\y' Digitized by the Internet Arciiive in 2007 witii funding from IVIicrosoft Corporation http://www.archive.org/details/experimentalpharOOhermrich A MANUAL OF EXPERIMENTAL PHARMACOLOGY. \(L EXPERIMENTAL PHARMACOLOGY. A HAND-BOOK METHODS FOR STUDYING THE PHYSIOLOGICAL ACTIONS OF DRUGS. BY L. (HERMANN, PROFESSOR OF PHYSIOT-OOY IN THE UXIVERSITY OF ZURICH. TRANSLATED, WITH THE AUTHOR'S PERMISSION, WITH NOTES AND ADDITIONS, BY ROBERT MEADE SMITH, M.D., DEMONSTRATOR OF PHYSIOLOGY IN THE UNIVERSITY OP PENNSYLVANIA. WITH THIRTY-TWO ILLUSTRATIONS ON WOOD. H55-IB 1883 PHILADELPHIA: HENRY C. LEAVS SON & CO 1883. Entered according to the Act of Congress, in the year 1883, by HENRY C. LEA'S SON & CO., in the Office of the Librarian of Congress. All rights reserved. C U L L 1 X S , P R I N '1' R R TRANSLATOR'S PREFACE, The translation of Hermann's Manual of Pharma- cology was undertaken to furnish the student with a work that would assist him in his studies of the physio- logical action of drugs, enabling him to make the experiments himself that would otherwise require the assistance of the instructor. The translator has attempted to elucidate the text with a careful selection of illustrations; and he trusts that his voluminous additions, which constitute nearly one-half of the entire volume, will render the work a more perfect guide to the student. Frbruary 1, 18S3. 87766 TABLE OF CONTENTS. Intkoductiox. PAGE Definition of a Poison — Scope of Pharmacology — Methods of Study — Methods of Pharmacological Investigation . 13 PART I. STUDY OF THE ACTION OF A POISON ON ISOLATED ORGANS. Section I. — Action on the Blood 1. Alterations in the Consistence of the Blood . 2. Alterations in the Reaction of the Blood 3. Alterations in the Red Blood-Corpuscles 4. Alterations in the White Corpuscles 5. Alterations in the Coagulability of the Blood . 6. Alterations in the Coloring Matter of the Blood 7. Alterations in the Gases of the Blood and in the Power of Absorbing Gases .... 8. Alterations in the Ozone and Ozonizing Power of the Blood Section II. — Action on the Muscles . 1. Examination of Indirect Muscular Irritability 2. Examination of Direct Muscular Irritability . 3. Examination of the Physiological Conductivity of Muscle 4. Measurement of Muscular Energy . 5. Examination of Alterations in the Chemical Proper ties of Muscle ...... Section III.— Action on the Nerves . Section IV. — Action on the Heart 20 23 23 25 28 29 29 30 30 31 37 46 47 48 48 49 52 Vlll TABLE OF CONTE^^TS. PART 11. INVESTIGATION OF THE UENERAL ACTION OF POISONS. PAGE I. — Selection of Animals 55 Section I. — Modes of Securing Animals ... 60 II. — Administration of Poisons 63 Section I. — Injection into the Bloodvessels . . 65 Section II. — Subcutaneous Injections and Injec- tions into Serous Sacs, Lymph Sacs of the Frog, ETC 70 Section III. — Insertion of Poisons into the Mucous Cavities of the Body 70 Section IV. — Administration of Gases and Vapors THROUGH THE LlTNGS ....... 73 III. — Investigation of the Paths of Elimination and Changes of Poisons in the Body . . . 77 Section I. — Passage of Drugs through the System without Change . . . .' . . .78 Section II. — Deposit of Drugs in the System through Assimilation 80 Section III. — Chemical Alteration of Poisons in the Economy ......... 80 a. Displacement of Acids or Bases in vSalts . . 81 h. Formation of Chemical Compounds with Innjredients of the Tissues and Excretion under Modified Forms 82 c. Decomposition of Poisons in the System and Excre- tion of the Decomposition Products .... 82 d. Decomposition of Poisonous Substances and Excre- tion of their Products ...... 84 IV. — Explanation of the Symptoms produced by Poisons 85 Section I. — Action on the Circulatory Apparatus . 88 Mode of Conducting an Experiment on Blood- Pressure 92 TABLE OF CONTENTS. IX PAGE Causes of Changes in the Ch'cuhitory Mechanism . 105 The Cardiac Ganglia 106 The Cardiac Inhibitory Nerves . . . . .107 The Accelerator Nerves . . . . . ,108 The Vaso-Motor System 110 Indirect Results of Circulatory Disturbances . .128 Section II. — Action on the Respiratory Apparatus 130 a. Dyspnoea . . . . . . . .131 h. Cessation of Respiratory Movements . . .134 1. Reduction of the Respiratory Stimulus through Saturation of the Blood with Oxygen, and Diminu- tion of its Carbon Di-oxide . . . . ,134 2. Reduction in Irritability of the Respiratory Centre 134 3. Paralysis of the Respiratory Muscles c. Alterations in the Frequency of the Respiratory Movements ....... d. Appearances in the Larynx .... Section III. — Action on the Digestive Apparatus a. Alterations in the Movements of the Digestive Organs . . , , 1 . Movements of the Jaws 2. Deglutition 3. Movements of the Stomach 4. Movements of the Intestines h. Alterations in the Sensibility of, and Production of Abnormal Sensations in the Alimentary Canal c. Alterations in the Digestive Secretions . d. Alteration in the Digestive Processes Section IV. — Action on Glandular Organs a. Secretory Glands ...... 1. Action on the Salivary Secretion 2. Action on the Biliary Secretion 3. Action on the Kidneys 4. Action on the Sweat Glands 5. Lachrymal Glands 6 Lacteal Glands . h. Non- Secretory Glands . 135 135 136 136 137 137 137 137 139 140 141 144 144 144 145 150 152 157 158 158 158 TABLE OF CONTENTS, Section V. — Alterations in Tissuk Metabolism 1. Energy of the Animal Oxidizing Processes 2. Deposit of Fat in the Body . 3. Diabetes ......' Section VI. — Alteuations in the REPUODrcTivE Functions Section VII. — Alterations in Temperature Section VIII. — Action on the Muscles 1. Action on the Pupil .... Section IX — Action on the Nervous System A. Action on the Organs of Conduction B. Action on the Peripheral Nerve Endings C. Action on the Central Nervous System . 1. Interference with the Automatic Functions 2. Reflex and Co-ordinated Functions 3. Action on the Sensory Functions PAGE 159 160 161 161 162 164 164 165 169 169 172 175 177 177 182 V. — Investigation and Explanation of the Ana- tomical Alterations produced by Poisons . .185 VI. — Investigation of Chemical Chan(^:s produced BY Poisons 188 APPENDIX. 1. Dose, Immunities, Form, and Solvents of Poisons . . 189 2. Methods of Producing Narcosis . . . . .199 Antagonism of Drugs . . . . . . .194 Index 19 1 LIST OF ILLUSTRATIONS. PIO. PAGE 1. Various Forms of Canult«. (Brunton) ... 20 2. Diagram of a Frog, showing lines of different incis- ions. (Cyon) ........ 34 .3. Diagram of tlie Muscles of the Leg of a Frog. (Cyon) 35 4. The "Nerve-muscle Preparation." (Cyon) . . 36 o. Du Bois Reymoud's Induction Apparatus. (Foster) . 38 6. Pohl's Commutator or Double Key. (Sanderson) . 39 7. Du Bois Reymond's Key. (Sanderson) ... 40 8. Arrangement of Apparatus for Experiments on Mus- cle and Nerve. (Foster) ..... 42 9. Muscle Holder and Electrodes. (Foster) ... 43 10. Plluger's Myographion. (Sanderson) .... 44 11. Non-polarizable Electrode. (Sanderson) ... 44 12. Marey's Comparative Myograph ..... 45 13. Czermak's Rabbit-holder. (Sanderson) , . .61 14. Bernard's Dog-holder 62 15. Improved Form of Bernard's Dog-holder and Brun- ton' s Dog-holder . . . . . . .62 16. Sanderson's Cardiograph. (Sanderson) ... 89 17. Marey's Tympanum and Lever. (Sanderson) . . 90 18. Ludwig's Manometer. (Foster) . . . . .93 19. Fick's Spring Manometer. (Fost<.'r) .... 95 20. Ludwig's Kymographion. (Cyon) .... 96 21. Large Kymographion, for continuous tracings, (Foster) 98 22. Arterial Canula 102 23. Blood- pressure Tracing 103 24. Hypothetical Nervous Apparatus of the Heart. (Brun- ton) 106 25. Last Cervical and First Thoracic Ganglia in the Rabbit. (Foster) 108 Xll LIST OF ILLUSTRATIONS. FIG. PAilK 26. Diajrram of the Ijast Cervical and First Thoracic Gan- glia in the Dog. (Foster) . . . . .109 27. Ludwig and Coats' s Frog Manometer. (Cyon) . .117 28. Roy's Heart Apparatus 119 29. Nervous Apparatus of the Heart . . . .123 30. Arrangement of Apparatus for Studying the Respiratory Movements. (Foster) 132 31. Veins of the Submaxillary Gland of the Dog. (Ber- nard) 146 32. Parts Exposed in Operations on the Submaxillary Gland of the Dog. (Bernard) 147 INTRODUCTION Those substances are called poisons which, when introduced into the animal economy, produce disturb- ances of its normal functions. Occasionally the term is restricted to substances which are active in minute quan- tity, and when the disturbance produced by their action threatens the life of the organism. But since these distinctions are merely relative, they are superfluous, especially since the scope of toxicology can be defined by other considerations than by a definition of the word poison ; the latter being only important from a medico- legal point of view. Pharmacology in its widest scope embraces the study of drugs from all possible points of view, and the information thereby acquired may be useful under the most diverse conditions ; — to the physician, to enable the recognition and proper treatment of cases of poisoning, or to permit of the use of drugs for therapeutic purposes; — to the public, to permit the avoidance of noxious substances ; — to the physiologist and pathologist, to enable the application of information derived from the study of the action of poisons to the advancement of their sciences. The study of phar- macology can therefore be limited according as one or more of these points of view occupy the first place in the mind of the investigator. The public desires to know only what substances are poisonous, that they may be avoided, while their modus operandi is a matter of indifference. Those poisons which are suitable for use at the bedside will prove most interesting to clinicians. Pure pharmacology is best advanced by the avoidance of 2 14 INTRODUCTION. any special stand-point, in order that all of its bearings may be equally appreciated, and still more, since the advancement of pure science is always retarded by a search for that only which promises immediately practi- cal results. The history of the progress of the sciences teaches that nearly all the most important discoveries, even those- subsequently of the greatest practical value, resulted from investigations untrammelled by a contin- uous mindfulness of the merely practical. Thus phy- siology has rendered such inestimable assistance to the progress of practical medicine that she can well be re- garded as her handmaid ; but, nevertheless, physiology is a pure science, which, like physics and chemistry, should be studied for its own worth, without being hampered by doubts as to whether its results are immediately applicable to practical medicine or not. So also pharmacology is growing more and more worthy of occupying a similar position, though it must be acknowledged that, as yet, it is not bounded by such sharply drawn lines as to consti- tute a distinct science. Much, how^ever, can be gained in this direction by constantly bearing in mind that pharma- cology has for its object the recognition and study of all changes which a foreign body can undergo or produce, otherwise than traumatically, in the organism, while the questions as to whether the substance under study can ever be Jikely to prove a poison to man, or whether it has properties which warrant its use as a medicament, should be kept in the background. Consequently every substance which possesses ant/ active properties should prove of interest to the investi- gator in the domain of pharmacology; while naturally those substances will be preferred which are either quite unknown, which show results entirely novel, or whose action admits of predetermination from a theoretical point of view, as from the stand-point of chemical compo- sition. And it should, moreover, be remembered, that even substances which themselves evoke no symptoms in the organism, may form worthy subjects of pharmaco- logical investigation as throwing possible light, in the TNTRODUCTTON. 15 changes which they undergo in the s^^stem, on the beha- vior of other more active poisons. The object of pharmacology, therefore, is to acquire familiarity with the peculiarities and actions of poisons, to carefully analyze all processes which they evoke so as to obtain a complete picture of their mode of action. This object cannot be attained by mere observation of cases of poisoning in man, although such cases, when properly studied, may be of the greatest service ; since it is often only by such means that we are enabled to form conclusions as to the action of the drug on man. Experiment must be the instrument most relied on in pharmacology ; not only because it alone permits the study of all poisons in all doses, and on the most various organisms ; but because it is indispensable to the acquire- ment of any more profound knowledge of the modus operandi of poisons than can be obtained by a mere in- spection of cases of poisoning. Observation of cases of poisoning only furnishes a coarse method of observing the prominent features of the action of the poison, while experimentation alone ren- ders possible that analysis of the information so acquired which enables the deduction of an opinion as to the changes which the poison itself undergoes, the means by which those changes are produced, and their results and the special action which they may exert on individual organs. The extent to which such deductions will be- come possible will depend upon the perfection of the experimental art and the state of our knowledge of the normal functions. Experimentation on living animals is chiefly employed by physiologists, who are consequently pre-eminently suited for the study of pharmacology. But this is not the only explanation of the fact that the authors of most of our most valuable papers on the action of drugs are practical physiologists ; a deeper-lying reason for the devotion of physiologists to pharmacology is to be found in the fact that nearly every addition to our knowledge of the action of a poison marks at the same time an ad- 16 INTRODUCTrON. vance in our knowledge of the normal organism, and can hence be regarded as a step in the development of the science of physiology. Physiologists, therefore, rightly regard pharmacological investigation as one of the most important modes of advancing their science. Occasion- ally, also, pharmacology furnishes an instrument of experimentation of the most delicate character ; as an illustration of this we have only to mention curare, whose employment in pure physiology has been most fruitful of valuable results.^ 1 [In this connection f^ee Bernard's valuable paper on " Les poisons comme methode de vivisection," in tlie Revue Scientifique, 1875.] METHODS OF PHARMACOLOGICAL INVESTIGATION. The first indication as to the poisonous action of any substance is usually to be found in reports of cases of poisoning occurring in man. But the histories of such cases, though they may indicate the most promising line of study, in the majority of instances give us only an imperfect, and in the light of experiment, often an inaccurate picture of the action of the poison. The consideration of suggestions derived from such sources, though they may often facilitate the attainment of de- finite results, just as a qualitative assists a quantitative chemical analysis, will, however, for the present be de- ferred. When it is desired to determine the mode of action of a substance of whose modus operandi no conception has been formed, one of two lines of investigation may be followed : Either an animal is suitably brought under its influence and a general picture of its working obtained, Avhich, imperfect though it be, is far better than the gene- rality of reports of cases of poisoning, and which may serve as a starting point for the explanation, by subse- quent experiments, of individual symptoms; or the action of the drug on separate, isolated organs, may first be studied, and, assisted by this preparatory knowledge, its influence on the animal system then determined. In general, the first method leads most directly to the desired end. Nevertheless, we will here follow the latter 2* 18 METHODS OF INVESTIGATION. plan, since the analysis of results obtained in the animal organism presupposes a certain amount of experience in explaining elemental disturbances ; this the beginner can best acquire by the method first indicated. We will there- fore commence with the methods for the examination of the action of poisons on isolated organs. PART I. STUDY OF THE ACTION OF A POISON ON ISOLATED ORGANS. The organs of the cold-blooded vertebrates, especially the frog, are best suited for this method of pharmacologi- cal investigation, since, as a rule, they are equally with those of mammals susceptible to the action of poisons, and they may be isolated from .the circulation for quite a while without undergoing any essential alteration. Not only excised organs, such as the heart, muscles, nerves, etc., can be used for this purpose, but the action of the drug can even be restricted to certain portions of the economy while still in the body ; since, on the one hand, their exposure does not necessarily entail any general dis- turbance of function, and, on the other, the exclusion from the circulation of certain parts of the body neither destroys the functions of the isolated parts nor interferes with the normal condition of the remainder. For ex- ample, the action of the poison can be limited to one extremity ; or the entire body, with the exception of one extremity, can be exposed to its influence. Until quite recently, the only organ of warm-blooded animals which was capable of isolation for pharmaco- logical studies was the blood, whose physiological status, especially when kept at the normal temperature, is readily maintained outside of the body. [By improved methods of research this line of study on mammals can now be greatly extended. The methods will be given in their appropriate chapters.] 20 ACTION OF POISONS ON ISOLATED ORGANS. Section I. — Action on the Blood. Blood in considerable quantities can be readily ob- tained only from warm-blooded animals, the selection of the animal depending on the special point to be studied : thus, when alterations in the haemoglobin are to be ex- amined, it is advisable to employ easily crystallizing blood, such as that of the horse, dog, or guinea-pig. [In order to collect blood, either arterial or venous, uncontaminated with foreign matters, it is necessary to isolate the artery or vein and insert a canula into the vessel. Various forms of canulae may be employed. The simplest, and therefore the best, is readily prepared by drawing out in a lamp or gas-flame, a piece of narrow glass tubing until the desired diameter is attained ; when by further heating the points of junction of the narrow portion with the remainder of the tube, and gently draw- ing out the tube, a constriction is made at these points, a and h (Fig. 1, D). The narrow portion of the tube Fig. 1. A is the ordinary form of metal canula, with a ring at e by which it can be tied to any larger tube. B is a holder made of a metal tube with a wooden point to facilitate the introduction of A. 1) represents the manner of making glass canulse. is then gently heated over a small flame, drawn out and then filed across at c. The point of the canula thus made is then to be ground down obliquely by rubbing on a hone and the edges rounded in the flame ; the large end of the canula is now tied into a short piece of rubber ACTION ON THE BLOOD. 21 tubing and is ready for use. In this way a number of canulae, which are easily cleaned and inserted, can be made in a few minutes. In order to insert a canula into a vessel the surface must first be freed from hair, and after narcotization, when permissible, the skin divided by an incision about an inch Ion": in the line of the vessel. The connective tissue and subcutaneous muscles over the vessel may then be torn away with a pair of blunt hooks, or two pairs of forceps, and the vessel carefully and thoroughly freed from its con- nective tissue sheath ; on the success of this step, particu- larly in the case of veins, will depend the readiness with which the canula can be inserted, since after the vein has been opened it will immediately collapse and it will then be found much easier to insert the canula into the space between the sheath and vessel than into its proper place. Ordinarily, except in the case of large animals with strong connective tissue fibres, this method of exposing the vessel is preferable, in the avoidance of hemorrhage, to the use of any cutting instrument; when, however, knife or scis- sors must be employed, the bleeding, if any is caused, must be controlled by ligatures or torsion. After the vessel has been exposed, a pair of forceps can be passed under it and then opened, thus serving to maintain the vessel in a position where it can be readily operated on. Three ligatures are then passed under the vessel ; if it is an artery, the one farthest removed from the heart is first tightly tied, so as to occlude the vessel, and the one nearest the heart is then tied in a slip-knot so as to be readily removed. A snip is then made in the vessel midway between the two ligatures with a pair of scissors which cut well at their points, and the canula, which may conveniently be held on a piece of wood, then inserted towards the heart and bound fast by the middle thread, the knot being tied around the neck of the canula. The canula is further prevented from slipping out by bring- ing the ends of the middle ligature parallel with the tube and then encircling them with a thread tied around the large end of the tube, and tying the ends of both sets 22 ACTION OF POISONS ON ISOLATED ORGANS. together. The same manipulations are used when it is desired to insert a canula into a vein, with the exception that the proximal lii^ature is first tied so as to distend the vessel, and the slip- knot then tied with the distal liga- ture, the canula pointing towards the periphery instead of towards the heart, as in the case of the artery. In- stead of slip-knots, spring-clips may be used to compress the vessels. Blood is then collected by connecting the canula with a clean glass tube leading to a well-cleaned vessel of any sort, preferably glass, and then untying the slip-knot, or removing the bull-dog forceps or clip. In order to collect blood free from access of air, the canula may be connected by tubing with the upper end of a burette, protected by a stopcock, the lower end of which communicates, a stopcock intervening, with a movable vessel containing mercury. The mercury reser- voir is first to be raised to such a height that the mercury rises to the top of the burette and commences to flow over ; the lower stopcock is then closed and the reservoir depressed ; the clip or knot is then removed from the vessel and the instant the blood reaches the end of the tubing connected with the canula, all air being expelled, the end of the tube is slipped over the top of the burette and bound fast. On now opening the lower stopcock of the burette the mercury falls and draws after it into the burette the blood from the vessel. As soon as enough is obtained, the stopcocks are closed, and the tube may be shaken to defibrinate its contents.] In addition to the action of the drug on blood removed from the body, it is often advisable to examine the blood while still circulating in the vessels, as can be readily done in the tongue, or swimming bladder of frogs, or in the mesentery of mammals, with the aid of the microscope ; in such experiments the poison is injected into the general circulation. As far as pharmacological studies have yet taught, we may have to deal with the following forms of alteration of the blood produced by poisons. We commence with those most readily detected. action on the blood. 23 1. Alterations in Consistence, from Action on THE Albuminoids of the Blood. — Caustic alkalies can convert the blood into a gelatinous mass by the produc- tion of alkali-albuminate. By prolonged action, alcohol coagulates the albuminoids of the blood ; many metals, al- cohol by short action, aniline, etc., precipitate them. Precipitation of globulin is produced by acids, and when in concentrated solutions, other albuminoids also are thrown down. Alterations in color ordinarily accompany changes in consistency ; these will be subsequently studied. As a rule it will not be possible to determine the character of the precipitate ; at least when some general idea of the action of the substance experimented with is not already possessed, no general rule for its closer study can be given, since so little precise knowledge is pos- sessed of the alterations of the albuminoids, that each case requires a special chemical study. It may be recom- mended, however, in order to obtain some conception of the nature of the albuminoid to whose alteration the changes are due, not only to experiment with blood collected directly from the artery or vein, but also to examine into the action of the poison on defibrinated blood and on blood serum. 2. Alterations in the Alkaline Reaction of the Blood. — The reaction of the blood cannot be directly tested with litmus paper. One of the simplest methods is tliat recommended by Kiihne.^ It consists in placing the blood in a small dialyzer, made by moulding a piece of parchment paper into the form of a minute cup, and floating the dialyzer on the surface of a little distilled water in a watch glass. A little blood is then placed in the dialyzer thus constructed and after a short interval the reaction of the colorless drop of water in the watch- glass is tested. [This method is, however, not perfectly reliable, since ' Archiv f. Path. Anat., xxxiii. 95. 24 ACTION OF POISONS ON ISOLATED ORGANS. the blood will probably coagulate before the reaction can be determined, and the alkalinity may possibly be thereby altered ; but, though not giving, strictly speak- ing, the reaction of fresh blood, it will generally serve the purpose. Liebreich recommends the use of a slab of neutral plaster of Paris stained with neutral litmus solution ; a few drops of blood are allowed to fall on the slab, and, after a few seconds washed oif with a little water: the blue coloration can then be detected where the blood rested. In order to determine the degree of alkalinity, a standard solution of tartaric acid may be made by dis- solving 7.5 grm. of crystallized tartaric acid in a litre of distilled water ; 1 c. c. of this solution should exactly neutralize 0.004 grm. of sodium hydrate. The acid solution is added from a burette to 50 or 100 c. c. of the serum or blood, a drop of the mixture being placed from time to time upon the slab colored with litmus ; the ad- dition of acid is continued until the reaction is faintly acid. The alkalinity of the blood may then be expressed as corresponding to x milligrammes of sodium hydrate per 100 c. c. of blood.]i An even shorter method [based on the fact that blood coloring matter does not diffuse out of the blood cor- puscles into strong solutions of common salt] is that advised by Zuntz.^ A drop of blood is placed on a strip of glazed litmus paper which has . been previously moist- ened with a concentrated solution of sodium chloride, and, after a few minutes' contact, drawn up with a pipette or filter paper. It is only necessary to be sure that the salt solution, which itself often becomes alkaline when kept for any length of time in glass vessels, is neutral. By this process it is also possible to determine the degree of alkalinity of the blood by adding standard solutions of acid to the blood and employing this method to determine when the reaction is acid. [It may, how- ' Gamgee, Physiological Chemistry, vol. i. p. 177. 2 Centralb. f. d. Med. Wissen., 1867, 531. ACTION ON THE BLOOD. 25 ever, be objected to this method, that the addition of the salt causes alterations in the corpuscles, producing shrinkage and osmoses into the blood plasma. Schafer^ recommends the use of the delicately colored glazed English litmus paper ; all that is necessary, according to him, is to place a drop of blood on the paper and after a few seconds to wipe it off. The blue patch will indi- cate the alkalinity, since the alkaline salts will soak into this paper faster then will the haemoglobin.] 