium chloride in, 100 Plumbum, 525 Pluto water, 148 concentrated, 148 Pneumatic suit, Crile's, in shock, 225, 251 Pneumonia, camphor in, 217 digitalis in, 166, 195 ethylhydrocupreine in, 479 oxygen in, 580 quinine in, 477 strychnine in, 280 Podophyllum, 136 dose, 137 resin of, dose, 137 Poison, cumulative, 47 hemlock, 427 Poison-cup, 443 Poisoning from acetyl-salicylic acid, 485 from aconite, 235 treatment, 235 from alcohol, 344 after-effects, 345 treatment, 345 from ammonia, 222 treatment, 222 from analgesic antipyretics, 468, 469 from antimony, 552 from antipyrine, 468, 469 from arsenic, acute, 546 iron as antidote, 537, 547 treatment, 547 chronic, 547 642 INDEX Poisoning from arsenic, chronic, treat- ment, 548 cumulative, 547 from aspidium, 119 from aspirin, 485 from atropine, 405 treatment, 406 from barium, 212 from belladonna, 405 treatment, 406 from benzine, 576 from benzol, 577, 578 from bismuth, 531 from boric acid, 501 from bromides, acute, 370 chronic, 370 treatment, 371 from bromoform, 372 from caffeine, 261 treatment, 261, 262 from calcium, 100 from camphor, 216 from cantharides, 77 from carbon monoxide, 574 acute, 575 chronic, 575 oxygen in, 580 transfusion of blood in, 576 treatment, 576 from carminatives, 104 from chloral hydrate, acute, 362 chronic, 362 from chloroform, delayed, 302 from cocaine, 419 Magnan's sign in, 419 treatment, 419 from colchicum, 487 from copper, 529 from cyanides, 426 treatment, 427 from digitalis, 184 cumulative, 186 overwhelming dose, 184 single large dose by mouth, 185 symptoms, 186 treatment, 188 from drastics, 135 from early-bird mixture, 119 from epinephrine, 204 from ergot, 571 chronic, 571 from ethylhydrocupreine, 479 from formaldehyd, 511 from gas, oxygen in, 580 from gasoline, 576 from granatum, IIQ from illuminating-pas, 574 from inorganic acids, treatment, 87 from iodoform, 499 from ipecac, 565 from iron, 540 from kamala, 119 Poisoning from lead, 526 diagnosis, 528 treatment, 528 wrist-drop in, 527 from lithium, 93 from magnesium sulphate, 143 from manganese, 541 from mercury, 522 acute, 522 treatment, 523 calcium sulphide in, 524 chronic, 524 treatment, 525 decapsulation of kidneys in, 524 Hall's antidote, 524 Lambert-Patterson treatment, 523 salivation in, 522 venesecetion and transfusion in, 524 Wilms' treatment, 524 from methyl alcohol, 355 from morphine, 383, 384 chronic, 384 treatment, 383 from muscarine, 442 from mushroom, 442 treatment, 443 from mustard, 77 from nicotine, acute, 431 treatment, 431 from nitrites, 244 from oil of chenopodium, 118 from opium, 383 chronic, 384 pin-point pupils in, 380 from oxalic acid, 90 from papaverine, 389 from paraldehyd, 367 from phenol, 507 treatment, 508 from phosphorus, acute, 553 chronic, 553 from physostigma, 438 from pilocarpus, 441 treatment, 441 from potassium chlorate, 113 from pyridine, 431 from quinine, 476 from ricin, 27 from salicylic acid, 482 from saline infusion, 231 from santonin, 116, 117 from scarlet red, 80 from sodium chloride, 93 from stramonium, 394 from strychnine, 277 treatment, 278 from sulfonal, 364, 365 from thyroid gland, 561 from tobacco, 431 chronic. 435 INDEX Poisoning from trional, 364, 365 from veratrum, 238 from veronal, 365 from zinc, 530 ivy-, potassium permanganate in, 541 narcotic, strychnine in, 280 Poisonous fungi, 443 Poisons, protoplasm, general, 56 Poliomyelitis, anterior, epinephrine in, 205 Polycythemia, benzol in, 578 Polyporus albus, 41 2 Pomegranate root bark for tape-worms, 119 Port wine, 318 Porter, 317 Post and Nicoll's bacteria table, 490, 491 Postpartum hemorrhage, diluted acetic acid in, 89 epinephrine in, 205 ergot to prevent, 571 Potassa sulphurata in acne, 124 Potassium, 92 acetate, 101 alum, 535 bicarbonate, 92 bisulphate, 25, 26 bitartrate, 101, 102 dose, 138 carbonate, 92 chlorate, 113 in stomatitis, 113 poisoning from, 113 citrate, 101 dose, 138 effervescing, dose, 138 cyanide, 426 hypochlorite, 494 iodide, 245, 555 nitrate, 240 as preservative, 500 in bronchial asthma, 240 permanganate, 540 as antiseptic and deodorizer, 493 sulphate, dose, 138 tartrate, 101 dose, 138 Poulsson's experiment with strychnine, 170 Poultice, definition, 42 Poultices, 76 clay, 76 Powder, definition, 41 of ipecac and opium, dose, 373, 564 Powdered opium, 372 Precipitated carbonate of zinc, 530 chalk, 97 sulphur in acne, 124 to give bulk and soft consistency to feces, 125 Pregnancy, nausea and vomiting of, ingluvin in, 85 Pregnancy, nausea and vomiting of, treatment, 112 Prepared chalk, 97 Prepositions, Latin, 590 Prescription, 581 abbreviations, 597 special, 599 aromatics, 585 colors, 586 compound, 591 dating, 582 directions for compounding, 583 for label, 583 figuring quantities, 593 flavors, 585 form, 591 lazy man, 595 liquid, 583 measures, 584 name and quantity of each ingredient, 583. of patient, 582 of apothecaries' system, 581 of metric system, 581 shot-gun, 595 signature, 583 simple, 591 superscription, 583 sweetening agents, 585 vehicle, 585 writing, 581 good usage, 595 Preservatives, 489, 515 food. 500, 515 for anatomic material, 515 for antitoxins, 515 for vaccines, 515 pharmaceutic, 515 Preventive medicine, 17 Proctitis, silver nitrate in, 534 Propaesin, 424 Prostration, transfusion of blood in, 227 Protargol, 534 Protectives, 67 as antemetics, 112 Protoplasm poisons, general, 56 Protoveratrine, 236 pharmacologic action, 238 Prunus virginiana, 426 Pseudo-jervine, 237 Pseudoleukemia, benzol in, 578 Psoriasis, chrysarobin in, 81 Psychic antiseptics, 504 gastric juice, 107, 324 Psychosis, KorsakofT's, 347 Psychotherapeutic measures, 18 Psychotrine, 564 Psyllium seeds to give bulk to feces, 125 Ptomains, 23 Ptomatropine, 23 Pulmonary arteries, action of digitalis on circulation through, 180 644 INDEX Pulmonary circulation, 155 Pulse in anesthesia, 309 Pulsus alternans, digitalis in, 189 from digitalis, 176 Pulvis cretae compositus, 97 definition, 41 jalapae compositus, 137 Pumpkin-seed for tape-worms, 119 Puncture, lumbar, in delirium tremens, 349 Pupils, pin-point, in opium poisoning, 380 Pure alkaloids, 21 solubility of, 21 Purgative, 122 waters, 147 Purgatives, subcutaneous, 137 Purified animal charcoal, 109 Purins, 252 Pyloric spasm, papaverine in, 390 Pyorrhea alveolaris, emetine in, 566 Pyramidon, 462 Pyridine, 429 poisoning, 431 Pyrogallol, 504 QUASSIN, 26 Quebrachine as expectorant, 563 Quebracho as expectorant, 563 Quercitannin, 29 Quinidine, 470 Quinine, 21, 470 absorption, 473 administration, 478 amaurosis, 474 amblyopia, 474 and urea hydrochloride, 471 as anesthetic, 425 as local anesthetic, 476 as disinfectant, 476 as postoperative prophylactic, 478 bisulphate, 21, 471 as local anesthetic, 476 chocolates, 478 dihydrochloride, 471 elimination, 474 hydrobromide, 471 hydrochloride, 471 immunity, 474 in amebic colitis, 476 dysentery, 478 in bacterial infections, 477 in blackwater fever, 478 in cold, 477 in exophthalmic goiter, 476 in headache, 477 in hemorrhoids, 477 in influenza, 477 in malaria, 477 in menorrhagia, 477 in neuralgia, 477 Quinine in paroxysms of acroparesthesia, 477 in pin-worms, 476 in pneumonia, 477 in septicemia, 477 in skin diseases, 477 in tuberculosis, 477 in uterine inertia, 477 pharmacologic action, 471-476 poisoning from, 476 rash, 475 salicylate, 471 sulphate, 21, 471 tannate, 471, 478 therapeutics, 476 toxicology, 476 untoward symptoms, 476 RACE, dose and, 50 Rachitis, phosphorus in, 554 Rash, ether, 288 from bromides, 369, 370 quinine, 475 Receptive substance at neuromuscular