Medicines

Medicines. In the broad sense (German Heilmittel, French remede), the term M. refers to any means or any effect on a diseased organism, aimed at preventing, destroying, or weakening the pathological process, as well as its consequences. In the narrower medical sense (corresponding to German Arzneimittel and French medicament), the term M. and its equivalents medicinal substance and medicament (Latin medicamentum) mean only special substances used for the aforementioned purpose. Food substances used to compensate for material losses in the organism or to provide material for its growth are not included among M. In some cases, however, food substances are used for therapeutic purposes, which forms the basis of dietary treatment methods. Establishing an exact distinction between food and medicinal substances proves difficult, since the same substance, for example fish oil, in rickets can simultaneously be both a medicine and a food substance. Another class of substances, closely related to M., consists of poisons, which are directly opposite in effect to the former, since their characteristic feature is poisoning, i.e., causing harm to the organism with disruption of its normal life processes. Depending on the dose and method of application, many substances can be either poisons or M. Thus, all strongly acting M. are toxic even in relatively small doses. The fact that the same substance can be both a medicine and a poison is also reflected in the fact that, for example, the Greek word pharmakon, corresponding to our word 'potion', means both poison and medicine. The property of medicines to exhibit toxic effects in large doses has very great practical significance, determining the so-called breadth of therapeutic application of a given medicine. This term, otherwise known as the therapeutic index, denotes the relationship between the therapeutic and toxic doses (dosis curativa) _tt ^ ^l--ag1пайг.-шад ^{The greater} the distance from the first dose to the second (or the smaller the first dose compared to the second), the greater the aforementioned breadth. This breadth has particular importance in cases where it is necessary to use as high doses as possible, for example when using anesthetic (general and local), disinfectant, etc. drugs. The therapeutic dose of novocaine (causing anesthesia) is about three times greater than that of cocaine, but its lethal dose is almost 20 times greater, from which it follows that the breadth of its therapeutic application is approximately 7 times greater. The sources of M. are very diverse. It is difficult to name any substance or even any method of affecting the organism that has not been used for therapeutic purposes. The effect on the organism of certain medicinal substances (for example, laxatives, emetics) is undoubtedly known from prehistoric times, and the application of certain therapeutic methods is based on instinct, even observed in animals, for example, removal by biting off dead parts, licking wounds (keeping them clean), the tendency to eat young plant shoots when food is poor in vitamins. It is reliably known that many modern M. were known in ancient times. The ancient Egyptians used opium and squill for therapeutic purposes. The arsenal of therapeutic means of ancient Indians was very extensive. In the book Susruta, representing a comprehensive treatise on ancient Indian medicine, there is a description of the properties of 760 medicinal substances from the plant kingdom. Among these M. are mentioned opium, hashish, aconite, laxatives including Oleum ricini, emetics, astringents, etc. Along with plant substances, mineral substances were also used, among which mercury preparations (black, white, yellow, and red mercury) were especially highly valued, and a physician well acquainted with their properties was likened to a god. Many of the drugs currently in use belong to so-called folk medicine, although they have long been recognized by official medicine as well. Thus, foxglove, long used as a folk diuretic, has been well studied and introduced into general medical practice by Withering in the 18th century. Much later, already in the second half of the 19th century, folk remedies lily of the valley and marsh marigold, studied primarily by Russian physicians, gained general recognition. A number of substances became known in Europe through travelers who became acquainted with various means (quinine, coca, cola, etc.) of indigenous peoples of various countries. Sometimes M., before being used in medicine, were used by persons without special medical qualifications, for example the same quinine, introduced in Europe by Countess del Cinchon and initially used almost exclusively by Jesuit monks. With the development of the chemical industry, a great many chemical compounds have been proposed as medicines, and their number increases every year. When introducing various substances into the medicinal arsenal, in addition to direct observation of the effects of these substances in health and disease, the level of scientific knowledge, as well as the philosophical systems and religious beliefs of the given era, have always been of great importance. Thus, among the ancient Indians, water of the sacred Ganges was placed above all other means. In the Middle Ages, it was believed that the very appearance and form of a medicine served as an indication of its specific therapeutic properties. According to this doctrine, poppy heads should help with head ailments, salep tubers, resembling testicles in shape, should affect sexual function, etc. In the era of belief in materia peccans—the disease-causing principle—along with the use of bloodletting, prescription of laxatives and enemas was also widespread, aimed at eliminating this hypothetical principle from the patient's organism, which found an echo in Molière's famous comedy 'The Imaginary Invalid.' For the possibility of rational application, every M. before its introduction into practice must be studied, first from the therapeutic effect and second from the toxic effect. This study is conducted on animals and humans. Experimental research on animals has the advantage that an animal can be placed in any conditions when analyzing the effect of a drug, and both vivisection and administration of toxic doses are used. In addition to studying the effect of M. on the whole animal, it is very useful to study the effect of M. on isolated organs, the life of which is maintained by passing defibrinated blood or special nutrient fluids through their circulatory system: The main advantage of this technique, which has also been extensively applied in Kravkov's laboratory, is that the conditions for studying the effect of M. are significantly simplified in this way. In some cases, such studies were also conducted on human organs (heart, fingers, intestines, etc.), but in most cases, obtaining sufficiently fresh and therefore suitable for experimentation organs from human cadavers presents considerable difficulties. The disadvantage of studying M. on animals is the known difference in reaction to M. between humans and animals, and this difference is not always possible to