3. Alterations in the Red Blood-Corpuscles. — For studies on this point, when the poison is a liquid and not volatile, a few drops of perfectly fresh, defibrinated blood are placed on an object-glass, covered with a cover- slip, and a drop of the poison placed on the slide and allowed to mingle with the blood under the cover-slip. If it is not desired to study all the steps in the process of change, if any should be produced by the drug in question, the poison and the blood may be first mixed and a drop of the mixture then placed upon a slide and examined under the microscope. If, however, the drug is in the form of a solution, great care must be observed in attributing the results to the action of the drug, as there is scarcely any 'known solvent which does not itself produce change in the red blood-corpuscles ; in such cases control experiments must be made with the solvent alone. In suitable cases, 0.5-0.7 per cent, solution of sodium chloride, which itself produces no sensible action on the corpuscles, m^y be used as a solvent. If the drug is a volatile liquid, the blood may be subjected to the action of its vapor by passing air or any indifferent gas through the liquid and then through the blood, in the manner to be described under the study of the action of gases [or any of the gas-chambers, e. ^., Strieker's may be used]. The simplest method of subjecting blood to the action of gases or vapors, is to pass them through a tube reaching ' Journal of Physiology, Jan. 1882. 28 ACTION OF POISONS ON ISOLATED ORGANS. to the bottom of the vessel in which the blood is contained. The process may be accelerated by closing the vessel which contains the blood after the air has been displaced by the gas, and then agitating. If it is desired, during the action of the gas, entirely to prevent the access of air, a small quantity of blood may be passed up into an ordinary Torricellian barometer tube, and then the gas conducted through it ; the action of the gas may then be facilitated by closing the open end of the tube with the finger and then shaking, though it should be remembered that shaking blood w^ith finely divided solid particles, and therefore probably also with the globules of mercury, may itself cause an alteration in the blood corpuscles.' The continuous passage of gases through undiluted blood, as is here desirable, is, by any of the methods yet mentioned, an extremely unsatisfactory and incomplete procedure on account of the foam produced ; since each gas bubble only comes into partial contact with a limited portion of the blood, and the complete result of the treat- ment may only appear after a long interval of time. By the following method,^ however, the object is rapidly attained ; a vertical glass tube, about 5 mm. in diameter, and on which there may with advantage be blown a number of bulbs, is to be bent at its lower end so as to form a short arm formino; an acute anHe with the verti- cal portion of the tube. A small portion of blood is now drawn by suction into the tube so as to occupy a part of both of its arms and the shorter arm is then connected with the gas generator. The gas then forces the blood up into the vertical arm, bursts through it in bubbles, and the blood flows back along the sides of the tube to be again forced up by the gas, thus always bringing fresh surfaces into contact with the gas, and producing a com- plete action in the shortest possible time. In certain special cases, it may be desirable to keep 1 Compare A. Rollet, Sitzungsber. d. Wiener Acad. Math. Natur. Wissen. CI. 2 Abth. lii. 246. ■^ Hermann, Arch. f. Anal. u. Phys. 1865, 471. ACTIOxV ON THE BLOOD. 27 the blood, which has been subjected to the action of the gas, free from access of air ; it is then only necessary to seal the tube, after introducing the blood and gas, by fusion at two points where it has previously been drawn out to a thread. If it is necessary to observe the action of the gas at a high or low temperature, the tube may be bent in the form of a V? ^^^ during the experiment immersed in a water-bath or cooling-mixture. The methods as yet described do not permit of continu- ous observation from the commencement of the action of the gas on the blood-corpuscles ; this, however, is ren- dered possible by the use of the dift'erent forms of gas- chambers for microscopic use, most of which also permit of the object being studied at different temperatures.^ The alterations of the red blood-corpuscles produced by different agents,^ as far as are yet known, may be changes in shape or color, or complete decolorization or solution. The latter two processes, of which the first may, for ex- ample, be produced by water, and the second by ether, cause the blood to assume the appearance known as " lak^^" While normal blood, even in the thinnest layers, is perfectly opaque, and when allowed to flow" down the side of a orlass forms irre«!;ular streaks, after decolorization, or solution of the red corpuscles, it be- comes transparent and perfectly homogeneous, like red varnish. Under tlie microscope, in both cases, the serum is seen to be colored, and the corpuscles are either entirely invisible, or in simple decolorization, occur in the form of perfectly pale, scarcely perceptible spheres. [" Stro- mata" according to Rollet.] The change of the disk-shape into the spherical form seems always to precede the loss of color, even when the latter is caused by the total solution of the corpus- cle. In addition to this spherical alteration in the shape of the red blood-corpuscles, they may also take on ' Kiihue, Arch. f. Path. Aiiat. xxxiv. 423, and Strieker's Hand- biicli, p. 411. 2 The alterations produced by heat, cold, electricity, etc., do not fall within the province of this work. 28 ACTION OF POISONS ON ISOLATED ORGANS. a jagged, contracted form (crenated) from the action of certain reagents, for example, as occurs on the addition of concentrated salt solution or on drying. Alterations in color of the corpuscles will be mentioned under the heading of changes in the coloring matter of the blood. 4. Alterations in the White Corpuscles. — The white blood-corpuscles may be studied in precisely the same manner as the red. In the former case, however, it is necessary in addition to examine into the eft'ect of the agent on the contractility of the white corpuscles : this may be accomplished by experimenting with a drop of blood on the warm stage of the microscope. — In order to form any conclusion as to this point, it is evidently necessary to subject the blood to the action of the poison the instant that it leaves the bloodvessels. Co- agulation may be either accelerated, retarded, or pre- vented. Should the blood, after the addition of the poison, appear to coagulate more rapidly than normal, a control experiment must be made by adding some of the poison to defibrinated blood in order to determine whether the coagulation is due to fibrin-formation or to the coagu- lation of albuminoids, etc. [The coagulum formed, and the process of its formation, may also advantageously be examined under the microscope.] According to the researches of Alexander Schmidt,^ retardation or prevention of coagulation depends upon action of the poison either on the fibrinogen or the fibrino- plastin. When, therefore, coagulation is retarded, the mode of action may be determined by allowing the drug to act either on isolated fibrinogen or fibrinoplastic substance, and then determining their individual activities. Fibrinogen » Arch. f. Aiiat. ii. Pliys. 1B61, p. 545, 675 ; 1862, 428, 533. AcrroN ON THE blood. 29 can be readily obtained in the pericardial fluids of man or other mammals, and in most hydrocele fluids ; its pres- ence, however, in these liquids must be first established by the production of a coagulum when they are added to the serum obtained by subjecting blood-clots to pressure. Fibrino plastic substance may be obtained from the fluid thus obtained from blood coagula. Fuller details for in- vestigations on these points must be obtained from Schmidt's memoir. [The comparatively recent researches of Hamraarsten^ on the chemistry of blood coagulation have rendered necessary some modification of the theories of Schmidt and Buchanan. According to his investigations the evi- dence is decidly in favor of the view that fibrin is pro- duced by the decomposition or change of fibrinogen, and that this change is connected with the presence of a ferment derived from the breaking down of the white corpuscles, or, perhaps, from the granular bodies recently described by Bizzozero. Paraglobulin, or the fibrino- plastic substance, is therefore only indirectly, if at all, connected with the process ; at any rate the idea that fibrin can only be formed by the union of fibrinogen and fibrinoplastin in the presence of a ferment is no longer tenable. The same methods, however, can be employed as indi- cated above, since the ferment is contained in the serum expressed from blood clots.] 6. Alterations in the Coloring Matter of the Blood. — For studies on this point it is advisable to dilute the blood which has been treated wMth the poison, with water, so as to be able to study changes in its color w^ith transmitted light ; generally the dilution should precede the addition of the poison. Changes in haemaglobin are best and easiest studied by means of the spectroscope, as described in Hoppe- ' Pfliiger's Archiv, xiv. xvii. xviii. xix. 3* 30 ACTION OF POISONS ON ISOLATED ORGANS. Seyler's Chemische Analyse. [See also the paper by Gamgee on the action of " Nitrites on the Blood," Proc. of the Roy. Soc, 1868, p. 339.] 7. Alterations in the Gases of the Blood and IN THE Power of Absorbing Gases. — From the fact that when blood is drawn from a vessel changes in the proportion of its contained gases at once commence, the action of a drug on the blood gases can be only partially determined. For example, if oxygen is diminished in proportion, or entirely absent, it would be made evident by the change of color to a dark venous hue and by the characteristic spectroscopic changes ; changes in percentage of carbonic anhydride are however much more difficult to establish. iVccurate experiments on either of these questions are extremely difficult ; the blood must be collected without access of air and then subjected to the action of the poison and the gases then determined ; or its power of absorption for certain gases established after the blood, from which all gases have been exhausted, has been brought under the influence of the poison. Both these processes are complicated and will be rarely requisite in pharmacological studies ; they Avill therefore not be entered into here. 8. Alterations in the Ozone and Ozonizing Power OF THE Blood. — For the determination of the first of these points, the blood must be preserved throughout free from air, since ozone is formed as soon as blood comes in contact with the atmosphere. The blood must therefore be collected in a vacuum, or in an atmosphere free from oxygen, then mixed with the poison, and the surrounding air, which is then allowed access, tested with freshly prepared guaiacum test-paper (or strips of paper moistened with a solution of iodide of potassium and starch ; if ozone is formed it will unite with the potassium, the iodine will be set free and color the starch blue). ACTION ON THE MUSCLE3. 31 Full details for such studies will be found in Kiihne and Scholz on " Ozone in the Blood. "^ In order to determine the ozonizing power of the blood, it must be treated with carbon monoxide gas, ex- hausted of oxygen, and then brought under the action of the poison; the presence or absence of ozone in the air can then be determined by test papers. In order to determine the readiness with which the blood yields up its ozone (?) a more delicate test than guaiac must be employed ; the best process is to add a small quantity of tincture of guaiacum to a drop of oil of turpentine and then a few drops of the blood Avhich has been acted on by the poison. If the power of transferrence is unaltered, the fluid will immediately become dark blue. For the study of other alterations of the blood, such as precipitation, or alterations in the poison produced by the action of the blood, no general rules can be given. Section II. — Action on the Muscles. Only a few poisons are suitable for direct application to excised muscles ; of course in these cases, the muscles of cold-blooded animals alone can be used, those of the frog being nearly always selected. Since most poisons must be used in the form of a solu- tion, and since nearly all solvents, even distilled water, are irritating to muscles, the direct immersion of a mus- cle in a solution of a poison is always a doubtful experi- ment. A solution of common salt, 0.5-0.7 per cent., is the most neutral solvent that can be selected. ^ A better method than the immersion of the muscle in the solution, is to determine the local action of the poison by injecting the solution into the bloodvessels ; [this can be readily accomplished in the frog by insert- ing a canula in the bulbus aortcie, washing out the circu- ^ Arcli. f. Path. Anat., xxiii. p. 96. 2 Sf^e Nasse, Arch. f. d. ges. Physiol, ii. 97. 32 ACTION OF POTSONS ON ISOLATED ORGANS. lation with salt solution, and then making an injection of the poison. By this means the effects of local action on the muscles can be readily studied.] Gases and vapors are best suited for direct applica- tion to the muscles ; to accomplish this, the muscle is sus- pended in a bottle, or cylindrical vessel, closed by a cork through which pass two tubes ; one simply traversing the cork, the other, through which the gas is to be conducted, passing to the bottom of the vessel and dipping under the surface of a layer of water. When the gas is forced through the vessel it comes in direct contact with the muscle and, at the same time, keeps the atmosphere around the muscle saturated with aqueous vapor, a con- dition absolutely necessary for all experiments on muscles or nerves. It is convenient to so suspend the muscle, that it can be readily irritated while still within the vessel. A fine wire, passing through the cork and ending in a hook on which the tendon or bone is suspended, can serve as one electrode ; a very light metal hook, connected with a fine spiral wire which also passes through the cork, can be inserted in the other tendon and serve for the second electrode. For experiments with gases and vapors the thinnest possible muscles, such as the sartorius of the fro,£:, must be selected, since the gases act solely on the superficial fibres. For the majority of poisons it is best to first adminis- ter the drug, in a way which will be later indicated, to uninjured animals, and then, after the action of the poison has become evident, to excise their muscles for investigation. It is very often desirable, as a control experiment, to study at the same time an unpoisoned muscle of the same animal. In the frog, which is alone suitable for such experiments, single groups of muscles may readily be protected from the poison by ligation of their arteries before the drug is administered. This is most easily accomplished by shutting off the blood supply from one entire limb by ligation of the common iliac artery, or the femoral artery may be ligated at the ACTION ON THE MUSCLES. 33 upper part of the thigh and the foot and leg of that side be thus cut oft' from tlie circulation. [Ligation of the bloodvessels of a limb will not inva- riably succeed in preventing access of the poison to that member, since Ringer and MurrelP have found that cer- tain substances, such as potash salts, are capable of be- ing diffused through tissues shut off from the circulation almost as rapidly and as thoroughly as when their blood supply has not been interfered with. In cases, therefore, where ligation of the blood supply of a limb appears to produce no modification in the character of the symptoms, which on other grounds are presumably of peripheral origin, the tissues should always be examined for the presence of the poison.] The ligation of a common iliac artery is performed in the foUowins; manner : The froor beiuiz; fastened on his belly, in the lower part of the back three bony lines are easily detected, the two iliac bones and between them the coccyx ; an incision is to be made, parallel to these bones, between the ilium and coccyx, through the oblique muscular mass, the ileo-coccygeus ; the iliac plexus can then be seen, composed of the prominent nerve trunks, lying deep within the peritoneal cavity, and at its inner border, the common iliac artery. The artery can then be readily isolated with a delicate blunt hook, and a fine thread passed around it and ligated. To ligate the femoral artery, a frog is fastened in the same manner and a longitudinal incision, m, n (Fig. 2.), made through the skin in about the middle of the posterior surface of the thigh; a deep longitudinal furrow is then seen lying between the vastus externus on the outer side and the semimembranosus on the inner side, with the thin round biceps lying in the furrow (Fig. 3) ; on drawing the vastus with the biceps towards the outer side and cut- ting through the fascia, the sciatic nerve and femoral artery are seen running together, the latter being easily recognized by its black pigmentation ; it is to be sepa- ^ Joiirii. of Phys., vol. i. pt. i. 34 ACTION OF POISONS ON ISOLATED ORGANS. rated from the nerve with a blunt hook and ligated. If it is desired to ligate the artery near the knee-joint, the Fi-. 2. JJiagram of a fi'oj( to show the lines of various iucisious. biceps is first to be divided at its lower end and turned upwards ; the artery can then be readily reached. The method of preparation of the muscle for study after poisoning, will depend upon the special point to be investigated. For the examination of the relative irritability, etc., it is always advisable to isolate the muscle with as long a piece of its nerve as possible ; for most purposes, especially when it is desired to load the suspended muscle, the gastrocnemius in connection with ACTION ON THE MUSCLES. 35 the sciatic nerve and femur is the most suitable prepara- tion. Ordinarily, however, the condition of irritability is alone dealt with, and for the examination of this point the method of Du Bois Reymond is perhaps the simplest. His preparation is made as follows : After destruction of Diagram of the muscles of the leg of a frog, posterior surface, a, triceps femoris ; ft, biceps femoris ; c, semimembranosus ; d, coccygeo-iliacus ; e, /, tendo Achillis ; g, gastrocnemius ; h, head of gastrocnemius ; k, peroneus, the outer muscle marked k is the tibialis anticus ; I, rectus internus ; n, pyriforniis ; .r, coccyx ; y, ilium ; a', vastus externus. the central nervous system, by thrusting a wire down the spinal canal and into the cerebral cavity, the frog is cut in two in the lower dorsal region with a pair of strong scissors, and the skin stripped off the lower extremities ; the furrow between the vastus externus and semimem- branosus is then sought for, and the sciatic nerve isolated as near the knee as possible. A blade of a sharp pair of scissors is then carefully passed under the nerve and the leg amputated near the knee, care being taken not to injure the nerve. The foot is then held between the fingers, and the nerve carefully dissected out from below upwards to the spinal column, and all branches divided. 36 ACTION OF POISONS ON ISOLATED ORGANS. Fig. 4. great care beino; taken not to stretch the nerve or injure it with the scissors. The most difficult part to isolate safely is where the nerve enters the abdominal cavity. \¥hen the spinal column is reached, the plexus which forms the sciatic is to be divided. [The preparation generally known as the " nerve-muscle preparation" is obtained by a slight modification of this method. The femur is divided about half an inch above the knee and the nerve prepared as above ; the gastrocnemius muscle is then exposed, its tendon divided as near the foot as possible, and the muscle sepa- rated by a blunt probe from the rest of the leg which is then divided helow the knee. The preparation then consists of the entire sciatic nerve from the knee up to the vertebral column, the knee-joint with a portion of femur by which it can be suspended, and the gas- trocmius muscle (Fig 4).] All preparations of frogs' nerves and muscles must be carefully protected from drying. 1. Measurements of the electro-motive power of poi- soned muscles will be seldom required, since there seems to be ground for believing that the electro-motive power runs parallel Avith its irritability. Should, however, it be desired to examine into this question, the methods may be obtained in Du Bois Reymond's writings. 2. The alterations which are generally met with in muscles subjected to the action of poisons are changes in irritability, occurring in various degrees. Muscular irritability may be estimated either by the direct or the indirect method. In general, the presence of muscular excitability, as evidenced by indirect stimulation (^. e. by nerve irritation) presupposes the existence of di- rect excitability, although it is conceivable that muscles The nerve- iiniscle preparatiou. F, end of femur ; N, sciatic nerve ; I, tendo achil- lis ; i', origin of lesser tendon of gastrocne- mius. ACTION ON THE MUSCLES. 87 may be susceptible only to stimuli coming through the nerves. Examination of indirect muscular excitability includes, therefore, the examination at the same time of nerve excitability. 1. Examination of Indirect Muscular Irrita- bility. — The general rule for this class of experiments is that two muscle preparations, a poisoned and non- poisoned, must be continually compared in order to elimi- nate changes in irritability produced by the drug from natural changes, such as would accompany the death of the nerve, etc. An exception to this rule is only permis- sible when the changes produced by the drug are of the most marked character, sucli as the production of entire loss of irritability. Both preparations must be taken from the same animal and should be corresponding animal parts, one having been previously protected from action of the poison by ligation of its bloodvessels- The method has already been given. Convulsions or fibrillar contractions caused by the operative procedure, must be allowed to pass oiF be- fore the^ changes in irritability, if such exist, are mea- sured. Unless there is some indication for the employment of a special form of stimulation [such as mechanical, ther- mal, or chemical], electricity is always preferable, and the most convenient form is the tetanizing induction cur- rent. [For the ordinary application of the induced tetanizing current the most convenient apparatus is the Du Bois Reymond induction coil. This instrument, as arranged for use, is seen in Fig. 5. The positive pole, a;, of the bat- tery is connected by a wire with the binding post a, and the negative wire, - a a ACTION ON THE MUSCLES, 4B which the preparation is prevented from drying by cover- ing the bottom of the chamber with layers of filter paper moistened with normal salt solution, while evaporation is prevented by the glass shade. The nerve-muscle prepa- ration and a convenient form of electrodes are shown on a larorer scale in Fig. 9. Below the moist chamber is seen Fig. 9. Enlarged repieseutatiou of holder aud electrodes seen in Fig. 8. (From Foster's Physiology.) a simple loaded lever by which the height of muscular contraction, or the form of the muscle-curve, can be studied by allowing it to record its movements on the smoked paper of the revolving drum of the kymographion. In- stead of the simple lever, which will of course, when ele- vated, describe an arc of a circle, Pfiliger's myographion lever (Fig. 10) may be employed. In very accurate experiments non-polarizable electrodes should be used (Fig. 11). These are readily made by plugging up one end of a short piece of glass tubing a, with clay, ^, mois- tened with normal salt solution ; a few drops of saturated solution of sulphate of zinc are then poured into the tube as seen at , for recording the movements of the column of mercury on the revolving surface r. At pb is a box containing a pressure-bottle, filled with a saturated solu- tion of sodium carbonate, which can be elevated or de- pressed at pleasure. The entire system of tubes between the surface of the mercury in the tube m of the manometer and the artery and pressure-bottle being filled with sodium carbonate, by which the blood is prevented from clotting, the clamp >>» t^ 1 — ' rt ba ; 00 O ■>> 9! =^ a .--2 3 g ^ 3 l>.j:j 5 o '3 "2 .2 "^ 3 ^ -^ fe "S %-< PLIOt ««; «^ »"3 g ^ ® d g*:! § • a a? ai 'i -.2 ® >^« b ti rf a> 5 ^^ - ^ ops P ll t d O M 03 u O « OJ CD !i3 na CC N « o W 11 o o PhPi o^ d j-td 4) > !> o"© O o3 c3 ga o o d a ^^^d ass's 23 cS sS tiS COOQCB OQ 5J » rd 0-® oj O paqsinitnip 9q ^^ra 9jnss3.id-pooia pasuejoni 9q Xbhi eanssaad-pooxa 112 GENERAL ACTION OF POISONS. After having determined in tlie manner indicated on page 113, the general action of the poison on the circu- lation, the comparative effects of diff"erent doses must be studied. It must also be remembered that muscular contractions will cause an increased blood-pressure ; hence when the poison being experimented with produces convulsions, or is a respiratory poison, enough curare must be given to paralyze the motor nerves of the voluntary muscles, and artificial respiration maintained. For this purpose an ordinary bellows, run at the proper rate by a gas or water motor, or even by the hand, or any of the various forms of air-blasts, such as Sprengel's air-pump, may be used and the blast rendered intermittent by an electro- magnet by which a weight that compresses the air-tube can be alternately elevated and depressed. In the explanation of the results obtained in blood- pressure experiments, it will not be necessary to here give a complete analysis of all the methods employed in settling each point ; enough only will be given to show the general plan to be followed.] As already said, the causes of changes in the circula- tory mechanism may lie either in an action of the poison on the muscular apparatus of the heart, its nervous appa- ratus, or on the bloodvessel system. The conditions which modify the functional activity of the cardiac muscle can- not be separated from those governing the other muscles of the body ; hence, general muscle poisons, especially those which exert a paralyzing influence, such as the de- privation of the blood of oxygen, will act in the same man- ner on the heart. But since an important part of the car- diac nervous mechanism is contained witliin the heart, it is often difficult to decide what effect should be attributed to action on the nervous system and what to action on the muscle. It can, however, be positively stated, that a poison acting on the muscular tissue of the heart alone, may change the force of contraction, but never produce any change in rhythm; therefore, as a rule, it can only be held that the poison acts on the cardiac muscle when it produces progressive or total paralysis without change in ACTION ON THE CIRCULATORr APPARATUS. 