BJOLOGY LIBRARY G THE PHYSIOLOGICAL ACTION OE DRUGS THE 'HYSIOLOGICAL ACTION OF DRUGS " II AN INTRODUCTION TO PEACTICAL PHARMACOLOGY BY M. S. PEMBREY, M.A., M.D. JOINT-LECTURER ON PHYSIOLOGY IN GUY'S HOSPITAL MEDICAL SCHOOL AND C. D. F. PHILLIPS, M.D., LL.D. EXAMINER IN MATERIA MEDICA AND THERAPEUTICS IN THE UNIVERSITY OF ABERDEEN LATE EXAMINER IN THE UNIVERSITIES OF EDINBURGH AND GLASGOW LONDON EDWARD ARNOLD 37 BEDFORD STREET, STRAND 1901 PREFACE H THE experiments described in this elementary work have been ^ made as simple as possible, so that they may be performed by j a medical student. For a similar reason they have been limited to those operations which can be performed upon a brainless frog. The law relating to experiments on animals renders necessary the destruction of the animal's cerebral hemispheres. It is hoped that this small work may be of some value as a contribution to the knowledge of the physiological action of drugs. The results of the experiments are based upon numerous observations and graphic records ; the drugs have been dissolved in normal tap-water saline solution, and, for the determination of the poisonous effects, have been administered by hypodermic injection under the skin of the back. The tracings are portions of continuous records, and have been checked by control experiments. We wish to thank Professor Stockman, Dr. Dixon, Dr. Beddard, and Mr. Leonard Hill for reading through the proofs and for some valuable suggestions. 357693 CONTENTS INTRODUCTORY EXPERIMENTS EXPT. PAGE 1. COMPLETE DESTRUCTION OF THE CENTRAL NERVOUS SYSTEM . ". . . . _ . 1 2. DISSECTION OF A MUSCLE AND NERVE PREPARATION ~. 2 3. SINGLE MUSCULAR TWITCH DIRECT AND INDIRECT STIMULATION . . . . . .3 4. PREPARATION OF THE HEART AND THE V AGO-SYMPATHETIC NERVE INHIBITION OF THE HEART BY STIMULATION OF THE VAGUS ; ACCELERATION BY STIMULATION OF THE SYMPATHETIC . . . . . 4 5. THE EFFECT OF TEMPERATURE UPON THE CONTRACTION OF VOLUNTARY MUSCLE r, . . . 7 6. THE EFFECT OF TEMPERATURE UPON THE HEART . 9 7. THE INHIBITORY REGION OF THE HEART STANNIUS' EXPERIMENT . . . . . .10 8. THE CARDIAC PLETHYSMOGRAPH . . . .12 PHYSIOLOGICAL ACTION OF DRUGS 9-10. DISTILLED WATER . . . . .14 11-13. NORMAL PHYSIOLOGICAL SALINE SOLUTION . .17 14. NORMAL TAP-WATER SALINE SOLUTION . . .18 15-18. ALCOHOL . ... . .22 19-21. ETHER . . . . . . .26 22-25. CHLOROFORM . . . . . . 29 26-29. CHLORAL HYDRATE . . , .33- 30-33. STRYCHNINE . 4 . . . . .36 34-38. HYDRASTINE .... .41 39-42. MORPHINE . . . . . .47 43-46. CAFFEINE . 49 viii THE PHYSIOLOGICAL ACTION OF DRUGS EXPT. PAGE 47-50. CURARE . . .52 51-54. NICOTINE . 58 55-58. ATROPINE . ... 63 59-62. COCAINE . .66 63-66. PILOCARPINE . 71 67-70. MUSCARINE . .75 71-74. VERATRINE 79 75-78. DIGITALINE . 83 79-82. PHYSOSTIGMINE . .89 83-87. EXTRACT OF SUPRARENAL GLAND . . .92 THE ACTION OF DRUGS UPON THE CONTRACTION OF THE EROG'S HEART . . .94 ANTAGONISM . . . . .99 COMPARISON OF ORDINARY DOSES AND LETHAL DOSES IN THE FROG AND MAN 100 INTRODUCTORY EXPERIMENTS THE following directions for the dissection and preparation of various portions of the frog's body and the performance thereon of some simple experiments will serve as an introduction to the main purpose of this work the study of the action of drugs. It is necessary that a knowledge of the normal should precede the investigation of the changes introduced by the action of a drug. The law relating to experiments on animals renders necessary the destruction of the animal's cerebral hemispheres, ^AA| and thus limits the experiments, which can be properly performed by a student, to observations upon frogs. Even apart from this legal obligation, there is one great advantage in the selection of this animal. The various tissues of a cold-blooded animal, such as the frog, retain their individual vitality for hours after the death of the animal, and are thus most suitable for experiments. EXPERIMENT I. Complete Destruction of the Central Nervous System. The articulation of the head of the frog with the vertebral column can be readily felt with the finger. At this point the skin and other tissues should be rapidly pierced, and the brain destroyed by the insertion of a probe or a blanket-pin. If, after this operation, the eye be touched with the finger, the eyelid is not closed the " corneal reflex " has been abolished. The probe is now pushed down the spinal cord, and convulsive movements of the limbs will be observed ; these are due to the impulses sent down the motor nerves, when the B THE PHYSIOLOGICAL ACTION OF DRUGS nerve-cells are stimulated in the process of destruction. The contractions quickly cease, and now no reflex movements can be obtained in any part of the body. In experiments in which it is desirable to prevent any loss of blood, the cerebral hemispheres can be destroyed by quickly compressing the skull between the blades of a pair of Spencer Wells forceps. EXPERIMENT II. Dissection of a Muscle and Nerve Prepara- tion. The frog used in the last experiment is placed belly downwards and pins are fixed through the feet. The skin around the ankle is divided and the tendo Achillis is exposed, and a thread * is passed under the tendon and tied just above the sesamoid bone ; the tendon is then divided below the sesamoid bone. The tendon and its muscle, the gastrocnemius, FIG. 1. FIG. 2. Diagrams of a Muscle and Nerve Preparation. FIG. 1. The first stage of dissection. FIG. 2. The second stage of dissection. The sciatic nerve exposed and the gastrocuemius muscle covered by skin. are pulled upwards and carry with them the skin ; the bone of the leg and the remaining muscles are removed by a cut 1 A simple aneurism needle can be made by fixing a needle with a large eye into a pen-holder. INTRODUCTORY EXPERIMENTS 3 below the knee-joint, and the gastrocnemius muscle is protected from drying and contact with foreign substances by drawing- down the " trowser " of skin. The skin over the posterior surface of the thigh is next divided by a longitudinal incision in the mid-line ; the muscles are separated, and the sciatic nerve is dissected up to its exit from the vertebral column, a small piece of which is bisected and cut away with the nerve. A pin is pushed through the lower extremity of the femur, and the thigh is severed from the body by a cut close to the articula- tion of the head of the femur. The nerve r is allowed to lie among the muscles until it is required for stimulation ; the lymph of the muscles keeps the nerve moist, and thus preserves its excitability. EXPERIMENT III. Single Muscular Twitch Direct and In- direct Stimulation. The last dissection is* used for this experi- ment. The sciatic nerve is raised from between the muscles of the thigh, and is laid upon a pair of electrodes. A very weak induction-shock is passed ; the muscle does not contract. The strength of the induction-current is gradually increased until a twitch of the muscle is observed ; this is a minimal stimulus. After steadily increasing the strength of the stimulus, a point is reached at which the greatest contraction is observed, and further augmentation of the stimulus leads to no increase in the contraction of the muscle ; this is the maximal stimulus for indirect stimulation of the muscle by means of its nerve. The electrodes are now applied directly to the muscle and the experiment is repeated. It will be found that the stimulus required for the muscle is stronger, proving that the excitability of nerve is greater than that of muscle. This difference in the excitability of muscle and nerve can be measured approximately by noting the distance of the secondary from the primary coil of the inductorium when 1 The nerve should not be pinched, but should be lifted by the piece of the vertebral column. 4 THE PHYSIOLOGICAL ACTION OF DRUGS the minimal and maximal points are determined. The following figures give the results of such a measurement. Nerve. Muscle. Nature of Induction Shock. Minimal. Maximal. Minimal. Maximal. cm. cm. cm. cm. Make 39 7 20 5 Break 48 10 30 7 The table shows, moreover, that the break-induction- shock is a more effective stimulus than the make ; this is due to the greater strength and more rapid rise in the intensity of the break-shock. In comparative estimations of the excita- bility of a tissue it is therefore necessary to use only the make or only the break- shocks. The determination of the strength of the minimal stimulus for a muscle or nerve serves as a gauge of the excitability of those tissues under different conditions, and in this way the effect of drugs upon muscle and nerve can be studied. EXPERIMENT IV. Preparation of the Heart and the Vago-Sympathetic Nerve Inhibition of the Heart ~by Stimula- tion of the Vagus; Acceleration by Stimulation of the Sympathetic. A pithed frog is placed on its back, and, by a median incision of the skin, the sternum and floor of the mouth are exposed ; the flaps of Diagrams of the frog's heart. A. skin are removed on each side, and Anterior view. B. Posterior h h sternum is Carefully Cut view, heart turned up. 1, ven- tricle ; 2, left auricle ; 3, right away without any damage to the auricle ; 4 and 5, aorte coming heart> The pericardium is slit open off from truncus artenosus ; 6, frsenum ; 7, left superior vena and the beating heart is exposed. cava ; 8, right superior vena The contr action of the sinUS venOSUS cava ; 9, inferior vena cava. is followed by that of the two auricles and of the single ventricle, which is in turn succeeded by the pulsation of the truncus arteriosus. The chambers of the heart 1 The crescentic groove which separates the sinus venosus from the auricles is indicated by the interrupted line. INTRODUCTORY EXPERIMENTS 5 during diastole are distended and flushed with blood ; during systole the colour pales, the chambers become smaller and tense. The vago-sympatbetic nerve is readily exposed by the following dissection. The skin in the middle line of the back is divided and the scapula is lifted up and cut away ; the fore limb is pulled outwards and removed. A finger is placed in the frog's mouth in order to place the structures of the side of the neck and the floor of the mouth on the stretch. The following nerves can now be easily seen : the thick brachial plexus, divided by the removal of the fore limb ; in front of it a much smaller nerve, the hypo- glossal, which passes down to the floor of the mouth ; then the vago- sympathetic, which comes FIG. 5. Diagram of nerves in the frog's neck. from the skull, and, running by the side of the carotid artery, crosses under the hypoglossal nerve ; and lastly, issuing from the same foramen as the vago-sympathetic, the FIG. 6. Diagram of a cardiograph. glosso-pharyngeal nerve, which for a short distance runs N ^ 2^ >> ? H ^ S . frilll* ill! 1 ! *! j ^s^ i SI'. I! Sav-S^-J s *- js r 2 =* . O JU f ^ -,5 ^' K S S '* ^ 1 1 "3 i -s ! = 1 - 2 ^ 1 .1 * '- >113sl s^^l ^ ^ S.2 o O -*^ (V -4^ K s i o* s i* -*-^ O r- Sj CC fl g^-sill 9 2 i 2 g 1 I ^^ S^cg 00 o INTRODUCTORY EXPERIMENTS 7 parallel with the vago-sympathetic but soon turns downwards and forwards to the floor of the mouth. A pair of electrodes are placed under the dissected vago- sympathetic nerve and the frequency of the heart's beat is noted; a weak faradising current is passed through the nerve ; the heart beats more rapidly owing to the stimulation of the sympathetic fibres of the nerve. The strength of the induction-currents is increased and the effect of the strong stimulus is excitation of the vagus ; the heart stops beating in the diastolic phase. These effects can be recorded graphically. The frog is placed on a myograph ; the ventricle is supported by the tip of the finger, and a small bent pin is placed through the apex of the ventricle. A thread connects this small hook with a recording lever, as shown in the diagram (Fig. 6). The accelerating effects of the sympathetic and the inhibitory influence of the vagus are shown by the curves (Figs. 7 and 8). It is important to remember that the fibres of the vagus and sympathetic nerves run together, and that the pure vagus can only be stimulated inside the skull before it is joined by the sympathetic. EXPERIMENT V. The Effed of Temperature upon the Con- traction of Voluntary Muscle. The gastrocnemius muscle is prepared without a covering of skin and is attached to a myo- graph in the ordinary way (Fig. 9). One wire of the electrodes is fixed to the pin which passes through the lower extremity of the femur ; the other wire is joined to a piece of .capillary copper-wire, which has been threaded by means of a needle through the tendo Achillis. In this way the electric current can be passed through the length of the muscle, and the very fine wire will prevent any friction or obstruction to the free movement of the muscle when it contracts. Cold tap-water saline solution, 1 which has been cooled by ice, is slowly poured upon the muscle ; the temperature of the 1 Tap-water containing '6 per cent of sodium chloride. 