junction, 153 Rectal administration of salicylic acid, 484 anesthesia, 306 injections, 143 irrigations of saline solution, 145 suppositories, 42, 145 treatment, 143 Rectum, administration by, 55 disinfectants, 517 Recuperating power of heart, action of digitalis on, 177 Red wine, 318 Reddening, 72 Reduced iron, 537 Referred pains, 73 Reflex emetics, in Reflexes, 271, 272 convulsive, 272 from strychnine, 272 coordinated, 272 simple, 272 varieties, 272 Regulin to give bulk and soft consistency tofeces, 125 Remote local action, 52 Rennet, 84 clotting of milk by, calcium in, 99 Rennin, 84 Repeated doses, 47 Resin, gum, 40 of jalap, dose, 137 of podophyllum, dose, 137 of scammony, dose, 137 Resins, 36 gum, 36 Resistance to disease, alcohol and, 352 INDEX 645 Resorcin, 503 Resorcinol, 503 Respiration, artificial, in strychnine poisoning, 279 Cheyne-Stokes, 377 Respiratory paralysis, collapse and, 249 system, effect of digitalis on, 183 tract, disinfectants, 517 troubles after ether anesthesia, 298 Retention of urine from digitalis, 181 of water, digitalis in, 182 Rhamnus frangula, 133 purshinana, 133 Rheum, 134 Rheumatism, chronic, disaphoresis in, .45 cimicifuga in, 488 formic acid in, 89 salicylic acid in, 483 sodium bicarbonate in, 96 Rheumatoid arthritis, liquid petrolatum in, 33 thyroid gland in, 562 Rhinitis tablets, 213, 396 Rhubarb, 134 pills, compound, 133 Rhythm, coupled, of heart, from digitalis, 176 nodal, of heart, from digitalis, 170 of heart, influences affecting, 152 normal, 165 digitalis in, 191 reversed, from digitalis, 171 Ricin, 27 poisoning, 27 Ricinus communis, 27 Rickets, cod-liver oil in, 72 phosphorus in, 554 thyroid gland in, 562 Ringer-Locke solution for saline infusion, _228 Ringer's solution for saline infusion, 228 Risiccol, 128 Roaf and Moore theory of narcosis, 282 Rochelle salts, 101 Rose-water and glycerin, 31 Round-worms, remedies for, 116 Rubefacient, 72 Rubijervine, 236 Rum, 319 Russian bath, 444 mineral oil, 125 SABADILLA, 237 Sabadine, 237 Sabadinine, 237 Saccharin, 68 Saccharum, 27, 69 lactis, 28, 69 Safrol, 107 Sajodin, 555 Sal ammoniac, 223 granulatus effervescens, definition, 42 Salads as cathartic measure, 123 Salicin, 24, 25, 486 Salicyl alcohol, 25 Salicylic acid, 480 absorption, 481 administration, 484 as surgical antiseptic, 483 dose, 480 excretion, 482 hypodermatic use, 484 in bromidrosis, 483 in chorea, 483 in corns, 483 in diabetes, 484 in gout, 484 in pain, 484 in rheumatism, 483 in skin diseases, 483 in sweating of feet and hands, 483 in warts, 483 intravenous administration, 484 pharmacologic action, 480-482 poisoning from, 482 preparations and doses, 480 rectal administration, 484 therapeutics, 483 toxicology, 482 allies, 484 jag, 483 Salicylic-acetanilid, 486 Salicyliden-para-phenetidin, 486 Salicylism, 482 Salicyl-para-phenetidin, 486 Saligenin, 25 Saline cathartics, 137 doses, 138 in constipation, objections, 143 Moreau's loop and, 141 pharmacologic action, 139-142 preparations, 138 therapeutics, 142 time to give, 56 infusion, 227 by enema, 230 by hypodermoclysis, 230 colon irrigations, 145 continuous drop irrigation, 145 contraindications, 231 Dawson's solution, 227 effects, 228 of rate of flow, 230 of temperature of solution, 230 on respiration, 230 when volume of blood has not been decreased, 228 is below normal, 229 in cholera, 230 in collapse, 230 in ether collapse, 309 in hemorrhage, 230 646 INDEX Saline infusion in shock, 230 in strychnine poisoning, 279 in toxemic conditions, 230 intravenous, 227 Locke's solution, 227 normal, 227 poisoning by, 231 rectal irrigations, 145 Ringer-Locke solution, 228 Ringer's solution, 228 therapeutics, 230 toxicology, 231 waters, 147 alkaline, 147 Saliphen, 486 Salipyrine, 462 Saliva, effect of pituitary extract on flow of, 210 Salivation in mercury poisoning, 522 Salol, 485 for coating pills, 586 Salophen, 462, 486 Salt, Epsom, as anesthetic, 313 dose, 138 Glauber's dose, 138 granular effervescent, definition, 42 retention, relation of, edema to, 93 Salt-free diet, prolonged, results of, 93 Saltpeter, 240 as preservative, 500 Salts, alkaloidal, 21 differences in physiologic actions, 24 solubility of, 21 bile, 126 metallic, caustic, 78 of tartar, 92 Salvarsan, 542. 549 contraindications and cautions, 551 in cerebrospinal syphilis, 550 in general paresis, 550 in locomotor ataxia, 550 in non-syphilitic cases, 552 in syphilis, 549 therapeutics, 549 untoward effects, 550 Salves, 32 Santonica for round- worms, 116 Santonin, 26, 116 poisoning from, 116, 117 Santoninum, 116 Sapo, 31, 127 mollis, 31 Satterlee and Hooker's method of blood transfusion, 226 Scammony, resin of, dose, 137 Scarlet red, 79 Schleich's infiltration anesthesia, 425 Sciatica, magnesium sulphate in, 315 Scientific therapeutics, 58 Scilla, 160 Scilkun, 1 60 Scillitoxin, 160 Scoparius, 428 Scopolamine, 409 hydrobromide, 396 Scopolamine-morphine anesthesia, 409 as preliminary to general anesthesia, 410 Scopolamine-narcophin anesthesia, 409 Scotch whiskey, 319 Seasickness, chloretone in, 364 treatment, 113 Secretin, 85 Secretion, atropine to diminish, 406 threshold in diuresis, 457 Sedatives, central, as antemetics, 112 local, as antemetics, 112 Seidlitz powder, 138 Selective drugs, 56 Semisolids, 41 Senega as expectorant, 563 Senna, 133, 134 tea, 133 Sepsis, transfusion of blood in, 227 Septicemia, quinine in, 477 Serum, Beebe's, 562 mercurialized, intraspinal injection, 521 salvarsanized, in cerebrospinal syphilis, 550 sickness, atropine in, 408 calcium in, 100 Sevum, 30 Sex, dose and, 50 Sexual feebleness, strychnine in, 280 hyperesthesia, bromides in, 371 Shakes, brass, 530 Sheet, drip-, 461 Sherrington's theory of action of strych- nine on muscles, 273 Sherry wine, 318 Shock, 248 alcohol in, 354 anaphylactic, epinephrine to check, 205 camphor in, 217 carbon dioxide in, 252 Crile's anoci-association as prophy- lactic, 249, 250 pneumatic suit in, 225, 251 epinephrine in, 206, 251 gelatin in, 71 massage of heart in, 251 mechanical measures in, 251 pituitary extract in, 210, 251 saline infusion in, 230 stimulants in, 251 symptoms, 250 transfusion of blood in, 226, 251 treatment, 250 prophylactic, 250 Shot-gun prescription, 595 Sickness, mountain-, oxygen as prevent- ive, 579 INDEX 647 Sickness, serum, atropine in, 408 calcium in, 100 Sign, Magnan's, in cocaine poisoning, 419 Signature of prescription, 583 Silver, 533 as antiseptic, 534 and disinfectant, 500 colloidal, 534 gelatose, 534 horn, 533 nitrate, 533 as prophylactic against gonorrheal ophthalmia, 533 in chronic gastritis, 533 in colitis, 534 in hyperchlorhydria, 533 in proctitis, 534 therapeutics, 533 protein, 534 untoward effects, 535 vitellin, 534 Sinalbin, 26 Sinapine sulphate, 26 Sinapis, 77 nigra, 77 Sinigrin, 25, 26 Sinus arhythmia, digitalis in, 189 from digitalis, 166 node, action of digitalis on circulation through, 165 Sinuses, chronic, Beck's treatment, 532 Skin, administration by, 55 diseases, disinfectants in, 516 quinine in, 477 salicylic acid in, 483 disinfectants, 516 irritation, production of, 72 Sleep, 356 twilight, 410 Verworn's theory, 356 Sluggish liver, calomel in, 131 ulcers, burnt alum in, 536 Smoking, 429, 432 effects of, 435 Snake-bite, potassium permanganate in, 540 Snakeroot, black, 488 Snuff, 429 Soamin, 542 Soap, 31 as cathartic, 127 Castile, 30, 31, 127 detergent, 31 green, 31 tincture of, 31 hard, 31 liniment, 213 soft, 31 liniment of, 31 soluble, 31 Socaloin, 133 Soda, baking, 92 Sodii arsenas