Narcotic Substances

NARCOTIC SUBSTANCES, narcotica, or stupefacientia (from Greek narco, corresponding to Latin stupefacio - I stupify). The classification of pharmacological agents in the group of N. substances was determined from ancient times by their ability to cause either depression of the sensory and motor functions of the nervous system or clouding and loss of consciousness. For a long time, however, no sufficient distinction was made between the primary and secondary occurrence of these symptoms. Thus, as late as the middle of the 19th century, digitalis was included in N. substances, belonging to the rather numerous group of so-called narcotica acria, s. nauseosa ('acute', i.e., causing irritation of sensory nerves, vomiting, diarrhea, etc.), which caused symptoms of depression of the central nervous system only due to circulatory disorders (the same group included tobacco, autumn crocus, hellebore, water hemlock, aconite, ergot). In addition, in former times, there was often confusion between N. substances and substances causing any nervous symptoms without sufficient distinction between symptoms of depression in the overall picture of the action of a pharmacological agent. Thus, as late as the 1860s, strychnine was included in the so-called narcotica tetanica despite the fact that symptoms of depression occur in strychnine poisoning only after the particularly characteristic convulsive symptoms of this substance (the same group included brucine and picrotoxin). Finally, substances causing depression not of central but (as was later found) of peripheral origin were previously also included in the group of N. substances (for example, curare). From the large department of N. substances of the old pharmacological classification, only the group that bore the name narcotica vera ('true' N. substances), s. cephalica, s. cerebrantia (acting on the brain), has remained in the present time, to which preparations of opium, henbane, datura, belladonna, lactucarium, and hashish belonged. The current pharmacotherapeutic division of N. substances is as follows: hypnotics (sleep-inducing), sedatives, analgetica, or anodyna (pain-relieving). Since the widespread use of substances like chloroform and ether, so-called general anaesthetics have been added to these divisions. Unlike the previously known N. substances of plant origin, a very extensive group of newly studied N. substances are derivatives of methane and its homologs, containing besides general anaesthetics also hypnotics and sedatives and received the name of N. substances of the fatty series (Schmiedeberg). Later, wishing to distinguish them from narcotically acting alkaloids, i.e., substances of an alkaline nature, Overton proposed to call them indifferent N. substances. The study of the type of action of N. substances of the fatty series led to the concept of narcosis as such a depression of the central nervous system which is harmlessly tolerated by the organism due to the complete reversibility of this depression when the concentration of the pharmacological agent is reduced or it is removed. Comparative pharmacological research of these substances on various living objects of animal and plant origin revealed that they can cause similar depression of any process characterized by life. Therefore, in general pharmacology, the term 'narcosis' is significantly broader than in medicine, where it is applied only in relation to the central nervous system. The universality of the narcotic action of N. substances of the fatty series, making them general cellular or protoplasmic poisons, led to them becoming agents by means of which pharmacology seeks to elucidate the nature of narcotic action. Since the state of narcosis is primarily characterized by loss of excitability, this problem stands in direct connection with the problem of excitation and is developed equally by pharmacologists and physiologists.

The large number of N. substances of the fatty series, easily synthesized and easily subjected to various substitutions, the comparative simplicity of their chemical composition and structure gave rise several decades ago to the study of the dependence between their physicochemical, chemical, and narcotic properties. Among the narcotically acting compounds of the fatty series there are simple hydrocarbons, monatomic alcohols, aldehydes, ketones, simple and complex esters and halogen-substituted named compounds. In studying the dependence between the structure and composition of the latter, on the one hand, and their narcotic properties, on the other, a number of the following regularities were discovered: 1. Enhancement of narcotic properties with increasing number of carbon atoms in the members of the homologous series. This regularity, established by Richardson (1869) for monatomic alcohols (increase in narcotic properties in the series: ethyl, butyl, propyl, and other alcohols), was later confirmed for other compounds of the fatty series. 2. Weakening of narcotic properties in those isomers in which there is branching of the carbon chain. This regularity, established by Efron (1885) with respect to normal and isopropyl alcohols (CH₃CH₂CH₂OH is a stronger narcotic than CH₃CH₂CHOHCH₃), was later confirmed for other compounds of the fatty series.