8 THE PHYSIOLOGICAL ACTION OF DRUGS solution is noted, and the contraction produced by the passage FIG. 9. Diagram of a myograph. of a single maximal stimulus is recorded upon a revolving FIG. 10. The effect of temperature upon the contraction of the gastrocnemius muscle. The time is marked in T ^ 7 second. The tracing should be read from right to left. cylinder covered with smoked paper. The experiment is repeated with solutions with a temperature of 13, 23, and INTRODUCTORY EXPERIMENTS 9 33 respectively. The contraction, it will be observed, is more rapid in its onset and of shorter duration when the muscle is exposed to a higher temperature. These points are illustrated by the curves (Fig. 10). This method is simple and effective, but it is obvious that, if exact results be needed, the muscle must be suspended in FIG. 11. Curve of the shortening of the gastrocnemius muscle during heat-rigor. tap-water saline solution of the given temperature, until its substance has attained that temperature. This experiment shows that the temperature of the sur- roundings has a marked effect upon muscular contraction. It is important, therefore, to observe the temperature during an investigation of the action of a drug upon muscle. On another portion of the drum is recorded the effect of saline solution heated to 50 or 60; the muscle shortens but does not relax ; it is in " heat-rigor " and will have lost its excitability. This heat-rigor depends upon the coagulation of the proteids of the muscle. EXPERIMENT VI. The Effect of Temperature upon the Heart. A graphic record of the heart's contraction is taken, 10 THE PHYSIOLOGICAL ACTION OF DRUGS and under the curve the time is marked in seconds ; against this record is noted the temperature of the room. The effect of temperature is then observed by pouring over the heart tap- water saline solution at temperatures of 3, 13, 23, 33, and 43 respectively, and recording separately the results. A rise of temperature quickens the rate and diminishes the force and duration of the heart's contraction, as shown in the following curves (Fig. 12). In the tracing obtained at the low temperature it will be observed that three contractions of the ventricle occur in ten seconds, and the contraction of the auricles is well shown as a slight rise preceding the systole of the ventricle. At 13 there are five ventricular contractions in ten seconds, and the contrac- tion of the auricles occurs before the ventricle has completely relaxed; at 23 the contractions of the ventricle are six in ten seconds ; the auricular contraction occurs still earlier on -the down-stroke, due to the relaxation of the ventricle: at 33 the frequency of the heart-beat is increased to ten in ten seconds, and the height of the contraction is reduced to one-third of the value at 3. When the tap- water saline solution at 43 is poured on the heart, it beats irregularly in force and rhythm. The application of the solution at 53 will stop the pulsation, and will cause the heart to pass into heat-rigor and its proteids to coagulate. This simple method is not rigorously exact, for the warm tap-water saline solution rapidly cools and the entire mass of the cardiac muscle is not raised to the temperature of the liquid. The results, however, show clearly the influence of temperature upon the beat of the heart, and the importance of observing the temperature of the surroundings during investiga- tions upon the heart. EXPERIMENT VII. The Inhibitory Region of the Heart Stannius Experiment. The heart of a pithed frog is exposed, and a thread is tied to the frsenum, a slip of pericardium which passes from the posterior wall of the pericardium to the 1AAA/IAAA/WWVWWV \/\/W\/V\AJV FIG. 12. C - - a t the r^ ie effect of temperature upon the contraction of the ph (Brodie d^art. The time is marked in seconds. 12 THE PHYSIOLOGICAL ACTION OF DRUGS posterior surface of the ventricle (Fig. 4). The attachment of the frsenum to the pericardium is cut, and the heart is pulled upwards, so that its posterior surface is well exposed. At the junction of the sinus with the right auricle will be seen a crescentic groove, known as the inhibitory region of the heart. To this point electrodes are applied, and it will be found that the passage of a faradising current through this portion of the heart will cause it to cease beating during, and for a short time after, the stimulus. In the inhibitory region are found a plexus of the cardiac nerves and ganglion cells. 1 Stannius 3 Experiment. By means of a large-eyed needle, a thread is passed under the two aortse just above the truncus arteriosus ; the heart is pulled towards the mouth by means of the ligature upon the frsenum, and then the thread is tied tightly round the junction of the auricles with the sinus venosus. The beat of the auricles and ventricle ceases, "but that of the sinus venosus continues. By this " Stannius' ligature " the contractions of the auricles and ventricle can be suspended for a considerable time, and the cardiac muscle in a quiescent condition can be used for experiments. EXPERIMENT VIII. The Cardiac Pletliysmograph. For the investigation of the action of drugs upon the heart, the passage of the drug, dissolved in blood or some innocuous fluid, through the heart is often desirable, for thereby the drug- is brought into intimate contact with the tissues of the heart. Schafer's cardiac plethysmograph (Fig. 13) may be used for this purpose. There are, however, considerable disadvantages attached to this method. Much practice is necessary in the somewhat difficult manipulation. The heart is easily injured, and, owing to the ligature around its base, it is impossible to investigate the influence of drugs upon the cardiac nerves. It is in fact a preparation of the ventricle. In this s'of pe.of experiments i See p. 97. I P ericar ' INTRODUCTORY EXPERIMENTS 13 the simple method of application of the drug to the outside of the heart will be employed ; the manipulations are easier, V FIG. 13. Diagram of Schafer's cardiac plethysmograph. The heart is tied to a double canuula, through which the fluid containing the drug can pass to and from the cavity of the ventricle. The heart is then inserted into the air-tight bulb of the apparatus which contains oil. The alterations in the volume of the ventricle are communicated to the piston and thus a tracing is obtained. involve much less injury to the heart, and allow the influence of the vagus and sympathetic nerves to be readily studied. 1 PHYSIOLOGICAL ACTION OF DRUGS Drugs must be in solution if they are to be readily absorbed and carried by the blood to the various tissues of the body. Water is the best solvent, and its effects upon the body must be studied before conclusions can be drawn concerning the action of any substances dissolved in it. In the following experiments upon the action of various drugs it is important to remember that the doses necessary to produce characteristic effects upon isolated but still living muscle and nerve are often much larger than those sufficient to produce symptoms or even death of the animal. Further, it is obvious that in some cases a drug produces in the more highly- developed mammal effects different from those observed in the froo- This does not, however, invalidate such a method of o 1 The solution of the drug can be passed through a frog's heart by means of a cannula inserted into the hepatic veins. The contraction is recorded with the simple cardiograph (Brodie and Dixon). 14 THE PHYSIOLOGICAL ACTION OF DRUGS study, for on the whole the effects are similar, and even the differences often throw light upon the mode of action of the drug. Distilled Water Distilled Water, H 2 0, should be free from ammonia and traces of copper or other metals, which may be dissolved when the water is condensed in a metal worm and collected in metal receivers. It is important to study the action of water upon living tissues, for it is frequently used as a solvent of drugs. EXPERIMENT IX. The Effect upon the Heart. A record of the contraction of the heart is taken, and then by means of a small pipette distilled water is passed in a gentle stream over the heart. If the heart contains a large quantity of blood it may be necessary to allow it to escape by a small incision in one of the auricles ; otherwise the salts contained in the blood will pass into the distilled water and make it a saline solution, and the effect of pure water will not be readily observed. After the heart has been thoroughly treated with distilled water, its contractions become less frequent, but more pro- longed (Fig. 14, Curve II. ; Fig. 16, Curve II.; and Fig. 17, Curve I.). A further application will reduce the frequency and force of the contraction until the heart ceases to beat (Fig. 14, Curve III. ; and Fig. 17, Curve III.). The heart, however, is not dead, and if it be treated with normal saline solution, or, better, with normal tap-water saline solution, the contractions may be restored (Fig. 16, Curves II. and III. ; and Fig. !7, % Curves III. and IV.). Another method of observing the effect of distilled water is to cut out the heart, and, after washing away the blood, to place it in a watch-glass filled with pure water. As a control, another heart is treated in a similar way, except that normal tap-water saline solution is used instead of water. The heart exposed to the action of the distilled water ceases to beat at a time when the control-preparation is contracting vigorously. 