exsiccatus, 541 bicarbonas, 94 nitris, 239 Sodium, 92, 93 acetate, 101 acetyl arsanilate, 542 aminophenyl arsonate, 542 arsanilate, 542 . arsenate, 541 dried, 541 solution of, 541 aurate as antiseptic and disinfectant, 500 benzoate, 501 bicarbonate, 92, 94 administration, in ether anesthesia, 299 effect of, on alimentary tract, 94 on mucous membranes, 94 in acidosis, 95 in diabetes, 95 in rheumatism, 96 time of administration, 95 bisulphite, 493 borate as preservative, 500 cacodylate, 542 carbonate, monohydrated, 92 chloride, 93 as preservative, 500 as prophylactic against hemoptysis, 94 poisoning, 93 citrate, 101, 102 dose, 138 dimethyl arsenate, 542 glycocholate, 126 hydroxide, 30 hyposulphite, 493 iodide, 555 nitrite, 239 dose, 239 effect, 242 oxymercury orthonitrophenolate as antiseptic, 519 perborate, 493 phosphate, dose, 138 effervescing, dose, 138 salicylate, dose, 480 sulphate, dose, 138 sulphite, 493 tartrate, 101 dose, 138 taurocholate, 126 thiosulphate, 493 Sodium-benzosulphinide, 68 Sodium-saccharin, 68 Sodium-salvarsan, 543 Soft soap, 31 liniment of, 31 Soldiers, irritable heart of, 435 Solid albolene, 33 Solids, 41 r 648 INDEX Solids, administration, 586 semi-, 41 Solubility of alkaloidal salts, 21 of alkaloids, 21 of atropine, 21 sulphate, 21 of pure alkaloids, 21 Solution, definition, 40 of aluminium acetate, 536 of ammonium acetate, 224 of arsenous acid, 541 of epinephrine hydrochloride, dose, 197 of iron and ammonium acetate, 224 of sodium arsenate, 541 hypochlorite, 494 Sore, oriental, antimony in, 552 tongue after ether anesthesia, 298 Sores, venereal, mercury in, 519 Spanish fly, 77 Sparkling mineral waters, 146 wine, 318 Sparteine sulphate, 428 in spasmodic asthma, 428 Spasm, Hoffmann's anodyne in, 288 of urethra, cocaine in, 421 papaverine in, 390 pyloric, papaverine in, 390 Spasmodic asthma, lobelia in, 428 sparteine sulphate in, 428 stramonium in, 408 Spasmophilia, cod-liver oil in, 72 magnesium sulphate in, 315 Specific treatment, 60 Spelter chills, 530 Spermaceti, 32 Spices, 107 Spigelia for round-worms, 117 Spinal anesthesia in strychnine poisoning, .279 with cocaine, 414, 415, 421 with stovaine and strychnine, 415 Spirit, definition, 40 of bitter almond, 426 of glonoin, 240 of hartshorn, 218 of mindererus, 224 of nitrous ether, 240 Spirits, 318 Spiritus ammoniac aromaticus, 218 definition, 40 frumenti, 319 glycerylis nitratis, 240 vini gallici, 319 Spirosal, 486 Splint, bowel, 375, 376 Spoonfuls, 584 Sporotrichosis, copper sulphate in, 529 Spotted boy, 535 Squibb's diarrhea mixture, 146, 213 test for aconite, 232 Squill, 1 60 Squill, compound syrup of, 552 as expectorant, 564 fluidextract of, dose, 160 syrup of, 1 60 compound, 160 tincture of, dose, 160 Staphisagria, 236 Starch, arrowroot, 28 corn-, 28 water, 28 Starches, 27 Stavesacre, 236 Steady drinkers, 346 Stearin, 29 Stearoptens, 35, 106 Stenosis, aortic, digitalis in, 194 mitral, digitalis in, 194 Sterilization, 489 Still mineral waters, 146 Stimulants, central nervous, 252 circulatory, 157 peripheral nervous, 436 Stimulation, 57 Stokes' expectorant, 160, 564 treatment of morphinism, 386 Stomach, diseases of, cocaine in, 421 disinfectants, 517 distention of, after ether anesthesia,. 297 ulcer of, orthoform in, 424 scarlet red in, 80 Stomatitis, mercurial, 522 potassium chlorate in, 113 Stout, 317 Stovaine, 423 and strychnine, spinal anesthesia with,. 415 . Stramonium, 394, 395 dose, 395 in spasmodic asthma, 408 ointment, 396 tincture, 396 Strong wine, 318 Stronger ammonia water, 218 Strontium salicylate, dose, 480 Strophanthin, 24, 160 dose, 160 elimination of, 183, 184 intravenous use, 196 Strophanthus, 160 absorption, from alimentary tract, 183; constituents, 160 dose, 1 60 hispidus, 1 60 Kombe, 160 preparations, 160 and doses, 160 reliability of, 162 tincture of, dose, 160 Strychnine, 268, 269 absorption, 269 action on reflexes, 280 INDEX 649 Strychnine, administration, 281 as tonic, 280 Bernard's experiment, 271 caffeine and, comparison of action, 275 contraindications, 281 convulsive reflexes from, 272 excretion, 277 in cough, 276 in diminished vision, 281 in narcotic poisoning, 280 in nervous diseases, 280 in paralysis, 280 in pneumonia, 280 in sexual feebleness, 280 nitrate, 269 dose, 269 pharmacologic action, 269-277 poisoning from, 277 treatment, 278 poisonous action, 275 Poulsson's experiment, 270 preparations and doses, 268 Sherrington's theory, 273 sulphate, 269 dose, 269 testing clinically, 275 therapeutics, 280 tolerance, 277 toxicology, 277 Strychnos nux vomica, 268 Stupe, 75 Stupor, 282 morphine-, 410 of alcoholics, 344 Stypticin, 574 Styptics, 115 Subcutaneous administration, 53 superficial, 54 injection of epinephrine, effects, 199 purgatives, 137 Subinvolution of uterus, ergot in, 572 Sublimed sulphur as laxative, 125 Succinyl disalicylic acid, 485 Succus, definition, 40 Suet, 30 Sugar, 69 of milk, 28, 69 susceptibles, 68 Sugars, 27, 28 Suggestive measures, 18 Sulfonal, 364 poisoning from, 364, 365 Sulphocarbolates, non-toxic, 508 Sulphonmethanum, 364 Sulphonethylmethanum, 364 Sulphur dioxide, 493, 494 flowers of, as laxative, 1 25 lotum to give bulk and soft consist- ency tofeces, 125 prsecipitatum to give bulk and soft consistency to feces, 125 Sulphur, precipitated, in acne, 124 to give bulk and soft consistency to feces, 125 sublimatum as laxative, 125 sublimed, as laxative, 125 to give bulk and soft consistency to feces, 124 washed, to give bulk and soft consis- tency to feces, 125 waters, 147 Sulphurated waters, 146 Sulphuric acid, action of, 78 aromatic, 86 . in night-sweats of tuberculosis, 88 Sulphurous acid, 493 Sun cholera drops, 213 mixture, 146 Sunday-morning paralysis, 345 Superheated air, 450 Superscription of prescription, 583 Suppositoria glycerini, 31 Suppositorium, definition, 42 Suppository, definition, 42 glycerin, 31 rectal, 42, 145 urethral, 42 vaginal, 42 Suppression of urine from digitalis, 181 Supracapsulin, 196 Suprarenal gland, dried, dose, 197 Suprarenalin, 196 Suprarenalum siccum, 197 Suprarenine, 23 Surgeon's hands, disinfectants for, 516 Surgical instruments, disinfectants for, 515 supplies, disinfectants for, 515 Susceptibility, dose and, 50 Sweat, character of, in diaphoresis, 447 Sweating, excessive, agaricin in, 412 morphine to induce, 387 of feet and hands, salicylic acid in, 483 of hands, feet, and axillae, aluminium chloride in, 536 profuse, 443 rationale of, 445 Sweet spirit of niter, 240 wine, 318 Sweetening agents, 68 for prescription, 585 Symptomatic treatment, 60 Synergists, 57 Syphilis, cerebrospinal, neosalvarsan in, 55 salvarsan in, 550 iodides in, 558 theory of action, 557 mercury in, 519 neosalvarsan in, 549 salvarsan in, 549 sodium cacodylate in, 542 Syrup, definition, 40 INDEX Syrup of lactophosphate of lime, 97 of phosphates of iron, quinine, and strychnine, 537 dose, 269 of squill, 1 60 compound, 160 of tar, 35, 504 of wild cherry, 426 of yerba santa, 109 Syrupus calcii lactophosphatis, 97 definition, 40 picis liquidas, 35, 504 Systemic action of drugs, 52 arteries, action of digitalis on circula- tion through, 178 TABACUM, 429 Tabella compressa, definition, 41 triturata, definition, 41 Tablet, compressed, definition, 41 triturate, definition, 41 triturates, 587 Tablets, compressed, 587 hypodermic, 53, 587 Tachycardia, paroxysmal, digitalis in, 189 from digitalis, 170 Tasnia nana, 116 saginata, remedies for, 119 Taka-diastase, 85 Tallow, 30 Tannalbin, 115 Tannate, egg-albumin, 115 Tannic