113 rhythm ; and the supposition is rendered more probable, when the drug is known to aifect other muscles in a similar manner. There is a large group of poisons, of which curare is a good example, which have no action on the muscular ap- paratus of the heart, but which paralyze the nerve ter- minations of its motor apparatus. The exact mode of termination of these nerves has not yet been determined (?), but it has been found that these poisons only act in slight degree, if at all, on the intra-muscular cardiac nerves. The second and roost usual action of a poison on the heart is on its nervous system. [Let us suppose a case in which the drug causes quickening of the pulse ; by reference to the table, we see that the heart may be caused to beat more rapidly by stimulation of the accelerator nerves or ganglia, either directly or by diminished blood-pressure, or by paralysis of the inhibitory nerves or ganglia. If the pulse is ren- dered quick by decreased blood-pressure, increasing the pressure by compression of the aorta, or by an injection of defibrinated blood, should slow the pulse ; if, however, it should happen that the rapid pulse is associated with an increased pressure, this possibility of course does not exist. If, therefore, we assume that we are dealing with a case in which increased blood-pressure is accompanied by a rapid pulse, the question will be narrowed down as to whether the inhibitory apparatus of the heart is para- lyzed, or the accelerator apparatus stimulated. If we divide both pneumogastrics in the neck before the experi- ment, and still find that the pulse is further increased after the administration of the drug, we can assume that the cardio-inhibitory centre in the medulla was not para- lyzed, and if we find that the irritation of the central end of a divided vagus, the other being intact, can reduce the rate of pulsation, we can infer that the cause of the disturbance does not lie in the inhibitory apparatus. Suppose, however, we find that the irritation of the central end of the vagus has no effect; then the trouble 10* 114 GENERAL ACTION OF POISONS. must lie either in the vagus fibres, in the heart ganglia, or in the medullary ganglion. The latter may be par- tially excluded by the above experiment of dividing the pneumogastrics ; the question may be still more de- cisively answered in the following manner : It is known that after a poison has been injected into the circula- tion, it is only gradually distributed throughout the entire system, and its characteristic effects are only produced when the percentage of poison in the blood reaches a certain height ; and of course the percentage is great- est at the point of entrance. Let us now suppose that we are dealing with a case in which either the cardiac or medullary inhibitory centre is either paralyzed or irrita- ted; if we inject the poison into the jugular vein towards the heart and the symptoms (quick pulse for paralysis, slow pulse for irritation) instantly appear, the probabil- ity is, that the poison acts directly on the heart. But if some time, say a minute or more, is required before the effects appear, the evidence then points to implication. of the centres in the medulla, and if we find that injection of the drug into the carotid causes the instant appear- ance of the symptoms, the evidence is conclusive. It might, however, be necessary to determine whether the vagus trunks are paralyzed ; if the cardiac ganglia are intact, this can be readily settled by testing whether their irritation slows the heart. If the cardiac ganglia should be paralyzed, the condition of the vagus may still be determined by the presence or absence of muscular contractions in the larynx after irritation of the vagus above the origin of the laryngeal nerves. After paraly- sis of all portions of the inhibitory apparatus are thus excluded, the conclusion can be formed that the drug acts by stimulation of the accelerator apparatus, and this can be located in the heart, if it should be seen after section of the accelerator nerves. The explanation of the production of a slow pulse is reached in a somewhat similar manner. Slow pulse from irritation of the inhibitory centre in the medulla, or of the vagus trunks, is excluded by section of the pneu- ACTION ON THE CIRCULATORY APPARATUS. 115 raogastrics low down in the neck, while stimulation of the peripheral ends of the vagu« is rendered impossible by previously giving enough atropia to paralyze the pneumogastrics. Or the comparative degree of excita- bility of the vagus trunks may be tested by noting the strength of current required to slow the heart before and after the administration. By methods similar to those here outlined, the action of a drug on the extrinsic cardiac nervous system can be determined with tolerable accuracy ; the study of the action of the drug on the heart itself is, however, a matter of considerably greater difficulty.] Since there are at least three independent cardiac centres, viz., the intrinsic cardiac centres and the two cerebro-spinal regulating centres (the accelerating and inhibitory centres), and since all these centres may be influenced by the numerous nerves with which they are connected, a poison acting on the heart through the modium of the nervous system may produce its charac- teristic action in several different ways ; and the ques- tion is still further complicated by the fact that nearly all heart poisons act on the heart in several different ways at the same time, and the mode of action may vary in different stages of poisoning with the same drug. The following methods will serve to give some idea of the course to be followed in attempting an investigation of these points. The action of the poison on the ganglia in the heart can be tolerably well isolated by allowing the poison to act on the excised frog's heart, or in mammals by sepa- rating the heart from the extrinsic nervous system by section of all the nerves passing to it, an extremely difficult operation,^ or by division of both pneumogas- trics and sympathetics in the neck and the spinal cord be- between the occiput and atlas. By either of these meth- ods, however, the intracardiac ganglia are not completely isolated, since there are numerous poisons, such as ^ Ludwig iind Thiry, Wiener Acad. Sitzgsber. 1864, 18 Feb. 116 GENERAL ACTION OF POISONS. curare, nicotine, atropine, etc., which produce their char- acteristic effects bj action on the intracardiac terminal fibres of the different cardiac nerves, especially of the vagus. In order to establish a condition of paralysis of these nerves, examinations must be made, before proceed- ing to the isolation of the heart, as to whether irritation of these nerves will produce the characteristic normal re- sult after the poison has been given ; for instance, if the drug paralyzes the intracardiac endings of the pneumo- gastric nerve, the irritation of the nerve after the admin- istration of the poison will fail to slow the pulse. To determine whether the slowing of the pulse or arrest of the heart, produced by the poison, is due to irritation of the vagus endings in the heart, atropia or curare, which in large doses are known to paralyze these struc- tures, is administered before the drug, artificial respira- tion kept up, and the drug then given; in such a case, if the action of the poison is to slow the heart by stimula- tion of the vagus endings, the previous administratioa of a drug, such as curare, which paralyzes these structures, will, of course, prevent the appearance of the usual symptoms. After eliminating in this way, the possible action of the poison on the termination of the nerves in the heart, the study of the action of the drug on the isolated heart will then render it possible to form conclusions as to the action on the cardiac gancrlia. [From reasons already given, the heart of the frog is much better suited for the study of drugs than is that of the mammal, though recent improvements in the methods of research have rendered the heart of warm-blooded animals much more accessible for this purpose. The methods of studying the local action of poisons on the heart in situ have been already given ; for the excised heart, several plans may be followed. The old modes of study, alluded to on page 88, have now been univer- sally supplanted by the methods of investigation intro- duced by Ludwig; his plan was to keep the heart sup- plied with serum and attached to a manometer, bv which ACTION ON THE CIRCULATORY APPARATUS, ll7 the pulsations of the heart could be recorded. His origi- nal instrument has been considerably modified bj several investigators, and several new forms of instruments for this purpose are now in use ; of these, only two forms will be described, accounts of the others can be found in the various physiological hand-books. The apparatus used by Ludwig and Coats in their ex- periments on the vagus nerve is shown in Fig. 27 ; it is Fig. 27. Ludwig aud Coats's frog maaouieter. the simplest form of frog manometer, and can be readily extemporized. It consists of a manometer E^ connected by a canula B' with the bulbus aortae of a frog ; at D is another canula inserted into the sinus venosus and con- 118 GENERAL ACTION OF POISONS. nected by the tube Q with a reservoir A containino; di- luted rabbit serum, or even normal salt solution. J^is a heavy glass rod, moving on a sliding clamp, for holding the frog. The frog's heart is prepared by destroying the brain and spinal cord and then cutting across the body below the liver so as to remove the lower extremi- ties; the sternum and forelegs are then removed, leaving only a flap of skin large enough to cover the heart, which is exposed in the usual manner ; one canula is then in- serted in one aorta, pushed into the bulb and bound fast, while the other aorta is ligated ; another canula is then inserted in the sinus venosus. The liver and lungs are then removed and an opening made in the stomach, and the glass rod J passed through the mouth and down the oesophagus ; the aortic canula is then connected with the manometer and the venous canula with the reservoir, the stop-cock B opened and the serum allowed to flow through the heart and out at F^ until all air bubbles are displaced and the heart and vessels completely filled with serum. The clamp on F is then closed and the pressure bottle raised to such a height that there is a certain tension exerted on the heart even during diastole. This method of using this appa-. ratus, in which there is no circulation, the serum simply being forced out of the ventricle at each systole and fall- ing back at each diastole, is especially suited for the study of drugs on the vagus nerve. The vagus is seen in the drawing, and may be readily found below the greater horn of the hyoid bone lying alongside of the laryngeal nerve, which can be readily recognized by tracing it to its destination. After normal tracings have been taken with this ap- paratus and the eff"ects of the vagus tested, some of the poison may then be added to the serum in the reservoir and the results noted. In many cases, it is better to have an active circulation through the heart, and to be able- to substitute normal for poisoned serum. This can be readily accomplished by having two reservoirs standing on the same level, the one containing normal ACTION ON THE CIRCULATORY APPARATUS. 119 serum, and the other serum containing poison ; their flow through the heart can then be regulated by a two-waj cock, while by opening slightly the clamp F^ the serum that is pumped through the heart can be allowed to escape. In the comparison of results obtained in this manner with normal and poisoned serum, care must be taken that the conditions are always uniform ; that the resistance at F^ and the pressure in the reservoirs are always the same. By varying the resistance at F^ the effects of increased or diminished capillary resistance Fig. 28. Koy's heart apparatus. may be imitated and the effect of varying blood-pressure studied on the action of the heart. By means of an instrument devised by Dr. C. S. Rpy^ 1 Journ. of Physiol., vol. i. No. 6. 120 GENERAL ACTION OF POISONS. the accurate study of poisons on isolated portions of the frog's heart is greatly facilitated. The instrument is represented in Fig. 28. The small bell-glass (i?) rests on a round plate of brass (6) to which it is fixed by the aid of a little stiff grease. In the upper opening of this vessel is fitted a short glass canula, which is perforated to allow the passage of the heart canula ; inside this canula is a second tube of metal measuring about 1 mm. in diameter. It extends from the lower extremity of the canula to a point about 5 mm. from its upper end, where it passes through its canal, and projects for a sufficient distance to allow of an India-rubber tube being tied on it (c). B}^ means of this canula, diluted blood, or other fluid, can be kept constantly circulating through the auricle or ventricle, which is fastened on it, the rapidity of the flow being regulated by the difference in height of the two reservoirs which are in connection with the two tubes of the canula. In the brass plate on which the bell-jar rests are two openings, one of which forms the inlet to a short tube d which is provided with a stop-cock e ; the other opening is situated in the centre of the brass plate and forms the inlet to a short cylinder closed below by a non-elastic flexible membrane to which is attached, by a piston-like disk and needle, a long light lever. The ventricle, or auricles, as the case may be, having been fastened on, and the canula and reservoirs filled with diluted blood, the heart is introduced into the bell-glass (which has been previously fixed on the plate), and its cavity filled with olive oil. On now opening the stop-cock (e) the oil begins to flow out through the tube c?, and renders the pressure within the bell-glass sub-atmospheric ; when the piston has thus been drawn up to the point repre- sented in the figure the stop-cock is closed. With the apparatus thus arranged, each contraction of the heart will cause an elevation of the lever, and each relaxation a fall, from the varying volume of the contracting heart. Observations on the isolated ventricle may be made by ACTION ON THE CIRCULATORY APPARATUS. 121 cutting away the base of the heart nearly down to the auriculo-vcntricular sulcus, inserting the canula into the ventricle through one of the auricles and then binding it fast by a ligature passing around the auricular wall near the ariculo-ventrical groove. Where the ventricle is very small the auricular septum may interfere with the introduction of the canula ; in such cases the auricular septum should be slit through with a pair of very fine blunt-pointed scissors. To fasten on the auricle to the perfusion canula the lower two-thirds of the ventricle is clipped off with scis- sors and the auricular septum slit through with blunt- pointed scissors, one blade entering each auricle from the ventricular aspect, great care being of course taken to avoid cutting the walls of the auricles. The venae cavge superiores and inferior are then ligated, the posi- tion of the ligature around the sinus venosus varying in different experiments ; the end of the canula is then in- troduced into the auricular cavity from the opened ven- tricle, and is fastened by a ligature passing around the sulcus, the upper third of the ventricle or around the lower part of the auricular walls as the case may re- quire. The movements of the sinus venosus may also be studied in the same manner by introducing the canula into its cavity. It is seen that by this method it is rendered perfectly feasible to study the action of poisons on each separate portion of the heart ; tracings may first be taken with the organ supplied with diluted blood and then with blood containing definite proportions of the drug. It is possible to experiment on the toxic changes which the heart undergoes as regards its electric irritability by using the canula as one electrode and by surrounding the canula where it passes through the stopper with rub- ber, and outside of it a sheet of tin- foil whose projecting edge is cut into a fringe ; outside, the tin-foil is connected with the other pole of the induction apparatus, while in- side any portion of the fringes may be i3laced in contact with the heart and serve as the second electrode. The recent application to the mammalian heart by 11 122 GENERAL ACTION OF POISONS. Prof. Martin,^ of Baltimore, of the Leipzig method of maintaining circulation through the organs of warm- blooded animals has rendered possible the study of drugs on the isolated mammalian heart. The principle of this method is to prevent circulation through all parts of the body of a warm-blooded animal but the heart and lungs ; from want of blood, the brain, spinal cord, and sympa- thetic ganglia soon die, and so the heart is liberated from the control of nerve centres outside of itself. The animal being tracheotomized and narcotized, the carotids are exposed and tied, and canulne placed in their central ends ; the vagi are then divided in the neck. The next step is to expose the heart and great vessels by resecting the front and sides of the thorax, all bleeding vessels being ligated. The right and left subclavian arteries are then tied below the origin of their first branches, thus cutting off nearly all blood from the head. Next a metal canula, curved at one end so as to present a long limb and a short limb at right angles to one an- other, is inserted into the aorta just above the diaphragm and pushed up until its end reaches the arch, where it is bound fast, thus blocking all circulation through the systemic arteries, with the exception of the coronaries. The next step is to tie the systemic veins leading to the right auricle ; a ligature is placed around the inferior vena cava above the diaphragm, another around the vena azygos near its entry into the superior vena cava, and the latter is then ligated on the cardiac side of its last tributary. On the cardiac side of this ligature a large tube, in communication with a flask containing defibri- nated diluted blood, is introduced, the carotids opened, and all the blood previously present in the heart and lungs displaced by defibrinated blood. A thermometer being inserted in the left carotid, and the right connected with the manometer tube, the animal is then transferred to a warm moist chamber. 1 Trans, of the Med. and Chir. Fac. of Maryland, April, 1882, p. 203. ACTION ON THE CIRCULATORY APPARATUS. 123 The aortic canula is connected with a long rubber tube having at its distal end a bent glass tube from which the blood, forced out by each contraction of the left ventricle, is poured into a funnel ; from this funnel a tube leads to a Mariotte's flask exactly like that in connection with the right auricle. The blood taken by the right heart under definite pressure from one Mariotte's flask is thus pumped into another, from which, by changing a couple of stop-cocks, it can a second time flow into the right heart. Varying blood-pressure can be produced by elevating or depressing the end of the aortic exit-tube, while the addition of the poison to the blood in the venous reservoir will enable its action on the isolated heart to be studied. In the attempt to localize the action of heart poisons on different portions of the ganglionic apparatus of the heart, one of two ways may be followed, though neither in the present state of cardiac physiology deserves to be designated as a method. Either the poison may be administered to pulsating fragments of the frog's heart by means of Roy's apparatus, and some conclusion attempted from the known anatomical peculiarities of the part, or the method of antago- nisms may be followed. In gen- eral, the latter, although it is true that its data are largely based on assumptions, will lead to the most reliable results. Thus in the dia- gram. Fig. 29, the fibres repre- sented by the dotted line A, are said to be paralyzed by nicotine, the ganglion i irritated by mus- carine, and the fibres B paralyzed by atropine. Suppose, therefore, we -find that a drug produces in- creased rapidity of the pulse in an excised or isolated heart ; we may first irritate the vagus, we find it fails to slow the pulse ; we then irritate the sinus venosus, still without Fig. 29. Diagram of the hypotheti- cal nervous apparatus of the heart. 124 GENERAL ACTION OF POISONS. effect ; we then add a few drops of muscarine and still find that the heart is not slowed. We then know that the fibres b must be paralyzed by the drug in question. Or suppose a case in which muscarine could slow the pulse, while irritation of the vagus failed ; w^e then know that the fibres A were paralyzed. If the drug should slow the pulse, and the subsequent administration of nicoline should not restore the normal rate, we would suppose that some portion of the ganglionic apparatus nearer the motor centre than a must be affected, and if we found that atropine would remove the effect of the drug, it would be probable that the drug in question produced slowing of the pulse by stimulation of the in- hibitory ganglion I. As regards the action on the accelerator apparatus our knowledge is not so complete. When we find that a drug quickens the excised heart, we have one of two possibilities to consider ; either the paralysis of the in- hibitory apparatus or the stimulation of the accelerator apparatus. The former may be excluded by previous paralysis of the inhibitory ganglia by atropia. If now the drug produces quickening we know that it must be by action on the accelerator apparatus ; further than this we cannot at present go, as the list of drugs which act on the accelerator ganglia is very limited and not yet well worked out.] The third cause of modifications in the action of the heart and in blood-pressure produced by a poison, lies in the condition of the peripheral vascular system. The degree of contraction of the bloodvessels, particularly of the arteries, not only influences the degree of blood-pres- sure in the vessels, but also the frequence and energy of the heart's contractions. Thus, by ligation of any large arterial trunk, such as the descending aorta, the pressure in all the other arteries and in the left side of the heart can be so increased that the distended heart will be only able to perform very feeble contractions. It has also been experimentally determined that the calibre of the smaller arteries is subject to variation depending upon ACTION ON THE CrRCULATORY APPARATUS. 125 the degree of contraction of their muscular walls, and that this contractility is governed by the impulses coming, by the efferent vaso-motor nerves, from the principal vaso- motor centre in the medulla ^ Many poisons influence the degree of arterial con- traction either by direct action on the arteries (either by action on their muscular fibres or on the hypothetical peripheral vaso-motor ganglia), or on the vaso-motor centre in the medulla, so as to produce either paralysis and dilation of the arteries with a consequent reduced blood-pressure, or a reduction in calibre with a conse- quent great increase in blood tension. Experiment has further shown that each increase in pressure is usually accompanied by a reduction in the pulse, and each reduc- tion in pressure by an increase in the pulse.^ It is, therefore, unwarrantable to form any conclusion as to the cause of modifications in the heart's action until the possible reflected influence of changes in the conditions of the bloodvessels has been considered. The reflex influence of the central vaso-motor centre on the heart can be eliminated, without interfering with the activity of the accelerating nerves, by section of the spinal cord on the level of the second dorsaP vertebra, or by division of the splanchnic nerves.* But even with this procedure the possibility of direct toxic action on the muscular fibres of the arteries still remains. Observations as to the condition of the bloodvessels arc most readily made on the ear of the rabbit, especially after depilation with sulphide of calcium,^ in the wing of the bat, or in the retinal vessels of all animals capa- ble of being examined with the ophthalmoscope ; the mesentery or swimming bladder of the frog can also be used for the same purpose. ^ For the exact location of this centre see Owsjannikow, Sach. Acad. Ber. 1871, p. 135. 2 See Ludwig and Thiry, Wiener Acad. Sitzgsber., 1864, Feb. 18. 3 V. Bezold, Untersuch. aus d. physiol. Lab. in Wiirzburg, 2 Heft, 1867. 4 See M. and E. Cyon, Arch. f. Anat. u. Physiol., 1867, p. 395. * See Samuel, in Moleschott's Untersuch., ix. p. 654. 11* 126 GENERAL ACTION OF POISONS. [Exclusive, then, of modifications dependent directly upon the heart, the blood-pressure may be modified by the direct action of the drug on the afterent vaso-motor nerves, on the vaso-motor centre in the medulla (and cord?) and on the efferent nerves. Consequently, when it is found that a drug produces a reduction in blood- pressure, after the exclusion of the causes depending on cardiac action, the condition may be due to paralysis of the vaso-motor centre from direct action of the drug, to paralysis of the afierent or efferent vaso-motor nerves, to irritation of the depressor nerve, or to direct local action on the bloodvessels. When the cause has been located in the vaso-motor apparatus, the precise seat of the paralysis can only be determined by working from the periphery to the centre ; thus the normal, or abnormal, condition of the arterial walls must be first determined, then that of the efferent vaso-motor nerves, then tlie vaso-motor centre, and finally that of the afferent vaso-motor nerves. In most cases it is extremely difficult to separate direct toxic action on the bloodvessels from action on the efferent vaso-motor nerves, though some deductions may be drawn from the characters of the circulation in excised organs ; the methods for carrying on these studies will be given under their appropriate heads. If the poison produces reduced blood-pressure from direct action on the vascular walls, whether on their nerve-ending or muscular fibres, we would expect that after arterial tension has been reduced through section of the cord, and the influence of the vaso-motor centre thus eliminated, the administration of the drug would be followed by a still more marked fall in pressure. Local action on the bloodvessels may be excluded, as was done by Filehne in the case of nitrite of amyl, by maintaining artificial circulation with normal blood through the vessels of the external ear of a rabbit, and then administering the poison either by injection into the venous system at large, or through the trachea when in the form of a vapor. Should the vessels then dilate, ACTION ON THE CIRCULATORY APPARATUS. 127 local action on their walls or on the nerve endings would be excluded. Another method, also employed by Filehne for the same purpose, is to maintain a condition of moderate contraction of the auricular vessels by stimulation of the cervical sympathetic on one side with a weak interrupted current ; if dilatation should not appear on that side after administration of the drug, but exist on the ear of the opposite side, the dilatation could be attributed to dir minished tonus of the vaso-motor centre. The irritability of the efterent vaso-motor nerves may be determined by irritating the dorsal spinal cord, or the splanchnic nerves, when, if the efferent vaso-motor fibres preserve their functions, the blood-pressure will be greatly increased from contraction of the abdominal arterioles ; should they or the arterial walls be paralyzed, no such rise will be produced. Or the central end of the divided cervical sympathetic may be stimulated in a rabbit and the auricular vessels directly inspected; should they con- tract, it will be evident that the vaso-motor paralysis is located in the centre or in the afferent nerves. The irritability of the vaso-motor centre may be de- termined by screwing one gimblet electrode into the occipital bone and the other into the atlas, until their points penetrate the neural cavity, and passing an in- duced current through them. Or the vaso-motor centre may be irritated by compressing the carotid arteries in the neck by raising them on threads ; in a normal con- dition this experiment produces an increase in blood- pressure. If the blood-pressure is increased by eithar of these modes of stimulation, it may be considered de- monstrated that the vaso-motor centre and efferent nerves preserve their functions, and it will then be necessary to determine the condition as regards the power of trans- mitting impression possessed by the afferent vaso-motor nerves. This is accomplished by irritating the central end of the divided sciatic nerve, a procedure which normally is followed by an increase in blood-pressure. Should all these experiments demonstrate a normal 128 GENERAL ACTION OF POISONS. state of irritability of the vaso-motor apparatus, atten- tion must then be directed to the depressor nerve. This nerve, which is a branch of the pneumogastric nerve, or rather a root of the latter, which in the rabbit joins it at the level of the superior laryngeal nerves, possesses the power through its irritation of inhibiting the vaso-motor centre in the medulla and thus producing a marked fall in blood-pressure. If, therefore, both these nerves are cut in the rabbit before the administration of the poison the possibility of their influence in the production of reduced blood-pressure will be excluded. It should, moreover, be always remembered that drugs which produce paralysis of the vaso-motor system usually, especially with small doses, first cause a condition of irritation of this apparatus, hence the fall of blood-pres- sure is generally preceded by an initial rise.] Indirect Results of Circulatory Disturbances. — In cold-blooded animals marked disorders of the circu- latory apparatus are without effect on other functional activities ; it is only when they are long continued that general disturbances appear, and after a time, after com- plete arrest of the heart, the animal gradually becomes more and more sluggish, its loss of power gradually pass- ing into complete paralysis and death. ^ The secondary cause of these disturbances, after arrest of the circula- tion, probably lies in increasing deprivation of oxygen affecting the central nervous system and muscles simul- taneously. Increased rapidity of heart pulsation is entirely without effect. In warm-blooded animals, on account of their constant need of fresh supplies of oxygen, every considerable re- duction in the rate of the heart's beats, and especially arrest of the heart, is accompanied immediately by the gravest general disturbances, and the recognition of this interdependence of general functional activities and the state of the circulation, first pointed out by Rosenthal,^ ' [See in this connection Ringer and Murrell, Journ. of PhysioL, vol. i. No. 1. p. 72.] « Arch. f. Anat. u. Phvsiol., 18l)5. COl. ACTION ON THE CIRCULATORY APPARATUS. 