take into account. Particular difficulty arises when studying the effect of M. on a diseased organism, since not all human diseases can be induced in animals, and the course of the pathological process in the former and the latter is often very different. Nevertheless, a number of new medicines, such as antisyphilitic preparations of mercury and bismuth, were not only studied but also developed through experimentation on animals. Due to the insufficiency of the experimental method in studying M., research on humans is necessary. Among such studies, clinical research has the greatest value, when the effect of M. is studied on all functions of the patient's organism as much as possible. A supplementary method for judging the value of M., as well as other therapeutic measures, is the application of statistical methods. However, to obtain reliable results here, it is necessary, in addition to extensive material allowing application of the statistical method, to have identical conditions both when using the M. under study and in the control when the given medicine is not used. Since both the experimental method of studying the effect of M. on animals and the clinical method on humans are based on our knowledge of the functions of the healthy and diseased human organism, the strictly scientific application of M. became possible only after the recent advances in medicine, especially its branches—experimental pharmacology and physiology, pathological anatomy, and bacteriology—when it became possible, not being satisfied with knowledge of the total effect of medicines, to study their mechanism of action on both healthy and diseased organisms. True, even now medicines are often prescribed on the basis of empirical data without exact understanding of their effects, however, the area of such empirical therapy is shrinking every year. It should be noted, however, that the scientific advances of the last half-century have also caused some damage to the prestige of medicinal therapy. Thus, the discoveries of Pasteur and his followers highlighted the importance of sero- and vaccine therapy in the treatment of a number of diseases, in which previously ordinary M. were used with incomparably less success.

Further development of knowledge in hygiene, as well as experimental and clinical studies in dietetics and physiotherapy, made it possible to turn to the aid of these disciplines partly for the prevention and partly for the treatment of such pathological conditions, in which drug treatment had been used almost exclusively. The so-called 'preventive direction in medicine' plays the same role in the USSR. To a large extent, strangely enough, successes in chemistry undermined faith in drug treatment methods. The latter led to the flourishing of the chemical industry, which began to flood the market with countless patented medications, advertised as valuable remedies. Many of these substances proved to be insignificant, and the natural disappointment gave rise to some skepticism toward medicines in general. According to apt comparison by Kobert, physicians of the recent past have experienced an era similar to the era of the discovery of the New World, when Europe was flooded with numerous medicines brought from newly discovered countries, and of these L. only very few turned out to be truly valuable. All these reasons have led to some decrease in attention to the drug treatment method. This in particular found its echo in the curricula of medical higher educational institutions in the USSR, from which pharmacy and pharmacognosy were eliminated as separate disciplines. Such a view is of course incorrect. On the one hand, if new therapeutic methods in many cases are very useful, in others they still cannot successfully replace the pharmacotherapeutic method. Moreover, it is precisely at the present time that the study of the action of medicinal substances has achieved such successes that it makes possible their strictly rational application, and in a number of diseases (e.g. malaria, syphilis, rheumatism, a number of cardiac disorders, etc.) no other method can give as favorable results as the pharmacotherapeutic one. One should also not lose sight of the fact that in the last decade quite a number of extraordinarily valuable medicinal substances have been discovered (adrenaline, insulin, salvarsan, new bismuth preparations), and almost all of these substances were discovered not by chance, but as a result of systematic research, which especially proves the firmness of the foundations of pharmacotherapy. However, for the successful application of medicines, as well as for the further scientific development of pharmacotherapy, it is necessary that physicians be well acquainted both with the physicochemical nature of medicines and with all aspects of their effect on the organism, for which, of course, appropriate training of physicians in medical higher educational institutions is also necessary. The goal pursued in prescribing L. is not always the same. In those cases where a drug acts on the causative agent of the disease, it is called etiotropic (e.g. quinine in malaria or salvarsan in syphilis). Often such L. are called specific (specifica). The latter term can however be applied also in the case where there is a specific effect on the pathological process itself, regardless of the effect on the factor that caused the disease. Thus, a specific L. in the treatment of pancreatic diabetes is insulin, which restores the disturbed carbohydrate metabolism. If L. act predominantly on certain organs or tissues, then such L. are called selectively acting: strychnine affects predominantly the central nervous system, atropine on the parasympathetic nervous system, curarine on the endings of motor nerves in the striated muscles. In those cases when L. are intended to act on a particular symptom, they are called symptomatic. Such L., if they do not affect the course and outcome of the disease, are often called palliative (pallium - cloak). - Usually medicinal substances are divided into groups according to their effect on the organism. Thus, cardiac, narcotic, hypnotic, diuretic, laxative and other remedies are distinguished. Such a classification is not always convenient for the systematic study of medicinal substances, because often the same substance affects various systems and therefore must be included in several groups at once, e.g. caffeine, which affects the central nervous system and is at the same time a cardiac and diuretic agent. On the other hand, classifications according to the chemical composition of medicines have the disadvantage that substances of different action can be included in the same group. Buchheim deserves credit for creating a classification (later developed by Schmiedeberg), in which both the action of medicinal substances and their chemical nature are taken into account. In this case, medicinal substances are divided into groups of substances of similar action and at the same time related in chemical composition. This principle was later followed in many pharmacological guides, including in Kravkov's textbook. According to their sources and methods of