16 THE PHYSIOLOGICAL ACTION OF DRUGS EXPERIMENT X. The Effect upon Muscle and Nerve, The gastrocnemius muscle and the sciatic nerve are dissected on each side of a pithed frog ; each preparation is placed in a watch-glass and the minimal stimulus (see Expt. III. p. 3) is determined for both muscles and nerves. The excitability of the two preparations will be practically the same. One preparation, A, is now placed in a vessel of distilled water ; the other, B, is covered with a wet watch-glass in order to prevent drying of the tissues. About five minutes later the excita- bility of the nerve and muscle in both preparations is again determined ; the one, B, shows little or no change, but in the case of A there is a decrease in the excitability of both muscle and nerve. The preparation A is replaced in a fresh quantity of distilled water for about forty-five minutes ; at the end of this time the nerve and muscle will have lost their excitability and will show obvious changes : the nerve will be whiter, more opaque and stiffer as compared with the control-specimen B; the muscle A will show a similar change, due to the action of the distilled water upon the globulins of the muscle. The ex- citability of the muscle and nerve in the preparation B will be retained for a long time, if precautions be taken to prevent evaporation. This is necessary, because living tissues contain a large percentage, at least three-quarters of their weight, of water. This experiment shows that distilled water is a poison to muscle and nerve. It does not contradict the fact that distilled water can be swallowed without any obviously bad effects, for in the alimentary canal the water becomes a weak saline solution ; salts are dissolved from the tissues or the contents of the digestive tract. The practical importance of the different physiological effects of distilled water and of weak saline solution is seen in the transfusion of saline solutions after severe haemorrhage ; distilled water rapidly breaks up the blood -corpuscles, but weak saline solutions do not. A nasal douche with weak saline solution causes less discomfort than one with distilled water. NORMAL PHYSIOLOGICAL SALINE SOLUTION 17 Normal Physiological Saline Solution Normal physiological saline sohitian is made bv the addition of 0*6 to 0'7 per cent, of sodium chloride, Nad, to pure distilled water. This fluid possesses the same osmotic pressure as the liquid of living tissues, and is called an " isotonic " solution. By its use the transference of water or salt from the tissue to the fluid is partly prevented, and the normal environment of the living cells is much less disturbed than it would be by distilled water. EXPERIMENT XL The Effect upon Red Blood- Corpuscles. The action of " isotonic/' " hypoisotonic," and " hyperisotonic " solutions can be studied upon red blood-corpuscles. A drop O * 1 II. IIL FIG. 15. Diagrams to show the effect upon human red blood-corpuscles of I. isotouic, II. hypoisotonic, and III. hyperisotonic solution. or two of normal physiological saline solution is added to a drop of human blood l just drawn from the finger, and the shape of the corpuscles is observed under a microscope ; the corpuscles are not deformed, for the solution is isotonic. Distilled water is added to another drop of blood and is soon found to produce swelling and destruction of the cor- puscles with the liberation of haemoglobin ; the water is hypoisotonic and passes into the corpuscle. If a third drop of blood be treated with strong salt solution, the corpuscles become crenated owing to the loss of water to the hyper- isotonic solution. 1 For human blood an isotonic solution should contain 0'9 per cent, of sodium chloride. C 18 THE PHYSIOLOGICAL ACTION OF DRUGS EXPERIMENT XII. The Effect upon the Heart. Although the application of normal saline solution will often restore an irregularly beating heart, and the rhythmic power to a heart, which has been treated with distilled water, yet it soon causes a more feeble and slower contraction. The continued applica- tion of the solution results in the cessation of all contraction, and the heart stops in diastole. If by means of distilled water the heart's contraction be greatly diminished in frequency and rendered irregular (Fig. 16, Curve II.), normal saline solution will restore the beat (Fig. 16, Curve III.), but not to such a marked degree as tap- water saline solution (Fig. 17, Curves II. and IV.). It sometimes happens that the heart beats irregularly but with a definite rhythm before the application of any fluid. In such cases normal saline solution generally restores and main- tains for a considerable time a regular beat (Fig. 16, Curve 1.). The action of normal saline solution in these cases should be compared with that of a saline solution of similar strength but made with tap-water (Expt. XIV.). EXPERIMENT XIII. The Effect upon Muscle and Nerve. Two muscle and nerve preparations are made from a pithed frog ; they are placed in watch-glasses, and the minimal stimuli for the nerves and muscles are determined. The one prepara- tion, A, is covered with distilled water, the other, B, with normal saline solution. A marked decrease in the excitability of both nerve and muscle of A will soon be observed (see Expt. X.), but in the case of B the excitability will be retained for hours and only gradually diminishes. This experiment shows conclusively the value of the addition of a small quantity of salt in removing the poisonous effects of distilled water. Normal Tap-water Saline Solution The researches of Einger have shown that the best saline medium for maintaining the contraction of the frog's heart is a 20 THE PHYSIOLOGICAL ACTION OF DRUGS solution containing small quantities of calcium salts. Thus a 6 per cent, solution of sodium chloride made with the New River tap-water has much greater sustaining properties in the case of the frog's heart than a solution containing a similar amount of sodium chloride but. made with distilled water. Living tissues are, as Nageli, Locke, and others have shown, extremely sensitive to traces of compounds of various heavy metals, such as copper, and are easily poisoned and killed thereby. It is important, therefore, to take tap-water after the water lias been allowed to " run " for some time, and thus remove the water which has been stagnant in the service-pipes and has there dissolved small quantities of metal. * EXPERIMENT XIV. The Effect upon the Heart. A record of the contraction of the heart is taken before and after the blood has been allowed to escape. 1 This portion of the tracing will serve as a control. The record is continued, and from a pipette a gentle stream of normal tap- water saline solution is allowed to flow over the heart. A regular beat may be maintained for hours, if the heart be moistened from time to time with the solution. Distilled water is then applied until the heart -beat is greatly diminished in force (Fig. 1 7, Curve I.) ; at this stage normal tap-water saline solution is supplied and the heart soon regains its former power of contraction (Curve II.). For a second time distilled water is allowed to flow over the heart until its contractions cease (Curve III.). The heart, however, can be again restored by the application of normal tap-water saline solution, and will continue to beat for hours with con- siderable force and regularity (Curve IV.). This experiment shows conclusively that (i.) normal tap- water saline solution is a good medium for the heart ; (ii.) distilled water is poisonous and reduces the force of the heart- beat until it ceases ; and (iii.) the contraction of the heart can 1 See p. 14. f 1 1 s-s II IS 22 THE PHYSIOLOGICAL ACTION OF DRUGS be restored and maintained for a long time by normal tap- water saline solution. In practical medicine and surgery normal tap-water saline solution, which has been previously sterilised by boiling, is the most suitable fluid for transfusion, washing out the peri- toneal cavity, and in some cases cleansing the cavities of wounds. Alcohol Ethyl alcohol (alcohol ethylicum), C 2 H 5 OH, is a colourless volatile liquid prepared by the fermentation of malt sugar with yeast (saccharomyces cerevisise). The equation C 6 H 12 6 = 2C 2 H 5 OH-h 2C0 2 approximately expresses the process. It has a characteristic odour and taste, a specific gravity about 0-794, boils at 78'3 (173 F.), and has been converted into a solid at a temperature of 130'5. It mixes in all propor- tions with water. EXPERIMENT XV. The Effects of Poisonous Doses. The cerebral hemispheres of a frog are destroyed, and after the slight shock of this operation has passed off, 15 minims (0'888 c.c.) of a mixture, containing 1 part of absolute alcohol to 2 parts of tap-water saline solution, are injected under the skin of the back. The immediate effect is a short stage of excite- ment. Within five minutes a delay is observed in the re- covery of the hind legs after a jump, and, if placed upon its back, the frog does not readily turn over. Keflex movements soon become more and more sluggish, and the frog lies in a toneless and almost completely paralysed condition. Under the skin the slow and forcible beating of the heart can generally be seen, and from time to time the respiratory movements' of the floor of the mouth. After about half-an-hour recovery begins; the muscles slowly regain their tone, and the frog assumes a more natural attitude and crawls about in a sluggish manner. If the frog be kept moist under a bell-jar, complete recovery from the action of the drug occurs after several hours. ALCOHOL 23 Alcohol produces paralysis by its action upon the central nervous system, for if, during the paralysis, the sciatic nerve and the gastrocnemius muscle respectively be stimulated with a weak induction-current, a ready response is obtained. A fatal dose for a frog is one containing about 10 minims (0'592 c.c.) of absolute alcohol; the quantity of water used to dilute the drug will obviously affect the rate of absorption and excretion. It will be observed in the next experiment that strong doses paralyse the heart and thus stop the circulation of the blood. Examination of the body after death shows the ventricle to be firmly contracted but the auricles distended with very venous blood. EXPERIMENT XVI. The Effect upon the Heart. A tracing of the heart-beat of a pithed frog is taken in the ordinary way ; two or three drops of tap- water saline solution are placed on the heart and the effect recorded. Now two drops of a mixture of 1 part of absolute alcohol to 2 parts of tap-water saline solution are placed upon the heart. There is an immediate effect ; the heart loses tone and contracts more slowly and feebly. This is quickly followed by contractions of progressively increasing energy and slower relaxation, so that there is produced a "staircase" effect (Fig. 18, Curve L), and the cardiac muscle soon recovers its tone (Fig. 19). After a minute or two the heart may cease to beat in the diastolic phase, but will respond to a single electrical stimulus with a series of forcible beats and then cease to beat for another period (Fig. 18, Curve II.). A further electrical stimulus will start another series of beats, and then the heart may beat regularly with greatly increased force and so continue for many minutes (Fig. 18, Curve III.). Alcohol, when it is applied in this manner, diminishes the frequency but greatly increases the force of the cardiac contrac- tion. In strong doses the effect is to remove the automatic power of rhythmic contraction, but not to paralyse the muscle, for electrical stimulation will bring about a series f 5, Jssjs J8*** 31 o c . < iissss ALCOHOL 25 of vigorous but slow contrac- tions. Still stronger doses kill the heart. It is necessary to re- member that the effect of the drug depends upon the dose and its penetration into the muscle. 1 The alcohol evaporates, and thus the dose is gradually diminished. EXPERIMENT XVII. The Effect upon the Nervous System. The results of the first experiment show that alcohol first excites and then paralyses the central nervous system; for a time reflex action is abolished, but re- covery may occur, if the dose be not too large. EXPERIMENT XVIII. The Effect upon Muscle and Nerve. Large doses of alcohol applied directly to muscle and nerve at first diminish and then destroy the excitability of both tissues. This can be observed by the dissection of the gastrocnemius muscle and th)e sciatic nerve in its entire length on each side of a pithed frog, placing the muscle of preparation A in 1 See note p. 30. 