acid, 29, 114 and alkaloids, incompatibility, 22 astringents, 114 of coffee, 264 of tea, 265 therapeutics, 115 Tannigen, 115 Tannin, 114 formaldehyde-, 115 hexamethylenamine-, 115 Tannins, 29 Tannoform, 115 Tannopin, 115 Tape-worms, dwarf, remedies for, 119 remedies for, 119 Tar, 504 oil of, 35 syrup of, 35, 504 Tartar, cream of, 101, 102 dose, 138 emetic, 552 salts of, 92 Tartaric acid, 88, 90 Taste of alkaloids, 22 Tea, 253, 264, 265 action, 265, 266 Appalache, 253 black, 265 Tea, green, 265 habit, 266 Paraguay, 253 senna, 133 tolerance, 266 Temperature, dose and, 50 Teniacides, 119 Teniafuges, 119 Terminal disinfection, 515 Terra silicea purificata, 1 1 1 Test, Squibb's, for aconite, 232 urotropin, 512 Tetanus, Epsom salt in, 314 magnesium sulphate in, 314 phenol in, 509 calcium in, 98, 100 Tethelin, 211 Tetra-iodo-pyrrhol, 499 Theobroma cacao, 267 Theobromine, 252, 253, 263, 264 diuretic action, 456 sodiosalicylate, 264 Theocine, 264 diuretic action, 456 Theophylline, 23, 252, 263, 264 diuretic action, 456 Therapeutic dose, 47 Therapeutics, 62 definition of, 17 empiric, 58 scientific, 58 Thermal mineral waters, 146 Thiersch's solution, 500 Thiol, 509 Thiosinamine, 26, 80 Thirst after ether anesthesia, 297 Thornapple, 394 Thread-worms, remedies for, 116 Throat, diseases of, cocaine in, 421 disinfectants, 516 tuberculous ulcers of, lactic acid in, Thymol for hookworms, 117 in trichinosis, 117 iodide, 499, 504 Thyreoglobulin, 560 Thyreoidectin, 563 Thyroid gland, 560 after thyroidectomy, 562 in colloid goiter, 562 in creatinism, 562 in delayed union of fractures, 562 in hypothyroidism, 562 in infantile wasting, 562 in myxedema, 562 in obesity, 562 in osteomalacia, 562 in rheumatoid arthritis, 562 in rickets, 562 iodine content, 556, 560 pharmacologic action, 561 poisoning from, 561 relation to adrenals, 561 INDEX Thyroid gland, therapeutics, 562 Thyroidectomy, thryoid gland after, 562 Thyroideum siccum, 560 Thyroidin, 560 Tic, cocaine as diagnostic agent in, 421 Tinctura antiperiodica, 471 cardamomi composita, 107 cinchonae composita, 109 dose, 470 definition, 40 gentianas composita, 109 lavandulse composita, 107 moschi, dose, 394 Tincture, definition, 40 of green soap, 31 Tobacco, 429 amblyopia, 435 effects of smoking, 435 habit, 423 heart, 435 in asthma, 430 Indian, 428 poisoning from, 431 chronic, 435 therapeutics, 430 tolerance, 431 toxicology, 431 Toleration, dose and, 50 Toluene parasulphochloramin, 498 parasulphondichloramin, 498 Toluol-azotoluol-azobetanaphthol, 79 Tone-waves, 398 Tongue, sore, after ether anesthesia, 298 Tonic, morning, 345 Toothache, chloral hydrate in, 362 chloroform in, 292 Torpor, 282 Toxalbumins, 26 Toxemic conditions, saline infusion in, 230 Toxic dose, 47 Toxicology, definition, 62 Toxins, 26 Toxitabella hydrargyri chloridi corrosivi, Si8 Tragacanth, 28, 29 Transfusion and venesection in mercury poisoning, 524 of blood, 225 conditions indicating, 226 in anemia, 226 in carbon monoxide poisoning, 576 in collapse, 226 in hemophilia, 226, 227 in infectious conditions, 227 in malnutrition, 227 in prostration, 227 in protracted weakness, 227 in sepsis, 227 in shock, 226 and collapse, 251 Lindemann's method, 226 Transfusion of blood, Satterlee and Hooker's method, 226 Treatment, expectant, 61 scope of, 60 specific, 60 symptomatic, 60 Trichinosis, thymol in, 117 Trichloracetic acid, 89 Trichlorethyl-glycuronic acid, 361 Trifacial neuralgia, aconite in, 236 butyl chloral hydrate in, 363 veratrum in, 238 Trigeminal neuralgia, alcohol in, 354 Trimethol, 504 Trimethyl xanthine, 252 Trimethyl-benzoxy-piperidine, 423 Trimethyl-methoxy-phenol, 504 Trimethylxanthine, 253 Trinitrin, 239 Trional, 364 poisoning from, 364, 365 Trioxymethylanthraquinone, 131 Trioxymethylene, 510 Trioxypurin, 252 Triturates, tablet, 587 Trituratio, definition, 41 Trituration, definition, 41 Troche, definition, 41 Trochiscus, definition, 41 Tropacocaine, 423 Truxilline, 41 2 Trypanosomiasis, antimony in, 552 Trypsin, 27 Tub-bath, 461 Tuberculosis, cod-liver oil in, 72 iodides in, theory of action, 557 mercury succinimide in, 521 night-sweats of, sulphuric acid in, 88 quinine in, 477. Tuberculous cavities, Beck's treatment, 523 laryngitis, antipyrine in, 469 ulcers of throat, lactic acid in, 89 Tubules of kidneys, functions, 451, 452 Tully powder, 374 dose, 374 Turkish bath, 444 Turpentine, oil of, for tape- worms, 119 Turpeth mineral in croup, 521 Twilight sleep, 410 Tympanites, carminatives in, 105 counterirritants for, 78 hormonal in, 85 pituitary extract in, 210 Typhoid fever, citric acid in, 89 Tyramine, 567 dose, 568 effect on circulation, 569 ULCER, gastric, scarlet red in, 80 of stomach, orthoform in, 424 652 INDEX Ulcer, sluggish, burnt alum in, 536 tuberculous, of throat, lactic acid in, 89 Ulcus corneae serpens, ethylhydrocupre- ine in, 479 Uncinaria americana, treatment, 117 Unguentum, definition, 42 hydrargyri as antiseptic, 519 dilutum as antiseptic, 519 United States Pharmacopoeia, 45 Urea, diuretic action, 455 Uremia, diaphoresis in, 448 oxygen in, 580 Ureteral stone, papaverine in, 390 Urethane, 366 Urethra disinfectants, 516 spasm of, cocaine in, 421 Urethral suppository, 42 Urethritis, copper sulphate in, 529 zinc sulphate in, 530 Uric acid, 252 Urinary tract, disinfectants, 517 Urine, constituents, 452 of diuresis, 450. See also Diuresis. retention of, from digitalis, 181 suppression of, from digitalis, 181 Urothropine, 24, 512 test, 512 Useful drugs, book of, 47 U. S. P., 45 Utensils, disinfectants for, 515 Uterine inertia, quinine in, 477 pituitary extract in, 210 Uterus, subinvolution of, ergot in, 572 VACCINES, preservatives for, 515 Vagina disinfectants, 516 Vaginal suppository, 42 Vaginismus, cocaine in, 421 Vaginitis, copper sulphate in, 529 zinc sulphate in, 530 Vagus system, 150 depression, 151 stimulation, 151 Valerian, 393 ammoniated tincture of, 107 dose, 394 preparations and doses, 394 tincture, dose, 394 Valerianates, 394 Valerianic acid, 394 Val let's mass, 537 Vapor bath, 445 Vaseline, 33 in dry arthritis, 33 liquid, 33, 125 white, 33 Vasoconstriction from epinephrine, 199 Vasoconstrictors, 152 Vasodilators, 152 Vasomotor reversal, 199. 569 Vasotonin, 425 Vegetable astringents, 114 cathartic pills, 137 Vegetables as cathartic measure, 1 23 Vehicle for prescription, 585 Vein anesthesia, Bier's, 422 Veins, action of digitalis on, 180 administration by, 55 contraction of, 154 dilatation of, 154 Venereal sores, mercury in, 519 Venesection, 245 action, 246 and transfusion in mercury poisoning, 524 therapeutics, 246 Venous engorgement, digitalis in, 181 Ventricle, right, of heart, action of digitalis on, 167 Ventricular fibrillation from digitalis, 171 Veratridine, 236, 237 Veratrine, 236, 237 action, 238 dose, 237 pharmacologic action, 237 therapeutics, 238 Veratrum, 236 album, 237 constituents, 236 dose, 237 fluidextract, dose, 237 in eclampsia, 238 in trifacial neuralgia, 238 pharmacologic action, 237, 238 poisoning from, 238 preparations and doses, 237 therapeutics, 238 tincture, dose, 237 toxicology, 238 viride, 236 Verbs, Latin, 590 Vermouth wine, 320 Veronal, 365 poisoning from, 365 toxicology, 365 Veronal-sodium, 365 Verworn's theory of narcosis, 283 _of sleep, 356 Vesicant, 72 Vesicle-producing, 72 Vinegar, 160 definition, 40 Vinum portense, 318 xericum, 318 Vision, diminished, strychnine in, 281 Volatile oil of mustard, 26 oils, 34 as antiseptics, 504 occurrence, 34 Vomiting after anesthesia, 297 and nausea of