preparation, medicines can be subdivided into 1) crude substances (cruda) - parts of plants and animals (and according to some, mineral substances), not subjected to any processing and used in their raw form; 2) chemical preparations (chemicalia), obtained by chemical processing of organic and inorganic substances; 3) galenic preparations (see) (halenica), obtained from crude substances and chemical preparations by simple pharmaceutical manipulations; 4) organopreparations (see) (organotherapeutica), obtained from organs of normal animals by special processing aimed at extracting specific substances from the organs; 5) vaccines or therapeutic sera (vaccinae et sera), obtained from cultures of microbes and from specially prepared animals. Galenic preparations, chemical preparations used in medicine, and organopreparations also bear the common name medicinal preparations. - The list of medicines that should be dispensed by pharmacies is published in the official publication - the Pharmacopoeia (see), which describes the properties of medicines determining their quality, methods of control and rules for storing L. and the maximum doses of poisonous and potent substances. At the same time, from the general list are distinguished: List A - poisonous medicinal substances, which must be stored in pharmacies under lock; List B - potent medicinal substances, which must be stored with precautions, separately from other medicinal substances. The action of L. can be local, when L. exerts this effect at the place of its application, e.g. the action of local irritants, cauterizing or astringent, many laxatives, etc., or general (resorptive), which is manifested after the absorption of L. and its penetration into the blood. In the latter case, L. is carried throughout the organism, various parts of which may be affected by the received L. A special kind of local action of L. is reflex action, in which a drug, by irritating sensitive nerve endings, causes certain reflexes. A characteristic example can be reflex vomiting when taking copper salts or ipecacuanha. - By mechanism, the action of L. can be direct, depending on the effect of L. on certain elements of the organism, and secondary, indirect, manifesting as a further consequence of the direct action. Secondary action can sometimes be desirable, and it is counted on when prescribing a drug, e.g. the diuretic effect of digitalis in 'cardiac' dropsy, occurring as a result of improved blood circulation in the edematous organs and kidneys; but it can sometimes also be a harmful complication of the therapeutic effect, e.g. cases of collapse when using antipyretics, depending on the effect on the heart of a sudden drop in temperature, or secondary pneumonia after sulfonal, caused by the entry into the lungs of contents from the oral cavity and pharynx due to a decrease in protective reflexes from the respiratory tract. Furthermore, from a therapeutic point of view, the main action of L. is distinguished, for which L. is used, from side effects, which are usually undesirable phenomena. Examples can be the secondary phenomena already mentioned - collapse when using antipyretics and pneumonia after sulfonal, as well as tinnitus from quinine, runny nose with prolonged use of iodine, etc. The action of L. on the cells of the organism is carried out 1) directly and 2) by changing the properties of the medium in which the cells are located. In both cases, the effect is possible only when there is some connection between the elements of the organism and the medicinal substance. This connection is not always the same. There may be 1) dissolution of the medicinal substance in the juices and tissues of the organism (or, conversely, dissolution in the medicinal substance of the body's secretions, and sometimes of its elements), 2) adsorption of the medicinal substance by the organism and finally 3) chemical combination of the medicinal substance with the elements of the organism (and its secretions). In this case, one type of connection does not exclude another. - The dissolution of medicinal substances can occur both in the liquid media bathing the cells (blood, lymph, etc.) and in the cellular elements themselves (and other solid formations - fibers, membranes, etc.). When considering the action of L., the solubility of L. in water, which makes possible the transport of L. by blood and lymph throughout all parts of the organism, and the solubility in lipoids (see Absorption) are of particular interest.

The solubility of substances in lipoids is interesting also from the point of view that the latter are an essential component of the central nervous system. According to the Overton-Meyer theory, the narcotic action of fatty substances depends on the solubility of these substances in the lipoids of the central nervous system, and the factor determining the strength of the action is not the absolute solubility of the substance in the lipoid, but its comparative solubility in relation to its solubility in water, the so-called coefficient of distribution --^r£^-z^™--------- г г >"

solubility in water According to the mentioned theory, this coefficient determines how vigorously a given substance is extracted by the central nervous system (lipoids) from the blood (water). Along with dissolution in the body, medicinal substances can also be adsorbed (see Adsorption), i.e., accumulate on the surfaces limiting the media in the body. Here we encounter both external adsorption—the accumulation or retention of a substance on the surface of the skin or mucous membranes—and adsorption within the body, e.g., on the surfaces of cells bathed by lymph or blood. The latter type of adsorption can have a sharp effect on cells, and according to Traube, it is to this (and not to dissolution in lipoids) that the narcotic action of fatty series substances on the central nervous system should be attributed. In addition to adsorption, which depends on the substance reducing the surface tension of the solvent, as observed in the case of adsorption of fatty series substances, certain alkaloids, etc.,—in the perception of M. by the body, their electrical adsorption also occurs, caused by the attraction of particles carrying a specific charge M. by elements of the body (or microbes present in it during disease) with an opposite charge. Some authors explain by such a process the effect of colloidal metals on microbes in septicemia. The chemical combination of medicines with elements of the body can occur with the complete destruction of the latter, as seen in the action of energetic cauterants (strong acids and alkalis), and on the other hand be such that the structure of cells, as can be judged from the preservation of their functions and external structure, suffers relatively little. In the latter case, it is often difficult to determine whether a true chemical combination or adsorption of the substance is taking place. The nature of the bond between M. and the cell has a significant importance for the effect of the direct action of the former on the latter. In the case of dissolution or adsorption of M. by the cell, the effect is naturally less permanent