Pharmacology

Pharmacology. Systematic writers on the subject differ considerably in the exact meaning which they attach to the term pharmacology (41appaKov, a drug; Xayos, a discourse), some making it much more comprehensive than others. Binz, for instance, defines it as treating of the origin, nature, chemical and physical qualities, physiological actions, and therapeutical uses of drugs; in France and in Italy it is restricted to the mere description of medicines and their preparations, the action and uses of which as remedies are included in the term therapeutics. In English-speaking countries, and by the majority of German writers, the meaning is now restricted to the study of the action of chemical substances (as apart from foods) on all kinds of animals, from bacteria up to man; it is, in fact, a comparative study of the action of chemical bodies on invertebrate and vertebrate animals. One of its practical aims is to obtain a wide and accurate knowledge of remedial substances in relation to their application in the treatment of disease, while another is to discover new or improved remedies. This meaning of the word has now become fixed in the English language by use and wont. The term pharmaco-dynamics (4 appaKov, Suvapas, power), which is etymologically more correct, is often used as its equivalent, but it has never become widely adopted. The study of pharmacological actions was at first almost entirely confined to those of remedial agents, and especially to the remedies in the different national pharmacopoeias, but in many cases it has now been extended to substances which are not used for curative purposes. The introduction into practical use of many medicines, such as paraldehyde, phenazone and strophanthus, has followed the study of their actions on animals, and this tends to be more and more the case. Pharmacology is a branch of biology; it is also closely connected with pathology and bacteriology, for certain drugs produce structural as well as functional changes in the tissues, and in germ diseases the peculiar symptoms are caused by foreign substances (toxins) formed by the infective organisms present in the body. The effects of many of these toxins bear a close resemblance to the action of certain wellknown drugs, as in the case of tetanus toxin and strychnine, and are studied by the same methods of observation and research. It is impossible also to dissociate pharmacology from clinical therapeutics; the former investigates the agents which are used in the treatment of disease, the latter is concerned with their remedial powers and the conditions under which they are to be used. Hence the word "pharmaco-therapy" has come into use, and most of the newer standard textbooks combine together the consideration of pharmacology and therapeutics. Pharmacology is also related to toxicology, as many remedial and other agents are more or less poisonous when given in large doses, but it does not include the detection, tests, and the other strictly medico-legal aspects of poisoning.

Pharmacology proper began as the result of the application of strictly experimental methods to physiology. The discovery istory. (early in the 19th century) that plants owe their H  remedial and poisonous qualities to small quantities of definite active principles, such as alkaloids and neutral bodies, which can be extracted in a chemically pure condition, had also a very important effect on its development. We meet first with experiments made by investigators who perceived that observations on man and animals might lead to a better understanding of the action of drugs. In 1676 Wepfer and Conrad Brunner demonstrated on dogs the tetanizing action of nux vomica, and similar rough experiments were repeated from time to time with other substances by later investigators. In 1755 Menghini published an elaborate study of the action of camphor on a great variety of different kinds of animals. Albert von Haller (b. 1708) sought to elucidate the action of remedies by observations on healthy men, and in 1767 William Alexander made experiments on himself with drugs, which were, however, brought to an abrupt termination by his nearly killing himself. In 1776 Daries, by observations on himself and on cats, established the mydriatic action of belladonna and other atropaceous plants. Hitherto no attempt had been made to determine what particular parts of the body were especially affected by drugs, but Fontana showed, in his great work (Florence, 1765) on the venom of the viper and on other poisons, that the general symptoms were brought about by an action on particular organs. He performed more than six thousand experiments, more than four thousand of which were on animals, and he determined the effects on the heart and other important structures. These analytical methods of research were well known to the second Monro in Edinburgh, and to his pupils, one of whom, William Alexander, wrote a thesis in 1790 entitled "De partibus corporis animalis quae viribus opii parent." His methods were doubtless known also to the French physiologist Magendie, who improved upon them, and who in 1809 published a research on the Upas Tieute and other strychnine-containing plants, in which he showed that their effects were due to an action on the spinal cord. The researches of his pupil, Claude Bernard, on curare, were equally exact and logical, and have served as the model for many subsequent investigations. In consequence, from the time of Magendie pharmacology may be said to have been put on a more exact basis. By the middle of the 19th century there were many workers on the subject, and the actions of such drugs as digitalis, morphine, alcohol, and many others had been frequently and minutely investigated. About this time Buchheim, professor of materia medica in Dorpat from 1846 to 1879, founded the first pharmacological laboratory on modern lines in Europe, and he introduced a more rational classification of drugs than had hitherto been in use, arranging them in groups according to their pharmacological actions. In the herbals and older treatises on materia medica and therapeutics no explanation is usually offered of the action of medicines, and in such works as that of Cullen (1789) only a few of the more obvious actions are occasionally explained according to the current theories of physiology and pathology. In works such as Pareira's Elements of Materia Medica and Therapeutics (1842), the physiological effects of medicines are usually described, but very briefly as compared with the materia medica. At the present day most textbooks dealing with medicinal agents and treatment devote a large part of their space to pharmacology, and a corresponding change has taken place in the teaching of the subject in universities and medical schools. Since Magendie's time numerous papers dealing with pharmacological subjects have appeared in the Journal of Anatomy and Physiology, the Journal of Physiology, Virchow's Archiv, and the principal medical periodicals of all countries. In 1873 the Archiv fiir experimentelle Pathologie and Pharmakologie first appeared, in 1895 the Archives Internationales de Pharmakodynamie, and in 1909 The Journal of Pharmacology and Therapeutics (published at Baltimore, U.S.A.), all of which are chiefly or entirely devoted to pharmacology.