It has also been confirmed for other compounds. 3. The unsaturation of a compound increases its narcotic properties (for example, acetylene and ethylene). 4. The introduction of a halogen into the hydrocarbon molecule increases its narcotic properties (e.g., chloroform, chloroethyl, chloral hydrate, bromoethyl, avertin, etc.). 5. The presence of a free carboxyl group leads to the disappearance of narcotic properties, which can reappear upon its esterification. 6. An increase in the number of hydroxyl groups reduces the narcotic properties of the molecule (compare the reduction in narcotic properties in the series: ethyl alcohol, glycol, glycerin). 7. The introduction into the molecule of alkyl radicals of large atomic weight increases its narcotic properties (an exception is methyl alcohol, which is more toxic compared to ethyl). This regularity, first established by Baumann and Kast (Baumann, Kast; 1890) for sulfonal and trional, is in direct connection with Richardson's law and was later confirmed for urethanes, for derivatives of barbituric acid, etc. In assessing the role of various alkyl radicals, it is noteworthy that the ethyl group, while giving the molecule sufficiently pronounced narcotic properties, at the same time does not give it the toxic side properties inherent in compounds containing radicals of higher homologs. However, in diverse in composition and structure derivatives of the fatty series, there is no necessary dependence between their narcotic action and the presence of a certain atomic grouping. Therefore, if the above regularities played a major role in the synthesis of new N. v., then in the search for general factors that determine the distribution of N. v. between the cell and the surrounding medium and their pharmacological action, research turned to their physical features. Among the characteristic physical properties of N. v. of the fatty series should be mentioned: 1) the low solubility of most of them in water along with good solubility in organic solvents and lipoids. 2) Capillary activity, i.e., the ability to reduce the surface tension of a liquid, and therefore to accumulate at its boundary with a neighboring phase. 3) Connected with the previous property, the ability to be adsorbed from solutions on the surface of a solid base.--As numerous studies have shown, the strength of the narcotic action of hydrocarbons and their derivatives follows with sufficient regularity each of these physical properties. Changing with the magnitude, composition and structure of the molecule, these physical properties with a certain constancy lead to the same changes in the strength of the narcotic action that have been established in Richardson's rule, Efron's rule, etc. In interpreting the role of these physical properties in the narcotic action, researchers attribute dominant significance to one or another of them. On the basis of studying the dependence of the narcotic action on the solubility of N. v. in fats and lipoids, the so-called lipoid theory of narcosis by Meyer-Overton arose (H. Meyer, 1899; Overton 1901). The study of the ability of N. v. to reduce surface tension gave rise to Traube's theory (Traube, 1904; "Haftdrucktheorie"), and finally the basic importance of the adsorption factor is emphasized by Warburg's theory (Warburg; 1921). Each of the named theories is forced to a greater or lesser extent to be based on experiments of a model character, which complicates the use of the conclusions drawn.-The Meyer-Overton theory, keeping in mind the significance of lipoids in the function of each cell (the doctrine of the lipoid shell by Overton, 1898), and especially the nervous one, seeks to establish a more or less complete parallelism between the narcotic action and the coefficient of distribution of N. v. between oil and water (more precisely the ratio of solubility oil \ _tt "water;- ^HU^HNO however, it should be borne in mind that depending on the choice of oil (olive, castor, etc.) this coefficient turns out to be different. Even greater variations in the numerical expression of the coefficient are found in the case, for example, if instead of water one takes blood serum, and instead of oil an extract or emulsion from brain tissue. The difficulty of choosing a suitable model experiment is further complicated by the fact that according to the data of a number of authors, undenatured cellular lipoids themselves are partially soluble in water. - The dependence of the narcotic action on the capillary activity of N. v. was discovered by Traube as early as 1891, when he showed that the dissolution in water of alcohols of the homologous series reduces surface tension in the ratio 1 : 3 : З²: З³... Fuhner discovered that in the homologous series of primary monatomic alcohols with an unbranched chain, each subsequent member of the series is three times more poisonous than the previous one. In relation to Traube's doctrine, among other objections, there is also the fact that when N. v. act on the body, one can only speak of a change in surface tension at the boundary of liquid-liquid or liquid-solid phase, whereas Traube uses the value of surface tension at the boundary of liquid-air. Warburg's theory, related to the previous theory in that the capillary activity of a substance determines its ability to accumulate on the surface of a liquid bordering a solid phase and to be adsorbed by it. Warburg believes that N. v. are adsorbed by the structural elements of the cell, thereby disrupting its vital activity. Model experiments for Warburg served as experiments with blood charcoal, the particles of which, suspended in a solution of amino acids, by absorbing them, promote their catalytic oxidation. The addition of narcotic substances