pregnancy, ingluvin in, 85 INDEX 653 Vomiting and nausea of pregnancy, treatment, 112 bismuth in, 532 bromides in, 371 center, action of digitalis on, 183 cerium in, 532 chloroform in, 292 morphine in, 387 papaverine in, 390 Vulva, itching of, cocaine in, 421 epinephrine in, 205 WARBURG'S tincture, 133, 471 without aloes, 471 Warts, glacial acetic acid for, 89 lunar caustic for, 533 nitric acid for, 87 salicylic acid in, 483 trichloracetic acid for, 89 Wash, black, 520 lead and opium, 373, 525 yellow, 520 Washed sulphur to give bulk and soft consistency to feces, 1 25 Wasting, infantile, thyroid gland in, 562 Water, 39 as cathartic measure, 1 24 as diaphoretic, 444 diuretic action, 455 Pluto, 148 concentrated, 148 starch, 28 Water-retention, digitalis in, 182 Waters, acid, 147 alkaline, 147 saline, 147 alum, 147 arsenical, 147 bromine, 147 chalybeate, 147 ferruginous, 147 iodine, 147 lithia, 147 mineral, 146 effervescing, 146 non-effervescent, 146 non-thermal, 146 sparkling, 146 still, 146 thermal, 146 purgative, 147 saline, 147 sulphur, 147 Wax, white, 32 yellow, 32 Waxes, 29, 32 Weakness, protracted, transfusion of blood in, 227 Weight, body, dose and, 48 Weights and measures, 43 apothecaries', 43 Weights and measures, apothecaries', exact equivalents, 44 metric, 43 Wet brain, 348, 350 Wet-cupping, 247 Whey, 84 Whiskey, 319 Irish, 319 Scotch, 319 White arsenic, 541 petrolatum, 33 precipitate ointment, 520 as antiseptic, 519 vaseline, 33 wax, 32 wine, 318 Whooping-cough, antipyrine in, 469 bromoform in, 372 Wild cherry, fluidextract of, 426 infusion of, 426 syrup of, 426 Wilms' treatment of mercury poisoning, 524 Wine, definition, 40 of antimony, 552 of coca, therapeutics, 420 of colchicum root, 487 seed, 487 white, 318 Wines, 317 dry, 318 fortified, 318 heavy, 318 light, 318 Madeira, 318 port, 318 red, 318 sherry, 318 sparkling, 318 strong, 318 sweet, 318 Vermouth, 320 Wood alcohol, 355 naphtha, 355 Wood-charcoal, 109, no Worms, intestinal, anthelmintics for, 115 pin-, quinine in, 476 remedies for, 116 round-, remedies for, 116 tape-, dwarf, remedies for, 119 remedies for, 119 thread-, remedies for, 116 Wormseed, Levant, 116 Wormwood, 320 Wounds, disinfection of, Dakin-Carrel treatment, 495 open, disinfectants in, 517 Wrist-drop in lead poisoning, 527 XANTHINE, 252 dimethyl, 252 trimethyl, 252 654 YELLOW jasmine, 428 wash, 520 wax, 32 Yerba santa, 109, 425 syrup of, 109 Yohimbine, 424 Young's rule for dosage, 49 ZINC, 530 as antiseptic and disinfectant, 500 carbonate, 530 INDEX Zinc chills, 530 chloride, 530 irritant salts, 530 ointment, 530 oxide, 530 poisoning, 530 precipitated carbonate, 530 soothing salts, 530 stearate, 530 sulphate, 530 Zincum, 530 SURGERY and ANATOMY W. B. SAUNDERS COMPANY Elsberg's Surgery of Spinal Cord Surgery of the Spinal Cord. By CHARLES A. ELSBERG, M. D., Professor of Clinical Surgery, New York University and Bellevue Hospital Medical School. Octavo of 330 pages, with 153 illustrations, Cloth, $5.00 net. Published July, 1916 There is no other book published like this by Dr. Elsberg. It gives you in clear definite language the diagnosis and treatment of all surgical diseases of the spinal cord and its membranes, illustrating each operation with original pictures. Because it goes so thoroughly into symptomatology, diagnosis, and indications for operation this work appeals as strongly to the general practitioner and neurologist as to the surgeon. Cullen on the Umbilicus Embryology, Anatomy, and Diseases of the Umbilicus. By THOMAS S. CULLEN*, M. B., Associate Professor of Gynecology, Johns Hopkins University. Octavo of 680 pages, with 269 illustrations. Cloth, $7oO net. Published May, 1916 In Dr. Cullen' s ne\v work you get chapters on embryology, anatomy, infections in the newborn, hemorrhage, granulation tissue at the umbilicus, umbilical polypi, gastric mucosa at the umbilicus, Meckel's diverticulum, intestinal cysts, patent omphalomesenteric duct, prolapsus of the bowel, concretions, abscess, etc. The editions you find here may not be the latest. Write us about any books in which you are interested SAUNDERS 1 BOOKS ON Albee's Bone-Graft Surgery Bone-graft Surgery. By FRED H. ALBEE, M. D., Professor of Orthopedic Surgery at the New York Post-graduate Medical School. Octavo of 417 pages, with 329 text-illustrations and 3 colored plates. Cloth, $6.5O net. Published November, 1915 ORIGINAL This book presents Dr. Albee's original applied technic for bone-graft work. The suc- cessful outcome of any procedure to restore the skeletal architecture depends not only upon a proper operative technic, but in many cases in a greater degree upon the skill with which the postoperative external fixation dressing is applied and in the convalescent management of the case. Dr. Albee here gives you his own successful technic and his own methods of dressing and management, all illustrated with original pictures. Dr. Albee is a firm believer in the autogenous graft, and in making it he uses the most improved instruments and tools, all of which are shown you, and their use in actual work. This is the only book going fully into this important qnestion of bone surgery, a field of sur- gical endeavor that is attracting pronounced attention over the entire surgical world. Smithies and Ochsner's Cancer of the Stomach Cancer of the Stomach. By FRANK SMITHIES, M. D., Gastro- enterologist to Augustana Hospital, Chicago. With a chapter on the Surgical Treatment of Gastric Cancer, by ALBERT J. OCHSNER, M. D., Professor of Clinical Surgery, University of Illinois. Octavo of 500 pages, illustrated. Cloth, $5.75 llCt. Published January, 1916 A STUDY OF 921 CASES This work gives you the information Cleaned from a study of 921 operatively and path ologically demonstrated cases of gastric cancer. This new work is the first monograph upon this subject for more than a decade, and represents some ten years' study of cases at the University Hospital of Ann Arbor, The Mayo Clinic, and the Augustana Hospital of Chicago. The wonderful advances made within this time are of the greatest importance to the clinician, the pathologist, and the surgeon. Dr. Smithies presents these advances in a most practical way. The chapter on Operative Treat- ment, by Dr. Ochsner, gives you the most approved and successful technic, illustrating the various operations with original pictures. SURGERY AND ANATOMY Hornsby and Schmidt's The Modern Hospital The Modern Hospital. Its Inspiration ; Its Construction ; Its Equipment; Its Mangement. By JOHN A. HORNSBY, M. D., Secre- tary, Hospital Section, American Medical Association ; and RICHARD E. SCHMIDT, Architect. Large octavo of 644 pages, with 207 illus- trations. Cloth, $7-00 net. March, 1913 HOSPITAL EFFICIENCY " Hornsby and Schmidt" tells you just exactly how to plan, construct, equip, and manage a hospital in all its departments, giving you every detail. It gives you exact data regarding heating, ventilating, plumbing, refrigerating, etc. and the costs. It tells you how to equip a modern hospital with modern appliances. It tells you what you need in the operating room, the wards, the private rooms, the dining room, the kitchen every division of hospital housekeeping. It gives you the duties of the directors, the superintendent, the various staffs, their relations to each other. It tells you all about nurses' training-schools their management, curriculum, rules, regulations, etc. It gives you hundreds of valuable points on the