The methods of research are essentially those employed by physiologists, the action of substances being studied in the usual way on bacteria, leucocytes, frogs, rabbits and other animals. Not only are the general symptoms investigated, but it is necessary to carry out experiments'on the nerves, muscles, circulation, secretions, &c., so as to get a more exact knowledge of the reasons of the general action. It is true that many of these animals react somewhat differently to drugs, both as regards each other and as regards man, but for the most part the differences are quantitative rather than qualitative. After carrying out a series of observations on animals, the drug can be assigned to its special group, and a good idea can be obtained of its possible practical value or the reverse; hence there is a saving of time and an avoidance of the necessity of testing its effects on man. The action of a drug may be called direct when it acts on any part to which it is immediately applied, or which it may reach through the blood; and indirect when one organ is affected secondarily to another, as, for instance, in strychnine poisoning when the muscles are violently contracted as the result of the action of the alkaloid upon the spinal cord. In a few cases the action is merely physical, but most frequently it is chemical in its nature, and is exerted on the living cell, the activity of which is either stimulated or depressed. In some cases the substances actually enter into a chemical combination with the protoplasm, which may be temporary or (much less frequently) permanent; in other cases they seem simply to modify or disturb the usual chemical activity of the cells. Prolonged or excessive stimulation invariably leads to depression or paralysis, the tissues becoming fatigued, and from this condition they may recover or they may not. When we come to consider more in detail the results of these actions we find that the various secretions of the body, such as the sweat, gastric juice, bile, milk, urine, &c., may be increased or diminished; that the heart may have its muscular or nervous apparatus stimulated or depressed; that the nerve-centres in the brain, medulla and spinal cord may be rendered more sensitive or the reverse; and that the general metabolism of the body may be altered in various ways. In addition, the fluid constituents, such as the lymph and blood, may have their composition and bulk considerably altered, while the special senses, the temperature, and, in short, every function and tissue, may be more or less affected.

Some drugs given in excess are poisons to all forms of protoplasm, but when given in doses much short of the lethal they usually exhibit a distinct tendency to affect specially, and at an early period, certain organs or tissues, and hence result differences in action; others may act only on certain organs, leaving the others practically untouched. It is often possible by appropriate dosage to contrive that these special parts or organs may be affected and the rest of the body left practically intact, and it is by taking advantage of these selective actions that remedial or therapeutical effects are usually obtained. Some substances have a very wide range of action, and involve a great variety of structures, while others, such as purgatives, have a very limited sphere. The action of drugs is often modified by circumstances peculiar to the individuals or animals to whom they are administered. In man the most important of these circumstances is age, but speaking broadly this is really a question of bulk, the child being affected like the adult, but by smaller doses. There are exceptions to this, however, as children are more affected in proportion by opium and some other substances, and less by mercury and arsenic. In old age also the nervous system and the tissues generally do not react so readily as in youth. Habit,. race, personal temperament, emotional conditions, disease, the time and circumstances of administration, and other accidental causes may also modify the action in man. Some species of animals are much more susceptible to the action of certain drugs than others, a condition which depends on obvious or unknown structural or metabolic differences. In the same way some individuals show a special tendency to poisoning by doses of certain drugs which are harmless to the great majority of mankind, and hence we get unexpected or unusual results, these arising from special susceptibility on the part of certain organs. These idiosyncrasies are not confined to drugs, but are seen with a few articles of food, such as eggs and shellfish. It is well known that the habitual consumption of certain drugs, such as tobacco, Indian hemp, opium, arsenic, alcohol and many others, gradually induces a condition of tolerance to their effects, so that large doses can be taken without causing symptoms of poisoning. In all cases, however, there is a limit, and after it is reached the ordinary effects of these substances are seen. Some individuals, however, never become tolerant, and show poisonous effects on each repetition of the dose. The degree of tolerance often differs in individuals at different times and in different circumstances, and may become lost by breaking off the habit for a short time. The explanation generally given is that the nerve and other cells become accustomed to the drug, so that they cease to react, or that an antitoxin is formed which antagonizes the poison, or that the poison is rapidly destroyed in the body. Recent researches on arsenic and atropine, however, point to the leucocytes as playing an important part in the production of tolerance, as these gradually become capable of ingesting large amounts of the foreign substances, and thus render them more or less harmless to the tissues, until they are gradually excreted from the body. When the amount is too large to be dealt with by the leucocytes, poisoning seems to occur even in the most habituated. Tolerance is therefore analogous to, but not identical with, the immunity which takes place with the toxins of infectious diseases and snake poison. Certain substances, notably digitalis, lead, mercury and strychnine, exhibit what is called a cumulative action - that is to say, when small quantities have been taken over a period of time, poisoning or an excessive action suddenly ensues. The explanation in these cases is that the drug is absorbed more rapidly than it is excreted, hence there is a tendency to accumulation in the body until a point is reached when the amount becomes poisonous. .

Bodies which have a close resemblance in their chemical constitution exhibit a similar resemblance in their pharmacological action, and as the constitution of the substance becomes modified chemically so does its action pharmacologically. Numerous researches have demonstrated these points with regard to individual groups of substances, but hitherto it has not been possible to formulate any fixed laws regarding the relationship between chemical constitution and physiological action.

When drugs are swallowed no absorption may take place from the alimentary canal; but, as a rule, they pass from there into the blood. Absorption may also take place from the skin, from the rectum, from the respiratory passages, or from wounds, and from direct injection into the subcutaneous tissue or into a blood vessel. Very rarely, as in the case of silver salts, excretion does not take place; but usually the drug is got rid of by the ordinary channels of elimination. Just as drugs act upon the tissues, so they themselves are in many cases reacted upon, and broken up or altered. While in the alimentary canal they are subjected to the action of the digestive fluids and the varied contents of the stomach and intestines, and after absorption they come under the influence of the constituents of the blood and lymph, and of the chemical action of the tissue cells. Inorganic bodies, such as metals, may enter into albuminous combinations which may greatly modify their effects, and organic substances may be split up into simpler compounds by oxidation or reduction, or may be rendered more complex by synthesis.