26 THE PHYSIOLOGICAL ACTION OF DRUGS a watch-glass containing 1 part of absolute alcohol to '2 parts of tap-water saline solution, but leaving the nerve outside ; the nerve of preparation B is placed in another watch-glass containing alcohol of the same strength, while the muscle is in this case left outside. In about ten minutes the excitability of the tissues is so diminished that a very slight response is seen when the nerves are stimulated with a strong induction current. A few minutes later the muscle A and the nerve B no longer respond to stimulation with the strongest current. Ether Ether, (C 2 H 5 ) 2 0, is a colourless, very volatile and inflam- mable liquid with a specific gravity about 0'740. It has a characteristic odour and a pungent taste : its boiling-point is 34-9 (95 F.). It is not very soluble in water, 1 part in 9 parts of water. Ether is prepared by the distillation of alcohol with sulphuric acid ; the chemical change is represented by the following equations : SO H t H j - - c ^ H J k L V EXPERIMENT XIX. The Effects of Poisonous Doses. Under the skin of the back of a frog, whose cerebral hemi- spheres have been destroyed, are injected 7 minims ('414 c.c.) of ether. The immediate effect is great excitement, which soon subsides ; the frog becomes quieter but shows inco- ordination in its movements. The hind legs become more and more helpless, and about fifteen minutes after the administra- tion of the drug the frog is profoundly anaesthetised and lies in a toneless paralysed condition. Respiratory and reflex movements cease, and, apart, it may be, from the slow and 28 THE PHYSIOLOGICAL ACTION OF DRUGS if 5 & o "S s -u C P. 1 forcible beating of the heart, the frog- appears to be dead. If, however, the frog be kept moist for several hours in a shallow plate, filled with water and covered by a bell-jar, complete recovery from the effects of the drug may occur. The anaesthesia and paralysis are due to the action of the drug upon the central nervous system, for if during the stage of paralysis the sciatic nerve and the gastrocnemius muscle are exposed and stimulated with a weak induction shock, there is a ready response, showing that these tissues are still excitable. A fatal dose for a frog is 8 to 10 minims (0*473 to 0'592 c.c.). After death from an overdose of this drug the ventricle of the heart is found to be firmly contracted, but the auricles greatly distended with very venous blood. EXPERIMENT XX. The Effect upon the Heart.' 1 A tracing of the heart-beat of a pithed frog is taken for a minute or two in order to obtain a normal curve ; then two drops of tap- water -saline solu- tion saturated with ether are placed upon the heart. The effect is some loss of tone and diminished frequency, but increased force in the contraction of the ventricle (Fig. 20, Curve I.). After a record has been taken for about two minutes a further dose is applied ; the heart may then cease to beat and may remain in the diastolic phase for about 1 See note p. 30. ETHER CHLOROFORM 29 half a minute. Isolated beats now follow, and then the heart heats regularly with increased force (Fig. 21, which has been reduced to one -half the size of the actual tracing). The further effect is well shown in Figure 20, Curve II.; the rate of contraction is four in fifteen seconds, as compared with seven before the application of the drug, but the height of the contraction is almost doubled. A drop of pure ether will reduce the rate of contraction still further, and will retard the relaxation of the ventricle (Fig. 20, Curve III.). A still stronger dose greatly diminishes the force of the con- traction ; the ventricle contracts and relaxes slowly (Fig. 20, Curve IV.). EXPERIMENT XXI. The Effect upon Muscle and Nerve. Two muscle and nerve preparations are made, and the minimal stimulus for each nerve and muscle is determined. The muscle of one preparation (A) is then placed in a watch-glass filled with normal tap- water saline saturated with ether, but its nerve is left outside ; the nerve of the second preparation (B) is placed in the liquid, but its muscle is kept outside. The excitability of the nerve B rapidly decreases, and in a few minutes is entirely lost ; the muscle B contracts readily to direct stimulation. In the case of the muscle A there is a gradual loss of excitability to direct and indirect stimulation ; the muscle becomes whiter and somewhat contracted, and soon shows a marked decrease in its excitability. In pure ether the muscle rapidly passes into a shortened and rigid condition. These experiments show that ether is a poison to both muscle and nerve. Similar effects are pro- duced by the vapour of ether. Chloroform Chloroform, CHC1 3 , is a colourless heavy liquid with a pleasant odour and a sweet taste. It has a specific gravity, 1*490 ; it is volatile and is soluble in water in the proportion of 1 to 200. Its boiling-point is 62 (143 F.). 30 THE PHYSIOLOGICAL ACTION OF DKUGS It is prepared by the distillation of alcohol with chlorin- ated lime and slaked lime. The reaction may be represented by the following equation : 8CaCl 2 2 = Alcohol Calcium hypochlorite 2CHC1 3 + 3Ca(CO-OH) 2 + 5CaCl 2 + 8H 2 Chloroform Calcium form'ate Calcium chloride Water. EXPERIMENT XXII. The Effects of Poisonous Doses. Under the skin of the back of a frog, whose cerebral hemi- spheres have been destroyed, is injected a dose of "> minims (0*296 c.c.) of chloroform. At first there is a stage of great excitement, which is quickly followed by a period of rest. In about six minutes the frog shows marked inco-ordination and its hind legs are partly paralysed. A few minutes later there will be marked anaesthesia, paralysis, and total absence of reflexes. If, however, the frog be kept moist in a shallow plate full of water and covered by a bell-jar it may, after seven or eight hours, completely recover from the effects of the drug. Chloroform affects the central nervous system, for it can be shown by stimulation of the sciatic nerve and the gastroc- nemius muscle that these tissues are excitable even when the general anaesthesia and paralysis are most profound. A fatal dose for a full-sized frog is 8 minims (0'472 c.c.). An examination of the heart after death shows that the ventricle is empty and contracted, but the auricles are greatly dilated and distended with very venous blood. EXPERIMENT XXIII. The Effect upon the Heart. 1 A record of the contraction of the heart is taken both before and after it has been moistened with normal tap- water saline solution. These curves will serve as a control. Two or three drops of normal tap-water saline solution saturated with pure chloro- 1 Brodie and Dixon have recently found that in the case of chloroform, ether, and alcohol a different effect is observed if the drug is perfused through the heart. CHLOROFORM 31 form (about 1 in 200) are now placed upon the heart ; the first effect is generally a loss of tone ; the heart dilates slightly, and the base line falls a little ; the beat is smaller and slower. In a few minutes the contraction improves, and in some cases may become more forcible and of longer duration than it was before the application of the drug. If a larger dose of the solution or one drop of pure chloro- form be applied, the heart gives one or two feeble beats and FIG. 22. Contraction of the heart of a frog. I. The heart had been moistened only with normal tap-water saline solution. II. The effect of a previous application of several drops of normal tap- water saline solution saturated with chloroform (1 in 200). The time is marked in seconds. then ceases to contract for one or two minutes (Fig. 24, Curves I. and II.). It then begins to beat with increased vigour; the height and duration of the contraction are greater, but the frequency is not so great as in the normal heart. The strength of the dose has been diminished by the evaporation of the chloroform. The standstill of the heart in diastole is generally followed by big but slow contractions ; this effect is probably due to the storage of energy, of combustible material, in the heart during the abnormally long period of rest. The prolonged action of the solution of chloroform causes marked dilatation of the auricles ; they may be distended with fluid but contract so feebly that they cannot force it into the ventricle. At this stage the ventricle may be contracting well. CHLOROFORM CHLORAL HYDRATE 33 EXPERIMENT XXIY. The Effect upon the Nervous System. The first experiment upon the action of chloroform showed that it affected the central nervous system, and produced inco-ordination, then deep amesthesia and paralysis. If the dose be not too large, the effects gradually pass off arid com- plete recovery from the action of the drug occurs. EXPERIMENT XXV. The Effect upon Muscle and Nerve. Two muscle and nerve preparations are made, and the minimal stimuli for muscle and nerve are determined. The muscle of preparation A is placed in a watch-glass filled with normal tap-water saline solution saturated with chloroform ; the nerve is kept outside; the nerve of preparation B, on the other hand, is placed in the fluid ; the muscle remains outside. In a few minutes stimulation of the nerves A and B fails to pro- duce a contraction, but the muscles respond to direct stimula- tion. There is, however, a rapid decrease in the excitability of the muscle A, and in a few minutes more it becomes shorter, rigid and opaque, arid loses its excitability. The muscle B retains its excitability and contracts vigorously when it is directly stimulated. Chloroform is, therefore, in doses of 1 in 200, a rapid poison of muscle and nerve. 1 Chloral Hydrate Chloral hydrate, CC1 8 ' CHO ' H 2 0, the hydrate of trichlor- aldehyde, is a white crystalline substance with a peculiar pungent odour, a caustic taste and a neutral reaction. It is readily soluble in water and melts at a temperature of 46 (115 R). EXPERIMENT XXVI. The Effects of Poisonous Doses. Under the skin of a brainless frog are injected 10 minims (0-592 c.c.) of a 2 per cent, solution of chloral hydrate in normal tap-water saline ; at first there is some excitement, then inco-ordination of movements, sluggishness and a marked 1 Similar effects are produced by the vapour of chloroform. D 34 THE PHYSIOLOGICAL ACTION OF DRUGS decrease in excitability. Recovery from the influence of the drug will occur in about twelve hours, if the frog be kept in a plate full of water and covered by a bell-jar. A dose of 10 n^ (0*592 c.c.) of a 4 per cent, solution will in about twenty minutes abolish all reflex action and the frog lies in an apparently lifeless condition. An examination of the web of the foot under the low power of a microscope shows that the heart -beat is feeble and the circulation is failing. The heart soon ceases to beat and death is the result. At the seat of injection there is some local irritation, and the skin becomes discoloured. The ventricle and auricles are found after death to be slightly distended with venous blood. EXPERIMENT XXVII. The Effect upon the Heart. A record of the contraction of the heart is taken ; a few FIG. 25. Contraction of the frog's heart. I. before and II. after the application of chloral hydrate, 1 part in 100 parts of normal tap-water saline solution. The drug causes a smaller and slower beat. The further action of the drug is shown in the first three contractions of the next tracing (Fig. 26). The time is marked in seconds. drops of normal tap -water saline are applied and the record is continued. Stimulation of the vago - sympathetic CHLORAL HYDRATE 35 nerve will stop the beat and the inhibition will be followed by the characteristic after-effect (Fig. 8). A few drops of a 1 per cent, solution of chloral hydrate in normal tap- water saline are applied. The beats Sllpl ^ 1J will soon become smaller and slower SlSSiSllI lH & - (Fig. 25, Curve II.). Stimulation of the vago-sympathetic nerve will still inhibit the heart, but the recovery is delayed and the after-effect is much ^^^^^^^ less marked (Fig. 26). A further '^^H^l ^ -g "S application of the drug causes con- siderable dilatation of the auricles, and later a smaller dilatation of the i>l " o EXPERIMENT XXIX. upon Muscle and Nerve. Two muscle and nerve preparations are made, and their excitability is tested in the ordinary manner. The nerve of preparation A and the muscle of preparation B are placed in a watch- ventricle. B^BI ^ '* ^^ Sj EXPERIMENT XXVIII. The Effect ^^^ upon the Nervous System. The -. i ~* - results of the first experiment upon ^^^^^^^ the action of chloral hydrate show *t HH ' ^ % that it first increases the excitability of the central nervous system, then diminishes it and causes inco-ordina- tion. A stronger dose abolishes all reflex action. The nerves and wzqsmam*?