XIII The Action of Drugs
Long after the Renaissance, the practice of medicine was still under the influence of magic. Whatever things were rare and precious were held to be good against disease—gold, amber, coral, pearls, and the dust of mummies; whatever took strange forms of life—toads, earthworms, and the like; whatever looked like the disease, after the doctrine of signatures—pulmonaria for the lungs, because the spots on its leaves were like tubercle, a kidney-shaped fruit for the kidneys, a heart-shaped fruit for the heart, and yellow carrots for the yellow jaundice. Among the drugs in the 1618 Pharmacopœia are cranium humanum, mandibula lucii, nidus hirundinum, sericum crudum, linum vivum, and pilus salamandræ. In the Pharmacopœia of 1667 are exuviæ serpentis, telæ aranearum, saliva jejuni, cranium hominis violentâ morte extincti, and worse obscenities.
Soon after the publication of this Pharmacopœia, on 14th February 1685, King Charles II. died; and in the Library of the Society of Antiquaries there is a manuscript account in Latin, by Dr. Scarbrugh, how the case was treated. The King had sixteen physicians, and nine consultations in five days; and to say “everything was done that was possible” gives no idea of the vigour of the treatment. Finally, the day he died, they gave him, eleven of them in consultation—totus medicorum chorus ab omni spe destitutus—they gave him, as more generous cardiacs, the lapis Goæ, and the Bezoar-stone. The lapis Goæ was a dust of topaz, jacinth, sapphire, ruby, pearl, emerald, bezoar, coral, musk, ambergris, and gold, all made into a pill and polished; and the bezoar is a calculus found in the intestines of herbivorous animals. Half a century later, the Pharmacopœia of 1721 still included ants’ eggs, teeth, lapis nephriticus, and other horrors; and in the Pharmacopœia of 1746, though the dust of Egyptian mummies was ruled out, vipers and wood-lice were retained.
Certainly these “last enchantments of the Middle Ages” were slow to depart. Clinical observation, anatomy, and pathology, had all failed to bring about a right understanding of the actions of drugs. It was the physiologists, not the doctors, who first formulated the exact use of drugs; it was Bichat, Magendie, and Claude Bernard. That is the whole meaning of Magendie’s work on the upas-poison and on strychnine, and Claude Bernard’s work on curari and digitalis. Of these four substances, two only are of any use in practice; yet Magendie’s study of strychnine41 was of immeasurable value, not so much because it gave the doctors a “more generous cardiac,” though that was a great gift, but because it revealed the selective action of drugs. Contrast his account of strychnine with Ambroise Paré’s story how they tested the bezoar-stone on the thief instead of hanging him; contrast Bernard’s chapter on curari with Dr. Scarbrugh’s notes on the King’s death, with all the Crown jewels inside him: you are in two different worlds. The selective action of drugs—the affinity between strychnine and the central nerve-cells, between curari and the terminal filaments of the motor nerves—that was the revolutionary teaching of science: and it came, not by experience, but by experiment.
Take Professor Fraser’s address on “The Action of Remedies, and the Experimental Method” at the International Medical Congress in London, 1881:—
“The introduction of this method is due to Bichat; and, by its subsequent application by Magendie, pharmacology was originated as the science we now recognise. Bichat represents a transition state, in which metaphysical conceptions were mingled with the results of experience. Magendie more clearly recognised the danger of adopting theories, in the existing imperfections of knowledge; and devoted himself to the supplementing of these imperfections by experiments on living animals. The advantages of such experiments he early illustrated by his investigation on the upas-poison; and afterwards by a research on the then newly-discovered alkaloid, strychnia.... He demonstrated the action of this substance upon the spinal cord, by experiments upon the lower animals, so thoroughly, that subsequent investigations have added but little to his results.”