The antagonism between certain drugs has been much studied in relation to their use as antidotes in poisoning, the aim being to counteract the effects rather than to obtain a direct physiological antagonistic action. Substances which directly antagonize each other by acting on the same tissue are few in number, but there are numerous instances in which the effects or symptoms may be obviated by acting on another tissue. Thus curare may stop strychnine convulsions by paralysing the terminations of motor nerves, and chloroform may exercise the same effect by abolishing the irritability of the spinal cord. If two poisons act on the same tissue, one stimulating and the other paralysing it, the paralysing substance removes the action of the stimulant substance, not by bringing the tissue back to its normal state, but by abolishing its excitability; hence, although life may be saved by such an action, yet it can only be so within certain limits of dosage, because the antagonism is never complete at every point.

Speaking in the widest sense, every substance has an action on living protoplasm, but for convenience pharmacological substances have come to be limited to those which are used as drugs, or which have a distinct action upon the animal organism. Such substances are derived from (z) the chemical elements and their compounds; (2) plants; and (3) animals. The first class includes such substances as iodine, mercury, iron, carbon, and their various compounds, and such bodies as alcohol, chloroform and chloral, all of which are found in nature or can be prepared by ordinary chemical processes of manufacture. From plants many substances are obtained which at the present time we are unable to make in the chemical laboratory, and of the constitution or composition of which we are in many cases ignorant. Some of these, such as resins, gums, essential oils and fats, are readily obtained as natural exudations or by very simple manipulations, while others, such as the alkaloids, glucosides and vegetable acids, often require to be extracted by very complex processes. Substances obtained from animals include gland secretions, pepsin and other ferments, musk, cod-liver oil, &c., and to these may be added various antitoxins. The classification of substances having pharmacological actions presents so many difficulties that no satisfactory or universally adopted method has yet been proposed. Our knowledge presents so many gaps, and the mode of action of many remedies is so obscure and imperfectly understood, that any arrangement adopted must be more or less tentative in character. The close alliance between pharmacology, therapeutics and clinical medicine has induced many authors to treat the subject from a clinical point of view, while its relationships to chemistry and physiology have been utilized to elaborate a chemical and physiological classification respectively as the basis for systematic description. Certain writers in despair have adopted an alphabetical arrangement of the subject, while others have divided it up into inorganic, vegetable and animal substances. These last-mentioned methods are far behind our present state of knowledge, and need not be discussed here. The objection to a strictly chemical classification is, that while many substances closely allied chemically have a somewhat similar action in certain respects, yet in others they differ very widely - a striking example of which is given in the case of sodium and potassium. A physiological classification according to an action on the brain, heart, kidney or other important organ becomes still more bewildering, as many substances produce the same effects by different agencies, as, for instance, the kidneys may be acted upon directly or through the circulation, while the heart may be affected either through its muscular substance or its nervous apparatus. A clinical or therapeutical classification into such divisions as anaesthetics, expectorants, bitters, and so on, according to their practical applications, also leads to difficulties, as many drugs are employed for numerous purposes. The ideal method of grouping pharmacological substances would be in reference to their chemical action on living protoplasm, but as yet our knowledge is too scanty for this. At the present time the method adopted by Buchheim, or some modification of it, is the most scientific. As the result of painstaking investigations he grouped together all those substances having similar actions, giving to each group the name of its best-known or most thoroughly investigated member. Once the groups were more or less fixed any new substance could, when its action was determined, be referred to its own group, and thus be placed or classified. As few substances are absolutely identical in action, but only broadly similar, it is often difficult to divide sharply one group from another. In a resume' it is manifestly impossible to pass in review every pharmacological substance, and we shall therefore confine ourselves to those groups which are of practical importance. Many individual drugs are described under their own headings.

Group I. Acids. - This includes sulphuric, hydrochloric, nitric, phosphoric, tartaric, citric, acetic and lactic acids, all of which owe their action to their acidity. Many of the other acids, such as carbolic and salicylic, have specific effects which have no relationship to their acid reaction. The concentrated acids have an intense local action, varying from complete destruction of the tissues to more or less irritation. When considerably diluted they are only slightly irritating; externally applied and in the stomach they have an antiseptic action; they increase the secretion of saliva, and thus assuage thirst. In the intestine they combine with ammonia and other alkalis present, and are absorbed into the blood as neutral salts, being excreted chiefly in the urine. In small doses they somewhat increase general metabolism. Boric acid only belongs partially to this group, as it and its compound borax have certain specific actions in addition.

Group Ii. Alkalis. - This includes caustic potash, caustic soda, solution of ammonia, their carbonates and bicarbonates, borax, soaps, lithium carbonate and citrate, quicklime, slaked lime, chalk, magnesia and magnesium carbonate. All these substances, apart from any other actions, exert a similar effect upon the body in virtue of their alkalinity. When they are taken internally in small amounts they neutralize the acids in the stomach and other parts of the alimentary canal, and at the same time they increase the normal acid secretion of the stomach. After absorption into the blood, which they make somewhat more alkaline, they are excreted chiefly in the urine, to which they impart an alkaline reaction if given in sufficient quantity. Some of them by stimulating the kidney cells act as diuretics, but others apparently lack this action. Caustic potash and caustic soda are locally very irritating, and destroy the tissues, but lose this quality when combined with acids as in the case of their carbonates, bicarbonates and borax. Quicklime is also caustic, but magnesia is bland and unirritating. Weak solutions applied locally saponify fats, soften the epidermis, and thus act as slight stimulants and cleansers of the skin. Calcium salts form insoluble soaps with fats, and combine with albumen in a manner which makes them soothing and astringent rather than irritating. Apart from alkaline effects, these metals differ considerably pharmacologically. Potassium and lithium have a depressing action upon the nervous system, ammonium salts have a stimulating action, while sodium practically speaking is indifferent. Calcium and magnesium have actions somewhat similar to that of potassium. Most of these substances are normal constituents of the body, and indispensable for healthy existence. They are contained in sufficient amount in our ordinary dietary to supply the needs of the organism.

GROUP III. Easily absorbed Salts. - Sodium chloride may be taken as the type of those salts which diffuse readily, and are therefore easily absorbed. Sodium nitrate, potassium nitrate, potassium chloride, ammonium chloride, the alkaline iodides and bromides, also belong partly to this group, although most of them have also specific actions. Locally they cause considerable irritation, and when swallowed in concentrated solution may cause vomiting. From the stomach and intestines they are rapidly absorbed, and rapidly excreted from the blood, increasing all secretions and the general metabolism. These effects are apparently due to their irritating action upon individual cells.