than in their chemical combination, which sometimes proceeds as an irreversible reaction (e.g., in cauterants). An even greater significance for the effect of the direct action of M. on the cell is the physicochemical nature of M., which also determines the nature of its bond with the cell. Although general laws determining the dependence of the action of medicinal substances on their structure have not yet been established, such dependence has been determined for many series of chemical compounds. As examples, the following particular regularities can be cited: the toxicity of saturated hydrocarbons of the fatty series and their derivatives (e.g., alcohols) increases with the increase in the molecule from homolog to homolog; bases with primarily bound nitrogen are more toxic than bases with secondarily bound nitrogen, and the latter are more toxic than compounds with thirdarily bound nitrogen—piperidine and pyrrole are significantly more toxic than pyridine; the introduction of a halogen (especially chlorine and bromine) into the molecule of fatty series substances, as well as into the benzene nucleus of aromatic ones, significantly increases their physiological activity and toxicity; modification of a nitrogen-containing molecule of both fatty and aromatic series, leading to the transformation of a tertiary base into a quaternary one, gives the latter the ability of a curare-like effect on nerves. Substances with unsaturated valences, having double and triple bonds, are more active chemically and physiologically compared with substances of complete saturation. The works of P. Ehrlich (Ehrlich) have special importance for this question, who, applying to M. and poisons the principles of O. Witt's (O. Witt) theory of the importance of chromophores in coloring substances, points out that the toxic action of poisons (resp. medicines) depends on the presence in the latter molecule of special atomic groups—toxophores. Thus, the toxophore group in cocaine, which determines its anesthetic action, is the residue of benzoic acid. Along with toxophores, groups that enhance (reveal) or weaken the main action can be present in the molecule of a substance. Such groups are called positive and negative auxotoxins. An example of them is the nitrogen-containing group in cocaine. In addition to the mentioned groups, M., according to Ehrlich, must also contain for action on the body haptophore groups, by means of which the M. molecule attaches to the cell molecule (its chemoreceptor group). In cocaine, such a haptophore group is the methyl radical connected with ecgonine. Haptophore groups also determine the tropism of the medicinal substance, i.e., its action on certain cells of the body. Due to the fact that in cocaine the haptophore group is neurotropic, cocaine affects nerve elements containing corresponding chemoreceptors. On these and similar principles, Ehrlich built the theory of the action of M., which he called chemotherapy (see). Guided by it, Ehrlich carried out his famous works on obtaining salvarsan and neosalvarsan. Despite these brilliant achievements, Ehrlich's theory has not been accepted by most researchers as a universal theory explaining all aspects of the action of medicinal substances, all the more so that it is not always possible to determine which atomic group in the medicinal molecule determines its therapeutic (resp. toxic) action. It should be added that regardless of the chemical composition, the position that the toxophore group (or auxotoxin) occupies in the molecule has great importance for the toxicity of the entire molecule. Thus, of the two dichlorodiethyl sulfides, only the form /S./? (mustard gas), which has chlorine at the end of the chain, has a characteristic action, whereas the form a.a does not possess this action. Optically active isomers with opposite rotation of the plane of polarization also show different action, and as a rule, the levorotating isomer is significantly more active (adrenaline, hyoscine, etc.). In addition to the direct effect on cellular elements, M. can act on cells by changing the properties of the medium in which they are located. It should be noted that this medium (blood, lymph, liquid content of serous cavities, etc.) appears to be an extremely complex colloidal solution containing a number of organic and inorganic compounds and moreover possessing a number of physicochemical properties, the change of which affects the cells contained in this medium. Of the extremely numerous actions of medicines in this sense, the following main ones can be mentioned: influence on osmotic pressure, which has, e.g., special importance in certain laxatives, diuretics, mineral waters, etc.; influence on surface energy at phase boundaries, on which, as was indicated above, the adsorption of substances depends, determining their effect on cells; influence on the equilibrium of dissolved ions, with special importance being the ratio of ^ and ^ (see Calcium and Potassium) and the ratio of OH and H ions (determining pH) and having (according to works based on research by J. Loeb by A. M. and M. L. Petrun'kin) a decisive influence on the chemical combination of cellular proteins with a number of medicinal substances, e.g., alkaloids. Changes in the internal conditions of the medium also affect the dispersity of its colloids, and this in turn affects the cell contained in this medium, and consequently its functions. At this, it should be borne in mind that in connection with the importance for the life functions of cells of maintaining the considered conditions at a certain level, the body possesses a number of protective measures against the disturbance of these conditions (e.g., buffer systems maintaining the proper pH of the blood). Thus, a medicine that changes, e.g., the pH of the blood causes the corresponding buffer system to act, whereby those tissue elements that were in reserve before the disturbance of equilibrium can be mobilized _% Thus, the effect of M. extends much further than its first place of action—in this case the blood (e.g., the loss of alkalis by the body with prolonged use of Glauber's salt due to the action of H₂SO₄ secreted in the intestine). The physiological effect of the action of M. can be excitation and depression of the corresponding cells. The latter, if the reaction is irreversible, passes into the death of the cell. The effect of the action depends on a number of conditions for the use of medicines. The dose (resp. concentration) plays a significant role, and all substances, at a certain dose, disrupting the normal life conditions of cells, cause their depression or paralysis. On the contrary, in small doses and concentrations, many M., even paralyzing; in medium doses, act as stimulants (see Arndt-Schulz law). The question of the lower limits of doses at which M. can affect cells cannot yet be considered finally resolved. It is undoubtedly true that some substances, such as adrenaline, acetylcholine, aconitine, can have an effect even when used in extremely small doses. At least laboratory experiments on especially sensitive objects show a reaction at billionth and even trillionth dilutions.