Or take Professor Fraser’s account of digitalis:—
“It was introduced as a remedy for dropsy; and, on the applications which were made of it for the treatment of that disease, a slowing action upon the cardiac movements was observed, which led to its acquiring the reputation of a cardiac sedative. Numerous observations were made on man by the originators of its application, by Dr. Sanders and many other physicians, in which special attention was paid to its effects upon the circulation; but no further light was thrown upon its remarkable properties, with the unimportant exception that in some cases it was found to excite the circulation. It was not until the experimental method was applied in its investigation, in the first instance by Claude Bernard, and subsequently by Dybkowsky, Pelikan, Meyer, Boehm, and Schmiedeberg, that the true action of digitalis upon the circulation was discovered. It was shown that the effects upon the circulation were not in any exact sense sedative, but, on the contrary, stimulant and tonic, rendering the action of the heart more powerful, and increasing the tension in the blood-vessels. The indications for its use in disease were thereby revolutionised, and at the same time rendered more exact; and the striking benefits which are now afforded by the use of this substance in most (cardiac) diseases were made available to humanity.”
Or take Sir T. Lauder Brunton’s account of the action of nitrite of amyl in angina pectoris:—
“The action of nitrite of amyl in causing flushing was first observed by Guthrie, and Sir B. W. Richardson recommended it as a remedy in spasmodic conditions, from the power he thought it to possess of paralysing motor nerves. In the spring of 1867 I had opportunities of constantly observing a patient who suffered from angina pectoris, and of obtaining from him numerous sphygmographic tracings, both during the attack and during the interval. These showed that during the attack the pulse became quicker, the blood-pressure rose, and the arterioles contracted.... It seemed probable that the great rise in tension was the cause of the pain, and it occurred to me that if it was possible to diminish the tension by drugs instead of by bleeding, the pain would be removed.
“I knew from unpublished experiments on animals by Dr. A. Gamgee that nitrite of amyl had this power, and therefore tried it on the patient. My expectations were perfectly answered. The pain usually disappeared in three-quarters of a minute after the inhalation began, and at the same time the pulse became slower and much fuller, and the tension diminished.”
Of course it would be easy to lengthen out the list. Aconite, adrenalin, belladonna, calcium chloride, colchicum, cocain, chloral, ergot, morphia, salicylic acid, strophanthus, the chief diuretics, the chief diaphoretics—all these drugs, and many more, have been studied and learned by experiments on animals. Then comes the answer, that drugs act differently on animals and on men. The few instances, that give a wise air to this foolish answer, were known long ago to everybody: they do not so much as touch the facts of daily practice:—
“The action of drugs on man differs from that on the lower animals chiefly in respect to the brain, which is so much more greatly developed in man. Where the structure of an organ or tissue is nearly the same in man and in the lower animals, the action of drugs upon it is similar. Thus we find that carbonic oxide, and nitrites, produce similar changes in the blood of frogs, dogs, and man, that curare paralyses the motor nerves, alike in them all, and veratria exerts upon the muscles of each its peculiar stimulant and paralysing action. Where differences exist in the structure of the various organs, we find, as we would naturally expect, differences in their reaction to drugs. Thus the heart of the frog is simpler than that of dogs or men, and less affected by the central nervous system; we consequently find that while such a drug as digitalis has a somewhat similar action upon the hearts of frogs, dogs, and men, there are certain differences between its effect upon the heart of a frog and on that of mammals.
“Belladonna offers another example of apparent difference in action—a considerable dose of belladonna will produce almost no apparent effect upon a rabbit, while a smaller dose in a dog or a man would cause the rapidity of the pulse to be nearly doubled. Yet in all three—rabbits, dogs, and men—belladonna paralyses the power of the vagus over the heart. The difference is that in rabbits the vagus normally exerts but little action on the heart, and the effect of its paralysis is consequently slight or hardly appreciable.” (Professor Fraser.)
It would be strange indeed, if experts who work in micromillimetres and decimal milligrammes, and study the vanishing-point of microscopic structures, and measure and ordain infinitesimal changes in invisible organisms, were blind to such gross and palpable differences as exist between men and pigeons in their susceptibility to a dose of opium.