Group Iv. Salts absorbed with difficulty. - This group includes the sulphates of sodium, potassium and magnesium, the acetate and tartrate of potash, citrate of magnesium, sodium phosphate, sodium tartrate and similar salts. Locally their action is slight, but when taken internally, dissolved in water, they are not absorbed from the alimentary canal except in very limited amount. They therefore remain for the most part in the intestine, and as they attract and retain large quantities of water, and at the same time slightly stimulate the mucous membrane, they come to have a purgative action and form the well-known group of saline cathartics. The small portion which is absorbed exerts a diuretic action.

Group V. Heavy Metals. - These include iron, manganese, aluminium, chromium, zinc, copper, silver, gold, platinum, lead, mercury, and probably antimony, arsenic and bismuth. Although some of these differ very greatly in their actions after absorption, still locally they have certain effects in common due chiefly to their chemical action on albumen. Their soluble salts combine with albumen and preserve it, strong solutions being extremely irritant or caustic, while weaker ones are astringent simply, or even soothing. They are all antiseptics. Their insoluble compounds are much less active locally than the soluble, and in many cases are only effective to the extent to which they are dissolved by the secretions. Some metals are only absorbed from the alimentary canal to such a very limited amount that they exert no general action, while others readily pass into the blood and give rise to more or less marked effects. All of them injected into the blood in large doses act as muscle and nerve poisons, and during their excretion by the kidney usually irritate it severely, but only a few are absorbed in sufficient amount to produce similar effects when given by the mouth. When iron is injected directly into a vein it depresses the heart's action, the blood pressure and the nervous system, and during its excretion greatly irritates the bowel and the kidneys. When taken by the mouth, however, no such actions are seen, owing to the fact that very minute quantities are absorbed and that these become stored in the liver, where they are converted into organic compounds and ultimately go to form haemoglobin. Soluble salts of manganese, aluminium, zinc, copper, gold, platinum and bismuth have, when given by the mouth, little action beyond their local astringent or irritating effects; but when injected into a blood vessel they all exert much the same depressing effect upon the heart and nervous system. Silver resembles them closely, but differs by the circumstance that it is deposited permanently in minute granules in the tissues, and, without affecting the general health, stains the skin of a bluish colour (argyria). Mercury and lead are absorbed from the bowel in considerable quantities, and are capable of inducing acute irritant poisoning as well as chronic poisoning. Lead poisons the muscular and nervous systems, and gives rise to paralysis, wasting, colic and other symptoms, while in the case of mercury, tremors, salivation, anaemia and very marked cachexia are induced. Arsenic and antimony do not form combinations with albumen, but they both greatly depress the central nervous system and circulation; and, if their action be long continued in large doses, they cause fatty degeneration of the viscera and disappearance of glycogen from the liver. Locally they are both very irritating, and antimony has a special tendency to cause vomiting.

Group Vi. Halogens. - This group includes iodine, bromine and chlorine, in their free state or as compounds. Locally they are all three strongly irritant or caustic, owing to their chemical action on albumen. They are in addition powerful germicides, and by splitting up water may act as oxidizing agents. Owing to their strong affinity for the hydrogen of organic compounds they often act as bleachers and deodorizers. Iodine has a special interest, as it is a necessary constituent of food, and is present in the secretion of the thyroid gland. Apart from certain conditions of ill health, the iodides, as such, have no very marked influence on the healthy body beyond their saline action. Alkaline bromides, in addition to their saline action, have in sufficient doses a depressing effect upon the central nervous system, and less markedly upon the heart. Chlorine compounds are not known to exercise any action of a similar kind.

Group Vii. Sulphur. - Sulphur itself has no action, but when brought into contact with the secretions it forms sulphides, sulphites and sulphuretted hydrogen, and thereby becomes more or less irritant and antiseptic. In the bowel its conversion into sulphides causes it to act as a mild laxative. Baths containing sulphuretted hydrogen or alkaline sulphides have a slightly irritating effect upon the skin, and stimulate the general metabolism.

GROUP VIII. Phosphorus. - This includes phosphides, and, according to some authorities, hypophosphites. Phosphorus is present in all cells, in considerable quantity in the nervous tissue, and in the bones as phosphates. It is therefore, in some form or other, a necessary part of dietary. When taken by the mouth phosphorus is an irritant poison in large doses; in small doses the only effects noticeable consist in an increased formation of bony and connective tissue, although it is also supposed to exert a gently stimulating effect upon the nervous system.

Group Ix. Oxygen. - When pure oxygen is inhaled the only effect is a slight increase of the amount of the gas in the blood, but this has no particular physiological effect. The pharmacological action of hydrogen peroxide (H202), potassium permanganate, powdered charcoal and some other oxidizing agents depends on the readiness with which they give up oxygen.

Group X. Carbonic Acid. - Carbonic acid gas, carbonic oxide (CO) and some other irrespirable gases produce their effects practically by asphyxiation. When dissolved in water, however, carbonic acid gas is a gentle stimulant to the mouth, stomach and bowel, the mixture being absorbed more rapidly than plain water; hence its greater value in assuaging thirst. Nitrous oxide (laughing gas) was at one time believed to act simply by cutting off the supply of oxygen to the tissues, but it also has a specific effect in producing paralysis of certain parts of the central nervous system, and hence its value as an anaesthetic; when given in small amounts mixed with air it produces a condition of exhilaration.

Group Xi. Water. - Water acts directly as a diluent and solvent. It therefore increases all the secretions, especially those of the skin and kidneys, while it also stimulates the general metabolism of the body and the excretion of nitrogenous products. Mineral waters act in the same way, but their effects are very much modified by, and depend largely upon, other constituents, such as alkaline salts, iron, arsenic, sulphides, carbonic acid, &c.