However, this is still far from the dilutions at high homeopathic potencies, the effect of which must apparently be attributed to the psychological factor (see Homeopathy).--An important factor determining the effect of M. is the phase of their action. According to Kravkov, a phase of entry, saturation, and exit is distinguished, and while for most M. the phase of saturation is characteristic, some drugs exhibit particularly strong action in the phase of entry (e.g. adrenaline, muscarine) or exit (according to Kravkov-camphor). The duration of action of M. also affects the effect. From this point of view, M. (resp. poisons) are divided into cumulative, non-cumulative, and potential. For cumulative M., not only the single dose but also the total amount (dosis totalis) of the substance taken is important, even over a relatively long period. For gaseous substances perceived by respiration of this type, Haber's formula applies: W=ct, where W is the effect of action, c is the concentration of the substance in the air, and t is time (see Chemical warfare agents). The cumulative action of the substances under consideration is explained in some cases (e.g. cardiac substances of the digitalis group) by the accumulation of the substance in the body, in some cases by the accumulation of the effect, when the M. is destroyed or excreted as it is taken, but leaves behind a trace in the form of a certain weakening of cells (e.g. in the action of phosgene). For non-cumulative substances, the dose or concentration is decisive. If the doses are small or the concentration is low, the effect of M. can last indefinitely without causing an undesirable side effect (resp. poisoning). The latter is obtained only after applying doses or concentrations above a certain threshold. The formula determining the action of these substances is: W=(c-e)t, where the values of W, c, and t are the same as in the previous formula, and e is the threshold concentration, before which the effect is not obtained. An example of such poisons can be most M., including gaseous hydrocyanic acid. Substances called potential are those that exert particularly strong action at the beginning of entry. The formula determining the effect of their action is expressed as: W=-^; it shows that at each subsequent moment the effect weakens. An example can be adrenaline. The action of M. also depends on external conditions, such as temperature and light. E.g., diuretics are much more effective at high t°, because the effect of the latter adds to the action of the medicine. Some M. act more energetically in the light, which Tappeiner showed on solutions of quinine, which, like solutions of other fluorescent substances, are more poisonous for paramecia in the light than in the dark.--The action of M. also depends on whether M. is given alone or in combination with others. The interaction of M. can then express itself either in their antagonism (see) or in synergy. Similar to the first, synergy can be direct, when both substances act on the same elements, e.g. in mixed ether-chloroform anesthesia, and indirect, when the points of application of both M. are different. Thus e.g. the combined diuretic effect of digitalis and Kalii acetic-acid depends on the action on the heart of the first and on the kidneys of the second ingredient. The effect of the combined action of synergistic substances can express itself in the addition of their actions. This is usually the case with direct synergy (Burgi). With indirect synergy, the overall effect can exceed the sum of the effects of each substance. Such action is called potentiation of the action of one substance by another. It can also manifest in the case when one of the substances by itself does not possess the action of the other, e.g. the vasoconstrictive action of potassium salts with adrenaline + cocaine. In view of the fact that the action of M. is the result of the interaction of M. and the organism, the properties of the latter also influence the final effect. Here, on the one hand, there are M. possessing the ability to act on any living protoplasm,- so-called protoplasmic poisons (e.g. narcotics of the fatty series, many heavy metals, etc.). Sometimes, despite the fact that the objects are very different, the effect of action is similar. E.g., the loss of the ability to respond to irritation under the influence of narcotics, observed not only in all animals but even in motile plants, or the action of hydrocyanic acid, which reduces oxidative processes both in humans and higher animals and in plants. On the other hand, many substances possess a specific effect only on certain cells and in some cases only on certain species of organisms, e.g. caffeine, causing rigor of the striated muscles of the frog species R. temporaria and not having this action on the muscles of other animals, even of the frog species esculenta.--Regarding the action of M. on animal organisms as a general rule, it must be indicated that the higher a given species stands in the evolutionary order, the more sensitive it becomes to poisons. Such a difference in effect at the same physicochemical basis of action as in higher and lower animals can be explained by the fact that in higher animals, the damage to certain organs, especially to certain parts of the central nervous system and the heart, has completely different consequences for animals of different levels of organization--a decapitated bird still runs or flies, while a decapitated dog or cat is instantly immobilized. The effect of the action of M. depends, besides, on the height and complexity of development of the organism, as well as on its species and individual peculiarities, and also on the state in which the organism is. Here we have to do with various types of allergy (see), which can be both quantitative, when a larger or smaller amount of medicine (resp. poison) is required to obtain the effect compared to the norm, and qualitative, when the medicine or poison causes a different picture of action. In cases where allergy is expressed in increased sensitivity to M., it is called idiosyncrasy, and when in decreased sensitivity-immunity. Both types of allergy can be, as already indicated, species and individual--in the latter case also temporary and permanent. Examples of species allergy can be: quantitative--weak sensitivity of the rabbit to atropine and of the hedgehog to many poisons, including cantharidin, and high sensitivity of birds to CO; qualitative--different attitude to morphine of dogs and rabbits (depression) and of cats and ungulates (excitement). The action of M. depends on age and sex. Some M., as e.g. morphine, are particularly strongly acting on children. Similarly, women, especially during menstruation, pregnancy, and lactation, show a special attitude to M. Thus e.g. laxatives of the anthracene series, causing a rush of blood to the pelvic organs, are contraindicated both during menstruation and during pregnancy.