**.-'^. $ muscle, however, can be excited by SPlM^^ft jf stimuli applied to them. y 'SaMfB^;Ml- ! -I ' 36 THE PHYSIOLOGICAL ACTION OF DRUGS glass filled with a 1 per cent, solution of chloral hydrate in normal tap- water saline. An increase in the excita- bility of nerve A will be .observed, but the muscle B will show a marked decrease in excitability, and in about twenty minutes fails to respond to the strongest direct stimulation. The muscle looks whiter, and is wrinkled ; it has passed into rigor. The nerve A, even at the end of three-quarters of an hour, retains its increased excitability. A stronger solution at first irritates and then paralyses nerve. Strychnine Strychnine, C 21 H 22 N 2 4 , is a very poisonous alkaloid obtained from the seeds of Stryclinos nux vomica. It is a colourless crystalline substance sparingly soluble in water, 1 in 6700. The presence of acids makes the alkaloid more soluble in water owing to the formation of a salt. EXPERIMENT XXX. The Effects of Poisonous Doses Under the skin of a brainless frog are injected 10-15 fl^of a saturated solution of strychnine in normal tap-water saline. In two or three minutes it will be observed that the frog cannot readily draw up its hind legs after a jump, and soon the reflex excitability of the spinal cord is so much increased that a slight touch or puff of wind upon the skin brings about a general spasm of the muscles. Convulsions quickly follow, and the body becomes rigid and rests on the mouth and toes in a position known as emprosthotonus. This attitude is due to the different strength of the various muscles ; all are thrown into contraction, but the stronger overcome the weaker. The muscles are somewhat relaxed after the convulsions, but are again sent into tetanus by the slightest stimulus applied to the skin. These tonic contractions are followed by prolonged twitches or clonus. The spinal cord soon lo_ses its excitability, and the frog lies STRYCHNINE 37 in this condition for several hours ; if, however, it be kept in shallow water arid covered by a bell-jar the excitability will return and recovery from the action of the drug occur in less than twelve hours. This is due to the excretion of the strychnine by the kidneys. The urine of a frog poisoned by strychnine will produce the characteristic convulsions when it is injected into another frog. If, during the stage of convulsions, a probe be pushed down the vertebral canal, so as to destroy the spinal cord, the convulsions cease at once, showing that the drug acts upon the ganglion cells and their dendrites. The death of a frog from a larger dose is quickly followed by well-marked rigor mortis. EXPERIMENT XXXI. The Effect upon the Nervous System. The cerebral hemispheres of a frog are destroyed and then the gastrocnemius muscle is prepared. A strong ligature is placed under the gastrocnemius and tightly tied round the upper portion of the tibio-fibula and the remaining muscles ; the leg is then removed below the ligature ; this method of precaution prevents haemorrhage. A pin is placed through the lower extremity of the femur and is pushed firmly into the cork of the myograph ; a piece of moist flannel is then pinned down over the trunk to prevent the contractions of the muscles of the trunk from disturbing the lever connected with the gastrocnemius muscle. A dose of strychnine similar to that used in the last experiment is injected under the skin of the back. Twitches and convulsions soon begin, and if a signal marking seconds be simultaneously recorded the twitches of the tetanus can be observed to number about eight in a second. This is a measure of the rate of discharge of impulses from the nerve-cells of the spinal cord. The stage of incomplete tetanus is followed by one of clonus. The following curves illustrate the tetanus (Fig. 27) ; the curve of clonus is similar to that produced by hydrastine (Fig. 34). 40 THE PHYSIOLOGICAL ACTION OF DRUGS EXPERIMENT XXXII. The Effect upon the Heart. The vago-sympathetic nerve is exposed and a record is taken of the contraction of the heart. A few drops of normal tap- water saline solution are applied to the heart, the record is continued, and then the vago-sympathetic nerve is stimulated by a strong faradising current. The inhibitory action of the vagus and the after-effect are observed (Fig. 28, Curve I.). A few drops of a saturated solution of strychnine in normal FIG. 29. Contraction of the heart of a frog. The effect of prolonged action of a saturated solution of strychnine in normal tap-water saline solution (1 in 7000). The time is marked in seconds. tap- water saline (1 in 6700) are allowed to flow over the heart. In a few seconds the heart-beat becomes slower but larger ; the vago-sympathetic is again stimulated. Inhibition is not so marked ; there is an after-effect, but the contractions are slow (Fig. 28, Curve II.). Further doses of strychnine are given and the stimulation is repeated. The inhibitory effect of the vagus is removed (Fig. 28, Curve III.). The prolonged action of the drug is to produce a slow and feeble beat (Fig. 29). EXPERIMENT XXXIII. The Effect upon Muscle and Nerve. Two muscle and nerve preparations are made, and the minimal stimuli for both nerve and muscle are determined. The muscle of one preparation, A, is placed in a watch-glass filled with normal tap-water saline solution saturated with strychnine (1 in 6700) ; the nerve is left outside upon a piece of wet filter-paper. The nerve of preparation B is placed in the solution, but its muscle is placed outside upon the filter-paper. HYDRASTINE 41 The minimal stimuli are determined from time to time, and it will be found that the endings of the nerve in the muscle exposed to the strychnine are paralysed. Stimulation of the nerve A produces no contraction, but direct stimulation of the muscle readily evokes a response. In this respect strychnine resembles curare (see Expt. XL VI II.). Hydrastine Hydrastis canadensis, yellow root or golden seal, is a small herbaceous perennial, indigenous to most parts of the United States and Canada ; it belongs to the Kanunculaceae. Hydrastine is one of the alkaloids found in the rhizome of the plant ; it is a colourless, crystalline substance, almost insoluble in water ; its formula is C 21 H 21 NO ( ,. The hydrochlorate of hydras tine is readily soluble in water, and on this account is most suitable for experiments. EXPERIMENT XXXIV. The Effects of Poisonous Doses. The cerebral hemispheres of a frog are destroyed in the way already described 1 ; then 81 decimilligrammes (^ grain) dissolved in % 592 c.c. (10 n\J of tap- water saline solution are injected by a hypodermic syringe under the skin of the back. Within about ten minutes the muscles will begin to twitch and then convulsions will follow. The body during a spasm is rigid and rests on the mouth and toes of the hind limbs ; this posture is known as emprosthotonus. When the spasm has ceased, another can be evoked by touching or blowing upon the skin. The excitability of the spinal cord has been so increased that a very slight stimulus is sufficient to produce a general discharge of impulses to the muscles of the body. Paralysis and death of the tissues will soon follow. By careful observation the spasms are found to be com- posed of a rapid series of contractions, incomplete tetanus or tonus, followed after a pause by a series of prolonged twitches 1 P. 2. 42 THE PHYSIOLOGICAL ACTION OF DRUGS or clonus. These will be recorded graphically in a later ex- periment. A smaller dose will produce the characteristic effects, but if the frog be kept moist in a plate full of water and covered by a bell-jar for a day or two, recovery may occur. The drug is excreted by the kidneys. EXPERIMENT XXXV. The Effect upon the Heart. A preparation of the heart of a normal frog is made, and the cou- A few drops of solution of hydrastine hydrochlorate in tap-water, 1 in 200, painted on sinus. Curve taken twenty-five seconds later. A few drops of solution of hydrastine hydroclilorate in tap- water, 1 in 200, painted on auricles. Curve taken twenty-five seconds later. A few drops of solution of hydrastine hydrochlorate in tap-water, 1 in 200, painted on ventricle. Cnrve taken twenty-five seconds later. Before the application of the drug. The time is marked in seconds. FIG. 30. Contraction of the heart of a frog. These curves show that hydrastine acts chiefly upon the sinus. tractions are carefully observed and recorded upon a slowly HYDRASTINE 43 revolving drum ; then a few drops of tap-water saline solution are applied by a small pipette to the heart, and the effect, if VII. VI. IV. FIG. 31. Contraction of the heart of a frog. The effect of hydrastine hydrochloride. Curve I. is the normal. The remaining curves show the effect of increased doses of the drug. The time is marked in seconds. any, is recorded. Two or three drops of a solution containing 1 part of hydrastine hydrochlorate in 200 parts of saline 44 THE PHYSIOLOGICAL ACTION OF DRUGS are applied to the ventricle and a further record is taken. Now the sinu-auricular junction of the heart is treated in the same way, and a prompt effect will be observed (Fig. 30). The rate of the heart's contraction is diminished, but the force and duration are augmented ; thus in one experiment there were two contractions in fifteen seconds as compared with two in four seconds before the application of the drug, and the duration and force of the ventricular contraction were more than doubled. The curves (Fig. 31) illustrate these points. EXPERIMENT XXXVI. The Effect upon the Inhibitor// Power of the Vagus. In^jjithed frog the vagus nerve is exposed by the dissection elsewhere described, 1 and a small pair of electrodes are placed under it. The rate of the con- traction of the heart is observed, and then a strong faradising FIG. 32. Contraction of the frog's heart. Stimulation of the vago-sympathetic nerve after the action of hydrastine hydrochlorate. The time is marked in seconds. current is passed through the electrodes for a second or two. The heart beats much more slowly or ceases to beat. After the heart has recovered, two or three drops of a solution con- taining 1 part of hydrastine hydrochlorate in 200 parts of saline are placed upon the junction of the sinus and auricle. The effect is a slower and more forcible beat. An interrupted current of the strength previously used is again passed through the electrodes; the heart is not inhibited. It' the electrodes be now applied to the crescentic groove 2 and the current passed, the heart will cease to beat. The drug paralyses the endings of the vagus around the ganglia of the heart. The curve (Fig. 32) is a graphic record of such an experiment. 