Group Xii. Tannic Acid. - Tannic acid is present in small quantities in the great majority of plants, but in notable quantity in gall-nuts, oak bark, bearberry leaves, rhatany root, catechu, kino, red gum, bael fruit, logwood and witch hazel, all of which are largely used as medicines. In these the variety of tannic acid is not exactly the same, but although there are slight chemical differences, they all possess the power of tanning raw hides and of preserving albuminous tissues. The action of tannic acid is strictly local, and depends upon its power of precipitating albumen and of destroying germs. It thus acts as an astringent on all mucous membranes. After absorption into the blood it loses this effect, as it is partly broken up into gallic acid and partly combined with alkalis, both of which changes nullify its action upon albumen.

GROUP XIII. Local Irritants. - Although some of the drugs already considered have a local irritant action, they produce other more important effects, but the substances here ranged under this heading depend entirely for their action on their local irritant effects.

a. Those which act upon the alimentary canal: Simple bitters such as quassia wood, columbo root, taraxacum, gentian, chiretta, and many others, irritate gently the mucous membrane of the stomach and bowels, and by increasing the secretions improve the appetite and digestion. The aromatic bitters such as chamomile flowers, cascarilla bark, hops, orange peel and others contain in addition small quantities of essential oils which increase their local action. The active principles in some of these bitters have been isolated pure, and have been found to be alkaloids or neutral compounds. Substances like pepper, cayenne pepper, mustard, horse-radish and ginger irritate the stomach and bowel much in the same way, but are more pungent, and are consequently used as condiments. Some of these have a similar but less marked effect upon the skin. The large number of vegetable substances used as purgatives owe their action to an irritating effect upon the mucous membrane and the neuro-muscular apparatus of the bowel, whereby the secretions and peristalsis are more or less increased, as the result of which diarrhoea ensues. Some of them cause so much irritation that the discharge is very watery (hydragogue cathartics), while others, for example aloes, by acting gently on the lower part of the bowel and on its muscular coat, produce simply a laxative effect. A few of them, such as aloin and colocynthin, are also purgative when injected subcutaneously or into the blood, probably owing to their being excreted into the intestinal canal.

b. Those which act on the skin: The best known of these is cantharides (Spanish fly), the active principle of which is a colourless crystalline body - cantharidin - which is extremely irritating. On a mucous membrane or a delicate skin it exerts an irritant action, which occurs more quickly than on a thickened epidermis, such as the scalp, and according to the strength and period of application there may result redness, a blister, or an ulcer. Many other substances, such as chrysarobin, mustard, pepper, &c., are also capable of irritating the skin, the effect produced varying from mere dilatation of the cutaneous vessels to destruction of tissue. Group Xiv. Male-fern. - This includes the male-fern, santonin, cusso, pomegranate bark, pumpkin seeds and many other substances containing active principles which have a specific poisonous action on intestinal parasitic worms. Apart from this their actions vary considerably, but are of little practical importance.

Group Xv. Ethereal Oils. - This includes a very large number of substances which owe their action to the fact that they contain ethereal or essential oils. The best known of these are cloves, pimento (allspice), myrtle, eucalyptus, caraway, fennel, dill, coriander, rosemary, lavender, peppermint, spearmint, nutmeg, cinnamon, sandal-wood, turpentine, juniper berries, valerian and sumbul. In this group may be included the oleo-resins, such as copaiba, cubebs and Canada balsam; the gum-resins, such as asafetida, myrrh, ammoniacum and galbanum; and the true balsams, such as benzoin, storax, balsam of Tolu and balsam of Peru. The resins when taken internally have much the same action as essential oils, which are closely allied chemically, while the benzoic and cinnamic acids in the balsams modify their actions very slightly. Although individual essential oils may differ somewhat in action, chemically and pharmacologically they are fundamentally similar. They all have a poisonous action on protoplasm, which makes them useful in medicine as antiseptics, disinfectants, germicides, anti-fermentatives and parasiticides; when locally applied they are more or less irritating, and, when very dilute, astringent. When swallowed in small doses they slightly irritate the mouth and gastric mucous membrane, increasing the secretions and producing a feeling of warmth. At the same time they increase the movements of the stomach, and also in this way hasten digestion, an action which extends to the upper part of the bowel. They are readily absorbed into the blood, and they are excreted chiefly by the kidneys in a more or less altered form, and probably also by the different mucous membranes, and even by the skin. After absorption their action, speaking generally, is exerted on the brain and spinal cord, and is at first slightly stimulant and afterwards depressing, even to the causing of sleepiness and stupor. Locally applied they depress the terminations of sensory nerves, and may thereby lessen pain. On the heart and circulation the effects are stimulant unless large doses are given, when the pulse becomes slow and blood-pressure much lessened. During excretion they irritate the kidneys and the sweat-glands, and thereby increase the excretion of urine and of sweat. They also increase the number of leucocytes in the blood, and the more irritating of them increase the flow of blood to the pelvic organs, and may thus stimulate the uterus, or in large doses cause abortion. The various camphors, such as laurel camphor, Borneo camphor, menthol and cumarin, are oxidized derivatives of essential oils, and differ only superficially from them in their action. Group XvI. Phenol. - This includes a very large number of bodies chemically allied to benzol, such as carbolic acid, sulphocarbolates, creosote, wood tar, coal tar, oil of cade, thymol, salicylic acid, benzoic acid, naphthol, hydroquinon, cresol, guaiacol, ichthyol, saccharin and many others. These all resemble carbolic acid more or less closely, and may be described as general protoplasm poisons. Locally their destructive and irritating effects vary a good deal, but even when very dilute they all have a marked poisonous action on bacteria, white blood corpuscles, yeast and similar organisms. After absorption most of them exercise a depressing effect upon the nervous system, and are capable of reducing high temperature. They are mostly excreted in the urine.