--A factor influencing the effect of the action of M. is the state of health of the subject taking M. Generally, both with exciting (resp. irritating) and depressing action of M., the reaction of the diseased organ is very often far from what it is in a healthy one. This explains the contraindication to the use of chloroform in heart diseases, ether- in lung diseases, aromatic- in kidney diseases, etc. In diseases, new conditions can arise that promote the main action of M., e.g. the above-mentioned sensitivity of feverish patients to antipyretics. Another characteristic example of allergy (temporary) to M. in connection with the state of health we have in the diuretic effect of digitalis (see Digitalis). An example where disease lowers the sensitivity to M. can be the relatively weak sensitivity of cholera patients in the algid period to alcohol and strychnine.--The state of satiety or starvation is of very great importance for the action. Besides various conditions of absorption of M. from the digestive tract depending on the degree of its filling, the state of the liver plays a very significant role. During starvation and in the absence of glycogen in the liver, it loses much of its strength in its barrier function. Alcohol and many alkaloids are destroyed by it in this case much weaker than under normal conditions. At the same time, other organs, e.g. the kidneys, suffer much more severely. Chronic poisoning of animals with alcohol, relatively well tolerated when feeding, causes very sharp changes in the kidneys under the condition of starvation. Even such relatively indifferent agents as repeated injection of physiological NaCl solution into the blood of animals cause edema and changes in metabolism under the condition of starvation, which are not observed in control fed animals (M. Sokolova). It goes without saying that the longer the starvation, the sharper the changes in various organs and the more clearly the allergy to the medicinal substance manifests itself. Similarly to starvation, fatigue also influences, which, if it is caused by prolonged muscular work, is also accompanied by a decrease in the body's reserves of glycogen, which, as has been indicated, is of great importance in the body's fight with poisonous substances. Finally, the action of M. also depends on the individual peculiarities of the organism, individual allergy.

On the one hand, there is an abnormally strong or perverted action of medicines--idiosyncrasy, both quantitative and qualitative, and on the other hand, abnormally weak immunity--immunity. Individual idiosyncrasy is often hereditary. In some cases, idiosyncrasy can be explained by an increased ability of the body to absorb medicines or, conversely, by a decreased ability to excrete them. If the first case is comparatively rare, the second must be taken into account, at least in some cases of idiosyncrasy depending on disease, e.g., in kidney ailments, when a number of medicines are contraindicated. The manifestations of individual qualitative idiosyncrasy to medicines most often express themselves in skin phenomena (rashes, itching, etc.), observed in some people when taking quinine, antipyretics, opium, and many others, in gastrointestinal phenomena when taking the same medicines, abnormal nervous phenomena with bromides, iodine, etc. Sometimes these idiosyncratic symptoms have a paradoxical character, as in the case of feverish temperature elevation with quinine. The phenomena under consideration are not always easily explained. In some cases, these symptoms depend on an abnormal path of excretion of the medicine, e.g., in quinine rashes from large excretion of quinine through sweat. In this case, such an explanation is probable, since the application of atropine, which reduces perspiration, diminishes these phenomena. Individual immunity to medicinal substances can be of different nature and have different character. Similar to idiosyncrasy, it can be genotypic and acquired. Most often, the latter type of immunity develops as a result of habituation to poison. In this case, it is also called mithridatism after Mithridates, who, according to legend, developed such resistance to poisons through constant intake. It should be noted that in their ability to cause mithridatism, various medicinal substances show great diversity. Along with substances whose sequential intake quickly causes habituation (morphine, cocaine, nicotine), there are such (strychnine, arsenic) to which habituation either does not form at all or, if it does develop, then extremely difficult. In the development of habituation, not all symptoms of poisoning disappear in parallel with each other. Thus, while to obtain the analgesic effect of morphine in persons habituated to the poison enormous doses are required, constipation is caused by significantly smaller doses. The same is observed with habituation to nicotine. Symptoms of nausea, vomiting, so common in the first experiments with smoking, are no longer observed in habitual smokers, while the laxative effect of smoking persists. A characteristic feature of habituation to many medicines (resp. poisons) are the so-called withdrawal symptoms, which occur upon cessation of intake of