Anæsthetics must be reckoned among the drugs that have been studied on animals: but, for the discovery of them, men experimented on themselves. The first use of nitrous oxide (laughing gas) in surgery was 11th December 1844, when Horace Wells, of Connecticut, had it administered to himself for the removal of a tooth. The first use of ether was made by Dr. Long, of Athens, Georgia; but he did not publish the case, or follow up the work: and the honour of the discovery of ether went to Morton, of Boston, who made repeated experiments, both on animals and on himself. The date when he first rendered himself absolutely unconscious for seven or eight minutes, is 30th September 1846; and the first operation under ether was done on 16th October, in the Massachusetts General Hospital. The first use of chloroform was 4th November 1847, that famous evening when Simpson, George Keith, and Matthews Duncan took it together. The whole history of anæsthesia is to be found in the Practitioner, Oct. 1896.
It is sometimes said that the men who make experiments on animals ought to make them on themselves. But they do, hundreds of them, and suffer for it: Heaven knows the list is long enough—the discoverers of anæsthesia, Hunter, Garré, Koch, Klein, Moor, Haffkine, Grassi, Bochefontaine, Quesada, Sanarelli, Pettenkofer—these and hosts more, here or abroad, have done it, as part of the day’s work; and some—by accidental infection, like Chabry and Villa, or by deliberate self-inoculation, like Carrion—have been killed:—
“Dr. Angelo Knorr, Privat-docent in the Veterinary School of Munich, died on 22nd February from acute glanders, contracted in the course of an experimental research on mallein. Helmann, the Russian investigator who discovered mallein, himself fell a victim to accidental inoculation of the glanders virus. Some time afterwards another Russian, Protopopow, died of glanders contracted in a French laboratory. An Austrian physician, Dr. Koffman-Wellenhof, died of the same disease, contracted in the Institute of Hygiene at Vienna. On 17th January of the present year Dr. Guiseppe Bosso, of the University of Turin, died of infection contracted in the course of cultivations of tubercle-bacilli made in his laboratory. Not long before, Dr Lola, assistant in the maternity department of the Czech University Hospital of Prague, died of tetanus caused by an experimental inoculation made on himself. Some fourteen or fifteen years ago, a medical student of Lima proved that ‘verruga Peruana’ is an infectious disease by inoculating himself with it, an act of scientific devotion which cost him his life.42 Besides those who have died, there are many who have only escaped with their lives after long and painful illness. Professor Kourloff contracted anthrax in a laboratory at Munich, and was saved only by vigorous surgery. Dr. Nicolas supplied, in his own person, the first example of tetanus produced in man by inoculation of the pure toxin of the bacillus of Nicolaier.” (Brit. Med. Journal, 18th March 1899.)
This list is seven years old now; it is twice the length by this time. Typhoid, malaria, yellow fever, have all taken toll of those who study them. It is a long record of the men who fell ill, or died, or killed themselves over their work; and the deaths of Barisch, Dr. Müller, and Nurse Pecha, from plague at Vienna (October 1898) are another instance that there is danger in the constant handling of cultures. But these deaths at Vienna were due to the great carelessness of one man. In laboratories in all parts of the world there are stored cultures of all sorts of organisms, yet no harm comes of it. “More cases of infection occur amongst young medical men attending fever cases, whether in private practice or hospital wards, in a single month, than have occurred in the whole of the laboratories in the world since they were established.” (British Medical Journal, 29th October 1898.) Outside the laboratory, outside the fever hospitals, the risk is something less than a negligible quantity:—
“Apart from plague and cholera, in all the big laboratories studies are uninterruptedly pursued, from one end of the year to the other, upon anthrax, glanders, influenza, Malta fever, various tropical diseases which do not exist at all or are rare in the countries where they are being studied. The laboratories in question are situated in the largest and most important towns of their respective countries; and, within those towns, very often in the most fashionable or most populous centres.... On no occasion was there even a suspicion aroused of an epidemic having been produced by any of the above-mentioned institutes, or by those tens of thousands of operations against cholera performed in India.” (Haffkine, Madras Mail, 8th December 1898.)