Group Xvii. Alcohol. - This group also includes a very large number of chemical bodies, only a few of which are mentioned here. Ethyl alcohol is taken as a type of the action of methyl alcohol, amyl alcohol, propyl alcohol, ether, acetic ether, paraldehyde, sulphonal, chloroform, methyl chloride, ethyl chloride, chloral hydrate, butylchloral hydrate, and almost any number of derivatives from these. Some of them are so volatile that they produce their effects when inhaled, others when sprayed upon the skin cause intense cold and then anaesthesia; but taken in the broadest sense the action of all of them after absorption into the blood is very similar, and is exerted upon the central nervous system, more especially the cerebrum. In all cases there is a longer or shorter period of excitement, followed by intoxication or narcosis, and with large doses this passes into paralysis and death from depression of the respiratory centre or of the heart. Small doses of any of them dilate the blood vessels from an action on the vaso-motor centre in the medulla oblongata, as a result of which the heart beats more rapidly and the blood circulates more freely; but larger doses have a general depressing effect upon the circulatory system. Under their action more heat is lost from the body, the general metabolism is diminished and the temperature falls. With some of them, such as chloral and chloroform, the stimulation period is short compared with the narcotic period, while with others, such as ether, the reverse is the case.

GROUP XVIII. Nitrites. - This group contains amyl nitrite, ethyl nitrite, methyl nitrite, nitroglycerin, sodium and potassium nitrites, erythrol-tetranitrate, and many other compounds containing nitrous or nitric acid. The latter becomes reduced to nitrous in the body, and thereby exercises its characteristic effects. These consist chiefly in an action upon non-striped muscle, vasomotor centres, blood vessels and the blood. When they are given by inhalation or by the mouth their first effect is to produce marked dilatation of the small arteries, with a fall of blood-pressure and a greatly increased rapidity of the heart's action. At the same time the non-striped muscles slightly lose their tonicity, and when very large doses are given the haemoglobin of the blood becomes converted into the chocolate-coloured methaemoglobin. The volatile members of the group act much more rapidly and more transiently than the others.

Group Xix. Alkaloids. - This embraces a very large number of important pharmacological substances, which differ a good deal in the details of their action, but they all act upon muscle and nerve tissue. Some of them affect only certain portions of the nervous system, others have a much wider range of action; they may act in either case as stimulants or as depressants, and hence the symptoms produced by them vary very greatly.

i. Morphine and the other opium alkaloids (codeine, narcotine, laudanine, &c.) have two prominent actions - a narcotic followed by a tetanic action. In morphine, on the higher animals at least, the narcotic action is very marked, the tetanizing action slightly so; while in thebaine there is little narcotic effect, but a tetanizing action like that of strychnine. Morphine exercises its effects chiefly upon the cerebrum and the medulla oblongata in man. It has in addition a markedly depressing action upon the respiratory centre, it lessens all the secretions except the sweat, and diminishes bowel peristalsis and the size of the pupil. Men are much more affected by it than birds, rabbits, dogs and most other animals. Cats, however, show marked symptoms of cerebral excitement and increase of the reflexes. Compared with morphine, codeine and the other alkaloids are only slightly narcotizing.

2\. Strychnine and brucine very closely resemble each other in action, and under this heading curarine may also be included. These bodies stimulate the grey matter in the spinal cord and cause tetanic convulsions. In the case of curare these are masked almost at once by paralysis of the terminations of the motor nerves.

3\. Caffeine is the active principle in tea, coffee, kola, mate and guarana; while theobromine, a body closely allied to it, is found in cocoa and chocolate. They both stimulate the grey nerve-cells in the brain and cord, this being the foundation of their dietetic value and their use as nervine stimulants. They also markedly increase the secretion of urine by stimulating the secreting cells of the kidneys.

4\. Cocaine is the active principle of the coca leaf, which is chewed as a stimulant-narcotic in Peru and Bolivia. Small doses excite the nervous system, while larger doses are depressing. The chief action of cocaine from a practical point of view is its power of paralysing the terminations of sensory nerves.

5\. Atropine, hyoscyamine, homatropine, duboisine, daturine and some other bodies have a paralysing action upon the ends of the motor and secretory nerves. They therefore lessen all the secretions, and among other actions dilate the pupil and increase the rapidity of the heart by paralysing the vagus. In addition they have a stimulating action on the central nervous system.

6\. Nicotine, piturine and lobeline are the active principles of tobacco and other substances which are smoked as stimulant narcotics. In large doses they are powerful nerve poisons, but as usually taken they exercise a gently stimulant effect upon the nervous system. Pilocarpine has an action closely allied to that of nicotine, but as it is much less poisonous (the effects produced by small doses being chiefly excessive sweating and salivation), it is capable of being utilized in medicine. Muscarine has a very close resemblance in action to pilocarpine.

7\. Physostigmine, the active principle of the Calabar bean, acts chiefly as a stimulant to voluntary and involuntary muscles, and at the same time exercises a depressing effect upon the spinal cord. It contracts the pupil.

8\. Conine, gelseminine and sparteine all exert a paralysing effect on the terminations of the motor nerves, to the implication of which the weakened gait and other symptoms are due.

9\. Aconitine, delphinine and many of their derivatives have a very widespread depressing action on muscle and nerve.

10\. Apomorphine is essentially a muscle poison, but owing to the fact that minute 'doses stimulate the vomiting centre and cause emesis before any other symptoms are observable, its emetic action is the most prominent effect in man.

T. Emetine acts as a gradual depressant to the nervous system in animals. In man its chief effect is its emetic action, which seems to be due entirely to local irritation of the stomach.

12\. Quinine. Several of the other alkaloids found in cinchona bark act very much like quinine. They all depress the conducting power and the grey matter of the spinal cord, and to a much less extent that of the brain. They lessen the general metabolism and lower febrile temperature. The cinchona alkaloids have a specifically poisonous effect on the parasites of malaria when present in human blood, and are poisonous to all low organisms.

13\. Phenacetin, acetanilide, phenazone and many similar bodies act as antipyretics in virtue of an action on the heat-regulating centres in the cerebrum.