1 P. 5. ' 2 P. 12. HYDRASTINE 45 EXPERIMENT XXXVII. The Effect upon the Nervous System. It has already been mentioned that poisonous FIG. 33. Incomplete tetanus of the gastrocnemius muscle produced in a orainless frog by the action of hydrastine hydrochlorate. The time is marked in seconds. doses of the drug produce convulsions, and that the ex- citability is so much increased that a slight touch or puff of FIG. 34. Clonic contractions of the gastrocnemius muscle produced in a brainless frog by the action of hydi-astine hydrochlorate. This is a continuation of the tracing (Fig. 33). and its duration is the same, ten seconds ; the contractions are few but prolonged. wind suffices to send the frog into convulsions. The seat of origin of these convulsions can be traced by the following 46 THE PHYSIOLOGICAL ACTION OF DRUGS experiment. In a brainless frog the gastrocnemius muscle is prepared in such a way that the circulation of blood remains intact. 1 The body of the frog is fixed by a piece of moist flannel fastened by pins to the cork of the myograph, and the gastrocnemius muscle is connected with the lever ; when everything is in working order, 81 decimilligrammes (-| grain) of the drug dissolved in 0*592 c.c. (10 IT^) of tap-water saline solution are injected under the skin of the back. In about ten minutes the muscle will begin to twitch, then an incom- plete tetanus will be recorded, and, if the time be marked in seconds, the rate of contraction will be seen to be from eight to ten per second. The tonic contractions will soon cease, and there will occur well-marked twitches, clonus. The final result is paralysis and death of the tissues. If the spinal cord be destroyed by a probe during the stage of incomplete tetanus the contractions will cease at once, showing that the contractions were due to the action of the drug upon the nerve-cells and dendrites in the spinal cord. EXPERIMENT XXXVIII. The Effect upon Muscle and Nerve. From a pithed frog two muscle and nerve preparations are made, care being taken to obtain the entire length of the sciatic nerve. The minimal stimuli for direct and indirect excitation are determined, and then the muscle of preparation A is placed in a watch-glass full of a solution of hydrastine hydrochlorate, 1 in 200 parts of tap-water saline solution, but the nerve is kept outside upon a moist piece of glass or filter paper; in the case of preparation B the nerve is placed in the solution of the drug, but the muscle is left outside. Stimulation of the nerve A will soon fail to produce a contraction, but direct excitation will make the muscle contract. Excitation of the nerve B produces a contraction of its muscle. Soon the muscle A will become more opaque in appearance and will fail to re- spond to the strongest stimulus. The nerve B will retain 1 P. 37. MORPHINE 47 the power of evoking a contraction in its muscle for a con- siderable time. These experiments show that the drug acts first upon the terminations of the nerves in the muscle and then upon the muscle-substance itself. Morphine Morphine, C 17 H 19 N0 3 H 2 0, is an alkaloid prepared from opium, the inspissated juice of the poppy, Papaver somniferum. It is a colourless, crystalline substance, with a bitter taste and an alkaline reaction ; it is slightly soluble in cold water. On account of their greater solubility the salts of morphine will be used in the following experiments. One part of the hydrochlorate, C 17 H 19 N0 3 HC1 3H 2 0, is soluble in 24 parts of water at 15 ; the solubility of the acetate, C 17 H 19 N0 3 C 2 H 4 2> is 1 part in 2^ parts of water. EXPERIMENT XXXIX. The Effects of Poisonous Doses. Under the skin of a brainless frog are injected 10 minims (0*592 c.c.) of a saturated solution (about 4 per cent.) of morphine hydrochlorate in normal tap-water saline solution. No effect will be observed, for the frog is very tolerant of morphine. If a dose of 15 minims (0*888 c.c.) of a 10 per cent, solution of morphine acetate in normal tap -water saline solution be injected under the skin of a brainless frog, poisonous effects will be quickly observed. Within five minutes the frog becomes sluggish, cannot jump well, and does not readily turn over if it be placed on its back. Ten minutes later the frog will be lying with its limbs extended, and will be unable to jump or move in a co-ordinated manner ; reflex movements will be present, but will soon be less marked. Eespiration ceases, all reflexes are abolished, the circulation of the blood in the web of a foot examined under the low power of a microscope will have ceased, and the frog dies. A smaller dose, 5 minims (0'296 c.c.), will abolish all reflex movement, but, if the frog be kept moist in a plate of 48 THE PHYSIOLOGICAL ACTION OF DRUGS water, covered by a bell-jar, the reflex power will gradually return. The excitability will become abnormally increased, so that a slight touch will cause violent convulsions re- sembling those produced by strychnine (see Expt. XXX.). From these effects of the drug the frog may recover in several hours. EXPERIMENT XL. The Effect upon the Nervous System. The foregoing experiments have shown that morphine de- presses the excitability of the central nervous system, and in large doses produces paralysis and death. After non-lethal doses the stage of depression is succeeded by one of greatly increased excitability. Morphine has little or no direct effect upon the nerve fibres (see Expt. XLII.). EXPERIMENT XLI. The Effect upon the Heart. Small doses of morphine have little or no effect upon the heart of the frog ; in this experiment, therefore, a strong solution of the acetate will be used. Eecords are taken of the contraction of the heart before, MORPHINE CAFFEINE 49 and after, the application of a few drops of normal tap-water saline solution. Then the vago-sympathetic nerve is stimulated with a strong faradisiug current, and the inhibition and the after-effect are recorded. Several drops of a saturated solution (about 40 per cent.) of morphine acetate in normal tap-water saline solution are applied to the heart. The beat becomes slower, and if further doses be given from time to time the heart will contract and dilate more slowly and feebly (Fig. 35, Curves I. and II.). Stimulation of the vago-sympathetic nerve is still effective. EXPERIMENT XLI.L. The Effect upon Muscle and Nerve Two muscle and nerve preparations are made, and their ex- citability is measured by a determination of the minimal stimuli. The nerve of preparation A and the muscle of pre- paration B are placed in a watch-glass filled with normal tap -water saline solution saturated with morphine acetate. From time to time the excitability of the muscles and nerves is determined. Little or no change will be observed, if precautions be taken l to prevent drying of the tissues. Muscle and nerve are not affected by morphine. Caffeine Caffeine, C S H 10 N~ 4 2 * H. 2 0, is an alkaloid generally prepared from the dried leaves of Camellia thea, or from the dried seed of Cqffea arabica. It is a colourless, silky, inodorous, crystalline substance soluble in 80 parts of cold water. Coffee contains caffeine. The active principle of tea was formerly known as theine, but it has been proved to be identical with caffeine ; tea also contains theophylline. EXPERIMENT XLIII. The Effects of Poisonous Doses. Under the skin of a brainless frog are injected 10 minims (0'592 c.c.) of a saturated solution of caffeine in normal tap-water saline solution. The immediate effect is a stage of great excitement. See p. 16. E 50 THE PHYSIOLOGICAL ACTION OF DRUGS Within five minutes this is followed by rigidity of some of the limbs, which may persist for an hour or two : this rigidity passes off when the stage of paralysis begins. The reflexes are then entirely absent, and the frog is apparently dead. If, however, it be kept in a plate filled with water, and covered by a bell-jar, the paralysis will gradually disappear and the frog will recover from the effects of the drug in about twenty- four hours. EXPERIMENT XLIV. The Effect upon the Heart. A record of the contraction of the heart is taken, and after the effect, if there be any, of the application of normal tap-water saline solution has been recorded, a few drops of the fluid saturated with caffeine (about 1 part in 80) are placed upon the heart. There is a marked effect. The tone of the cardiac muscle is increased, and the heart only relaxes slightly during the diastole of the ventricle (Fig. 36, Curve I.). Further doses of the drug are applied ; the beat becomes slower and the ventricle contracts so feebly that the auricular contraction may be the higher (Fig. 36, Curves II. and III.). The further action of the drug will cause rigor of the ventricle, but the pulsation of the sinus and of the auricles may continue for several minutes after this stage. The vago-sympathetic nerve is not paralysed by the pro- longed action of the drug (Fig. 36, Curve III.). Caffeine acts most quickly upon the ventricle of the heart. If the heart of a pithed frog be excised and placed in a watch- glass filled with normal tap-water saline saturated with caffeine, the contractions are at first quickened ; the ventricle contracts more and more feebly, and then ceases to beat ; the auricles may still give a powerful contraction from time to time. EXPERIMENT XLV. The Effect upon Muscle ami Nerve. Two muscle and nerve preparations are made, and the minimal stimuli for the nerves and muscles are determined. 52 THE PHYSIOLOGICAL ACTION OF DRUGS The muscle of preparation A and the nerve of preparation B are placed in tap- water saline solution, saturated with caffeine (about 1 in 80). The minimal stimuli are again determined. The muscle under the influence of the drug contracts, becomes white and rigid, and in a few minutes fails to respond to the strongest stimulus ; the caffeine has caused rigor. The ex- citability of the nerve exposed to the drug is increased and is retained for a long time. It will be observed that this action of caffeine upon muscle is also shown in the case of the heart (Expt. XLIV.). EXPERIMENT XLVI. The Effect upon the Nervous System. The results of the first experiment with caffeine show that it increases the excitability of the central nervous system. This stage of excitement is followed by one of deep depression and the abolition of all reflex movements. Recovery slowly takes place. The excitability of nerve is increased by the direct action of caffeine. Curare Curare (Woorari or Urari) is a poisonous compound pre- pared from various plants of the genus Strychnos, and used as an arrow-poison by some of the savage tribes of South America. It is a brown amorphous substance, and contains an alkaloid curarine, C 10 H 15 N, which is soluble in water. EXPERIMENT XL VII. The Effects of Poisonous Doses. Under the skin of the back of a brainless frog are injected 2 minims (0*118 c.c.) of a 1 per cent, solution of curare in normal tap-water saline. Within about five minutes the frog will become completely paralysed and will lie outstretched in a toneless condition ; there will be an absence of respiratory movements and of reflexes. Direct stimulation of the muscles by an electric current will produce a contraction. An ex- amination of the web of the foot with the low power of a CURARE 53 microscope will show that the circulation soon ceases and the frog will die. A smaller dose will produce complete paralysis, but if the frog be kept moist in a plate full of tap-water and covered by a bell-jar, respiration can be maintained by the skin, and re- covery from the effects of the drug