business management of hospitals large and small. Howell Wright, Superintendent City Hospital, Cleveland " To me the book is invaluable. I have a copy on my desk and scarcely a day passes but what I consult it and find what I want." Allen's Local Anesthesia Local Anesthesia. By CARROLL W. ALLEN, M. D., Instructor in Clinical Surgery at Tulane University of Louisiana. Octavo of 608 pages, illustrated. Cloth. $6.00 net. COMPLETE IN EVERY PARTICULAR This is a complete work on this subject. You get the history of local anesthesia, a chapter on nerves and sensation, giving particular attention to pain what it is and its psychic control. Then comes a chapter on osmosis and diffusion. Each local anesthetic is taken up in detail, giving very special atten- tion to cocain and novocain, pointing out the action on the nervous system, the value of adrenalin, paralysis caused by cocain anesthesia, control of toxicity. You get Crile's method of administering adrenalin and salt solution, the exact way to produce the intradermai wheal, to pinch the flesh for the insertion of the needle all shown you step by step. You get full discussions of paraneural, intraneural, and spinal analgesia, intravenous and intra-arterial anesthesia, and Hackenbuck's regional anesthesia by circumferential injections. You get indica- tions, contraindications, an article on anoci-associaticn, with Crile's technic for producing anesthesia. Then the production of local anesthesia in the various regions is taken up in detail. Spinal analgesia and epidural injections are con- sidered in a monogragh of 45 pages. Published October, 1914 SAUNDERS' BOOKS ON The New Keen's Surgery Surgery: ITS PRINCIPLES AND PRACTICE. Written by 8 1 eminent specialists. Edited by W. W. KEEN, M. D., LL.D., HON. F.R.C.S., ENG. AND EDIN., Emeritus Professor of the Principles of Surgery and of Clinical Surgery at the Jefferson Medical College. Six octavos of 1050 pages each, containing 3100 original illustrations, 157 in colors. Per volume: Cloth, 37.50 net. VOLUME VI GIVES YOU THE NEWEST SURGERY ALL THE ADVANTAGES OF A REVISION AT ONE-FIFTH THE COST We have issued a Volume VI of " Keen " the volume of the newest surgery- In this way you get all the advantages of a complete and thorough revision at but one-fifth tJu- cost. It makes Keen's Surgery the best, the most up-to-date surgery on the market. In this sixth volume you get the newest surgery both general and special from the pens of those same international authorities who have made the success of Keen's Surgery world-wide. Kach man has searched for the new, the really ttscfu/, in his particular field, and he gives it to you here. Here you get the newest surgery, and fully illustrated. Then, further, you get a complete index to the entire six volumes, covering 125 pages, but so arranged that reference to it is extremely easy. If you want the newest surgery, you must turn to the new " Keen ' ' for it. Volunu- VI published March, 1913 Keen's War Wounds Treatment of War Wounds. By \V. \V. KEEN, M. D., LL.D., Major, Medical Reserve Corps, U. S. Army. 121110 of 169 pages, illus- trated. Cloth, $1.75 net Published August, 101 7 TREATMENTS BEING USED IN FRANCE This work, based on a report to the National Research Council, revieus the latest information. It is obtained by direct communication from the war hospitals in France. It gives the formulas, preparation, application, and results of Carrel-Dakin's solution, eupad. eusol. and other antiseptics being used with such marked success. It takes up the removal of toreign bodies, treatment and prevention of tetanus, gas infection and gas gangrene, head wounds, ab- dominal wounds, ambrine and \o. 7 paraffin for burns. It is an important book, instructive from cover to cover. SURGERY AND ANATOMY Crandon and Ehrenfried's Surgical After-treatment Surgical After-treatment. A Manual of the Conduct of Surgical Convalescence. By L. R. G. CRANDON, M. D., Assistant in Surgery, and ALBERT EHRENFRIED, M. D., Assistant in Anatomy, Harvard Medi- cal School. Octavo of 831 pages, with 265 original illustrations. Cloth, $6.OO net, Published May, 1912 SECOND EDITION PRACTICALLY REWRITTEN This work tells how best to manage all problems and emergencies of surgical convalescence from recovery-room to discharge. It gives all the details com-, pletely, definitely, yet concisely, and does not refer the reader to some other work perhaps not then available. The post-operative conduct of all operations is given, arranged alphabetically by regions. A special feature is the elaborate chapter on Vaccine Therapy, Immunization by Inoculation and Specific Sera, by Dr. George P. Sanborn, a disciple of Sir A. E. Wright. The text is illustrated. The Therapeutic Gazette "The book is one which can be read with much profit by the active surgeon and will be generally commended by him." Papers from the Mayo Clinic Collected Papers of the Mayo Clinic. By WILLIAM J. MAYO, M. D., CHARLES II. MAYO, M. D., and their ASSOCIATES at The Mayo Clinic, Rochester, Minn. Papers of 1905-1909. 1910, 1911,1912, 1913. Each an octavo of about 800 pages, illustrated. Per volume: Cloth, $5.50 net. 1916 Papers (June, 191?): Cloth, $6.50 net. THE NEWEST SURGICAL METHODS These volumes give you all the clinical teachings, all the important papers of W. J. and C. II. Mayo and their associates at The Mayo Clinic. They give you the advances in operative technir., in methods of diagnosis as developed at this great clinic. This ne\v volume, although called the igj6 -volume, gives you many papers that did not appear until ;>'.// info 1017, quite a few being scheduled for as late as May and June. You should acid this volume to your Mayo files. Bulletin Medical and Chirurgical Faculty of Maryland " Much of the work done at the Mayo Clinic and re on \,r<\ in these papers has been epoch- making in character. * * * Represents a most substantial block of modern surgical progress." A Collection of Papers (published previous to 1909). By WILLIAM J. MAYO, M. D., and CHARLES H. MAYO, M. D. Two octavos of 525 pages each, illustrated. Per set : Cloth, $10.00 net SAUNDERS' BOOKS ON Moorhead's Traumatic Surgery Traumatic Surgery. By JOHN J. MOORHEAD, M. D., Associate Professor of Surgery, New York Post-Graduate Medical School Lnd Hospital. Octavo of 760 pages, with 520 original line-drawings. Published February, 1917. Cloth, $7-OO net. FOUR PRINTINGS IN TEN MONTHS Here is a new book on just this side of your practice a work for the general practitioner, the surgeon, the mining, railroad and industrial physician, those having to do with Compensation Law, accident insurance and claims, and legal medicine. To those medical men engaged in or preparing for military service this work is proving of great value. For instance, it gives you at first hand the open air and sunlight treatment of wounds and Dakin's solution, its formula and application treatments the European War has brought forward so em- phatically. DaCosta's Modern Surgery Modern Surgery GENERAL AND OPERATIVE. By JOHN CHALMERS DACOSTA, M. D., Samuel D. Gross Professor of Surgery, Jefferson Medical College, Philadelphia. Octavo of 1515 pages, with 1085 illus- trations. April, 1914 Cloth, $6.oo net. SEVENTH EDITION A surgery, to be of the maximum value, must be up to date, must be com- plete, must have behind its statements the sure authority of experience, must be so arranged that it can be consulted quickly; in a word, it must be practical and