Group Xx. Digitalis. - This group-name has been given to a large number of substances which have an action similar to that of the foxglove leaves, including the active principles of strophanthus, squill, Urechites suberecta, Convallaria majalis, Nerium Oleander, Helleborus niger, Antiaris toxicaria (the upas tree), and several others. The active principles of these vary a good deal in chemical composition, but they are all non-nitrogenous neutral bodies. Their action is exerted upon muscle, and chiefly upon the muscle of the heart and blood vessels. The individual muscle-fibres contract and expand more perfectly, and thus the diastole and systole of the heart are rendered more complete, the pulse is slowed, and the blood-pressure is raised. The slowing of the heart is partly brought about by an action on the vagus centre.

Group Xxi. Picrotoxin. - In large doses the action of picrotoxin is exerted chiefly on the medullary nerve centres, whereby irregular tonic-clonic convulsions are produced; in minute doses it stops the secretion of sweat.

Group Xxii. Saponin. - Saponin and many allied bodies form an abundant soapy-looking froth when shaken up with water, and they are contained in a very large number of plants, the chief of which are the Quillaia saponaria, Polygala senega, sarsaparilla, and others, known collectively as soapworts. They all act as local irritants in the alimentary canal, and after absorption are more or less depressing to the muscular and nervous systems. They produce slight nausea and increased secretion of mucus.

GROUP XXIII. Cyanogen. - This includes compounds of cyanogen such as hydrocyanic (prussic) acid, cyanides of potassium, sodium, &c., cherry-laurel water, amygdalin, bitter almonds and other chemical and vegetable substances which readily yield hydrocyanic acid. Hydrocyanic acid is a general protoplasmic poison, all the lower organisms being very susceptible to its action, while in the higher animals it speedily depresses or paralyses all forms of nerve tissue. It enters into combination with haemoglobin, forming a bright scarlet compound and interfering with respiration. It kills by its paralysing effect on the motor ganglia of the heart and on the respiratory centre.

Group Xxiv. Ferments. These include such bodies as pepsin, diastase, the pancreatic ferments, papain, the pine-apple ferment, taka-diastase and others, and serve to convert starch into saccharine substances, or albumen into peptone and albumoses.

Group Xxv. Animal Glands and Secretions. - Of these the thyroid gland, the suprarenal bodies, the spleen, the bile, the bone marrow, the ovaries and some others have been investigated fully. Speaking generally, when given in small doses their action on the healthy organism is slight or nil, but in disease some of them are capable of acting as substitutes for deficient secretions.

Group Xxvi. Antitoxins. - These are substances which antagonize the toxins formed in the body by pathogenic organisms, the toxins of snake venom and other animal poisons, and vegetable toxins such as abrin, ricin, &c. A healthy person can be rendered insusceptible by gradually accustoming him to increasing doses of these poisons, and this immunity is due to antitoxins which are found in the blood-serum and which are products of the blood cells. The nature of these antitoxic substances is not definitely known, but they combine with and destroy the poisons. In specific germ diseases a similar antitoxin forms, and in cases which recover it counteracts the toxin, while the germs are destroyed by the tissues. Antitoxins can be prepared by immunizing a large animal, such as a horse, by injecting gradually increasing doses of specific toxins into its subcutaneous tissue. In due time the horse is bled, the serum is filtered free of blood corpuscles, and then constitutes the antitoxic serum, which can be standardized to a certain potency. Such serums are injected subcutaneously in diphtheria, tetanus, streptococcic infections, plague, snake-poisoning, cholera and other similar diseases. They do not as a rule harm healthy men even in large quantities, but when repeated they often cause serious symptoms due to the body becoming more sensitive to the action of the horseserum in which they are contained.

Group Xxvii. Neutral Fats. - This includes cod-liver oil, almond oil, olive oil, lard, &c., all of which act as foods when taken internally, and have a merely physical emollient action when applied externally. Lanolin, linseed oil, wax, spermaceti, &c., also belong to this group. The paraffins, glycerin and vaseline, although not fats, have much the same effect when applied externally, but they are not nutritive.

GROUP XXVIII. Sugars, Starches, Gums, Gelatin, &c. - Although these and allied bodies are used in various ways as remedies, their action is for the most part purely mechanical or dietetic.

Authorities.-T. Lauder Brunton, Pharmacology, Therapeutics and Materia Medica (3rd ed., London, 1891); The Action of Medicines  (London, 1897); H. C. Wood, Therapeutics: its Principles and Practice  (loth ed., London, 1905); A. Cushny, A Textbook of Pharmacology and Therapeutics (1906); C. D. F. Phillips, Materia Medica, Pharmacology, and Therapeutics (Inorganic Substances) (London, 1894) Binz, Lectures on Pharmacology (Trans., New Sydenham Society, London, 1895); Schmiedeberg, Grundriss der Arzneimittellehre  (3rd ed., Leipzig, 1895, Eng. trans. by Thos. Dixon, Edinburgh, 1887); Stokvis, Lecons de pharmacotherapie (Haarlem and Paris, 1898); Rabuteau, Traite de therapeutique et de pharmacologie  (Paris, 1884); Vulpian, Les Substances toxiques et medicamenteuses  (Paris, 1882); J. Harley, The Old Vegetable Neurotics (London, 1869); J. Mitchell Bruce, Materia Medica and Therapeutics; W. Hale White, Materia Medica, Pharmacy, Pharmacology and Therapeutics (London, 1909); Walter E. Dixon, A Manual of Pharmacology (London, 1906).

(R. S.*) Terminology in Therapeutics.  It may be useful to give here a general explanation of the common names used in the therapeutic classification of drugs. It is convenient to divide drugs and other substances used in medicine into groups according to the part of the system on which they chiefly act, though, as stated above, many drugs act in more than one manner and could come under several groups.