129 is to be regarded as one of the most important advances in scientific pharmacology. Arrest of the heart causes a complete stagnation of the blood in all the vessels, and as a consequence we have on the one side, a cessation of absorption of oxygen from arrested pulmonary circulation, and on the other side, the different organs are supplied with a diminished quan- tity of blood which rapidly gives up its oxygen and be- comes loaded with carbonic acid. This interruption in the oxygenation of the blood in warm-blooded animals rapidly destroys the functions of all organs and soon leads to general systemic death. Before, however, death occurs, there appears a series of phenomena depending upon the arrested circulation in the medulla oblongata. At first the respiratory centre is abnormally stimulated by the altered cliaracter of the blood, and when the venosity of the blood passes a certain degree, the stimu- lation extends to the neio-hborinsi; motor and vaso-motor CD O centres in the medulla, and contraction of all the small arteries, and then general convulsions follow. Hence, arrest of the heart is followed by the same train of symptoms as interruption of the circulation in the brain by ligation of the cerebral arteries or veins (which pro- duced the same arrest of cerebral circulation as stoppage of the heart), or as interference with respiration ; namely, in the first place, increasing vigor of respiration up to dyspnoia, then general convulsions and arterial spasm, while the phenomena of asphyxia first make their appear- ance when the amount of oxygen in the blood of the medulla oblongata has fallen so low that the nerve centres lose their irritability. These phenomena will be more closely- studied under the respiratory changes produced by poisons. It consequently follows from what has been said that arrest of the heart, or even every considerable reduc- tion in the heart's activity, must in warm blooded ani- mals cause dyspnoea, general convulsions and asphyxia. When therefore a poison causes convulsions in warm- blooded animals and not in frogs, it must always be 130 GENERAL ACTION OP POISONS. determined whether the drug does not in the first place cause stoppage of the heart. In this way other nerve centres, especially those governing the movements of the intestine,' and con- tractions of the uterus,^ are influenced like the respir- atory and vaso-motor centres by increased venosity of the blood, and consequently increased intestinal peristalsis and uterine contractions may be results of interference with the circulation. The consequences of less grave circulatory disturb- ance are to be explained as depending upon alterations of blood-pressure (see p. 91). Nearly all functions are intimately dependent upon the degree of blood-tension in the organ with which they are associated, and there- fore every marked change from the normal blood-press- ure, through toxic action on the heart or bloodvessel system, soon leads to functional disorders.^ The most marked and the earliest of these disorders occur in the functions of the cerebrum, where diminished blood- pressure leads to dizziness and syncope, and increased pressure to sense disturbances, delirium and loss of con- sciousness. Section II . — Action on the Respiratory Apparatus. A general idea as to the condition of the respiratory apparatus may be gained by mere inspections of the tho- rax. A greater degree of accuracy is attainable when inspection of the diaphragm is rendered possible by open- ing the abdomen ; or, without opening the abdominal cavity, by the insertion of a long needle through the body walls into the diaphragm. In order to reproduce • Mayer u. von Basch, Wiener Med. Jahrbiiclier, 1872. * Oser u. Schlesinger, Weiner Med. Jahrbiiclier, 1872. ' The best statement of these facts is to be found in a lecture by Ludvvig, Die Phvsiologischen Leistungen des Blutdruckes, Leipzig, 18t)5. ACTION ON THE RESPIRATORY APPARATUS. 131 the respiratory movements graphically Rosenthal's phrenograph or Marey's pneumograph may be used. In certain cases it is necessary to determine the volume of the respiratory movements ; for this purpose Hutchinson's spirometer or an ordinary gas-meter, con- nected with the trachea, may be employed. [The changes in the frequency and rhythm of the re- spiratory movements may be graphically represented by means of Marey's tambour, either arranged as in the figure (Fig. 30) or by connecting the tube d directly with the tracheal canula, which must then be provided with an opening at one side to enable the animal to obtain fresh air. KnolP recommends the insertion of the animal in a box which can be closed air-tight, the trachea of the ani- mal being connected with the exterior by a tube pass- ing through the top of the box, while the respiratory movements are recorded by connecting the interior of the box by a tube with a Marey's polygraph.] a. Dyspncea. — The most frequently observed effect of poisons on the respiratory apparatus is dyspnoea, made evident by an increased vigor of the respiratory move- ments and action of the accessory muscles of respira- tion ; usually, the frequency of the respiratory move- ments is also diminished. The cause of dyspnoea is invariably an irritation of the respiratory centre in the medulla oblongata ; this irrita- tion is always to be found in the blood which acts as an excitant to the respiratory centre in proportion as it be- comes poorer in oxygen and richer in carbon dioxide.^ These morbid states of the blood, which are therefore the final cause of dyspnoea, can exist either in the blood- vessels of the medulla or the head, as has already been 1 Sitzber. der Akad. zu Wein., 3 Abth. Bd. Ixviii. s. 245. 2 These alterations of the blood are mutually interdependent ; the question as to whicli of the two conditions is the true excitant still remains undecided. 132 GENERAL ACTION OF POISONS. ACTION ON THE RESPIRATORY APPARATUS. 133 mentioned on p. 128, or they may prevail in the blood at large ; this latter condition is the more usual. The reduction in percentage of oxygen in the blood and the excess of carbon dioxide, or, as Hering terms it, the increased venosity of the blood, may be due to any or all of the following conditions : 1 . Diminished or retarded absorption of oxygen in respiration. 2. Di- minished exhalation of carbon dioxide in respiration. 3. Expulsion or abnormal consumption of the oxygen origi- nally in the blood. 4. Abnormal absorption of carbon dioxide. The first two of these conditions are ordinarily pro- duced by interference with the respiratory movements, and may be produced by poisons through paralysis of the respiratory apparatus, either of the respiratory centre, nerves or muscles. In this case, however, to produce dyspncea^ the paralysis must be confined to individual respiratory muscles ; or they may be due to interference with the pulmonary circulation (see heart paralysis, p. 129), or finally, to inability for absorption of oxygen by the blood. This latter cause, with the exception of dyspnoea produced by heart-poisoning, is the most frequent factor in the toxic production of respiratory difficulties. The blood can be unfitted for absorbing oxygen either through alteration of the haemoglobin, or through destruction of the red corpuscles. The third of the above mentioned conditions which may act as causes of dyspnoea, the expulsion of the oxygen from the blood, can naturally only exist as such when it is produced so rapidly that the lost oxygen cannot be replaced with sufficient rapidity, to preserve a normal proportion, by the fresh oxygen taken in respiration, or when the blood is at the same time and by means of the same agent unfitted for absorption. Sulphuretted hydro- gen is an example of a poison which produces the first of these conditions, carbon mon-oxide, of the second. The fourth condition may occur when an atmosphere abnormally contaminated with carbon di-oxideis inspired. If, now, this poverty of oxygen and richness in carbon 12 134 GENERAL ACTION OF POISONS. di-oxide of the blood continues, the dyspnoea passes into general convulsions as the increasing irritation extends to other centres in the medulla. Should the deprivation of oxjgen still advance, the irritability of both the nerve centres and the muscles gradually fails, the convulsions cease, and are replaced by asphyxia, which is not death so long as the heart continues to beat and still possesses the poAver, through introduction of oxygen into the blood, of bringing the organism back to its normal condition. Should this occur, as, for example, through artificial res- piration, the irritability of the nerve centres is first re- newed, and convulsions are again produced ; the rapid disappearance of the irritation soon causes the convulsions to be replaced by dyspnoea and this finally gives place to normal respiration. The consequences of dyspnoea can- not be specified, since dyspnoea is essentially a compen- satory process, tending to remove the abnormal condition of the blood through increased absorption of oxygen and exhalation of carbon di-oxide by deeper breathing. h. Cessation of Respiratory Movements. — Besides dyspnoea, poisons may produce weaker respiratory move- ments or cause their complete suppression. The causes of these conditions may, in general, be either: — 1. Reduction of the Respiratory Stimulus through SATURATION OF THE BlOOD WITH OXYGEN AND DIMINU- TION IN ITS Carbon Di-oxide. — This condition, which can scarcely be regarded astoxicological,is termed apnosa, and may be produced by vigorous artificial respiration ; it is made use of experimentally when it is desired to study successive stages of the general action of a drug whose administration is otherwise followed by dyspnoea. 2. Reduction in Irritability of the Respiratory Centre. — This condition may be the result of either a direct action of the poison, or the consequence of such a reduction in the amount of oxygen in the blood that the nerve centres are no longer irritable, a condition which always occurs in the last stage of dyspnoea (see asphyxia, above). It is directly productive of death, since not only ACTION ON THE RESPIRATORY APPARATUS. 135 the respiratory centre, but all the other centres, especi- ally those of the heart, become simultaneously paralyzed either from the same cause or from the cessation of res- piration. If the asphyxia is the result of a direct action of the poison on the respiratory centre, the activity of the heart, and therefore life, can be preserved by artifi- cial respiration. If, on the other hand, the asphyxia is due to an absence of oxygen in the blood, artificial respi- ration will only prove effective when mere increased access of oxygen will serve to supply the deficiency. [Respiratory changes may be referred to direct action of the drug on the respiratory nerve centre when they occur after section of the vagi, and after the influence of circulatory changes has been excluded. This point may be determined by injecting the drug into the carotid artery toward the brain, while a blood-pressure observa- tion is made in the crural artery ; if respiratory changes occur before any disturbance of the circulation, the latter may be excluded as the active cause. Of course the possi- bility of the effects of the drug being due to alterations in the blood or its gases must be taken into consideration.] 3. Paralysis of the Respiratory Muscles.— This condition will be produced by drugs producing general paralysis, e. g., curare. Death results from deficiency in absorption of oxygen, ordinarily without preliminary dyspnoea or convulsions ; in such circumstances life may be preserved by artificial respiration. c. Alterations in the Frequency of the Respira- tory Movements — The rate of respiratory movement is dependent upon the rhythmical functions of the respi- ratory centre, upon the condition of excitation of the regulating nerves, especially those running in the pneu- mogastric, and upon mental or cerebral stimuli. Drugs may change the rate of respiration through any one of these paths : ordinarily the modus operandi may be ac- curately enough determined. Cerebral or mental sources of stimuli on the respira- tory centre may readily be established in man, and in 136 GENERAL ACTION OF POISONS. animals they may be excluded through previous narcoti- zation or extirpation of the cerebral cortex. Irritation of the regulator nerves, at least when start- ing from their peripheral terminations, may be eliminated by section of the nerve trunks. Changes in frequency persisting after exclusion of the two preceding modes of action must depend upon the direct action of the poison on the respiratory centre. Changes in the rate of respiration must be very marked to produce any evident general results. It should, however, be remembered that slowing of the res- piration may be an introductory symptom of complete cessation of respiration, increased respiration, of tetanus. In both cases the consequences will be the same, in a general way, as those which follow complete cessation of respiration. d. Appearances in the Larynx. — Poisons may affect either the sensory or motor functions' of the larynx. Insensibility of the larynx, ordinarily only one sign of more general anaesthesia, interferes with the normal pro- tective influence exerted by the larynx over the lungs by the absence of the possibility of reflex closure of the glottis ; a similar danger may also be produced in paral- ysis of either the laryngeal nerves or muscles. On the other hand, poisons may cause spasm of the glottis, and so interfere with normal respiration, either reflexly by irritation of the sensory nerves, as in inhala- tion of irritating gases and vapors, or by direct action on the nerve centres or muscles. Section III. — Action on the Digestive Apparatus. Under this head, which has been less studied, and is, therefore, more obscure than any other branch of phar- macology, distinction must be made between changes in the movements of the digestive organs, the production of ACTION ON THE DIGESTIVE APPARATUS. 137 abnormal sensations, alterations in the secretions, and, finally, changes in the digestive processes. a. Alterations in the Movements of the Diges- tive Organs. — 1. Movements of the Jaws. The only toxic eftect evidenced by movements of the jaws [except the masticatory movements which follow the introduction of drugs by the mouth, or their excretion, when perceptible to the taste, by the saliva] is trismus, a tetanic spasm of the muscles of mastication which is generally an introduc- tory symptom of general convulsions (see Nervous Sys- tem), and which, wdth the exception of the prevention of the prehension of food, leads to no special consequences worthy of separate study. 2. Deglutition. — Deglutition can be hindered by the action of poisons, either through action on the motor appa- ratus, when it is merely a symptom of general paralysis (see Nervous System), or by alteration of the secretions of the mouth and pharynx, as, for example, the dyspha- gia produced by belladonna poisoning. Whether spasm of the muscles of deglutition, as occurs in hydrophobia, may be produced by the action of poisons, is unknown. 3. Movements of the Stomach. — As the knowledge which we possess as to the conditions modifying the physiological movements of the stomach is of the most limited character, it follows that nothing can be said as to the effects of drugs on this function of the digestive organs. As regards the production of vomiting by toxic action, our knowledge is a little more complete. Vomiting is a complicated co-ordination of various mus- cles, having as a result the emptying of the contents of the stomach into the pharynx. With the exception of the opening of the cardiac orifice,^ the role of the stomach in vomiting is purely passive, the act being largely due to rhythmic contractions of the diaphragm and abdominal muscles. The co-ordination of these muscles is governed by a nerve centre lying in the medulla oblongata or » SchiflF, Moleschott's Unters., x. 363. 12* 138 GENERAL ACTION OF POISONS. brain^ which is capable of being set into activity by stimuli directly brought to it by the blood, or reflexly through various centripetal nerves, especially those com- ing from the digestive apparatus. The determination as to which of these modes is concerned in the production of vomiting by drugs cannot be reached by merely vary- ing the mode and location of administration of the drug, since the production of emesis after venous or hypoder- mic injections does not prove a direct action on the centre ; for the substances are carried by absorption to the stomach, and may there serve as reflex stimuli. This statement is proved by the fact that tartar emetic requires larger doses and a longer time to produce emesis when injected into a vein than when given by the stomach, and even in the former case the presence of antimony can always be detected in the vomited matters.^ It is, therefore, still doubtful whether the centre is capable of direct stimulation. Different animals vomit with different degrees of readi- ness ; while birds, dogs, and mice, vomit with the greatest ease, the contrary is the case with rabbits and frogs. Although, as has been said above, the stomach is pas- sive in the act of vomiting, it is conceivable that drugs may at the same time produce active contractions of the stomach ; to verify this, the voluntary muscles should be paralyzed with moderate doses of curare and artificial respiration kept up, when the conditions of the stomach may be directly inspected. The consequence of the act of vomiting is the removal of the contents of the stomach, and, therefore, the partial or total removal of the poison ; if it is desired to study the general action of a poison which produces vomiting, the drug should first be administered by some other means, as hypodermically, and if vomiting still occurs, it must be prevented by curare,^ or by ligature of the oeso- ' Hermann u. (jrimm, Arch. f. d. Ges. Physiol., iv. 205. 2 Hermann, Arch. f. d. Ges. Phys., v. 280. ? Giannuzzi, Centbl. f. d. med. Wissen., 1865, i. ACTION ON THE DIGESTIVE APPARATUS. 139 phagus, a procedure often employed in the older experi- ments.^ [In many cases vomiting may be prevented by section of the vagi, since these are the nerves by which the afferent impulses which cause the relaxation of the cardiac sphincter reach the medulla.] 4. Movements of the Intestines. — Alterations in the movements of the intestines, such as increase, dimi- nution, or suppression of the peristaltic motions, cannot be clearly studied either by inspection or palpation without opening the abdomen, and it is therefore gener- ally advisable to expose the abdominal contents by an incision in the linea alba ; but since the rapid loss of heat and drying of the intestines lead to changes in their cir- culation, and consequently to changes from the normal motions which might erroneously be attributed to the action of the drugs, it has been recommended with some show of success to immerse the animal, before opening the abdomen, in a bath of salt solution, J per cent., heated to the body temperature, Avhereby all cooling and access of air is prevented ; under such circumstances artificial respiration must be kept up through a tracheal canula and rubber tube.^ [Salvioli^ employed the following method for studying the movement of the small intestine. A piece of jejunum is excised with its mesentery, from a rabbit, laid on the inner surface of a piece of excised abdominal wall in a warm, moist chamber, and a mixture of 30 parts calves- blood and 70 parts j per cent, salt solution, well shaken up in the air, conducted through its bloodvessels ; one or more light levers resting on the surface of the intestine serve to register its movements. The action of drugs on the peristaltic movements may be studied by adding the poison to the circulating fluid ; thus Salvioli found that nicotine caused violent intestinal contractions and narrow- ing of the bloodvessels, while opium and atropine pro- 1 See Orfila's Toxicologie, 1839, 1. 29. 2 Sanders-Ezii u. van Braam Houckgeest, Pflliger's Arch. vi. 266. 3 Arcli f, Anat. u. Phys., 1880, s. 95. 140 GENERAL ACTION OF POISONS. duced the reverse. For particulars as to this method, as well as for the relations observed between the blood- pressure and the peristalsis, reference must be made to the original memoir.] Departure from the normal degree of peristaltic motion may be due either to direct action on the muscles of the intestine or on its ganglia, on the extrinsic motor or in- hibitory (splanchnic) centres, or indirectly to respiratory or circulatory changes. The experiments necessary for the proof, by exclusion, as to which of these modes of action is concerned, such as irritation and section of the appropriate nerves, will readily suo;fz;est themselves. [Direct action of a drug on the intestinal walls, or on their contained ganglia, may be proved by the absence of the characteristic symptoms, such as contractions, paralysis, etc., in a portion of the intestinal tube which has been protected from the access of the poison by pre- vious ligation of the branch of the mesenteric artery by which it is supplied. And, conversely, injection of the poison into a branch of the mesenteric artery should, under such circumstances, cause the symptoms first to appear in the portion of intestine supplied by that ves- sel.] It should, however, be mentioned that anaemia of the abdominal vessels, as well as dyspnoea, causes an increased peristalsis. As regards modification of the function of defecation, either diarrhoea, or constipation may be produced by drugs, but as yet it is not known whether the changes are due to action on the motor apparatus of the bowels or on their secretions.^ h. Alterations in the Sensibility of, and Produc- tion OF Abnormal Sensations in the Alimentary Canal. — Abnormal sensations, nausea, loss of appetite, 1 See Radziejewski, Arch. f. Anal. n. PliysioL, 1870, i. [and Hay, Journ. of Anat. and Physiol., 1881 and 1882]. ACTION ON THE DIGESTIVE APPARATUS. 141 and increased thirst, are very common effects of poisons, especially when ojiven by the mouth, and so brought into direct contact with the sense organs ; the same effects may, however, be often produced when the drugs are otherwise administered. Reliable observation of such effects can only be obtained in experiments on man ; this also applies to the numerous phases of painful sen- sations which often follow the administration of poisons, such as cardialgia, colic, etc., the causation of which is always obscure. c. Alterations in the Digestive Secretions. — Accurate study of such changes, further than the mere evidence of increase of saliva from its flowing from the mouth, or decrease by dryness of the parts, can only be obtained through the production of iistulae. [The methods of studying the action of drugs on the salivary and biliary secretion will be given under the heading of the action of drugs on glandular action. Occasionally some idea as to the action on the other digestive secretions is to be obtained by the analysis of gastric and pancreatic juice obtained through fistulge, and the examination of the digestive products obtained in the same manner. Our ignorance, however, of the conditions, such as nerve-influence, under which these secretions are formed, does not permit of any very accu- rate studies in this connection ; and very often quite as correct notions may be obtained by adding the drug to artificial digestive fluids. Dogs are most suitable for gastric fistuloe. The ani- mal is first narcotized with opium or chloroform, bound on his back, and the hair shaved from the epigastric region. An incision is then made through the skin, commencing at the lower border of the costal cartilages, and about an inch and a half to the left of the linea alba, and extending downward parallel to this line, for a dis- tance a little less than the diameter of the flange of the canula which it is desired to use. Each muscular layer is then to be divided in a direction parallel to its muscu- 142 GENERAL ACTION OP POISONS. lar fibres, and every bleeding point tied before opening the peritoneum. When it is certain that the bleeding has stopped, the peritoneum is to be opened on a director. On stretching open the wound, the stomach (which should have been distended before the operation by a full meal, or by inflation with air by means of a tube passed down the oesophagus) comes into view, its oblique muscular structure being plainly visible through its serous cover- ing. A point of the gastric wall should now be seized with artery forceps at a spot where there are not many large vessels, and drawn forward. Two strong silk threads are then passed into the walls of the stomach with a curved needle, at a distance from each other about equal to the diameter of the tube of the canula, and brought out at a similar distance from the points where they were introduced. An incision rather shorter than the diameter of the tube of the canula, is then made into the gastric walls between the two threads, and the opening stretched with blunt hooks until it is large enough to admit the inner flange of the canula. The stomach is then tied to the canula by the threads pre- viously passed into its walls, and their ends then passed through the abdominal walls and tied, thus serving not only to close the wound in the latter, but also to main- tain them in apposition with the stomach. The canula should be left uncorked for an hour or so after the ope- ration so as to prevent the passing of the gastric contents into the peritoneal cavity, should the animal vomit. The dog must be fed on milk for two or three days after the operation, and kept in a warm place. The form of canula almost universally used, is that designed by Bernard. It consists of two silver or nickel-plated tubes, each of which has at one end a broad flange ; one tube screws into the other, so that the dis- tance between the two flanges may be altered at will. On the second or third day after the operation, the mar- gin of the wound becomes very much swollen ; this arrangement of the tubes permits the lengthening of the canula, so that the skin is not ulcerated from pressure ACTION ON THE DIGESTIVE APPARATUS. 143 of the flange. The canula may be closed by a cork soaked in a decoction of colocynth, to prevent the dog from tearing it out with his teeth. Ordinarily the animal will be ready for experiment in about a week. Comparative experiments may then be made on the characters of the digestive process at stated intervals before and after the administration of the drugs, of the changes in the secretion or the drug, and of the absorbability of the poison. Gastric juice can also be collected for experiments on artificial digestion: or infu- sions or glycerine extracts of the mucous membrane of the stomach in 0.2 per cent. HCl. may be employed. The action of drugs on the pancreatic secretion is as yet an entirely unbroken field. The extreme suscep- tibility of the pancreas to disturbing influences will ren- der the study of the action of drugs on its secretion, as obtained in temporary fistulae, liable to complication, while it is probable that it is impossible to retain a nor- mal condition of the gland in permanent fistulge. If it is desired to attempt studies on these points, pro- bably the best method would be to open the abdomen of a dog under warm salt solution, insert a canula in the pancreatic duct, and inject the drug into the gland artery. The method for establishing temporary or permanent pancreatic fistulae, may be found in Sanderson's or Cyon's Hand-book, or in Bernard's waitings.] Diminution of the secretions may cause dysphagia or constipation, or changes in the digestive processes ; in- creased secretion may produce diarrhoea. The question as to whether the retained products of secretion in the blood produce further disturbance of function when the secretory processes are interrupted, can only be raised in the case of the bile, and even here it is clouded with a great deal of obscurity. At any rate, the retained substances cannot be regarded as bile, which, as such, is only elaborated in the liver. The possibility of retention of bile through toxic action on the intestinal canal (catarrh leading to obstruction of the bile-duct), should be borne in mind. Such a state of afi'airs is dis- 144 GENERAL ACTION OF POISONS. closed by the paleness and abnormal odor of the feces, through the jaundiced color of the skin and certain mucous membranes, and by the presence of the bile acids and coloring matters in the urine. The existence of icterus gravis would indicate that the retained bile products may, under certain illy-defined conditions, be the cause of further disturbances of function. d. Alteration in the Digestive Processes. — The presence of poisons in the alimentary canal can lead in the most various ways to digestive disorders ; either through alteration in the reaction of the digestive juices, through action on the food stuffs or their digestive products, through preventing the formation of normal secretions, or by action on their ferments, or finally by interfering with the normal fermentative processes. Any one or all of these conditions may be produced, either by directly swallowing the poison or through its passing from the blood into the secretions. The consequences of disordered digestion are first seen in sensory distur- bances, as loss of appetite, nausea, or colic ; then in motor disturbances, as vomiting, diarrhoea, or constipa- tion, and, when long continued, in emaciation and weak- ness. The proof of such toxic changes is best obtained through artificial digestion experiments in which the poi- son is mixed with the digestive fluids, though occasion- ally some idea as to the action may be obtained from examination of the vomited matters or feces, or by care- ful analysis of the symptoms produced. Section IV.