the given substance. These symptoms, often very distressing, often express themselves in phenomena opposite to those which the given substance causes in the absence of habituation; thus, upon cessation of morphine intake, diarrhea, increased secretion of glands, and extremely depressed state are observed; in severe cases, withdrawal of the poison can cause collapse with a fatal outcome. The formation of habituation is in many cases associated with the development in the body of the ability to more rapidly excrete, neutralize, or destroy the given poison. Thus, habituation to morphine depends partly on the fact that the body as it were learns to destroy the poison (Faust). Experiments with nicotine (Dixon, Lee) showed that the liver of an animal systematically poisoned with nicotine more energetically destroys nicotine than the liver of a normal animal. An example of neutralization of a substance with habituation is the increased ability of the body with repeated intake of camphor (and other aromatic substances, e.g., lysol) to form a compound with glucuronic acid, possessing significantly less irritating properties than camphor (Schmiedeberg, Meyer, Wohlgemuth).-A special type of immunity is represented by those cases when the body as it were changes its structure in connection with the changed conditions caused by the introduction of the poison. A characteristic example can be the increase in the number of red blood cells in the blood of animals chronically poisoned with CO, thanks to which, despite the relatively small amount of O₂ bound with Hb of each blood corpuscle, the total amount of O₂ in the blood proves sufficient for the tissue respiratory needs of the body. The phenomena of habituation were in some cases tried to be explained by a mechanism similar to that observed in the development of immunity to bacterial toxins, with the role of antigen being played by the medicine. However, convincing evidence in favor of such formation of immunity to medicinal substances not having a protein nature has not yet been obtained. In some cases, immunity acquired to a given substance increases the body's resistance to other substances acting on the same elements of the body. Thus, in morphinists an abnormally high tolerance to cocaine is observed; for anesthesia of habitual alcoholics more chloroform is required. A fully satisfactory explanation of these phenomena has also not yet been obtained. Probably here we are dealing with adaptations amounting to an increase in the resistance of especially suffering nerve elements in these poisonings. Application of medicines. In some cases, medicines are applied to the skin and external mucous membranes--external application, and in others per os--internal application. Such a division is obviously unscientific. What is essential is not external or internal application of medicines, but their local or resorptive action. Meanwhile, in the application of medicines on the skin, sometimes their resorptive action is counted on, and on the other hand, when prescribing per os, the purpose of giving the medicine may not be general but local action, e.g., prescription of bismuth preparations in stomach ulcer. If such a division of medicines into internal and external is preserved, then here practical purposes are meant, mainly the prevention of poisonings, which can easily occur with erroneous introduction into the stomach of strongly acting medicines intended for external application. Medicines can be applied both without violation of the integrity of the coverings and with violation.-When applied to the skin, medicines undergo relatively few changes, however, they are still exposed to the action of sweat and the contents of the sebaceous glands, especially in cases when rubbing is applied. Thus, mercury when rubbing in mercury ointment, penetrating into the depths of the sebaceous glands and hair follicles, under the action of their contents passes into soluble compounds and is absorbed. The main obstacle to the absorption of medicines by the skin is, as has been already indicated above, the fat-impregnated horny layer of the epidermis, through which gases, vapors and therefore volatile and fat-soluble (and fat-dissolving) substances can penetrate. Conditions that cause hyperemia of the skin, and especially electric (constant) current, causing phenomena of cataphoresis and iontophoresis of medicines, facilitate absorption through the skin. In those cases when absorption of volatile substances by the skin is counted on, measures are taken to limit their evaporation into the surrounding atmosphere (parchment paper, etc.). When applying medicines to the mucous membranes of the eye, nose, and pharynx, exclusively local action is intended, although here too the possibility of a resorptive effect must be taken into account. Thus, e.g., when introducing atropine into one eye, dilation of the pupil is often observed on the other. Application of cocaine for local effect in rhinitis can lead to the development of cocaineism. Although when applied to the indicated mucous membranes, medicines, as well as on the skin, undergo relatively few changes due to the weak chemical activity of the liquids washing these mucous membranes, however, some changes in medicines can still undergo in this case. Thus, calomel, applied in the form of a powder on the conjunctiva, can pass into solution. This can be explained on the one hand by the constant change of liquid and thus by a large amount of solvent, and on the other hand by the presence of proteins and salts in the liquid, contributing to the formation of a soluble mercury compound. When applying medicines per os, local action on the digestive apparatus (emetics, laxatives, astringents, etc.) is intended first of all, and on the other hand, resorptive action on the entire organism, which is the most frequent purpose of this method of application of medicines. With such application, the medicine is affected by a number of chemical-physical factors, namely: 1) a significant amount (several liters per day) of liquids in the digestive tract.