I. Drugs acting on the blood vessels, which either dilate the vessels when taken internally or applied locally, or contract the superficial arterioles. Irritants (Lat. irritare, to excite) include: Rubefacients (Lat. rubefacere, to make red), which cause the skin to become red from dilatation of the blood vessels; Vesicants  (Lat. vesica, a bladder), which irritate sufficiently to cause the blood-serum to exude and form vesicles or blisters, e.g. cantharides; Pustulants (Lat. pustula, a blister), still more powerful in their effects, causing the blisters to become filled with pus, e.g. croton oil. Escharotics (Gr. kvipa, hearth, brazier; hence mark of a burn, "scar") or Caustics (Gr. xaiecv, to burn), cause the death of the part, e.g. silver nitrate and nitric acid. The term counterirritant is used when an irritant is applied to the skin for the purpose of relieving pain or congestion by dilating the superficial vessels. Drugs which contract the vessels and diminish exudation comprise Astringents (Lat. astringere, to draw close), while Styptics (crrtckcv, to contract) or Haemostatics (Gr. aiµa, blood, o-rarCicos, causing to stand) are substances applied either locally or internally in order to arrest bleeding; cold, adrenalin, ergot and the per-salts of iron may be taken as examples.

II. Drugs acting on the digestive tract. Sialogogues (Gr. aia?ov, spittle, Iywybs, leading) increase the flow of saliva, e.g. mercury; Antisialogogues decrease the flow, e.g. belladonna. Aromatics  (Gr. ,pw j a, spice) or Bitters increase the flow of the gastric juice. Stomachics (Gr. Qro /L a X os) have the same effect. The term Carminatives (Lat. carminare, to card wool), adopted from the old medical theory of humours, is generally applied to pungent substances which hel p to expel gas from the stomach by stimulating the movement of its contents. Emetics (Gr. I i€ros, vomiting) are substances given for the purpose of causing vomiting, e.g. ipecacuanha or apomorphine. Anti-emetics or Sedatives (Lat. sedare, to compose) arrest vomiting either by their central or local action, e.g. opium, cocaine or cerium oxalate. Purgatives (Lat. purgare, to cleanse) aid the onward passage of the contents of the intestinal canal, either by increasing the contractions of its muscular coat as laxatives  (Lat. laxare, to loosen), e.g. as magnesia, or by increasing the flow of fluid. Some are termed drastics (Gr. SparTCKOI, active) or cathartics  (Gr. KaOaprucos, cleansing), which produce watery evacuations. Cholagogues (Gr. xoXi, bile, I ycoyos, leading) are purgatives which act by increasing the flow of bile, either by causing an increased secretion (e.g. podophyllum) or by sweeping it onwards by stimulating the intestinal contractions (e.g. calomel).

III. Drugs acting on parasites. Anthelmintics (Gr. Zuni, against, iXµcvs, EX,u vBos, a worm) are drugs which kill parasites inhabiting the intestine. The term vermicide (Lat. vermis, worm, caedere, to kill) is applied to drugs which directly kill the entozoa, while vermifuge (Lat. vermis, worm, fugare, to put to flight) is applied to the purgative usually given after the vermicide for the purpose of expelling the worm. Parasiticides or anti-parasitics destroy parasites; the terms are usually restricted to those acting on skinparasites as contrasted with intestinal ones.

IV. Drugs acting on the urinary system. Diuretics (Gr. Sca, through, oupov, the urine) increase the flow of urine, while lithontriptics (Gr. XLOos, stone, Tpi(3Ety, to rub, grind down) are drugs given to prevent the formation of urinary calculi.

V. Drugs acting on the generative system. Aphrodisiacs (Gr. 'A4)poSirn, the goddess of love) increase the action of the generative centre in the spinal cord; Anaphrodisiacs decrease its action. Ecbolics (Gr. to throw out) or oxytocics (Gr. kin, sharp, quick, roeos, parturition) stimulate uterine action. Emmenagogues (Gr. i u va, menses, aycoyOs, leading) are substances which increase the menstrual flow. Galactogogues (Gr. yiiXa, milk) increase the secretion of milk, while antigalactogogues (e.g. belladonna) have the opposite effect.

VI. Drugs acting on the respiratory system. Expectorants  increase the bronchial secretions; antispasmodics relax the spasm of the muscular coat of the bronchial tubes, e.g. stramonium. This latter term is also used for drugs which act as general depressants.

VII. Drugs or substances acting on the bodily heat. Antipyretics (Gr. avTi, against, xvp€r6 , fever) either increase the heat loss or diminish its production; e.g. phenacetin, cold water, &c.

VIII. Drugs or substances acting on the skin. Diaphoretics  (Gr. ScactiopEiv, to carry through) increase the amount of sweat, either by acting directly on the sweat centres or on the nerve terminals. The word Sudorific (Lat. sudor, sweat) is applied to them when they act very powerfully. Anhidrotics or Antihidrotics  (Gr. 1.5p6n, sweat) diminish the secretion of sweat. Emollients  (Lat. mollis, soft) are substances which soften and protect the parts. Demulcents (Lat. demulcere, soften), soothe the skin or mucous membrane.

IX. Drugs acting on metabolism. Alteratives are drugs which alter the course of a disease, the mode of action being unknown. Tonics are drugs which increase the muscular tone of the body by acting either on the stomach, heart, spinal cord, &c.

X. Drugs acting on the blood. Antitoxins are organic products designed to neutralize the formation of the toxins of certain diseases in the blood. Toxins are also injected in order to stimulate the blood plasma to form antitoxins (see Bacteriology). Antiperiodics inhibit a disease having periodic recurrences; e.g. quinine in malaria. Haematinics are drugs which increase the amount of haemoglobin in the blood.

XI. Drugs acting on the nervous system. Anaesthetics (q.v.)  diminish sensibility, either central or peripheral; Anodynes (Gr. av-, priv., o vo, pain) relieve pain only, but, as in Analgesics  (Gr. tiXynvcs, sense of pain), sensibility is unaltered. Stimulants  are those which lead to excitation of the mental faculties and in quantity may lead to delirium and incoherence. Hypnotics (Gr. i rvos, sleep) or Soporifics (Lat. sopor, a deep sleep) are drugs which produce sleep without causing cerebral excitement. Narcotics  (Gr. vcipKf, numbness) are those which besides producing sleep may in large doses depress the functions of respiration and circulation.

XII. Drugs which arrest the progress of putrefaction. This is either by inhibiting the growth of micro-organisms (Antiseptics)  or by destroying them when present (Disinfectants). (H. L. H.)