^ — Action on Glandular Organs. a. Secreting Glands. — The character of the influ- ence of poisons on glandular organs is best made out through study of their secretions ; nearly always the changes which will be detected will be of a quantitative nature, and are generally easily enough determined, while ACTION ON GLANDULAR ORGANS. 145 qualitative changes produced by toxic action have been but rarely studied. The mode in which drugs increase or diminish secre- tions is as obscure as the general physiological processes connected with the normal act. In many cases, doubt- less, the act is of a vaso-motor nature, as in the increased salivation produced by curare ; in other cases direct action on the secretory tissues or nerves must be con- cerned.^ A thorough investigation is possible in the case of but few glands ; in the case of the salivary glands, however, this branch of pharmacology has been compara- tively thoroughly worked out. 1. [Action on the Salivary Secretions. — In order to study the action of drugs on the salivary secretion it is necessary to establish temporary salivary fistulse in the lower animals, and expose the nerves through whose action modifications of the act of secretion can be pro- duced. Large dogs are the most suitable for such opera- tions. Since the submaxillary gland is the most accessible it is the gland which is ordinarily selected for such studies. To make a temporary salivary fistula in a dog, the animal is chloroformed, the hair shaved from the lower surface of the jaw and the side of the neck, and an inci- sion made along the inner border of the lower jaw, com- mencing about its anterior third and extending back to the transverse process of the atlas, dividing the skin and platysma muscle. After clearing away the connective tissue and fat, carefully avoiding all veins, the submaxil- lary gland comes into view, just below the angle of the jaw. It is then seen that the gland lies in an angle formed by the junction of two veins which go to make up the external jugular, one branch coming from above downward, directly behind the gland, and usually receiv- ing a small vein from the gland itself (as represented in Fig. 31), while the lower branch runs horizontally below ' Heidenhain, Pfluger's Archiv, v. 309. 13 116 GENERAL ACTION OF POISONS. the gland, and is formed by the junction of two other branches, one coming from above and the other from be- low ; this horizontal branch very constantly receives a vein from the gland. This dissection requires care, to avoid wounding these large veins. Fig. 31. Veins of the submaxillary gland of the dog. maxillary gland. B. Jugular vein. (After Bernard.) C. Glandular veil A. Sub. Both branches which go to form the horizontal branch are now to be tied, the one coming from above receiving a double liorature, one where it comes over the ramus of the jaw and the other Avhere it joins its fellow, the inter- mediate portion being removed. Having now carefully removed the cellular tissue from the portion of the wound in front of the gland, the thick belly of the digastric muscle comes into view, its fibres running forward from its origin on the temporal bone, to be inserted in the middle third of the ramus of the lower jaw, immediately in front of the insertion of the masseter, from which muscle it is separated by a slight groove. In front of the digastric the floor of the wound is formed by the transverse fibres of the mylo-hyoid muscle, crossed by the mylo-hyoid nerve, which comes out from under the jaw at the point of insertion of the digastric muscle. ACTION ON GLANDUL'VR ORGANS. 147 The connective tissue is then gradually to be cleared away, with a blunt hook, from the surface of the digas- fcJD trie muscle, and from the groove between it and the masseter muscle, taking care to avoid, as the deeper portion is reached, the facial artery, which passes over 148 GENERAL ACTION OF POISONS. the jaw to run between these muscles, and the artery to the gland which comes from the facial and goes in this groove back to the gland. In the same locality lie also the ducts of the gland and the chorda tympani nerve. The digastric muscle is now to be separated, with an aneurism needle, from the facial artery, avoiding all the adjacent structures, and its muscular arterial branch tied. The muscle is then divided at its anterior third, or where it is inserted into the jaw, and its posterior ex- tremity seized with a pair of artery forceps, and gradu- ally cleared back to its insertion into the temporal bone, and surrounded by a ligature. Now, when it is assured that there is nothing but muscular structure in the grasp of the ligature, it is pushed back to the temporal bone and tightened, and the digastric muscle divided in front of the ligature and removed. On carefully tearing away the connective tissue at the base of the wound, and draw- ing back the submaxillary gland, there is exposed a tri- angular cavity (represented in Fig. 32). This space is limited above and behind by the deep surface of the submaxillary gland, into the hilum of which enter the artery, chorda tympani, and sympathetic nerve fibres with the glandular duct. Its lower margin is formed by the genio-hyoid muscle, and the upper border by the ramus of the jaw and the masseter muscle ; the anterior portion of its floor is formed by the trans- verse fibres of the mylo hyoid muscle, on which ramify the branches of the mylo-hyoid nerve. At the posterior portion of this space the external carotid artery enters and runs along the base of the tri- angle, giving off first the lingual and then the facial arte- ries, from the latter of which comes the artery of the gland. Almost immediately after entering this space the caro- tid is crossed by the large h3^poglossal nerve, running forward to be distributed to the muscles of the tongue, etc. Now, if this nerve is divided at the point where it crosses the carotid, and the central end removed, the ACTION ON GLANDULAR ORGANS. 149 pneumogastric trunk comes into view, lying behind the artery. On pulling to one side the vagus trunk, below and behind it can be seen the white trunk of the sympa- thetic nerve, which here separates itself from the vagus to form the superior cervical ganglion, from* which two small filaments pass out to accompany the carotid and glandular artery to enter the hilum. Some of the sym- pathetic fibres also pass into the gland along the arterial branch which comes from the temporal artery and enters the superior part of the gland. Then, to expose the chorda tympani and the salivary ducts, the fibres of the mylo-hyoid muscle are to be divided transversely at about their middle, avoiding the nerve and tying all veins, and the upper half of the mus- cle reflected. The lingual nerve then comes into view, passing from under the ramus of the jaw, and running downward and forward about parallel in direction with the hypoglossal. On drawing the parts toward the mid- dle line, the two salivary ducts are seen passing along close together, immediately under the ramus of the jaw, the submaxillary duct lying nearest the bone and being a little the largest. On tracing back the lingual nerve to where it passes from under the jaw, it Avill be seen that a delicate ner- vous filament here leaves the lingual and curves back- ward, along with the ducts, to enter the hilum of the gland ; this is the chorda tympani. Immediately after the chorda leaves the lingual there is sometimes seen a small ganglionic enlargement, known as the sub- maxillary ganglion, and as the chorda enters the hilum it forms a slight ganglionic plexus with the fibres of the sympathetic. Each of the nerves, which it is desired to study, should be carefully isolated and surrounded with a thread, and a canula should be inserted into the submax- illary duct. To f^icilitate this last step the duct should be freed slightly from the connective tissue and closed with a clip or a ligature, as near the mouth as possible. Then the chorda should be stimulated, so as to distend 13* 150 GENERAL ACTION OF POISONS. the duct with saliva, and a small slip of wood or card passed under it, to act as a support. Now, if one edge of the duct, over the support, is seized by an assistant with a pair of line forceps, while the operator seizes the opposite edge, and the duct is snipped between the two with a pair of sharp-pointed scissors, the canula can be readily inserted. The secretion of submaxillary saliva is a reflex act, for which the lingual and glosso-pharyngeal nerves (to- gether with certain other nerves), serve as the aiferent fibres, the centre lies in the medulla, while the eff"erent secretory fibres, together with vaso dilator fibres, pass through the chorda tympani nerve. Drugs may, there- fore, cause an increased salivary secretion through stimulation of any of these three divisions of the reflex circle, while the majority of instances in which the secretion is diminished will be found to depend upon paralysis of the chorda tympani. Thus, when it is found that the injection of a drug into the venous system causes a diminution of the salivary secretion, determined by allowing the saliva to flow from the submaxillary duct into a graduated vessel, it will be ordinarily found (as in the case of atropia) that the stimulation of the chorda fails to produce a flow of saliva ; should, however, it be followed by the ordinary result, increased flow and increased vascularity of the gland, it may then be assumed that the paralysis lies in the centre or afferent nerves. When the paralysis has been located in the chorda tympani, the results of the antagonistic action of some known stimulus of this nerve, such as pilocarpine, should then be tested by injecting a few milligrammes into the carotid artery of the same side, or directly into the duct of the gland. In most instances it will be found that the paralysis of the chorda can be removed by pilocarpine, and toxic stimulation of the chorda, by atropine.] 2. [Action on the Biliary Secretion. — The action of drugs which modify the amount of bile discharged from the liver may fall under two categories : either action on ACTION ON GLANDULAR ORGANS. 151 the bile-secreting or the bile expelling mechanisms. It is probable that these two processes are closely united, though many instances might be given of drugs, such as gamboge or magnesium sulphate, which, although power- ful intestinal stimuli (and we know that it is from the stimulation of the intestinal mucous membrane with the acid chyme that the bile is normally discharged), and therefore probably possessing the power of causing a re- flex contraction of the gall-bladder and expulsion of bile, cannot be regarded as stimulants to the secretion of bile. The determination of the point as to whether a drug is a stimulant of the expelling mechanism is, however, very much less important than as to whether the substance is a true hepatic stimulant or not; we will accordingly at present simply give the methods of examining the action of drugs on the secretory functions of the liver. At the outset, we might say that drugs which stimulate in- testional secretion usually depress hepatic secretion, and while drugs which produce slight catharsis only slightly modify the amount of bile secreted, powerful purgation produces a marked depression. The method of study- ing the action of drugs on the hepatic secretion, as em- ployed by Rutherford,^ is by means of temporary biliary fistulse in curarized drugs . He has found that when artificial respiration is maintained in curarized dogs, the secretion of bile remains tolerably uniform duHng the first four or five hours after the commencement of the experiment, but falls slightly as a longer period elapses. The composition of the bile remains constant. The dog should receive a full meal of lean meat the day before the experiment, so as to allow of complete digestion and absorption before the investigation is un- dertaken. The animal is then fastened on his back, cur- arized and artificial respiration maintained, and a glass canula inserted through an opening in the linea alba into the common bile-duct, near its entrance into the duo- denum, and tied therein. A rubber tube is then attached ' Trans. Roy. Soc. of Ediiiburgli, vol. xxix. 1879. 162 GENERAL ACTION OF POISONS. to the canula, the gall-bladder pressed so as to expel its contents and fill the tube, and the cystic duct then clamped : the flow of bile can be estimated by allowing it to drop from the rubber tube into a graduated vessel. The wound in the abdomen must be closed, and the animal covered with cotton-wool to prevent loss of tem- perature. After estimating the rapidity of flow for half an hour or longer, the drug can then be*^ injected into the duodenum, by a syringe with a needle point. It should be mentioned that the bile always flows much more rapidly in the first few minutes of an experiment.] Wherever the direct contact of the poison with a mucous membrane is found to produce a catarrhal increase of secretion, or when, under similar circumstances, ana- tomical alterations can be made out in the glands of the mucous membranes, the results may always be attributed to direct actions on the tissues. 3. Action on the Renal Secretion. — Functional dis- turbances of the kidneys are during life only capable of being studied through the character of the secretion, which may, through the action of poisons, be increased, dimin- ished, or altered in character. These alterations may con- sist either in the admixture of the poison itself or in the pres- ence, induced by the poisoning, of abnormal ingredients, such as blood-corpuscles, haemoglobin, albumen, bile mat- ters, sugar, lactic acid, leucin, tyrosin,or finally in mere alterations in the quantitative composition of the urine re- sulting from modified tissue changes induced by the poison. The kidneys themselves are not always actively concerned in the production of these alterations in the urine. It may, however, be assumed that the kidneys are concerned in di- minution or abnormal quantity of urine, which, however, can also be a result of toxic alterations in blood-pressure, when blood-corpuscles or haemoglobin appear in the urine ; in such cases there exists a toxic inflammation of the kid- ney parenchyma which is capable of post-mortem demon- stration. On the other hand, it appears that toxic alter- ations of kidney structure, such as are often met with in ACTION ON GLANDULAR ORGANS. 153 fatty degeneration, may exist without rendering their presence at all evident by any alterations in the urine. Such appearances often produce definite effects on the entire organism. The excretion of the poison in the urine can, as already remarked, lead to the entire re- moval of the poison from the body, and can even render a poison absolutely innocuous. On the other hand, it is conceivable that the occurrence, during the poisoning, of a disordered functional activity of the kidney, may sud- denly increase the proportion of poison in the blood, and thus lead to intensified, or new symptoms of poisoning ; it is consequently a priori probable that a similar train of symptoms would follow the administration of the drug to a system in which the kidneys were already similarly affected. The presence of the poison in the urine may lead to inflammation of the bladder and ureters in the same way that the inflammation of the kidneys may be produced by the passage of the poison through the kid- neys into the urine. Anuria and polyuria, when of extended duration, may produce pathological effects upon the system ; urgemia and retention of water in the first case, severe thirst in the other. The presence of abnormal constituents in the urine is only of any general moment when they consist of unoxidized substances, such as sugar and albumen, and therefore entail a loss of nutritious principles. [The secretion of urine may be increased by all causes which produce an increased blood-pressure in the renal glomeruli : hence drugs may act as diuretics which in- crease the force or frequency of the heart's beat, which cause contractions of bloodvessels supplying other organs (as the skin), or which cause relaxation of the renal arteries. Thus, profuse renal secretion may be caused by section or paralysis of the renal nerves, from the increased pressure in the glomeruli consequent on tlie relaxation of the renal arteries ; while, conversely, diminished secre- tion may follow stimulation of the renal or splanchnic nerves. All drugs, therefore, which produce increased arterial tension will not act as diuretics unless they at 154 GENERAL ACTION OF POISONS. the same time cause relaxation of the renal arteries; thus, when strychnia is injected into the circulation it causes diminution of secretion from constriction of all the arte- rioles, so acting like stimulation of the medulla ; but when the splanchnics or renal nerves are first divided, injections of strychnia then produce increased urinary- flow. In addition, however, to the modifications of renal secretion duetto alterations in blood-pressure, drugs may act as diuretics by directly stimulating the renal epithe- lium. The rate of urinary secretion may be estimated by opening the abdomen and inserting canulse into the ure- ters ; the canulse are then attached to rubber tubes by which the secretion is conducted externally into graduated glass vessels. To introduce canulae into the ureters, their lower por- tion, just before their entrance into the bladder, should be selected. The abdomen may be opened, after emp- t^^ing the bladder and rectum, by an incision on each side of the recti abdominis muscles or directly opposite the sacro-iliac symphysis, and should be long enough to admit two fingers : when the last of the above-mentioned incisions is employed, the ureters can readily be recog- nized by the touch at the points where they cross the iliac arteries. Instead of the ordinary straight canuUie, it is better to employ glass or metal canulae bent at a right angle, the long arm having a length sufficient to extend through the abdominal wound after the short arm has been inserted and bound fast into the ureter ; by this means kinking of the tube is prevented. To study the changes in the renal circulation produced by poisons, either the method employed by Ludwig and Mosso may be used, or the oncograph devised by Dr. Boy. To maintain artificial circulation through the kidney according to Ludwig's method, the carotid artery of a dog is opened and as much blood as possible collected and defibrinated. The abdomen is then opened and a canula ACTION ON GLANDULAR ORGANS. 155 inserted into the renal artery and another into the renal vein, the vessels being first compressed with clips so as to prevent the entrance of air. The kidney is then ex- cised with the greatest possible care and placed in the warm chamber, the arterial canula being connected with the flask containing the defibrinated blood, under definite pressure, and the rapidity of blood-flow from the renal vein estimated. The substance being experimented with is then added to tlie arterial blood, and comparisons of this rate of flow made. This method as employed by Mosso^ also permits the estimation of changes in volume of the organ from varying blood-supply ; but since the plan pursued by Dr. Roy enables similar studies to be made on the kidney while still in connection with the natural blood-supply, it is to be preferred as less liable to error. Dr. Roy^ has found that the degree of expan- sion of the bloodvessels of the kidney furnishes an ex- tremely reliable idex as to the secretory processes going on in the organ. His method consists in inclosing the kidney, after its exposure through an incision in the lum- bar region, in a rigid metal box, of appropriate shape, containing oil, and of such a construction that while no hindrance is ofiered to the entrance or exit of blood by the renal arteries or veins, any change in the volume of the organ causes a rise or fall, corresponding in extent, of a recording lever writing upon the moving paper of the kymographion. The number of drops of urine which fall from a canula tied into the ureter can also be re- corded on the same paper, by allowing each drop as it falls to close an electric current flowing through the bobbins of an electro-magnetic signal. In all such ex- periments, the blood-pressure must be also recorded, other- wise serious errors may be made in drawing conclusions as to the nature of various changes in the volume of the organ. For recording changes in the volume of the kid- ney, two separate instruments are employed, the one in- 1 Ludwig's Arbeiten, 1874. 2 Journ. of Phys., Jan. 1828. 156 GENERAL ACTION OF POISONS. closing the organ and the other for recording graphically the changes in its volume. The form of box which Dr. Roy employed in his investigations on the spleen^ is equally suitable for studies of changes in volume of the kidney. It consists of an elongated sheet-metal box, composed of two symmetrical halves which are joined together by a couple of hinges. Each of these halves is composed of an outer and inner shell, the latter of which fits accurately into the former, and the two are capable of being firmly screwed to one another by means of screws on the upper and lower rounded edges of the box. Between the two shells is clamped the edge of a thin flexible membrane prepared from the peritoneum of the calf. The membrane is so arranged as to form an air-tight chamber which is bounded on the one side by the flaccid membrane, and on the other by the metal wall of the box. In each of the two chambers thus produced, there are two openings, one pair of which is connected with a T-tube, and thereby with the recording apparatus ; the other two openings are fitted with small taps, and are simply intended to allow the air to escape, when the chambers are filled with oil after the kidney has been introduced into the box. At the point of junction of the two halves of the box on the side opposite to the hinges is a narrow slit formed by an indent in the edges of the two halves, which slit is intended to permit of the passage of the renal vessels and ureter. The recording instrument communicates with the interior of the two chambers of the box ; its principle is similar to that of Dr. Roy's instrument already described for studying the work done by the heart. In order to make the experiment, the animal is anaes- thetized, a canula inserted into the carotid artery for blood-pressure observation, and one into the jugular vein for the injection of the poison. The kidney is then exposed by an incision in the lumbar region, and gently inserted into the box which should have been previously J Journ. of PhjsioL, Jan. 1882. ACTION ON GLANDULAR ORGANS. 157 warmed to the body temperature, and the two chambers of the box, and the tube connecting the box with the re- cording instrument filled with warm olive oil.] 4. Action on the Sweat Glands. — It is here worthy of notice, that many drugs may either produce an abnormal sweat secretion, may reduce the normal amount, or may themselves, or their products, pass into the excretion. [ rhe secretory activity of the sweat glands, like other secretory processes, is largely dependent upon the amount of blood supplied to the organ ; hence drugs which produce vaso-motor paralysis of the skin, will tend to produce an increased secretion of sweat, and conversely, a diminished blood supply to the sweat glands will reduce their secretions. The comparatively recent experiments, however, of Goltz, Luchsinger, Nau- roci, Vulpian, and others, show that there are special nervous mechanisms governing the secretion of sweat as complete as had been previously discovered in the case of the salivary glands. When the peripheral end of a divided sciatic nerve in a dog or cat is stimulated with an interrupted current, a profuse sweat is poured out on the ball of the foot. While this secretion, as in the case of the saliva which follows stimulation of the chorda tym- pani, is to a certain extent governed by the vaso-motor paralysis thereby produced, it is not entirely dependent upon it, as the same results will follow after clamping the aorta, or even in an amputated limb ; while the analogy with the salivary secretion is made still more complete by the fact that atropia will paralyze the secre- tory fibres of the sciatic, leaving the vaso-motor fibres intact. Then, again, it has been found that there exist special centres in the spinal cord through whose stimu- lation a reflex secretion of sweat can be produced. Thus, if the central end of a divided sciatic is stimulated, all the limbs, with the exception of the one in which the nerve has been divided, will perspire ; or, if after division of one sciatic the animal is exposed to a high tempera- ture, the sweat will appear in all portions of the body with the exception of the paralyzed limb. The sweat 14 158 GENERAL ACTION OF POISONS. centres are also excited by carbonic acid in the blood ; therefore, drugs which cause dyspnoea will tend to in- crease the secretion of sweat. Drugs may increase the secretion of sweat either by peripheral stimulation of the secretory nerves, or by direct action on the nerve centres ; as yet, we are unable to speak of action on the centripetal nerves. If a poison, when injected into the circulation, produces sweating in all the limbs of an animal in whom one sciatic nerve has been divided, it may be assumed that the action is a peripheral one ; if, however, the foot on the side in which the sciatic was cut remains dry, it will be probable that the drug directly stimulates the sweat centres. The antagonism of drugs may also be treated ; thus, atropia will check the secretion started up by pilocar- pine.] 5. Lachrymal Glands. — Increased secretion of tears, apart from any direct irritant action on the conjunctiva or nasal mucous membrane (reflex irritation), is to be expected from those poisons which paralyze the vaso-motor nerves, and can be established by direct inspection. [We are not yet familiar enough with the nervous mechanism governing this secretion to attempt to explain the 7nodus operandi of drugs.] 6. Lacteal Glands. — Very little is known as to the in- fluence of drugs in increasing or diminishing the secretion of milk, while it is well known that many poisons are excreted in the milk, and, therefore, give their toxic properties to this secretion. b. Non Secretory Glands. — To this group belong the spleen, and, with the exclusion of its bile-making fuction, also the liver. As regards toxic action on the other glands of this group, that is, the supra-renal cap- sules, thymus and thyroid, nothing is known ; while as re- gards the lymphatic glands, the most that can be said is that when situated in the neighborhood of tissues in a state of inflammation from the action of drugs, they also will become inflamed. ALTERATIONS IN TISSUE METABOLISM. 