may occur in a day or two. The curare is excreted by the kidneys, and the urine of the frog will produce the characteristic effects of the drug if it be injected into another frog. After the injection of non-lethal doses an excessive accumulation of lymph under the skin of the legs is sometimes observed. If curare be given by the mouth it is excreted so quickly by the kidneys that poisonous results do not obtain. EXPERIMENT XLVIII. Effect upon Muscle and Nerve. (a) The gastrocnemius muscle with the entire length of the sciatic nerve is prepared upon each side of a pithed frog. The mini- mal stimuli necessary to excite the muscle and nerve of each preparation are determined. The muscle of preparation A is then placed in a watch-glass full of a 1 per cent, solution of curare in normal tap-water saline solution, but the nerve is placed outside upon a glass-slide moistened with normal tap- water saline solution. The nerve of preparation B is placed in another watch-glass containing a similar solution of curare, but the muscle is left outside. In a few minutes a strong single induction-shock is applied to the nerve A ; the muscle does not contract, but direct stimulation of the muscle produces a response. A weaker stimulus is now applied to the nerve B ; the muscle contracts. These experiments show that the drug paralyses the ter- minations of the nerve in the muscle. The excitability of the muscle is somewhat diminished owing to the direct action of the drug upon the muscle-substance itself. (yS) The cerebral hemispheres of a frog are destroyed, and the sciatic nerve is exposed on each side. A strong ligature is now passed under the right sciatic nerve and is tightly tied 54 THE PHYSIOLOGICAL ACTION OF DRUGS around all the remaining structures of the thigh, in order to completely stop the circulation of the blood in the right leg. Examination of the web of this foot with the low power of a microscope should show that the stream of blood has ceased to flow. Stimulation of either sciatic nerve by an induction- shock will produce a contraction in the muscles it supplies. Under the skin of the back is now injected 1 minim (0'059 c.c.) of a 1 per cent, solution of curare. In a few minutes there will be marked paralysis, and stimulation of the left sciatic nerve will no longer produce a contraction ; stimulation, how- ever, of the right sciatic nerve will produce a contraction, for the poison in the blood has been prevented by the tight ligature from entering the muscles of the right leg. The muscle substance itself is still excitable in the leg exposed to the action of the drug, for the application of the electrodes directly to the left gastrocnemius will produce a contraction. The nerve-trunk on each side has been exposed to the action of the poison, and, as the previous experiment showed, is not affected thereby ; the muscle is excitable on each side ; the block in the nervous impulse must therefore be in the termina- tions of the left sciatic nerve in the muscle. This effect is the characteristic one of curare. EXPERIMENT XLIX. The Effect upon the Nervous System. The previous experiments show that the characteristic action of curare is to paralyse the terminations of the motor nerves, and thus produce general paralysis. The general excitability of the central nervous system is also lowered ; this is shown by the following experiment. Into a brainless frog is injected 1 minim (0*059 c.c.) of a 1 per cent, solution of curare. The general excitability will soon become much diminished, and well-marked signs of the commencement of paralysis will be observed. If 1 minim (0'059 c.c.) of a saturated solution of strychnine (1 in 6700) in normal tap- water saline be injected at this stage, the excitability of the central nervous system will be increased or even raised above that of the CURARE 55 normal. The strychnine has counteracted the depression produced by the curare. The next experiment shows that large doses of curare para- lyse the vagus nerve. EXPERIMENT L. The Effect upon the Heart. A record of the contraction of the heart is taken both before and after the application of a few drops of normal tap-water saline solution. The vago-sympathetic nerve is stimulated with a strong fara- dising current, and the inhibi- tion and after-effect are recorded (Fig. 37). These portions of the tracing will serve as con- trols for the investigation of the action of the drug. Several drops of a solution of 1 part of curare in 100 parts of normal tap- water saline solution are applied to the heart, and this dose is repeated from time to time during the record' of the beat. At first (Fig. 38, Curve I.) it will be possible to inhibit the heart by strong stimulation of the vago-sym- pathetic nerve, but after a large dose no effect, beyond an acceleration, is observed (Fig. 38, Curves II. and III.). The pre-ganglionic endings of the CURARE 57 vagus nerve are paralysed, but not the post-ganglionic fibres of the sympathetic. Stimulation of the sinus will still inhibit the heart-beat, until a dose strong enough to paralyse the post- ganglionic fibres of the vagus is given. IV. in. Fro. 39. Contraction of the heart of a frog. I. This is the normal contraction before the application of curare. II. Stimulation of the vago-sympathetic nerve after the continued action of the drug. There is no inhibition. The slight rise in the base line is due to an escape of current, which stimulated the muscles of the floor of the mouth. III. and IV. Later effect of curare ; the contractions are slower, and the auricular contraction becomes higher than that of the ventricle. The time is marked in seconds. The heart-beat becomes slower and feeble under the further action of the drug, and this effect is especially 58 THE PHYSIOLOGICAL ACTION OF DRUGS marked in the ventricle ; the auricular contraction becomes higher than that of the ventricle (Fig. 39, Curves III. and IV.). There is a marked contrast between curare and atropine ; small doses of the former quickly paralyse the endings of motor nerves, whereas atropine can only effect this when it is applied in large doses and for a considerable time. The endings of the vagus nerve are quickly paralysed by small doses of atropine, but the same result only obtains after the prolonged action of large doses of curare. Nicotine Nicotine, C 10 H 14 N" 2 , is a volatile liquid alkaloid present in tobacco as a malate, and obtained therefrom by distillation with an alkali. Pure nicotine is colourless and has little odour, but, if it be kept for some time, it becomes dark brown in colour, and acquires the characteristic odour of tobacco. It has a strongly alkaline reaction, a specific gravity of 1*027, and is readily soluble in water. EXPERIMENT LI. The Effects of Poisonous Doses. Under the skin of the back of a brainless frog are injected 10 minims (0*592 c.c.) of a solution containing 1 part of nicotine in 20 parts of tap-water saline solution. At once there is a stage of excitement, followed within a minute by tonic contraction of the front limbs and twitches in the hind limbs. The rigidity of the front limbs persists. A slight touch or a puff of wind may now send the frog into tetanus similar to that seen with strychnine. Paralysis follows in about fifteen minutes after the injection, and no reflex movements can be obtained even with the strongest stimulus. Recovery does not occur even if the frog be kept in shallow water for a day or two. An examination of the heart shows that the ventricle is firmly contracted, but the auricles are engorged with very venous blood. A dose of 5 minims (0*296 c.c.) of a 1 per cent, solution NICOTINE 59 of nicotine will produce poisoning from which the frog may recover, if precautions be taken to keep it moist. This and the following experiments show that nicotine acts chiefly on the central nervous system, the sympathetic ganglia, and the terminations of nerve-fibres. EXPERIMENT LII. The Effects upon the Heart. The vago- sympathetic nerve is exposed upon one side of a pithed frog, and the heart is connected with the cardiograph in the ordinary manner. A tracing of the heart's beat before and after it has been moistened with normal tap-water saline solution is taken as a control, and then the vago-sympathetic nerve is stimulated with a strong tetanising current. The heart ceases to beat. Two or three drops of a solution containing 1 part of nicotine in 1000 parts of normal tap- water saline solution are now allowed to flow over the heart. The record is continued during this application of the drug, and in two or three minutes the heart shows a slower but somewhat more prolonged contraction. Stimulation of the vago-sympathetic nerve with the same strength of current as that previously used will now cause no inhibition of the heart-beat ; there may even be an acceleration due to the stimulation of the sympathetic fibres. The pre- ganglionic terminations of the vagus nerve have been paralysed. Direct stimulation of the sinus at this stage will stop the heart-beat (Eig. 41), but if a further dose be given the con- traction becomes more prolonged, less frequent and less powerful, and stimulation of the sinus will now quicken the heart-beat ; on the cessation of the stimulation the heart will cease to beat for several seconds (Fig. 42, Curve L), or even for a minute (Fig. 42, Curve II.). The prolonged action of the nicotine has paralysed all the nervous elements of the heart, which therefore responds to stimulation of the sinus with a series of beats. The effect of nicotine upon the heart varies according to the dose; with solutions of 1 in 1000 or 1 in 500 parts of normal tap-water saline, the beats become slower but more forcible (Fig. 41, and Fig. 40, Curve I.). A stronger solution, I 1 62 THE PHYSIOLOGICAL ACTION OF DRUGS 1 in 100, produces a marked in- crease in the tone of the heart ; the beats are slower and the heart relaxes but slightly in the intervals between the pulsations ; this can be easily observed by the naked eye, and is well shown in the Curves II. and III. of Fig. 40, where the time -mark serves as a base-line. One drop of pure nicotine J ' causes the heart to rapidly pass into P, H a rigid and contracted condition, and ^' all pulsation and excitability are 3 i abolished ; the heart is dead (Fig. I I 43 >- i | I | EXPERIMENT LIII. The Effect & o 5 ^ upon the Nervous System. The first ^ 3 experiment upon the action of 5 '&c "I ' nicotine shows that the drug acts .5 - upon the central nervous system, 'Hi causing at first increased excit- 5 H ability, and then marked depression ^ and paralysis. The terminations of e | the vagus nerve in the heart are ^ ^ also paralysed (Experiment LIL), 5 1 and the next experiment will show ^ ^ that the drug resembles curare in ^ its action upon the terminations of 1 T motor nerves. EXPERIMENT LIV. The Effect upon Muscle and Nerve. Two muscle and nerve preparations are made, and their excitability is tested by a determination of the minimal NICOTINE ATROPINE 63 stimuli. The nerve of preparation A and the muscle of pre- paration B are placed in a watch-glass filled with a solution of nicotine containing 1 part of nicotine and 100 parts of normal tap-water saline solution. The muscle of preparation A and the nerve of preparation B are kept upon a piece of moist filter-paper. Within ten minutes there will be first a great loss in excitability on indirect stimulation of the preparation B, then no contraction on stimulation of the nerve B with the strongest induction-current, and a great loss in the excitability of the muscle B to direct stimulation. An examination of the nerve A will show a decrease in excitability ; a stimulus about twice as strong as the original stimulus is now necessary to evoke a contraction. Little or no change will be observed in the muscle A. This experiment shows that nicotine acts most readily upon the terminations of the nerve-fibres, then upon the muscle- substance itself, and finally upon the trunks of the nerves. Atropine Atropine, C 17 H 23 N0 3 , is an alkaloid prepared from the root of Atropa belladonna, deadly nightshade. It is a colourless, crystalline substance, sparingly soluble in water. In the following experiments sulphate of atropine will be used on account of its solubility in water. EXPERIMENT LV. The Effects of Poisonous Doses. Into a brainless frog are injected 10 minims (0'592 c.c.) of a 10 per- cent, solution of atropine sulphate in normal tap-water saline. There may be a short stage of increased excitability, but it is followed in a few minutes by a marked loss of tone ; the frog lies outstretched, and only responds to a stimulus after a long delay. The reflexes disappear, and the frog lies motionless for several hours. If the frog be kept in a plate of water covered by a bell-jar, recovery from the effects of the drug may occur within twenty -four hours. 