dependable. Such a surgery is DaCosta's. Always an excellent woik, for this edition it has been very materially improved by the addition of new matter to the extent of over 250 pages and by a most thorough revision of the old matter. Many old cuts have been replaced by new ones, and nearly 150 additional illus- trations have been added. Rudolph Matas, M. D., Professor of Surgery, TuLine University of Louisiana. " This edition is destined to rank as high as its predecessors, which have placed the learned author in the fore of text-book writers. The more I scrutinize its pages the more I admire the marvelous capacity of the author to compress so much knowledge vn so small a space." SURGERY AND ANATOMY Scrudder's Treatment of Fractures WITH NOTES ON DISLOCATIONS The Treatment of Fractures : with Notes on a few Common Dislocations. By CHARLES L. SCUDDER, M. D., Assistant Professor of Surgery at Harvard Medical School. Octavo of 734 pages, with 1057 original illustrations. Polished Buckram, $6.00 net. Published June, 1915 THE NEW (8th) EDITION. ENLARGED WITH 1057 ILLUSTRATIONS The fact that this work has attained an eighth edition indicates its practical value. In this edition Dr. Scudder has made numerous additions throughout the text, and has added many new illustrations, greatly enhancing the value of the work. In every way this new edition reflects the very latest advances in the treatment of fractures. J. F. Binnie, M.D., University of Kansas " Scudder's Fractures is the most successful book on the subject that has ever been pub., lished. I keep it at hand regularly." Scudder's Tumors of the Jaws Tumors of the Jaws. By CHARLES L. SCUDUER, M. D., Assistant Professor of Surgery at Harvard Medical School. Octavo of 395 pages, with 353 illustrations, 6 in colors. Cloth, $6.50 net. Published February, 1912 WITH NEW ILLUSTRATIONS Dr. Scudder in this book tells you how to determine in each case the farm of new growth present and then points out the best treatment. As the tendency of malignant disease of the jaws is to grow into the accessory sinuses and toward the base of the skull, an intimate knowledge of the anatomy of these sinuses is essential. Dr. Scudder has included, therefore, sufficient anatomy and a number of illustrations of an anatomic nature. Whether general practitioner or surgeon, you need this new book because it gives you just the information you want. SOUNDERS' BOOKS ON Cotton's Dislocations arid Joint Fractures Dislocations and Joint Fractures. By FREDERIC JAY COTTON, M. D-, First Assistant Surgeon to the Boston City Hospital. Octavo of 654 pages, with I2OI original illustrations. Cloth, $6.00 net. Published July, 1910 TWO PRINTINGS IN EIGHT MONTHS Dr. Cotton's clinical and teaching experience in this field has especially fitted him to write a practical work on this subject. He has written a book clear and definite in style, systematic in presentation, and accurate in statement. The illustrations possess the feature of showing just those points the author wishes to emphasize. This is made possible because the author is himself the artist. Boston Medical and Surgical Journal " The work is delightful, spirited, scholarly, and original, and is not only a book of refer- ence, but a book for casual reading. It brings the subject up to date, a feat long neglected." The Surgical Clinics of Chicago The Surgical Clinics of Chicago. By leading Chicago surgeons. Issued serially, one octavo of 2OO pages, illustrated, every other month (six volumes a year). Per Clinic Year (February to December): Cloth, $14.00 net; Paper, $10.00 net. SURGERY FROM THE CLINICAL SIDE This new bi-monthly considers all departments of surgery from the clinical side, giving particular emphasis to differential diagnosis and treatment. It gives you the actual word for word clinics of 40 great teacher-surgeons of Chicago, representing ail the important hospitals of that great center of post-graduate instruc- tion. You get the day-in and day-out teachings of these men. You get their tried and proved methods of diagnosis; their operative technic; their plans of man- agement; the benefit of their years of experience, with a wealth of clinical material unequalled for variety and quantity. Add to the matter of the books the illustrations by Tom Jones, and the result is practically applied, absolutely fresh teachings, em- bodying all the new methods. SURGERY AND ANATOMY Kelly & Noble's Gynecology arw Abdominal Surgery Gynecology and Abdominal Surgery. Edited by HOWARD A. KELLY, M.D., Professor of Gynecology in Johns Hopkins University; and CHARLES P. NOBLE, M.D., formerly Clinical Professor of Gyne- cology in the Woman's Medical College, Philadelphia. Two imperial octavo volumes of 950 pages each, containing 880 original illustrations, some in colors. Per volume: Cloth, $8.00 net. Volume I published May, 1907; Volume II published June, 19CS WITH 880 ILLUSTRATIONS TRANSLATED INTO SPANISH This work possesses a number of valuable features not to be found in any Other publication covering the same fields. It contains a chapter upon the bac- teriology and one upon the pathology of gynecology, and a large chapter devoted entirely to medical gynecology, written especially for the physician engaged in general practice. Abdominal surgery proper, as distinct from gynecology, is fully treated, embracing operations upon the stomach, intestines, liver, bile-ducts, pancreas, spleen, kidneys, ureter, bladder, and peritoneum. American Journal of Medical Sciences " It is needless to say that the work has been thoroughly done ; the names of the authors and editors would guarantee this, but much maybe said in praise of the method of presentation, and attention may be called to the inclusion of matter not to be found elsewhere.' 1 Cushing's Brain Tumors Tumors of the Nervus Acusticus and the Syndrome of the Cerebellopontile Angle. By HARVKV GUSHING. M. D., Surgeon-in- Chief, Peter Bent Brigham Hospital, Boston. Octavo of 296 pages, With 202 illustrations. Cloth, S;.OO net. Published November, 1917 A STUDY OF 65 CASES Dr. dishing presents here an exhaustive study of tumors of the acoustic nerve. He gives you his o\vn technic, and the results of study and observation of some thirty cases a thorough presentation of the subject, embracing history, analysis of symptoms, physical examination, morphology, histology, and operative technic. You are given not only the surgical aspects, but the historical, symptomatic, and pathologic as well. The illustrations are particularly noteworthy. io SAUNDERS' BOOKS ON Moynihan's Abdominal Operations Abdominal Operations. By SIR BERKELEY MOYNIHAN, M. S. (LONDON), F. R. C. S., of Leeds, England. Two octavos, totaling nearly 1000 pages, with 385 illustrations. Per set: Cloth, $11.00 net. Published October, 1914 THIRD EDITION. ENLARGED This new (jd) edition was so thoroughly revised that the work had to be reset from cover to cover. Over 150 pages of new matter and some 85 new illustrations were added, making 385 illustrations, 5 of them in colors really an atlas of abdominal surgery. This work is a personal record of Moynihan' s operative work. You get his own successful methods of diagnosis. You get his own technic, in every case fully illustrated with handsome pic- tures. You get the bacteriology of the stomach and intestines, sterilization and preparation of patient and operator. You get complications, sequels, and after-care. Then the various operations are detailed