159 The manifold, but still obscure, connections of the liver with the processes of nutrition would indicate its probably frequent implication in the causation of the dis- orders produced by poisons, but still all such disturbances, as for example, fatty degeneration, with the single excep- tion of those exhibited in the character of the biliary secretion, are only to be detected after death. Studies as to the possible effects of the drug on the glycogen, or possibly the sugar, of the liver, should be made immediately after death. The liver must be thrown instantly after death, after chopping up rapidly into a few pieces, into a large quantity of boiling water, pre- pared beforehand, and it can then, while in the water, be either chopped into fine pieces or rubbed up into a pulp; it is then to be faintly acidulated and filtered, and the filtrate precipitated with iodide of mercury and potassium solution and hydrochloric acid,* and after removal of the precipitate, the glycogen precipitated with alcohol. The sugar can also be determined in the first filtrate by Tromraer's test. [Changes in the circulation of the spleen may be studied by Roy's method. (See Kidney.) The method described for determining the character of the circulation in the case of the excised kidney is also applicable to the liver.] Section V.— Alterations in Tissue Metabolism. All poisons which disturb the normal digestive pro cesses, produce, when the condition of poisoning is long continued, changes in nutrition analogous to those occur- ring in prolonged fasting or with insufficient food ; that is, loss of weight, absorption of adipose tissue, paleness of the skin and mucous membranes, loss of strength, and in severe cases, death ; in growing organisms, growth 1 Briicke, Weiner Acad. Sitzgsber. Math. Natiirw. CI. 2. Abth. Ixiii. 1871, Feb. 3. 1(J0 GENERAL ACTION OF POISONS. ceases ; the generative function is suspended, and in the pregnant condition abortion may occur. Similar results in the nutritive functions may also be caused in cases of chronic poisoning without any clear disturbance of diges- tion being detectable. In addition to these general disturbances, single nutri- tive functions may be interfered with as a consequence of the action of poisons ; from the uncertainty sur- rounding our knowledge of the pliysiology of nutrition, many of these cannot be explained, and we will here only allude to the best known. 1. Energy of the Animal Oxidizing Processes. — The energy of the oxidizing processes occurring in the ani- mal economy is estimated either by measuring the quantity of oxygen consumed or of the two principal products of oxidation, carbonic acid and urea. For the estimation of these gases the methods have already been given, while urea may be estimated by Liebig's method of titra- tion ; on account of unavoidable errors, however, con- nected with this method, it is better to estimate the total quantity of nitrogen in the urine and feces. ^ An increase of oxidation processes, as occurs in fever, may, also, very probably, occur in toxic fevers. On the other hand, certain substances, such as arsenic, can diminish the excretion of the products of oxidation ; for none of these can any clear explanation be given. As general effects of toxic changes in these processes of oxidation we may have, when increased, elevation of temperature, rapid emaciation, and loss of strength ; when decreased, reduction of temperature, deposit of fat and excretion of sugar in the urine. The increase of temperature in the cases of toxic fever may, as in ordi- nary fever, depend upon other causes than increased oxi- dation. On the other hand, the deposit of fat and the excretion of sugar is not constantly associated with di- minished oxidation, but may depend upon other causes. * Segen, Zeit. f. Analyt. Cheinie, 1864, p. 155. ALTERATIONS IN TISSUE METABOLISM. 161 2. Deposit of Fat in the Body. — Chronic poisoning with many substances causes an increase in the normal amounts of adipose tissue in the body (in the subcutane- ous tissue, peritoneum and pericardium), and, in addi- tion, fatty degeneration of various organs, especially the muscles and certain glands, such as the liver and kidneys; the latter can also undergo acute fatty degeneration from the action of certain poisons when continued only for a few days, or even according to some authors, for a few hours. Deposit of fat, with the exception of increased panniculus adiposus, can only be recognized after death. The cause of such changes is entirely unknown, and probably varies in different cases ; diminution of the general oxidation processes and inflammatory irritation of the fatty parenchyma have been advanced as possible grounds, but no sufficient proof of their causative action has been given. General muscular weakness will follow fatty degeneration of the muscles, and when occurring in the heart the pulse will be weakened and life endangered not only in this way, but also by the possibility of rup- ture of the heart. 3. Diabetes. — A number of poisons cause the excre- tion of sugar in the urine, a condition which can be easily recognized by Troramer's test. Either an increased sugar formation in the liver, or a decreased consumption of sugar in the system will cause diabetes. As the latter state of affairs implies diminished oxidation, the presence of diabetes is a symptom of this derangement of the general nutritive functions, and may be caused by any poison which interferes with respiration, or even, though in both cases inconstantly, by mechanical ob- struction to respiration.^ One of the most remarkable forms of toxic diabetes, that which occurs in curare poisoning, cannot be explained in either of these ways, since curare does not cause an increase either of gly- cogen or sugar in the liver, nor can any reason be given why artificial respiration, or muscular contractions pro- 1 See literature of this subject in Arch. f. Path. Anat., xlii. 1. 14* 162 GENERAL ACTION OF POISONS. duced by direct stimulation should in curare poisoning interfere with the destruction of sugar. ^ From the physiological point of view, the results, of Pavy, Tscher- inoff, Dock, and others have necessitated a modification of the usual explanation of diabetes, so as to render the view probable in toxic diabetes, that there is either some change produced in the functions of the liver, whereby the change of sugar into glycogen is prevented, or by which the glycogen in the liver and also in the muscles is turned into sugar. It is, moreover, conceivable that toxic diabetes may be due to some process without any physiological analogue, whereby sugar is formed from some other sources than those recognized as physiolo- gical. For example, such a result might exist as a special action on certain tissues, either directly produced or indirectly through circulatory or respiratory changes. Indeed, it is not improbable that poisons which cause vascular paralysis may produce diabetes by modifying the blood supply of the liver. When, therefore, it has been established that a certain drug causes diabetes, the animal must be allowed to fast for several days, so as to free the liver from its store of glycogen, and the poison then given ; if in such a case diabetes still is found, it may be concluded that it was not entirely due to the modifications of the glycogen of the liver. Then it must, also, in all cases, be established whether the poison paralyzes the vascular system. A thorough study with prospect of positive results will in many cases be impossible.. Section VI. — Alterations in the Reproductive Functions. The general sexual functions, the secretion of sper- matozoa in the male, and ovulation and menstruation in the female, are so intimately connected with the general J Winqgradoff, Arch. f. Path. Anat., xxvii. 533. ALTERATIONS IN REPRODUCTIVE FUNCTIONS. 163 nutritive condition of the system, that no profound or long-continued departures from normal nutritive activity can be caused without being reflected on the generative functions. In addition to this, many drugs act directly on the sexual apparatus, either increasing or depressing its activity. As yet experimental pharmacology has only dealt with the action of drugs on uterine contractions. Poisons which cause contraction of the uterus may, during pregnancy, induce abortion, and during labor ac- celerate delivery. Abortion, following the administra- tion of a drug, cannot invariably be referred to the direct toxic induction of uterine contractions, since the nutritive changes alluded to above may also induce abor- tion " from weakness," or abortion may result from the death of the foetus through absorption of the poison from the maternal system. In the case of every poison which induces uterine contractions (a condition which can be best studied by opening the abdomen in young non-pregnant rabbits, in which the uterus is normally motionless), it must be determined whether the poison acts directly or reflexly on the motor apparatus, and in the former case, whether the uterine muscles, nerves, or centres are stimulated ; and as the uterus contains several centres, with which one the action is concerned : and, finally, whether the uterine centres are directly stimulated by the poison or reflexly through increased venosity of the blood. An analogous series of inquiries will arise in the case of drugs paralyzing the uterus, a condition which offers even less hope of thorough elucidation than in the case of uterine stimulants. [It is generally admitted that toxic uterine contrac- tions are, in the majority of cases, due to contractions of the arterioles, either supplying the uterus or the brain ; hence the uterine and cerebral and spinal nervous mecha- nisms are only indirectly stimulated by the drugs, the effects being primarily due to changes in blood-supply. When contractions fail after section of the cord after the xidministration of a poison which otherwise is capable of 164 GENERAL ACTION OF POISONS. inducing uterine contraction, it may be assumed that they were produced by circulatory changes in the brain.] The action of drugs on the development of the egg has not been studied, though it is known that poisons, in the case of birds, may pass into the ovum while still within the ovary ; or into the developing egg or embryo, by means of the placenta, while within the cavity of the uterus. Section VII. — Alterations in Temperature. The alterations of body temperature, frequently pro- duced by poisons, may depend upon either a modification of heat-production or of heat-loss ; in both cases the normal regulating processes must be interfered with. Increased loss of heat may occur when the cutaneous bloodvessels are paralyzed, or diminished loss of heat when contracted ; in nearly all other cases it will be found that the heat-producing functions are at fault. The muscles are the organs mainly concerned in heat- production ; so when a poison causes convulsions the temperature will usually be raised by increased heat- production, and muscular paralysis will lead to lessened heat-production, with the appropriate changes in the body temperature ; unless the losses of heat also suffer some disturbance which can nullify these results, and maintain a normal standard. [For methods of making calorimetric studies, see San- derson's Hand Book to the Physiological Laboratory, or Prof. H. C. Wood's Memoir on Fever.] Section VIII. — Action on the Muscles. Paralysis and abnormal muscular contractions are often produced by the action of poisons ; whether these depend upon direct action on the muscle, or through the medium of the nervous system, can readily be determined ACTION ON THE MUSCLES. 165 by simple experiments. In paralysis it is only neces- sary to stimulate the muscles directly, and if contraction occurs, the trouble is proved to be in the nervous sys- tem ; in convulsions a positive result may be obtained by section of the nerve of any selected group of muscles ; for if the convulsions persist, they must be due to some cause acting either directly on the muscular fibres or on the intra-muscular nerve endings. In order to discrimi- nate between these two possibilities, the animal must be poisoned with curare, w^hich paralyzes the intra-muscu lar nerve fibres (of course in such cases in warm-blooded animals artificial respiration must be maintained), before the administration of the drug under study ; if, under such circumstances, the convulsions do not appear, it may be confidently concluded that the intra-muscular nerve fibres were the seat of the stimulation, while their appearance would indicate action on the muscular fibre. Indeed, as will be shown presently, it can often be de- termined from the general character of the convulsions whether they are of central or peripheral origin, and in cold-blooded animals the methods of exclusion mentioned on page 32 may be employed. In warm-blooded ani- mals, a poison which produces its results through direct action on the muscles or peripheral nervous system, whether stimulant or depressing, will first produce its characteristic action after hypodermic- injection in the parts with which the poison comes in contact, so showing its peripheral mode of action. More extended experi- ments as to the changes in irritability of muscles, as well as alterations in energy and time of contraction, are best made on the excised frog's muscle, in the manner de- scribed on page 31. In many cases poisons will cause alterations in the normal positions of the limbs, from paralysis or spasm of individual muscles. Under this heading may also be considered the action of drugs on the pupil. 1. Action on the Pupil. — [The size of the pupil de- pends upon the degree of contraction of the two antago- 166 GENERAL ACTION OF POISONS. nistic muscular S3^stems of the iris, the circular constric- tor fibres, supplied by the oculo-motor nerve, and the radiating dilator fibres, supplied by nerv^es derived from the sympathetic system. Both sets of nerves are nor- mally in a state of constant excitation, since if the oculo- motor is divided or paralyzed the pupil dilates, and if the sympathetic is divided in the neck, or its terminal fibres paralyzed, the pupil contracts. In addition to changes in the size of the pupil dependent upon direct irritation or paralysis of these nerves, the pupil may be contracted, (1) reflexly through the oculo-motor nerve by stimuli applied to the optic nerve, which thus acts as the affer- ent nerve; (2) when the eye is accommodated for near vision ; (3) when the eyeballs are rotated inwards. The pupils are dilated, (1) during dyspnoea through irritation of the cilio-spinal centre, the irritation being transmitted through the sympathetic nerve to the dilator fibres of the iris ; this dilatation ceases when the dyspnoea passes into asphyxia, and does not occur after division of the cervi- cal sympathetics ; its production in this manner by drugs can be therefore readily excluded ; (2) during powerful irritation of sensory nerves ; and (8) during violent muscular movements. In addition, still, to these central mechanisms, there appears to be present in the eye itself some apparatus by which dilatation or contraction may be produced : for when the third nerve is divided, and the pupil dilated under the full influence of the sympathetic nerve, the instillation of atropia still further dilates the pupil ; and when physostigmine, under the same circumstances, is in- troduced into the eye or system, the pupil is contracted. It is probable, therefore, that the dilator and constrictor nerves of the iris produce changes in the size of the pupil by the transmission of stimuli to some local appar- atus seated in the eye itself. To determine the character of the action of drugs on the pupil, the effects of both local application and venous in- jection should be studied : the positive decision, however, as to the precise means by which the toxic mydriasis or ACTION ON THE MUSCLES. 167 myosis, as the case may be, is produced, is a matter of the greatest difficulty, the modus operandi oi Qvan such well- known drugs as atropia and eserine being still a matter of controversy. At the outset, reflex causes of change in the pupil, such as are produced by dyspnoea, etc., must be excluded. The question will then arise as to whether dilatation is due to paralysis of the oculo-mo- tor or excitation of the sympathetic, or both, or whether the action is purely local on the eye. Constriction of the pupil will of course be due to the opposite condi- tions. Let us first assume that we are dealino; with a druo; which produces dilatation of the pupil ; the first point then to determine is whether the sphincter muscle of the iris still preserves its capability of contraction. This may be determined by the method employed by Bern- stein and Dogiel ;^ four wires are connected with the poles of the secondary coil of an induction apparatus and their free ends (arranged in the form of a square, simi- lar poles occupying diagonal corners) placed on the inner edge of the iris. By this means the circular fibres of the iris will be stimulated, and if they retain their normal functions, the pupil will contract. If no change occurs in the size of the pupil w^hen this experiment is properly performed, it may be assumed that the drug produces dilatation of the pupil by paralysis of the sphinc- ter muscle, and no other experiments need'be made ; in the great majority of cases, however, the pupil will still contract, and it is then necessary to determine whether the dilatation is due to paralysis of the oculo-motor nerve, or spasm of the dilator muscle. In order to test the irritability of the oculomotor nerve, it is necessary to open the cranial cavity and re- move the cerebral hemispheres. To make this experiment, the drug is first instilled into the conjunctival sac in a dog or rabbit, and the change 1 Verhandl. d. nat. Med. Vereins zu Heidelberg, iv. 28, Her- mann. 168 GENERAL ACTION OF POISONS. in size of the pupil noted in millimeters. Tracheotomy is then performed, artificial respiration maintained, and both carotids ligated in the neck ; the next step is to remove the vault of the cranium with bone forceps and to elevate the cerebral lobes with a spatula ; after divi- sion of the olfactory and optic nerves, the oculo-motor nerves may be found on the sella turcica. The caver- nous sinus must be carefully avoided : bleeding from the posterior cerebral arteries may be Controlled by slight pressure with a moist sponge. The oculo-motor nerve on the side of the eye in which the poison was instilled, is then to be divided as near the brain as possi- ble and the peripheral end placed on the electrodes of an induction coil and stimulated ; if no contraction ot the pupil is produced thereby, it may be concluded that the terminal fibres of the nerve supplying the constrictor muscle of the iris are paralyzed. (For convenience of measurement of the size of the pupil, it is advisable to slit up the external commissure and draw down the lower eyelid by a weighted thread passed through it and the nictitating membrane.) Should the pupil contract on stimulation, it remains then to be seen whether the dilatation is due to stimu- lant action on the dilator apparatus ; and even when stimulation fails to narrow the pupil, it is well to see whether there is an associated spasm of the radiating fibres of the iris. This may be determined, as suggested by Bernstein and Dogiel, by placing the two electrodes of the induction apparatus on the side of the cornea ; if the pupil dilates still further, the integrity of the radiat- ing muscles is proved, while the functional condition of their nerve supply is tested by stimulation of the cer- vical sympathetic. The above experiments would serve to give a some- what decisive answer to the question as to the modus operandi of mydriatics were it not known that many drugs, such as atropia, are capable of producing dilata- tion of the pupil in the excised eye of the frog, where of course, there can be no question as to paralysis of the ACTION ON THE NERVOUS SYSTEM. 169 opulo-motor nerve endings which have been already sepa- rated from their nerve centre ; and even after division of the oculo-motor nerve (for methods see Cyon 31ethodik, p. 510, or Bernard, PJiysiologie Exp. de la Sy§. Nerv.) atropia is capable of still further dilating the pupil. In view of such facts it is necessary to assume the existence of peripheral ganglia in the iris itself, where indeed nerve-cells have been found in abundance. In the case of drugs which produce contraction of the pupil (myosis), the probability will lie in favor of a spasm of the sphincter muscle when there is also found by the ophthalmoscope to be spasm of the muscles of accommodation. Additional evidence will be added to this view when the drug produces a higher degree of contraction than follows section of the sympathetic, when atropia is capable of overcoming the myosis produced by the drug, and when irritation of the sympathetic, in an eye so treated, is capable of still further dilating the pupil.] Section IX.— Action on the Nervous System. In previous chapters reference has already been made to several derangements of the nervous system produced by the action of poisons, but it still seems advisable to again group them under their appropriate heading. A. Action on the Organs of Conduction. — Toxic action on the nerve trunks occurs much more seldom than on the nerve terminations. This may probably be due to the limited supply of blood which these portions of the nervous system normally receive, since they are equally sensitive to direct action with solutions of the poison (see p. 50). In the case of many poisons which act primarily on the nerve-endings, particularly in vascular organs such 15 170 GENERAL ACTION OF POISONS. as the muscles, the functional disturbance gradually spreads up the trunk of the nerve. The functional disturbances produced in the organs of conduction by the action of poisons, may be of two kinds : first, modifications in the normal nervous stimuli ; second, in abnormal stimuli. The first of these condi- tions may be manifested in diminution or abolition of irritability (loss of the power of conducting impressions), or in exaltation of irritability or in abnormal persistence of excitation. Loss of the power of conduction in nerve trunks is disclosed ^y the absence of the usual result of stimulation, as, for example, the non-appearance of vascular contraction after normal, central, or artificial stimulation of a motor nerve, and in the case of sensory nerves, in abolition of sensibility in the surfaces on which these nerves are distributed. [It should be noted that while but few drugs com- pletely destroy the power in nerves of conducting im- pressions, many poisons will depress the irritability of nerves below normal. When, therefore, it is found that after death both the muscles and nerves are capable of responding to stimulation, it should then be tested whether there has been any alteration in the degree of irritability. To accomplish this, the vessel in one hind leg of a frog is ligated, and the poison injected under the skin of the back. When the eftects of the poison are clearly marked, the sciatics are laid bare, and the strength of current which is necessary to produce con- traction determined for each limb : the irritability of the poisoned and non-poisoned sciatics can be thus com- pared.] Increase (accumulation) of the irritant action during its conduction along the nerve, has never been observed as a result of toxic action ; but, on the other hand, ab- normal persistence of stimulation, such as the production of tetanus or prolonged muscular contraction, as a result of a single stimulus, has been described in numer- ous instances. Abnormal irritations evoke convulsive muscular contractions where the motor nerves are con- ACTION ON THE NERVOUS SYSTEM. 171 cerned, and painful or abnormal sensations, or subjec- tive sensations for the nerves of special sense, when the stimulus affects a sensory nerve. The first point to be determined in the study of toxic effects of the above nature (convulsions, paralysis, etc.), is whether they are due to alterations in the organs of conduction. In the case of paralysis, this is readily determined by separate stimulation of nerve and muscle. If the latter (direct stimulation) produces a muscular contraction, while indirect stimulation does not, it may be concluded that there is some interruption in the con- ductivity of the nerve, and if the stimulus remains in- effective, even when applied to the nerve immediately before its entrance into the muscles, it would indicate that the loss of function lies in the intra-muscular portions. To decide in such a case whether the remainder of the nerve is implicated, the muscle may be excluded from the poisoned circulation in the manner described on page 32, or galvanic stimuli employed. If convulsions are produced, their nature will give some general idea as to their origin. Convulsions of central origin throw the entire muscle, and usually entire groups of muscles, into co-ordinated contractions ; on the other hand, convulsions originating in the nerves, or in their intra-muscular endings, usually implicate different muscular fibres at different times, and with different degrees of vigor, pro- ducing the so-called "fibrillar contractions." [Even fibrillar contractions, however, may be of cen- tral origin, since Von Anrep has found that after injec- tions of nicotine they occur in limbs protected from local action of the poison by ligation of, their blood- vessels.] Above all, however, it should be remarked that such contractions persist after separation of the nerves from the central organs, a procedure which will interrupt or prevent the appearance of convulsions of central origin. Finally, convulsions due to action on the organs of con- duction do not appear in limbs which have been protected from access of the poison by ligation of their blood- liZ GENERAL ACTION OF POISONS. vessels, while convulsions of central ori,2;in affect equally all members, whether connected with the circulation or not, provided only that the nerves remain intact. . [Con- vulsions of cerebral origin disappear after removal of the medulla, while convulsions of spinal origin persist.] B. Action on the Peripheral Nerve Endings. — Sufficient has already been said on page 50, as to the action of poisons on the peripheral terminal fibres of motor nerves ; at present we are only concerned with the peripheral endings of centripetal nerves. These organs are liable to toxic action whenever a poison, either by direct contact or by means of the circulation, is brought to the organs in which they are situated. The toxic influence may be manifested either by excita- tion or paralysis, or occasionally the latter condition may, as a result of the same drug, follow a condition of increased irritability. The consequences of stimulation of the sensory nerves may be evidenced either by various abnormal sensations (subjective sensations for the nerves of special sense), or in modification of reflexes, such as secretion of tears, saliva, or in vomiting. Paralysis of these organs is followed by insensibility and loss of reflexes. Such disturbances of function can be readily localized in either the central or peripheral nervous system. Symptoms of irritation which disappear on section of the nerve as near the periphery as possible, and symptoms of paralysis which are not evident when the stimulus is applied directly to the nerve-trunk, must be due to the action of the poison on the peripheral nervous apparatus. But, unfortunately, the only animals on which such de- cisive experiments can be made are the very animals which are most unsuitable for the study of the points in question ; therefore we are practically restricted, as far as accurate results are concerned, to such evidence of the state of the conductive sensory function as is found in the character of the reflexes, and in these experiments it is almost impossible to distinguish between results due ACTION ON THE NERVOUS SYSTEM. 