64 THE PHYSIOLOGICAL ACTION OF DKUGS Sometimes, during the recovery from the action of smaller doses of the drug, convulsions similar to those produced by strychnine are seen. EXPERIMENT LVI. The Effects upon the Heart. A pre- paration of the x heart is made; the vago-sympathetic nerve on one side is exposed and a pair of small electrodes are placed' under the nerve. A short record of the heart's beat before and after the application of normal tap-water saline is taken for a control ; a strong faradising current is passed through the nerve for a few seconds, and the heart stops beating (Fig. 8). When the after-effects of the stimulation have passed off, two or three drops of a 0*2 per cent, solution of atropine sulphate in normal tap-water saline are placed upon the sinus of the heart. The heart-beat is not much altered : it may be slightly slower and larger ; a marked effect, however, has been produced upon the vago-sympathetic nerve, for a strong faradising current now produces no inhibition, but an acceleration (Fig. 44. Curve I.). The vagus has been paralysed, but the sympathetic is unaffected. The sinus is now stimulated, but no inhibi- tion is produced ; the drug has paralysed the inhibitory mechanism. 1 Further doses of the drug are applied, with the result that the contraction of the heart, especially of the ventricle, becomes weaker and slower (Fig. 44, Curves II. and III.). The muscle of the heart is affected by the poison. The antagonistic action of atropine to muscarine will be observed later (Expt. LXVIIL). EXPERIMENT LVII. The Effect upon the Nervous System. The first experiment upon the action of atropine shows that the drug at first stimulates and then profoundly depresses the central nervous system. Small quantities of the drug rapidly paralyse the termina- tions of the vagus nerve (Expt. LVI.). 1 See p. 97. 66 THE PHYSIOLOGICAL ACTION OF DRUGS EXPERIMENT LYIII. The Effect upon Muscle and Nerve. Two muscle and nerve preparations are made, and their ex- citability is determined ; the nerve of the one (A) and the muscle of the other (B) are placed in a watch-glass filled with 1 per cent, solution of atropine sulphate in normal tap-water saline. From time to time the excitability of the preparations is determined, but little or no change will be observed even after the tissues have been exposed to the drug for fifteen minutes. Very large doses of atropine will paralyse the terminations of the motor nerves. There is a marked contrast, therefore, between atropine and curare ; small doses of the former paralyse the vagus, whereas large doses of the latter are needed to produce that effect ; small quantities of curare paralyse the terminations of motor nerves in voluntary muscle, but very large doses of atropine must be applied before similar effects obtain. (See " Curare," p. 5 5.) Atropine dilates the pupil of the eye by paralysing the terminations of the motor oculi. 1 Cocaine Cocaine, C ir H 21 N0 4 , is an alkaloid obtained from the leaves of cocoa (Erythroxylon coca}. Its hydrochlorate, C ir H 2r N"0 4 *HCl, is used in medicine ; it is a colourless, crystalline substance readily soluble in water, alcohol, and ether. EXPERIMENT LIX. The Effects of Poisonous Doses. Under the back of a brainless frog are injected 5 minims (0'296 c.c.) of a 1 per cent, solution of cocaine 2 -in normal tap- water saline. The excitability of the central nervous system will be rapidly depressed, and in a few minutes the frog will be completely paralysed. No reflexes will be present, but the heart will con- tinue to beat for some time. Death generally occurs within an hour of the injection. Smaller doses, 1 to 2 minims, will produce at first an increased excitability, lasting for a few minutes, and then 1 This effect can be shown by placing a few drops of the solution of atropine sulphate between the eyelids of a rabbit. The dilatation of the pupil thereby produced can be antagonised by physostigmine, muscarine, and pilocarpine. See pp. 75 and 92. ' 2 Cocaine hydrochlorate. U 2 -g a Ss gj-s 43 to a 5s" fl ^ r -2 ?s ia Tt< O n O > z 1 E a la s" 5 ing, not only a standstill of the heart in diastole, but also a change in its nutrition, a storing up of combustible material or anabolism. The after-effect of the stimulation of this nerve is a more power- ful contraction, and the restoration of a normal se- quence in the contraction of the various chambers of the heart, if the beat had been previously so irregular that a ventricular contraction did not follow that of the auricles ; the improvement in nutrition removes a block (Fig. 67). The sympathetic nerve, on the other hand, causes acceleration of the beat of the heart (Fig. 7), and increased destruction of combustible material or katabolism. Further, Gaskell has shown that the ganglion-cells of the heart are to be looked upon simply as peripheral efferent nerve-cells connected with the inhibitory fibres of the vagus nerve; the fibres of that nerve are medullated when they enter the heart, but non- medullated fibres are found in the auricles and ventricle. The accelerator fibres in the white rami communicantes THE PHYSIOLOGICAL ACTION OF DRUGS 97 from the second, third and fourth thoracic nerves are medullated, and are re- lated to the ganglion Stella turn, from which issue the non-medullated accelerator fibres, which form the sympathetic nerve passing to the heart. The action of drugs applied to the heart of a pithed frog may be due to the influence of the drug upon (1) the nervous elements in the heart, or (2) the muscle- substance of the heart, or (3) both of these tissues. The Influence of Drugs upon the Nervous Element* of the Heart. The drug may act upon the pre- ganglionic fibres, upon the post-ganglionic fibres, or upon all the nervous tissue found in the heart (Fig. 70). Different drugs select different parts, and the same drug may, according to the strength of be dose, act upon one or all of the nervous elements. Thus it has been shown (Expt. 10 12; FIG. 68. Diagram of the nerves of the heart. 1, Nerve -cell of the vagus centre in the medulla oblongata. 2, Medullated inhibitory fibre of the vagus. 3, Its termination around a ganglion-cell. 4, In the heart. 5, Post- ganglionic non-medullated fibre and its ter- mination. 6, In the muscular tissue of the heart. 7, Ganglion - cell giving rise to the medullated accelerator fibre. 8, In the white ramus communicans. 9, The termination around the nerve-cell. 10, Of the ganglion stellatum. 11, The post-ganglionic non- medullated nerve fibre and its terminations. 1 2, In the muscular tissue of the heart. The heart is roughly indicated in outline. H 98 THE PHYSIOLOGICAL ACTION OF DRUGS LII.) that nicotine at first paralyses the pre-ganglionic fibres of the vagus, so that stimulation of the vago- sympathetic nerve with a strong faradising current produces no standstill, but acceleration ; at this stage, however, the application of the electrodes to the sinus will cause standstill owing to the excitation of the post-ganglionic fibres of the vagus (Fig. 41). The further action of a strong dose of the drug is to paralyse all the nervous elements of the heart, and the contractions are extremely slow and may cease altogether, owing to the direct action of the drug upon the muscle-fibres ; stimulation of the sinus now causes a series of beats (Fig. 42), for the muscle still responds to stimulation. In a similar manner curare (Expt. L.) acts on the pre- ganglionic fibres around the nerve-cells before it acts upon the junction of the post-ganglionic fibres with the cardiac muscle. It has been shown (Expt. LVI.) that after very small doses of atropine stimulation of the vagus nerve and of the sinus will not produce inhibition ; the drug paralyses the terminations of the post-ganglionic fibres of the vagus. The Influence of Drugs upon the Muscle- Substance of the Heart. The action of drugs upon the muscular fibres of the heart may be either to increase or diminish the contraction of the heart ; the drug may act tonically or atonically. A good example of the former class is digitaline (Expt. LXXVI.) ; of the latter, muscarine (Expt. LXVIII.). A strong dose of digitaline causes the heart to pass into a firmly contracted condition and kills it in the systolic phase ; on the other hand, muscarine causes the heart to cease beating in a relaxed condition, in the phase of diastole. Veratrine and caffeine also act tonically upon the muscle of the heart (Expts. LXXIII. and XLIV.). The Influence of Drugs upon loth the Nervous and Muscular Tissues of the Heart. Many of the drugs which act most readily upon the nervous elements of the heart attack the muscular tissue if their action be prolonged or the dose be increased. This can be observed in the case of atropine : THE PHYSIOLOGICAL ACTION OF DRUGS 99 weak doses produce little alteration in the beat of the heart, but rapidly paralyse the post-ganglionic fibres of the vagus (Expt. LVI.) ; further doses act on the muscle and lengthen the duration of the contraction (Fig. 44). Mcotine and curare also show an action first upon the nerves and then upon the muscle. Antagonism. In the experiments upon muscarine and pilocarpine, it has been shown that the effects of the drug upon the heart can be removed by the action of atropine, and that further doses of muscarine, or pilocarpine, as the case may be, will again produce a slower and more feeble beat. Such an action is known as antagonism, and the drugs are said to be antagonistic. In true cases of antagonism, the opposed action is mutual; the action of the one drug can be reversed by the other, and that of the other by the one. An antidote is a remedy which counteracts the effect of a poisonous sub- stance, but it is not necessarily a true antagonist ; thus chalk is an antidote to oxalic acid, because it forms an insoluble chemical compound. In the case of most antagonists, there is no evidence of direct chemical interaction ; the two poisons mixed in a glass vessel do not form an inert chemical compound, but remain a mixture of the two poisons. The explanation of antagonism may possibly be found in different chemical changes set up in the tissues by the drugs. Strychnine affects the nerve-cells, and causes increased excitability and convulsive discharges of nervous impulses ; chloral hydrate diminishes the excitability and paralyses the nerve-cells ; the one drug is the antagonist of the other, and in appropriate doses will counteract its effects. 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