These liquids (the secretions of glands and food liquids) play the role of solvents for many medicinal substances and, by their large quantity causing dilution of the medicinal solution, also promote the ionization of medicinal electrolytes, which in turn increases the ability of M. to be absorbed, as well as their effect on the body's cells; 2) the different reaction of these liquids (digestive juices) in different parts of the digestive tract, which can promote the dissolution or precipitation of M. in the respective parts depending on the chemical properties of M.; thus, a number of medicinal substances are soluble only in an alkaline environment (tannins from ipecacuanha, aloe, salol); urotropin is decomposed only in an acidic one; 3) the presence in the intestinal contents of salts and proteins and other components that can also contribute to the dissolution or precipitation of medicinal substances, for example the dissolution of calomel in the presence of proteins and NaCl; the precipitation of silver chloride under the influence of HNO and chlorides of gastric juice when taking silver nitrate; the reduction and precipitation of heavy metals in the large intestines in the form of sulfides under the influence of H₂S, as well as the same action of the same agent when treating with iron preparations, causing blackening of teeth; 4) the presence of enzymes in the digestive juices that also affect medicines, for example the decomposition of salol or castor oil with the release of active parts, in the first case phenol and salicylic acid, and in the second ricinoleic acid, under the influence of pancreatic enzymes; 5) the presence of intestinal flora, causing for example the splitting of glycosides, which determines the action of anthracene laxative derivatives. The absorption of M. when taken per os begins for some substances in the mouth (alcohol) and is carried out with varying intensity by all parts of the gastrointestinal tract, and of course the changes just mentioned, which M. undergo in the digestive pathways, are also of great importance here. In the stomach, M. insoluble in lipoids are hardly absorbed at all. After passing from the stomach into the intestine, M. are absorbed especially vigorously in the small intestines. Moreover, even when introducing M. in the form of enemas, provided proper conditions are observed, one can expect just as complete absorption of M. as when taken per os. [For the significance for the absorption of M. of the presence of substances that dissolve lipoids (alcohol, ether), irritants (for example mustard), coating agents, high temperature and other conditions causing hyperemia, see Absorption.] The application of M. through the respiratory tract can pursue both local and resorptive action. Medicinal substances can be gases, vapors, fumes, and atomized liquids inhaled in the form of inhalations (see). M. introduced in this way undergo relatively minor changes, similar to what is observed when applying M. on open mucous membranes. The absorption of liquids and especially gases from the respiratory tract occurs extremely quickly, which is particularly valuable when using anesthesia by the inhalation method. - Into the urinary tract, M. are introduced exclusively for local action. Absorption by healthy mucous membranes of the urethra, bladder, and vagina is very weak, but is increased in inflammation, which is why the use of substances capable of causing resorptive poisoning, for example disinfecting douches of the vagina in the postpartum period, requires special caution.-Through violation of the integrity of the external coverings, M. are introduced in the form of injections under the skin, into the thickness of the skin, into muscles, into organs, into cavities, the spinal canal, and blood, and infusions under the skin and into the blood. The absorption of soluble M. in injections and their passage into the blood occur quickly, and the medicines do not undergo significant changes. Sometimes, however, substances are injected in the form of suspensions with the expectation of the formation of depots in the tissues, from where the substances slowly enter the blood, as for example happens with the subcutaneous introduction of calomel or bismuth preparations. When injecting M. into muscles, absorption occurs faster due to the well-developed capillary network in them. At the same time, when injecting irritating substances, it is relatively less painful due to the smaller number of nerve endings here that perceive pain. (For the comparative advantages and disadvantages of subcutaneous injections and introduction per os, see Injections and Absorption.) The introduction of M. into the blood (into a vein) is a method by which the maximum general effect of M. is obtained most quickly (see Infusion). This method is painless when introducing and such substances, the injection of which under the skin or into the muscle causes severe pain. At the same time, the speed of the resulting effect requires special caution in terms of the speed of introduction of M. Complete sterility and precautions against embolism are necessary, which could occur if the dissolved substance being introduced precipitates, for example hedonal when the temperature of the infused liquid decreases. M. introduced by various routes are absorbed by the blood and lymphatic pathways, and if absorption occurs from the stomach or intestine (except its lower part), M. enter the venae portae system and from there into the liver, where part of them is retained (heavy metals, some alkaloids), part is denatured (for example alcohol, nicotine, etc.). M. that have entered the blood remain there for a relatively short time. Part of the medicines is thrown into the tissues, in particular into connective tissue, and is retained by a number of organs, especially the liver and spleen, with the participation of the reticulo-endothelial apparatus. In the organs, M. are partly destroyed, partly changed, and as a result of these changes they usually lose their toxicity, for example aromatic substances, which form compounds with sulfuric and glucuronic acids. Sometimes, however, M. are converted in the body into more toxic compounds (for example the transition of nitroso compounds into nitro compounds). From the organs and tissues, M. in modified and unmodified form return to the blood. At the same time, M. are excreted from the blood with the help of excretory organs. The main pathways for the excretion of M. from the body are the kidneys, the digestive tract with its glands, the respiratory tract, and finally the sweat glands, which have less importance, as well as all glands with external secretion. The excretion of individual substances occurs by different pathways. Thus, gaseous substances are excreted mainly by the lungs, heavy metals and morphine by the intestines. However, the same substance is very often excreted by various pathways. Thus, alcohol is excreted simultaneously by all the pathways mentioned. Substances excreted in the upper part of the digestive tract (for example through the salivary glands, gastric mucosa, or liver) can be reabsorbed in the lower parts of the digestive tract. In view of this, it is recommended to perform gastric lavage in case of morphine poisoning even if this poisoning was caused by the subcutaneous introduction of the poison. As additional pathways for the elimination of M., one can name the mammary glands and the glandular apparatus of the respiratory tract and eyes. The excretion of medicinal substances into milk is important in that M. thus enters the infant and can have an undesirable effect on it. Among the substances that pass into milk, one can name chloroform, alcohol, arsenic, the active principles of many laxatives, etc. The excretion of M. by the respiratory mucous membranes and conjunctival tear glands is interesting because it can cause irritation and even inflammation of the corresponding mucous membranes, as is observed for example in bromism, iodism, etc. The time for the excretion of M. from the body, in other words the time they remain in it, varies greatly. There are medicines that are excreted very quickly, such as volatile substances, which is a particularly valuable quality for substances used for anesthesia. On the other hand, there are representatives of substances in heavy metals that are retained in the body for a very long time. As is known, argyria, caused by the deposition of silver in the skin and other organs, remains for a lifetime. The reasons for such a difference depend on the chemical-physical properties of medicines and mainly on the solubility and stability of the compounds in which these M. are deposited in the organs.