17B to action on the peripheral, conducting, or central sen- sory organs. The same class of experiments may be made as has been given for the study of the action of poisons on the motor nerves. When the action is localized to the point of application of the poison, or can be excluded from a limb by ligation of its bloodvessels, or when it appears more markedly and rapidly in an organ in whose arteries it has been injected, it indicates that the principal action is on the peripheral organs. If one possessed a means of paralyzing the peripheral endings of centripetal nerves, as curare paralyzes the centrifugal, all phenomena depending on irritation of these structures must be absent after the administration of such a poison, and the symptoms which appear before its administration, and fail to appear after it, must be due to stimulant action of the peripheral sensory apparatus ; unfortu- nately, no such drug has yet been discovered. [Various methods have been proposed for investi- gating the condition of the centripetal nerves ; all are, however, open to objection. Probably the best method is to ligate the bloodvessels in one limb of a frog, and then inject the poison into the dorsal lymph-sac ; after the effects of the poison have been developed, compari- sons can be made between the irritability of the central ends of the sciatic nerves ; that is, whether a stronger irritant is required on the poisoned than on the unpoison- ous side to produce reflex movements. The success of this experiment will depend upon the integrity of the motor nerves, for, if they are paralyzed, of course no reflexes can be produced. In such cases one hind limb of a frog may be partially amputated, leaving only the sciatic nerve intact, and the poison then injected into the amputated limb, and the capability of transmitting impressions tested by comparing the reflexes produced by stimulation of the skin of each hind foot. Von Bezold proposed a method of testing the irrita- bility of sensory nerves, in which the reflex contractions of a frog, feebly under the influence of strychnia, served ]5* 174 GENERAL ACTION OF POISONS. as an index of sensory excitation. This method, as modified by Pflliger, consists in the following : the blood- vessels are tied in the lower extremities of a frog, and these limbs then so severed from the body that their only connections are the sciatic nerves. These nerves are then kept constantly moistened, one with a solution of phosphate of sodium, and the other with a solution of the drug, both solutions being of the same degree of concen- tration. Then by irritating the central end of each sci- atic on the distal side of the solution, a general idea can be obtained as to the action of the drug on the sensory nerves. The objection to this method is the difficulty in comparing the osmotic equivalents, under such circum- stances, of diiferent drugs. In the case of drugs which have been proven to be inactive on the motor nerves, the first method is the best, even when the drug is known to mcjdify the functions of the spinal cord.] Another question, which also is difficult to answer positively, is whether the results above alluded to are due to specific action on the nervous apparatus, or to some action on the tissues in which they are located, as it is well known that every strong mechanical or chemi- cal lesion of a tissue acts as an irritant to the nerve- fibres of that organ. It is only possible, however, to express an opinion as to this point when the organ is the seat of gross anatomical changes ; w4ien these are not to be detected, we must conclude that the drug exerts a specific action on the nerve endings. But even should anatomical lesions be found, the possibility of a specific action on the nervous organ is by no means excluded ; for these changes, depending upon disturbances of circula- tion, leading to hypersemia and inflammation, may them- selves be the palpable reflex result of action on the nervous system. A specific action on the nervous system may be assumed when sensory or reflex phenomena (pain,, vomiting, sneezing) appear without any evident change, or with only tardy alteration in the tissue on which the drug is acting. A specific action can be fur- ther inferred when a drug produces different results ACTION ON THE NERVOUS SYSTEM. 175 when applied to different tissues of the same general functions, but with different nerve-supplj. C. Action on the Central Nervous System. — Action under the most manifold forms on the nerve centres is one of the most frequently observed effects of poisons. As the action on the nerve centres of the heart and intestine has been already studied, the present chapter will be confined to the consideration of toxic action on the brain and spinal cord. The separation of the action of poisons on the central system from that on other organs is usually easily attained. In a large group of these phenomena, the sensory, no doubt, can arise; and further, irregularity in a rhythmical motion can only depend upon action on a nerve centre, though alterations in the frequency of rhythm can be caused by action oh the centripetal regulating nerves, a possibility which is readily ex- cluded by section of those nerves. But in many other cases, the toxic phenomena are so manifestly of cen- tral nervous origin that no such control experiment is necessary. Co-ordinated contractions, such as the move- ments of deglutition; paralyses of muscular groups wh6se movements are governed by a special nerve centre, such as the muscles of respiration; painful sensations or anaes- thesia of the entire skin, or of surfaces in no direct com- munication with the point of absorption of the poison, are all, with great probability, to be referred to specific ac- tion on the nerve centres. Still, some limitation of this statement should be made for the group of motor pheno- mena, since many of the co-ordinated muscular move- ments, such as deglutition and vomiting, can also be pro- duced by toxic stimulation of certain peripheral organs. The cause of phenomena resulting from exaltation of function, such as convulsions or sensory phenomena re- sulting from toxic action, can be localized in the central apparatus by section of the nerves going to the affected organs, when of course the disappearance of the symp- toms would prove their central origin. In certain co- 176 GENERAL ACTION OF POISONS. ordinated movements, the possible peripheral origin may be excluded by section of the appropriate nerves. Motor and sensory paralyses, whose general character fails to give any indication as to their origin, must be regarded as central when the peripheral origin has been excluded by the means mentioned in the preceding chapter. In all toxic phenomena whose central origin has been established by these methods, the question arises as to w^hether they are due to direct specific action on the cen- tre, or to indirect action through changes in the, blood, or to local disturbances of circulation in the nerve centres by action of the drug on the heart or vessels; since any one of these departures from the normal relations will exert a profound influence on the nerve centres. Such points may be readily investigated in the frog; for if the same class of symptoms appear in the frog as in the warm-blooded animals they can be safely attributed to specific action on the nerve centres, since we have found that the func- tions of the nervous system are in cold-blooded animals independent of the state of the circulation. Should, however, the symptoms of poisoning vary in the two classes of animals, it cannot be concluded Avith the same degree of confidence, though the conclusion will be cor- rect in many cases, that in the higher animals they are due to indirect action on the nervous system, since the results may be attributable to different modes of action on the different species. The supposition as to indirect action will be greatly confirmed when it is known that the drug in question produces alteration in the function of the heart, respiratory apparatus or blood, it only being necessary to determine which group of phenomena first appears. In certain cases control experiments may be made in preventing, or compensating for the respiratory or circulatory action of the poison; for example, changes in the respiratory gases of the blood may be prevented by artificial respiration ; contraction of the bloodvessels, by large doses of curare. If, after experiments of this nature, the same symptoms do not result, it may be ACTION ON THE NERVOUS SYSTEM. 177 positively concluded that they are due to an indirect nervous action only. 1. Interference with the Automatic Func- tions. — The automatic functions of the medulla oblon- gata, especially the innervation of the respiratory move- ments, the regulation of the heart, vaso-motor tonus and pupil mechanism, are extremely often disturbed by the action of poisons. Many poisons act on all these func- tions simultaneously, therefore associating them in some- what the same functional analogy in so far as they are all brought into a condition of excitation by the venosity of the blood in dyspnoea. Poisons may either exagger- ate or annul these functions, or modify the frequency of the rhythmical movements under their control. Very often two stages occur in poisoning by one drug, first an in- creased vigor of function and acceleration of rhythm, then enfeeblement and retardation. The characters and methods of studying these changes have been already given. With these alterations of functions are intimately as- sociated the motor phenomena of irritation produced directly by the action of the poison, since in the present status of physiology, the so-called automatic central stimulations are regarded as conditions in which an irri- tant acts directly on the nerve centre, and not the con- duction of an irritant through the centripetal nervous system. As examples of this form of toxic stimulation may be mentioned vomiting, when not produced by toxic action on the peripheral nerve endings, intestinal and uterine contractions from action on the brain and cord, and general convulsions from action on the so-called '^ convulsive" centre in the medulla ; certain of these conditions may be produced by a high degree of veno- sity of the blood, a fact which should be remembered in forming an opinion as to the cause of the phenomena. 2. Reflex and Co-ordinated Functions. — In the normal state, the centripetal impressions produce orderly reflexes, which are capable of being controlled or pre- vented by automatic inhibitory centres in the brain or 178 GENERAL ACTION OF POISONS. by the will. Poisons can modify these phenomena in the following different ways : a. The limitation of the re- flexes to certain single normally associated motor appa- ratus can be so suspended that every centripetal impres- sion throws the entire mass of centrifugal fibres into ex- citement, thus producing general convulsions ; these re- flex convulsions are ordinarily tetanic in character, and each part of the body assumes the condition which must follow from the simultaneous contraction of all the mus- cles associated with it. Hence, in such states the back is hollowed (opisthotonos), the head extended, the jaws tightly closed (trismus), and the limbs extended. In weaker degrees of such action, as well as in initial stages of violent action, the reflexes are only abnormally increased in strength and in the number of associated muscles, so that the character of co-ordinated movements is lost. These convulsions differ from those described in the preceding chapter, in that they can only be inaugu- rated by centripetal impressions, for which, however, the lightest toucher jar will often suffice. The removal of all forms of external stimuli can only be accomplished, with any degree of certainty, in the case of frogs, by placing them under a bell-jar on some immovable support. h. On the other hand, poisons can weaken or entirely prevent the production of reflexes, when the animals lie absolutely insensible to all forms of stimulation : ordi- narily this condition follows the state of attairs described under a. c. The reflex inhibitory apparatus can be brought into either a condition of increased or diminished functional activity. This will be considered directly. [In order to study the action of drugs on the reflex functions, the method of Tiirck is probably the best : its principle consists in comparative measurements of the time required before and after poisoning for a given stimulus applied to the skin to evoke a reflex muscular contraction in a frog from whom the cerebral hemi- spheres have been removed. ACTION ON THE NERVOUS SYSTEM. 179 In order to determine the state of the reflex functions of the spinal cord, the brain and medulla are separated from the cord by an incision made through the occipito-atlantal membrane : this locality may be readily recognized by the touch as a depression lying in the median line of the back on a line drawn across the skull at a tangent to the posterior borders of the membrana tympani. To divide the cord, the frog is held in the left hand, and the head strongly flexed on the neck by the left thumb ; an inci- sion, a few millimetres in length, is then made with a sharp-pointed knife through the skin and membrane, care being taken not to extend it too far to the sides, when, on removing the blood with a sponge, the medulla will come into view, if the head is kept well flexed, and may be divided. This method is preferable to one thrust of the knife, or to the division of the cord with the scissors, when it can never be known whether the section is complete or not. The brain is then to be destroyed by breaking up the contents of the skull with a needle. The hemorrhage will usually soon cease : should it con- tinue, it may be checked by the insertion of a small plug of wood into the opening in the skull. After the oper- ation, the frog should be placed under a moist bell-jar for about an hour, until the shock of the operation has passed ofi". At first the limbs will all be extended, and probably no motion can be produced by irritation, but after a while the limbs will be drawn up and a more nearly normal attitude be regained, marking the returning tone of the spinal ganglia. When it is believed that the shock has entirely passed off, the frog can be suspended by a tack or hook passed through its nose to some suitable support, care being taken that no part of the frog's body comes in contact with any solid. Draughts of air must be avoided, and the skin must be prevented from drying by frequent im- mersions in a basin of water. A test liquid is then made by diluting with water 1 c. c. of sulphuric acid to a litre ; a few cubic centimetres of this acid are then placed in a small glass beaker, and the glass brought under the frog 180 GENERAL ACTION OF POISONS. and elevated until the tip of the longest toe just dips below the surface of the acid, and the length of time which is required before the frog withdraws his foot de- termined by counting the beats of a metronome. The instant the reflex movement occurs the entire foot must be washed in a large beaker of water to remove the ex- cess of acid and prevent corrosion of the skin of the foot. The time elapsing between the immersion and withdrawal of the foot is then to be written down, and after waiting five minutes, the experiment repeated, care being taken to immerse the same toe to precisely the same extent in each trial. These experiments are to be repeated until three successive trials give about the same numbers, when the drug can be injected and the time of reflex ac- tion compared with the normal standard. It is probable that most substances, which are at all irritating, will at first, from stimulation of the sensory nerves, reduce the spinal reflex irritability, or, in other words, lengthen the time of immersion. Every reflex action requires the functional activity of a sensory nerve, nerve centre, and motor nerve ; conse- quently, before the activity of the spinal ganglia can be studied, the sensory and motor nerves must be known to preserve their functions ; therefore, studies of the action of the drug on the peripheral nervous system and mus- cles, should precede the examination of the condition of the spinal cord. Should, however, for any reason, this not have been done, and it be found that after the admin- istration of the drug, reflex action gradually disappears, the condition of the motor nerves must be tested with a weak induction current ; if they preserve their irritabil- ity, it may be concluded that either the sensory nerves or spinal centres are paralyzed. The latter possibility may be excluded by first ligating the bloodvessels of the limb which it is proposed to stimulate, thus protecting the terminations of the sensory nerves from the poison ; if the reflex irritability is now depressed, it may safely be attributed to action on the nerve centres. The same method may be employed in studying reflex ACTION ON THE NERVOUS SYSTEM. 181 action in the case of drugs which are known to paralyze the sensory nerves ; while in the case of drugs which paralyze motor nerves or muscles, the limb opposite to the one stimulated may be protected by ligation. Having determined the action of the drug on the spinal cord, the question will now arise as to its action on the cerebral inhibitory centres of reflex movement. It has been discovered by Setschenow that the optic lobes in the frog contain centres, stimulation of which depresses the re- flex activity of the spinal cord, while their removal exalts it ; though no doubt can exist as to the accuracy of these facts, considerable controversy still exists as to their ex- planation, but until more conclusive proof is brought for- ward as to the falsity of Setschenow's theory, we will ac- cept with him the doctrine of special spinal inhibitory centres in the optic lobes, whose activity is capable of being stimulated or depressed by various agents. In order to study the action of drugs on these centres, all portions of the cerebrum, anterior to the optic lobes, must be removed by section with scissors through the skull, on a line with the anterior margins of the tympanic membranes. After observing the precautions mentioned above, the normal degree of reflex irritability is deter- mined and the drug administered; should the activity be depressed, the medulla is then divided on a line with the posterior margins of the tympanic membranes, and the reflex activity again tested. If it is then found that the reflex functions are greatly exalted, it may be concluded that the initial depression was due to stimulation of Setschenow's centres. Or, on the other hand, drugs may paralyze these inhibitory centres and so bring the reflex activity of the cord, even w^hen in connection with the medulla, up to the normal degree of the isolated cord. In the removal of the cerebrum, care must be taken to avoid hemorrhage, which is a stimulant to Setschenow's centre, as is also a decreased action of the heart. It has also been urged by W. T. Sedgwick,^ that the depression ' Journ. of PhvsioL, vol. iii. No. 1. 16 182 GENERAL ACTION OF POISONS. of reflex action following the administration of quinine is due to stimulation of the afferent fibres of the vagus nerve, an inhibitory effect on the spinal centres being produced in the same way as when any afferent nerve is stimulated.] In addition to these general disturbances of reflex action, poisons can also influence individual reflexes ; but since these reflex centres are, in all probability, identical Avith the co-ordinating centres, it cannot ordinarily, as in spasm of the muscles of deglutition, be determined whether the toxic action is exerted directly on the centres of co- ordination, or whether their reflex stimuli are only abnor- mally increased. The position is here much the same as in the case of general reflex convulsions (strychnia tetanus), where the question whether the spasms are evoked by external stimuli can only be settled on the frog, and not on the warm-blooded animals. 3. Action on the Sensory Functions. — As already stated, toxic disturbances of the sensory functions can be studied with any degree of certainty only on man. The class of drugs which can be thus examined is consequently extremely limited, adding still another difficulty to an already obscure subject. These toxic sensory phenomena consist of two consecu- tive stages: 1. The stage of excitation, with its conse- quent phenomena, a. The sensory perceptions no longer preserve their normal relation to the objective stimulant, but exist in relatively increased intensity, thus producing an increased sensibility ; errors in the estimation of the character of the stimuli may also be produced, and in marked toxic conditions sensory peceptions (subjective) may be produced without apparent cause. b. In slight degrees of this form of toxic action the flow of ideas is facilitated and the mental processes stimu- lated, though mental control is diminished ; in severe forms of intoxication the mental processes are entirely uncontrollable and disorderly, giving rise to the various forms of toxic mania and hallucinations. c. In slight degrees of poisoning the normal control ACTION ON THE NERVOUS SYSTEM. 183 of the voluntary movements is lost, the muscles, perhaps from disturbance of the muscular sense, contracting more or less powerfully than was intended, thereby pro- ducing various disturbances in locomotion or speech, while in severe forms of intoxication the power of performing normal movements is entirely lost, and complete paralysis or general or localized convulsions result. The cerebral stimuli of movement may also be disturbed and lead to various maniacal acts ; the highest forms of these sensory disturbances constitute delirium. 2, The stage of depression is characterized by phe- nomena opposed in every respect to those just mentioned; in moderate degrees of intoxication, sluggish senses, ob- tuse mental acts, and indisposition to move; in higher degrees, complete loss of consciousness (sleep), and de- pression of all the reflexes, with impossibility of being aroused (soper, coma, narcosis). In the case of many poisons these last-named phenomena may precede the above mentioned, or exist alone as special actions of the drug. Another sensory disturbance, less often produced by drugs than by other causes, is syncope ; it consists of loss of consciousness without the symptoms described above as constituting the initial stage of excitement. The only premonitory symptoms of syncope are found in disturbances of special senses (darkness before the eyes) and disturbance of muscular co-ordination (dizzi- ness, staggering), appearing before complete loss of con- sciousness is established. The toxic sensory disturbances may depend either upon direct action on the cerebrum or upon disturbances of respiration or circulation, both of which are, however* functions essentially under the control of the central nervous system. Disturbance of respiration may merely produce loss of consciousness, and that only in the stage of asphyxia through insufficient supply of oxygen ; while circulatory disorders may produce the most manifold sensory symptoms as soon as the blood-pressure in the cerebral vessels suflfers any considerable change ; thus 184 GENERAL ACTION OF POISONS. syncope may be caused by depression of the blood-pres- sure from diminished vigor of cardiac contraction. The effects of increased arterial pressure and of venous stag- nation are less clear ; both conditions, of which the first alone can be regarded as a direct toxic result (from pa- ralysis of the cerebral bloodvessels, increased force of the heart's action, or contraction of the peripheral vessels), are usually designated as congestion of the brain, and since post-mortem examinations in cases of poisoning accompa- nied by sensory phenomena often reveal positive changes, such as hyperaemia of the brain and its membranes, the anatomical conditions are supposed to be a cause of the symptoms. This hypersemic condition of the brain is often manifested during the action of the poison by con- gestion of the face, injection of the eyes and increased secretion of tears and saliva ; while in many cases even actual rupture of the vessels (cerebral apoplexy) may be produced. Though it is acknowledged, as is proved by the symp- toms occurring in cerebritis or meningitis, that hyperemia of the brain may cause symptoms similar to those de- scribed above, there is no means of proving absolutely, that, in the production of these symptoms by poisons, the same processes are concerned; accordingly, unless the contrary can be proved, it is not unwarrantable to as- cribe the sensory toxic effects of drugs to direct action on the cerebral centres. The proof of circulatory disturbance in the brain is only obtained with the greatest difficulty. The post- mortem appearances are apt to be deceptive, since it is conceivable that transient circulatory changes may exist without leaving any characteristic post-mortem appear- ances, and congestion etc. (except, of course, active in- flammation), may be produced during the death struggle. During life, observation of the retinal vessels with the ophthalmoscope will give a tolerably accurate idea as to the state of the cerebral circulation. Direct inspection in animals is rendered possible by trephining, a glass plate being inserted, after the method of Donders, in the EXPLANATION OF ANATOMICAL ALTERATIONS. 185 opening in the skull;* by this means, however, only the surface is exposed to inspection. As regards the general condition of the cerebral circulation, some idea may be obtained by manometric examination of the pressure within the skull, but this procedure, as far as is known, has never been applied to pharmacological studies.^ INVESTIGATION AND EXPLANATION OF THE ANATOMICAL ALTERATIONS PRODUCED BY POISONS. The anatomical changes produced by the action of poi- sons can be studied only in the most limited degree during life, as in inflammation at the point of absorption, when visible to the eye, or increase or decrease of fatty tissue, etc. Most anatomical changes can only be recognized after death, and it is, therefore, advisable, in order to obtain a complete picture of the morbid processes, to kill the animals experimented on in different stages of the poisoning. No general rules can be given for the investigation of these points, since they will depend upon the nature of the pathological process. An attempt, however, should in- variably be made to determine whetlier the changes are due to direct action on the tissue concerned, or whether they are secondary results from some functional distur- bance. In general, the latter state of affairs will be found to exist, except of course in cases in which the results are evidently attributable to inflammation of the absorbing surface. ' The procedure is described by Krause, in Anat. des Kaiiin- cheiis, p. 46. * Various methods of investigation of the cerebral circulation are given in the Medical Lancet, Oct. 1850, Moleschott's Untersuch., iii., Virchow's Archiv, xxxvii. 519, and Monographs by Jolly, Wurzburg, 1871, Althann, Dorpat, 1871, Pagenstecher, Heidelberg, 16* 186 GENERAL ACTION OF POISONS. A large number of poisons, among which are the nerve poisons -which probably produce some obscure chemical change in the nerve elements, leave no detecta- ble post-mortem trace of their action, thus proving that the most profound functional disturbance may exist without any palpable tissue change. In the examination of post-mortem appearances, ac- count must be taken of the changes which can be attri- buted to the act of dying, and it is not sufficient merely to separate the normal post-mortem processes of coagu- lation in blood and muscle and the changes of decompo- sition, from the effects due to the action of the drug. In most forms of death, a large number of changes, in no way characteristic of the special cause of death, are produced by the stoppage of circulation and respira- tion. Among these, the ordinary asphyxic appear- ances are the most usual, since nearly every form of death occurs under the symptoms of suffocation. It is further to be noted that the characteristic changes pro- duced by the poison, where such exist, may be modified or removed during the act of dying. Moreover, no re- liable conception can be obtained as to the state of the cerebral circulation, or the amount of fluid in the brain, from the post-mortem changes, since such conditions are sure to be disturbed in the death struggle, and the un- certainty will be the greater the longer the act of dying is prolonged. When, therefore, it is desired to examine into these points, the animal should be killed by punc- ture of the medulla, so as to prevent the signs of dys- pnoea or convulsions being confounded with those directly due to the poison. Alterations due directly to the action of the poison can, with any degree of certainty, be only detected at the point of absorption of the poison ; particularly when the poison is of a diffusive character, and so apt to pene- trate deeply into the tissues without following the vessels. Such chaniies are usually of a corrosive character ; that is, chemical destruction of the tissue elements, with its consequent inflammatory changes. EXPLANATION OF ANATOMICAL ALTERATIONS. 