with forceful clearness, discussing first gastric operations, following with intestinal operations, operations upon the liver, the pancreas, the spleen. Two new chapters added in this edition are excision of gastric ulcer and complete gastrectomy, giving the latest developments in these operative measures. Moynihan's Duodenal Ulcer Duodenal Ulcer. By SIR BERKELEY MOYNIHAX, M. S. (LONDON), F. R. C. S., Leeds, England. Octavo of 486 pages, illustrated. Cloth, $5.00 net. Published March, 1912 For the practitioner, who first meets with these cases, Mr. Moynihan fixes the diagnosis with precision, so that the case, if desired, may be referred in the early stage to the sur- geon. The surgeon finds here the newest and best technic as used by one of the leaders in this field. " Easily the best work on the subject ; coming, as it docs, from the pen of one of the mas- ters of surgery of the upper abdomen, it may be accepted as authoritative." London Lancet. Moynihan's War Surgery American Addresses on War Surgery. By SIR BERKELEY MOYNIHAN, M. S., F. R. C. S., Surgeon General, A. M. S. 121110 of 143 pages. Cloth, Si. "5 net. Published November, 1917 The experiences of this English surgeon, who has been in active service since the very beginning of the war, are contained in these lectures delivered on his recent visit to this country. He gives you treatments of war wounds preparation, technic of use, and relative values of Carrel-Dakin's antiseptic, Uipp, Wright's physiologic solution, Ruth- erford Morison's method repair of injuries to lungs, pleura, knee-joint, and periph- eral nerve.-. He gives you here a vital message from the front. SURGER Y AND ANA TOMY 1 1 Fenger Memorial Volumes Fenger Memorial Volumes. Edited by LUDVIG HEKTOEX, M. D., Rush Medical College, Chicago. Two octavos of 525 pages each. Per Set : Cloth, $ I 5 .OO net. Published May, 1912 LIMITED EDITION These handsome volumes consist of all the important papers written by the late Christian Fenger, for many years professor of surgery at Rush Medical College, Chicago. Not only the papers published in English are included, but also those which originally appeared in Danish, German, and French. The name of Christian Fenger typifies thoroughness, extreme care, deep re- search, and sound judgment. His contributions to the advancement of the world's surgical knowledge are indeed as valuable and interesting reading to-day as at the time of their original publication. They are pregnant with suggestions. Fenger' s literary prolificacy may be judged from this memorial volume over jooo pages. Owen's Treatment of Emergencies The Treatment of Emergencies. By HUBLEV R. OWEN, M. D., Surgeon to the Philadelphia General Hospital. Octavo of 350 pages, with 249 illustrations. Published June, 1917 Cloth, $2.00 net. METHODS AND PRINCIPLES Dr. Owen's book gives you not only the actual technic of the procedures, but also the underlying principles of the treatments, and the reason why a particular method is advised. You get chapters on fractures of all kinds, con- tusions, and wounds. Particularly strong is the chapter on gunshot wounds, which gives the new treatments that the great European War has developed. You get the principles of hemorrhage, together with it's constitutional and local treatments. You get chapters on sprains, dislocations, burns, sunburn, chilblain, asphyxiation, convulsions, hysteria, apoplexy, exhaustion, opium poisoning, uremia, electric shock, bandages, and a complete discussion of the various methods of artificial respiration, including mechanical devices. Radasch's Anatomy Manual of Anatomy. By HENRY E. RADASCH, M. D., Assistant Professor of Histology and Biology, Jefferson Medical College. Octavo of 489 pages, with 329 illustrations. Cloth, $3.50 net. Published August, 1917 Dr. Radasch's new handbook is complete in both text and illustrations. Every effort has been taken to make the study of anatomy both easy and in- teresting, the many illustrations contributing markedly to this end. AND ANATOMY Bryan's Surgery Principles of Surgery. By \V. A. BRYAN, M. D., Professor of Surgery and Clinical Surgery at Yanderbilt University, Nashville. Octavo of 677 pages, with 224 original illustrations. Cloth, $4.00 net. Dr. Bryan here gives you facts, accurately and concisely stated, without which no modern practitioner can do modern work. He shows you in a most practical way the relations between surgical pathology and the resultant symptomatology, and points out the influence such information has on treatment. Published November, 1913 Mumford's Practice of Surgery The Practice of Surgery. By JAMES G. MUMFORD, M. D., Instructor in Surgery, Harvard Medical School. Octavo of 1032 pages, with 68 1 illus- trations. Second Edition published June, 1914. Cloth, #7.00 net. Fowler's Operating Room Third Edition, Reset The Operating Room and the Patient. By RUSSELL S. FOWLER, M. D., Surgeon to the German Hospital, Brooklyn, New York. Octavo of 611 pages, illustrated. Published March, 1913. Cloth, $3.50 net. Whiting's Bandaging Bandaging. By A. D. WHITING, M. D., Instructor in Surgery at the Uni- versity of Pennsylvania. I2mo of 151 pages, with 117 illustrations. Cloth, 51.25 net. Published November, 1915 Nancrede's Essentials of Anatomy Eighth Edition Essentials of Anatomy, including the Anatomy of the Viscera. By CHAS. B. NANCREUK, M.D., Professor of Surgery and of Clinical Surgery, University of Michigan, Ann Arbor. Crown octavo, 430 pages; 154 cuts. With an Appendix containing over 60 illustrations. Based on Gray s Anatomy. Published October, 1911. Cloth, $1.25 net. In Sanndcrs Question Compends. Martin's Essentials of Surgery seventh Edition Essentials of Surgery. Containing also Venereal Diseases, Surgical Land- marks and Minor and Operative Surgery, and a complete description, with illustrations, of the Handkerchief and Roller Bandages. By EDWARD MAKIIX, A. M., M. I)., Professor of Clinical Surgery, University of Pennsyl- vania, etr. Crown octavo, 338 pages, illustrated. Published 1897. Cloth, $1.25 net. Iii Siuiinlers Question Metheny's Dissection Methods Dissection Methods and Guides. P-y DAVID GKKGC; MI-TIIF.XY, M. D., I.. K. C. P., I,. R. C. S. Helferich and Bloodgood on Fractures Atlas and Epitome of Traumatic Fractures and Dislocations By PROF. DR. H. HELFERICH, of Greifswald, Prussia. Edited, with ad- ditions, by JOSEPH C. BLOODGOOD, M. D. , Associate in Surgery, Johns Hopkins University, Baltimore. 216 colored figures on 64 lithographic plates, 190 text-cuts, and 353 pages of text. Cloth, $3.00 net. //; Soun- ders' Atlas Scries. Published June, 1902 American Pocket Dictionary New (ioth) Edition The American Pocket Medical Dictionary. Edited by W. A. NEWMAN DORLAND, A. M., M. D., Editor "American Illustrated Med- ical Dictionary." 707 pages. Full leather, limp, with gold edges, $1.25 net: with patent thumb index, $1.50 net. Published October, 1917 Zuckerkandl and DaCosta's Surgery IdS Atlas and Epitome of Operative Surgery. By DR. O. ZUCKER- KANDL, ot" Vienna. Edited, with additions, by J. CHALMERS DACOSTA, M.D., Samuel D. Gross Professor of Surgery, Jefferson Medical Col- lege, Philadelphia. 40 colored plates, 278 text-cuts, and 410 pages of text. Cloth, $3.50 net. In Saunders" 1 Atlas Series. Published I^C.T Si y 0AHvaan-v^ _ f ' u ) 35 y o i. _>3 c; t^ "^aiAIN.l -!\W S ? ' O /**"V~"* = I U. ?0 \- $ <-~x '. f* I s In i s 35. ^-J i I c- 3; rb j Si I -r, j. * < y '^ "*"-^ r. lilnl H (1 11 ^