187 [Degenerative changes and changes in the histological elements at the point of application will also fall under the heading of local action. Thus Erdss found that in- jections of oil of mustard into muscles caused fatty de- generation and disappearance of their transverse striae.] These alterations must, from their very nature, be restricted to the points with which the poison comes in direct contact, since after absorption by the bloodvessels the poison either undergoes chemical change, or is so diluted as to be unable to produce its corrosive effects. The action of poisons administered by the alimentary canal may, of course, be spread over a very extended surface. Usually, however, the corrosive action of a poison is restricted to the point of application, and to the depth to which, in a concentrated form, it is capable of diffusing. When the absorbing surface has thin walls, as is the case in the stomach or intestines, the irritant action may extend through diffusion, by continuity of surface, to neighboring organs, such as the liver, spleen, or dia- phragm. If the action leads to perforation, the poison may gain access to the body cavities, and thus come in contact with greatly increased surfaces. In addition to this irritant action and its sequellae (such as hypersemia, catarrh, swelling, suppuration, in- filtration, degeneration, and scarring), but few specific toxic anatomical changes can be detected. When such ex- ist, they are generally to be found in the glands and mus- cles (fatty degeneration), and skin (exanthemata), and are only produced when the action of the poison has not been rapidly fatal. The connecting links between the di- rect action of the poison and these secondary results are hidden in the greatest obscurity. It can only be said that they are due to changes in nutrition without any explanation being possible. In many cases the locality of these changes appears to depend upon the course of the poison in the system ; thus kidney changes may be produced by drugs eliminated through the urine, so, perhaps, showing that they are due to direct anatomical action of the poison. 188 GENERAL ACTION OF POISONS, VI. INVESTIGATION OF CHEMICAL CHANGES PRODUCED BY POISONS. Of the chemical processes resulting from the adminis- tration of drugs (see page 80), only those will be here alluded to which may serve to add to our knowledge of the mode of action of the drug. Changes in the composition of the poison will not here come under consideration. These investigations, so far as they do not concern alteration of the secretions, can only be undertaken post mortem, and here, even more than in the study of anatomical alterations, great care must be taken in excluding the results of post-mortem changes ; consequently, the examinations should be made immedi- ately after death. Since the normal chemical constitu- ents of different organs are but imperfectly known, and the actions of poisons probably involve obscure chemical changes, but little can be here said ; especially as the constituents, of which our knowledge is at all com- plete, are either products of tissue change, already des- tined for elimination, or decomposition products of the unstable tissue elements, produced in post-mortem changes or in the chemical manipulations required in the analysis. In the case of nerve and muscle poisons it cannot be stated whether their action is due to chemical change or not. In the case of the direct action of poisons on the blood, as far as combinations with the gases of the blood are concerned, our information is more definite. The study of toxic disturbances of nutrition often pro- duced by poisons, with the exception of estimation of sugar and glycogen, when post-mortem changes should be prevented by boiling water, are probably better carried on indirectly through examination of the excretions, rather than in direct analysis of the different organs. The greatest number of investigations as to the post- mortem presence of poisons in the body have been un- dertaken for medico-legal purposes, a class of study which does not fall within the province of this work. APPENDIX 1. Doses, Immunities, Form, and Solvents of Pox SONS. — To obtain a complete idea as to the action of a poison, it must be administered in doses varying from the smallest active quantity to maximum doses ; that is, until a point has been reached when increase in the dose causes no increase in the character or intensity of the resulting symptoms. This is not only necessary on prac- tical grounds (since to be of therapeutic value, it must be known what quantities are fatal and what is the smallest amount that will produce any effect), but more especially because very often the effects of a poison will be found to vary with the quantity used. This graduation of dose must be established for each class of animal experimented on, since it will often be found4hat corresponding doses will produce different results in different classes of ani- mals. Many poisons are entirely inert on certain species, while very virulent on others ; but occasionally it will be found that this immunity is only apparent, the result being due merely to a difference in the dose required. When such immunities are detected it is an interesting question to attempt to explain their cause. Before all, an apparent immunity must be separated from one which is actual ; apparent immunities exist when, although the fundamental action of the poison is exerted, it causes only such functional disturbances as do not produce any evident effect on the organism ; such as the apparent immunity of frogs to carbonic oxide. In actual immunities the ac- tion of the poison is not exerted, or only after the admin- istration of disproportionately large doses. The cause of 190 APPENDIX. such immunities cannot be positively stated, though the following may be urged as possible explanations : «, the chemical conditions necessary for the action of the poison do not exist in the animal experimented on; an example of this is seen in the immunity enjoyed by insects for carbonic acid, since their respiration is not carried on with haemoglobin ; 6, the nutritive changes occurring in the animal may be of such a character as to cause such an unusually rapid excretion or decomposition of the poi- son as not to allow the accumulation in the blood of a quantity sufficient to produce toxic action. Such a pro- cess- may be established when the prevention of excretion, as by ligation of the ureters, renders a much smaller dose active. Actual immunities may be determined by the detection of the poison in the animal tissues ; thus, the above explanation will not apply to the immunity of rab- bits to belladonna, for their flesh, after they themselves have received unharmed large quantities of belladonna, will produce symptoms of atropia poisoning when con- sumed by man or other animals. Under no circumstances can any explanation be attempted unless all the modes of action of the poison are thoroughly understood. With the exception of cases in which special immunities exist, the general law holds good that the dose required to pro- duce the general action of a poison is in accordance with the size of the animal ; this is readily understood when it is remembered that a certain percentage of poison in the blood is required before the effects of the poison are manifested, and of course as the amount of blood con- tained in a small animal is less than that of a larger one, a smaller dose is required to produce proportionate effects. This rule has, however, many exceptions. In many cases it is necessary to repeat the doses at intervals in order to prolong the period of poisoning, and permit extended observation of any particular stage ; often, however, this will be impossible, as ani- mals will frequently lose their susceptibility to repeated doses of a poison. Such reduced susceptibility occurs with nicotin, and, indeed, remains after the cessation of IMMUNITIES TO POISONS. 191 the administration of the drug ; such conditions may be described as acquired immunities, or the animal or per- son is said to become habituated to the poison : its ex- planation is one of the most difficult problems of phar- macology. The repeated administration of drugs is further neces- sary from another point of view, since many poisons only produce certain effects after repeated administration : ordinarily under such circumstances the organism under- goes such changes that a single dose is not capable of producing the characteristic eifects of the drug. Thus a number of poisons require prolonged contact, or that of their products, with the special organs on which they act ; consequently a single dose is not capable, on ac- count of rapid elimination, of producing its typical ac- tion. The effect cannot even be produced by increasing the dose of the poison ; because, on the one hand, it may cause death by some other mode of action, or, on the other hand, there is a limit to the quantity of poison capable of absorption, especially in the more insoluble poisons in which the amount administered is of little con- sequence, as the excess over and above that which can be absorbed is carried off by the feces, when given by the stomach, or by suppuration when given subcutane- ously. In such cases the repeated administration of the poison is indispensable for the production of the charac- teristic action. Such cases are designated by the expression chronic poisoning, an unfortunate term, since chronic .poisoning is not separated from the acute form by the time re- quired for its development, or the duration of its exist- ence, but by the fact that acute poisoning is caused by a single dose, chronic poisoning by doses repeated at in- tervals. (1) To this class of chronic poisonings belong the cases of so-called cumulative action; that is, effects which only appear after the repeated administration of separate doses, even though they be small, and which cannot be caused by the administration of a single dose, 192 APPENDIX. even though it be a large one. The cause can only lie in the explanation given above. Another case in which the characteristic action may only be produced by repeated small doses is when larger doses, by some special action, such as vomiting, or defe- cation, either prevent absorption, or cause such rapid elimination, that either no action, or a modified one, oc- curs. The physical form in which the poison is administered is of great influence on its mode and conditions of ac- tion. It is only when in solution that a poison can enter the blood by absorption, and the rapidity of absorption depends largely on the character of the solvent; and upon the rapidity of absorption will depend the character or even the existence of the general action. Poisons, introduced in the solid form, often find solvents in the difi'erent fluids of the body, especially in the water of the tissue juices and secretions, which will permit this ab- sorption. These natural solvents should not, however, be relied upon, but the drug be invariably administered in solution, since the abstraction of water from the tis- sues may set up inflammatory changes which might com- plicate the result, or the solvent might not be on hand in sufficient quantity to dissolve the amount of drug administered ; thus, for example, it is possible that in acute phosphorus poisoning, the phosphorus is ab- sorbed without producing local inflammatory changes when fat is found at the same time in the digestive canal. In the choice of a solvent, one must be selected that is itself absorbable and indifferent (inactive), and the solution should not be too concentrated, as concentrated solutions, like the solid body, tend to produce corrosive eff'ects. 2. Methods of Producing Narcosis. — For a num- ber of special pharmacological studies it is necessary, before giving the poison under study, to give some drug which will destroy certain functions which it is desired to METHODS OF PRODUCING NARCOSIS. 193 eliminate. Ordinarily it is desired to maintain the ani- mal in a passive condition, in which no voluntary mo- tions will be made, and curare, therefore, is the drug most frequently used, either to produce absolute motion- lessness in complicated experiments, as in blood- pressure experiments, or to eliminate, through paralysis of the motor nerve endings, the possible effect of the drug on these organs. In all cases of curare poisoning in warm-blooded animals, artificial respiration must be maintained. Curare must not be used in the study of • drugs which, a, act themselves on the motor apparatus, or, 6, which produce diabetes, since the latter is also caused by curare, or, c, it must be used only in very small doses when the drug under study itself acts on the vaso-motor nerves. Whenever any drug is used for these purposes, all its actions must be thoroughly understood, and must not be incompatible with the drug under study, unless the line of incompatibility can be sharply drawn, and may itseli serve such purposes as above alluded to. Chloral is often employed to destroy pain and keep the animal motionless, and does not require the main- tenance of artificial respiration ; it is especially suited for rabbits, which, as a rule, do not stand narcotics well. Chloral, however, cannot be used in the study of the action of poisons on the heart, vessels, or pupil. Morphia, or laudanum, may be used for the same pur- poses, and with the same limitations ; both are well suited for dogs. These drugs are not, however, as yet thoroughly enough understood to allow of certainty that they exert no antagonism on the action of the special poison which may be the subject of study ; they should therefore only be used in special cases, and control experiments should always be made without the use of any narcotic in order to determine the general action of any drug. 17 194 APPENDIX Antagonism of Drugs. [No study of the action of a drug can be considered complete unless some attempt has been made to discover its physiological antidote. The chemical antidotes of a drug, when such exist, are usually readily determined by its known chemical incompatibilities. The practical value of such knowledge is, however, restricted in cases of actual poisoning to the time during which the poison remains within the alimentary canal ; thus alkalies can only be useful immediately after the ingestion of acids ; iron hydrated sesquioxide, immediately after the admin- istration of arsenic. By physiological antagonism, how- ever, as expressed by Bartholow,^ is meant a balance of opposed actions on particular organs or tissues. This antagonism, or opposition of actions, may extend through- out the whole range of effects of two diiferent drugs, or it may be limited to a few points ; and, indeed, some of the most valuable instances of antagonism are thus limited, and there are few, if any, examples in which the opposition of actions is universal. In the search, therefore, for a physiological antagonist, a drug should be first selected in which the points of contrast in physi- ological action are most marked. Thus, when it has been determined that the poison under study destroys life by paralysis of the respiratory centre, a marked stimulant of that centre should first be tested as to its possession of antidotal powers. A cardiac depressant should be antagonized with a cardiac stimulant, etc. When a drug has been selected which offers the greatest number, or most pronounced, points of contrast to the poison under study, the first point, if not already settled, will be to determine the minimum fatal dose of the poison per pound weight of the animals experimented on ; then the minimum fatal dose of the drug wliich it is proposed to test as an antidote. This having been ' Antagonism between Medicines, Cartwriglit Lectures, 1880. ANTAGONISM OF DRUGS. 195 accomplished, the minimum lethal dose of the poison is administered, to be followed by the administration within a few minutes of the corresponding dose of the antidote. Should the animal survive, the same dose of the poison should then be administered a few days later to test whether the dose originally given was sufficiently large to cause death. After a drug which possesses antidotal pro- perties has been found, and the proper dose determined, the antidote and the poison may be given simultaneously. Experiments should also be made as to the time which may elapse and the poisoned animal still be saved by the antidote, and as to how much more than the minimum fatal dose of the poison may be given and the animal's life still be preserved by the antidote. A curious fact which has been over and over again demonstrated, and should be remembered in such investigations, is that when less than the minimum fatal doses of two poisons, which modify each other's action, are given simultaneously, death will often result. After a successful antagonism has been proved, it will then be interesting to see in what manner the fatal effects are prevented. To that end, if the drug is a circulatory poison, for instance, paralyzing the vagi and vaso-motor centre, a blood-pressure experiment should be made, and when the characteristic effects have been produced, an appropriate dose of the antidote should be given and the effects on the circulation noted ; whether the blood- pressure rises and the vagi and vaso-motor centre regain their irritability. If the action is on the heart or respi- ratory centre, experiments such as those already detailed under the heading of the circulation or respiration may be instituted.] INDEX. ABSORPTION of poisons, 64 Accelerator cardiac ganglia, 106 action of poisons on, 124 nerves, 108, 109 Administration of poisons, 63 Albuminoids of blood, action of poisons on, 23 Amoebae, action of poisons on, 59 Anatomical alterations produced by poisons, 185 Animals, modes of securing, 60 selection of, 55 Antagonism of drugs, 194 of poisons on heart, 123 Antidotes, modes of detecting, 194 Apnoea, 134 Appendix, 189 Arteries, injections into, 67, 68 | Artery, carotid, preparation of, 67 j femoral, ligation of, 33, 67 iliac, ligation of, 33 Artificial respiration apparatus, 76 Asphyxia, production of, 134 Assimilation of poisons, 80 Auricle, action of poisons on, 121 Automatic functions, interference with, 177 "DACILLI, action of poisons on. Bacteria, action of poisons on, 59 Bile, eflects of retention of, 143 Biliary fistulse, mode of making, 151 secretion, action of drugs on, 150 Blood, action of poisons on, 20 alterations in coagulability of, 28 I in coloring matter of, 29 in consistence of, 23 ' 17 Blood, alterations — in ozone of, 30 in reaction of, 23 cause of venosity of, 133 corpuscles, alterations in, 25, 28 gases, alterations in, 30 modes of collecting, 22 of passing gases through, 26 pressure, action of poisons on, 111 determination of, 102, 104 experiments, mode of con- ducting, 92, 98 tracings, 103 Bloodvessels, action of poisons on, 125 injections into, 05 ligation of, 33 modes of exa^iining, 125 Brain, changes in circulation of, 184 influence of disturbed circula- tion on, 130 Bronchi, injections into, 72 CANULiE, arterial, 102 methods of making, 20 mode of inserting, 21 Cardiac ganglia, 106 Cardiograph, Sanderson's, 89 Carotid artery, preparation of, 67, 99 Cats, mode of fastening, 61 Cerebrum, influence of circulation on, 130 Changes of poisons in the body, 77 Chemical changes in muscle, 48 in poisons, 80 produced by poisons, 187 Chloral as a narcotic, 193 198 INDEX. Chorda tympani nerve, mode of exposing, 149 Chronic poisoning, 191 Circulation of brain, changes in, 184 Circulatory apparatus, action of poisons on, 88, 105 causes of changes in, 105 changes, indirect results of, 128 Coagulation of blood, action of poisons on, 28. Coloring matters of muscle, changes in, 49 Commutator, Pohl's, 39 Conductivit}'^ of muscles, 47 Conjunctiva, application of drugs to, 71 Convulsions, mode of production of, 171 produced by dyspnoea, 184 Co-ordinated functions, interfer- rnce with, 177 Corpuscles of blood, action of poi- sons on, 25, 28 Cumulative action of poisons, 191 Curare, uses of, 193 Current-interrupters, 97 Czermak's rabbit-holder, 61 DECOMPOSITION of poisons, 81, 82 Degeneration, fatty, produced by poisons, 161 Deglutition, action of drugs on, 137 Deposit of drugs in the system, 80 Depressor nerve, action of poisons on, 128 Diabetes, production of, by drugs, 161 Digestive apparatus, action of drugs on, 136 changes in sensibility of, 140 organs, changes in movements of, 137 processes, alteration in, 144 secretions, alteration in, 141 Dog-holder, Bernard's, 62 Brunton's, 62 Dogs, modes of securing, 63 Dose, minimum fatal, mode of de- termining, 87 Doses of poisons, 189 Double-key, Pohl's, 39 Du Bois Reymond's induction coil , 37 key, 39 Dysphagia, production of,bv drugs, 137 Dyspnoea, as a cause of convul- sions, 134 causes of, 133 production of, by drugs, 131 ELECTRODES, 46 non-polarizable, 43 Electro-motor power of muscle, action of poisons on, 36 Elimination of poisons, 77, 82 Emesis, production of, by drugs, 137 Energy of muscle, measurement of, 48 Excretion of poisons, 77, 82 Eye, instillations into, 71 FASTENING animals, methods of, 60 Fat, deposit of, in the body, 161 Femoral artery, ligation of, 33 Pick's manometer, 95 Fistulae, biliary, 151 gastric, 141 pancreatic, 143 salivary, 145 urinary, 154 Forms of poisons, 189 Frogs, advantages in use of, 55 methods of fastening, 61 GANGLIA of the heart, 106 Gases, administration of, through the lungs, 72 application of, to blood, 25 of blood, action of poisons on, 30 Gastric fistulae, method of making, 141 General action of poisons, 55 Generative functions, action of drugs on, 162 Glands, lachrymal, action of drugs on, 158 lacteal, action of drugs on, 158 INDEX 199 Glands — non-secretory, action of drugs on, 158 submaxillary, mode of expos- ing, 148 sweat, action of drugs on, 157 Glandular organs, action of poi- sons on, 144 Glycogenesis, action of poisons on, 159" Guinea-pigs, method of fastening, 61 HEMOGLOBIN, action of poi- sons on, 29 Hallucinations produced by poi- sons, 182 Heart, accelerator nerves of, 108 action of poisons on, 124 action of poisons on, 52, 88, 104, 116 antagonism of poisons on, 123 application of electricity to, 121 ganglia of, 106, 123 inhibitory nerves of, 107 action of poisons on, 123 of frogs, mode of exposing, 53 of mammals, mode of expos- ing, 88 mode of isolating, 122 results of arrest of, 129 Hypodermic injections, 70 ILIAC artery, ligation of, 33 Immunities to poisons, 189 Indirect muscular irritability, ex- amination of, 37, 40 Induction apparatus, 37, 45 Infusoria, action of poisons on, 59 Inhibition of reflex actions, 181 Inhibitory cardiac apparatus, ac- tion of poisons on. 113, 123 ganglia, 106 nerves, 107 Injections into arteries, 67 into bloodvessels, 65 poisons unsuitable for, 68 into lymph sacs, 70 into mucous cavities, 70 Injections — into serous sacs, 70 into veins. 66 subcutaneous. 70 Instillation into conjunctival sac, 71 Intestinal movements, influence of circulation on, 130 Intestines, movements of, 139 Irritability of muscle, action of poisons on, 36 examination of, 37, 46 Isolated organs, action of poisons on, 19 JAWS, movements of, 137 Jugular vein, method of pre- paration, 66 KIDNEYS, action of poisons on, 152, 154 elimination of poisons by, 78 Kymographion, forms of, 97 use of, 91 LACHRYMAL glands, action of poisons on, 158 Lacteal glands, action of drugs on, 158 Larynx, action of drugs on, 136 Laudanum as a narcotic, 193 Lingual nerve, 149 Lud wig's and Coats's apparatus, 117 kymographion, 96 manometer, 92 Lungs, administration of poisons ' through, 72 elimination of poisons by, 78 Lymph sacs, injections into, 70 MAMMALS, method of isolating heart of, 122 peculiarity in action of poisons on, 56 Man, action of poisons on, 58 Mania, production of, by drugs, 182 Manometer, Tick's, 95 for frog, Ludwig's, 117 Ludwig's, 92 mercurial, disadvantage of, 94 200 INDEX Marey's comparative myograph, 45 tympanum and lever, 90 Masticatory movements produced by drugs, 137 Metabolism, influence of drugs on, 159 Micrococci, action of poisons on, 60 Milk secretion, influence of drugs on, 158 Morphia as a narcotic, 193 Motor nerves, action of poisons on, 50 Mucous cavities, injections into, 70 Miiller's valves, 74 Muscles, action of poisons on, 31, 164 application of gases and vapors to, 32 changes in coloring matters of, 49 chemical changes in, 48 conductivity of, 47 electro-motive power of, 36 energy of, measurement of, 48 mechanical stimulation of, 47 Muscular irritability, action of poi- sons on, 36 examination of, 37, 46 Myographion, Marey's, 45 Pfliiger's, 43 NARCOSIS, methods of produc- ing, 192 production of, by drugs, 183 Nerves, accelerator cardiac, 108 action of poisons on, 49, 169 chorda tympani, 149 current, negative variation of, 51 endings, action of poisons on, 172 inhibitory cardiac, 107 lingual, 149 motor, action of poisons on, 50 muscle preparation, 36 sensory, action of poisons on, 52, 172 trunks, action on, 170 Nervous system, action of poisons on, 169, 175 Non-polarizable electrodes, 43 Nutrition, influence of drugs on, 159 ORGANS, isolated, action of poi- sons on, 19 Oxidation of poisons, 83 processes, energy of, 160 Ozone of blood, action of poisons on, 30 PANCREATIC flstulfe, 143 Paralysis, mode of production of, 46, 50, 170, 172, 175 Peristalsis, action of drugs on, 139 Pfliiger's myographion, 43 Pharmacology, methods of study of, 15," 17 object of, 15 scope of, 13 Pithing, method of performing, 53 Pneumogastric, action of poisons on, 114 Pohl's commutator, 39 Poisons, absorption of, 64 action of, on circulatory appa- ratus, 88 on isolated organs, 19 administration of, 63 changes in, 77, 80 definition of, 13 elimination of, 77 explanation of symptoms pro- duced by, 85 general action of, 55, 85 local action of, 85 oxidation of, 83 Protoplasm, action of poisons on, 59 Pulse, action of drugs on, 113 and blood-pressure, relation between, 125 Pupil, action of drugs on, 165 "pABBIT-HOLDER, Czermak's, Rabbits, mode of fastening, 61 Reaction of blood, modes of test- ing, 23 Recovery from poisoning, mode of, 86 Reflex action, action of drugs on, 177 inhibition of, 181 Renal secretion, action of drugs on, 152 Reproductive functions, alterations in, 162 INDEX. 201 Respiratory apparatus, action of drugs on, 76, 130 centre, reduction in irritability of, 134 changes, modes of studying, 131 movement, cessation of, 134 changes in frequency of, 135 effects of interference with, 133 muscles, paralysis of, 135 Kigor of muscles, recognition of, 49 Roy's apparatus for frog's heart, 119 SALIVARY fistulas, mode of making, 145 secretion, action of poisons on, 145, 150 Salts, decomposition of, 81 Sanderson's cardiograph, 89 Sartorius of frog, action of poisons on, 46 Secretions, action of poisons on, 141 elimination of poisons in, 79 Securing animals, methods of, 60 Selection of animals, 55 Sensibility of alimentary canal, 140 Sensory functions, action of drugs on, 182 nerves, action of poisons on, 173 Serous sacs, injection into, 70 Setschenow's centre, action of drugs on, 181 Sinus venosus, action of poisons on, 121 Solvents of poisons, 189 Sphygmograph, use of, 91 Spleen, action of drugs on, 159 Spring manometer, Fick's, 95 Stomach, injection into, 70 movements of, 137 Subcutaneous injections, 70 Submaxillary gland, mode of ex- posing, 148 Sweat glands, action of poisons on, 157 secretion, influence of nerves on, 157 Symptoms, mode of observing, , 86 produced by poisons, explana- tion of, 85 Syncope, production of, by drugs, 183 TAMBOUR, Marey's, 90 Temperature, alterations in, 164 Time markers, 97 Tissue metabolism, action of drugs on, 159 Tracings of blood-pressure, 103 tabulation of, 104 Tympanum and lever, Marey's, 90 URINARY fistuliB, 154 secretion, action of drugs on, 152 Uterine contractions, influence of circulation on, 130 production of, by drugs, 163 Uterus, action of poisons on, 163 VALVES, MUller's, 74 Vapors, administration of, through lungs, 72 Vascular apparatus, action of poi- sons on, 125 Vaso-motor centre, 110, 125 action of drugs on, 127 system, 110 action of drugs on, 126 Veins, advantages for injections, 65 injections into, 66 jugular, mode of preparation, 66 Venosity of blood, causes of, 133 Ventricles, action of poisons on, 121 Vibrios, action of poisons on, 60 Vomiting, mode of production of, 138 production of, by drugs, 137 share of the stomach in, 138 CATALOGUE OF BOOKS PUBLISHED BY LEA BROTHERS & CO. 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