inhibits or completely stops this oxidation. Warburg believes that this action is connected with the fact that the molecules of N. v., due to their capillary activity, displace the molecules of amino acids from the surface of the coal, taking their place. Since according to Langmuir's doctrine adsorbed substances are arranged on the surface of the adsorbent in the form of a monomolecular film, then N. v., having a larger molecule, occupies a larger area and should give a more pronounced inhibitory effect. The figures calculated by Warburg for members of many homologous series fully correspond to these regularities. In contrast to the lipoid theory of narcosis, Warburg's school insists that N. v. can exert their depressing action in the absence of a lipoid phase and even under conditions of an inorganic process. Thus, Meyerhof found that Richardson's rule retains its force for the catalytic decomposition of hydrogen peroxide by colloidal platinum. However, the adsorption theory is not in complete contradiction with the lipoid theory of narcosis, since lipoids can take a large part in the adsorption of N. v. (Hober). It should be noted that according to the data of Loewi (1912), the absorption of N. v. by lipoids is rather of an adsorption character than of dissolution. In the discussion that has been going on for the last decades on the question of the role of physical properties of N. v. in the origin of narcosis, the opinion of Cushny is extremely instructive: "It seems incredible that the action of these substances is determined by any one physical property, although the total sum of all physical properties may of course prove to be sufficient for this." Despite the fact that all life processes are subjected to narcotic action, it has been assumed that the main symptoms of narcosis, for example, the loss of excitability, occur secondarily due to the damage to some basic life process. One of the more common physiological theories of narcosis is Verworn's theory (Verworn; 1904), which considers the phenomena of narcosis as secondary in relation to the disruption of oxidative processes caused by N. v. The factual material speaking in favor of such a view consists in that oxygen starvation leads to a state that in many ways resembles narcosis. However, it is fully established that N. v. cause inhibition of a number of life processes, such as excitability, motor function, etc., in concentrations that do not significantly disrupt oxidative processes (Warburg). On the other hand, with the help of poisons that specifically inhibit oxidative processes (hydrocyanic acid), it can be found that the concentrations of these poisons that sharply inhibit oxygen consumption are many times less than those that inhibit nerve processes. Finally, with the help of narcotic substances, it is possible to cause immobilization (resp. narcosis) of anaerobic organisms--ascarids, bacteria, etc. (Winterstein, 1913; Veszi, 1918).--Among other views that seek to find the main physiological substrate of the narcotic action, should be mentioned those that emphasize the importance of reducing the permeability of the cell membrane (Hober), the disruption of the process of generation of electrical potential (Beutner), etc. Since the narcosis of a multicellular animal is essentially the narcosis of the central nervous system (even with complete paralysis of the central nervous system, motor nerves retain their excitability), it is extremely important to clarify the conditions that make the central nervous system particularly susceptible to N. v."

Here the distribution of N. v. in the body is of great importance, which, based on the data of Nic-loux and others, turns out to be unequal, and in accordance with the lipoid theory of narcosis, N. v. are found in greater quantities in tissues rich in lipoids (central and peripheral nervous systems, subcutaneous fatty tissue, greater omentum, perirenal fatty tissue). In addition to the factor of selective distribution, one cannot disregard the phenomenon of particularly easy susceptibility of N. v. to those processes that are associated with the presence of a more complex structure, since the adsorption of N. v. by structural elements can lead here to particularly significant violations of function (N. Winterstein). Various functions of the central nervous system are affected in narcosis in a certain sequence, which makes it possible to distinguish at least three stages of narcosis. The first stage is characterized by a gradual violation of the functions of the brain (disorder of judgment, loss of control over behavior, weakening and loss of ability to external perceptions, and then also pain sensitivity, violation of motor and static innervation, unconscious state); the second stage is characterized by the loss of functions of the spinal cord (loss of _J reflex sensitivity and reflex muscle tone); the third by paralysis of the functions of the medulla oblongata, possessing the ability to automatism (respiratory center). At the end of the first stage of narcosis, more or less pronounced motor excitement is usually observed. In the origin of the latter, several factors may be of importance, among which should be named: 1) reflex irritation caused by N. v., especially during inhalation narcosis (chloroform and ether). 2) Violation or loss of activity of higher coordinating mechanisms, which can lead to a sharp violation of the normal ratios between the processes of excitation and inhibition in the central nervous system. According to the opinion of Schmiedeberg (1883), which is in complete agreement with the numerous experimental material of recent times, the stage of excitement is associated with the loss of inhibitory influences of the higher departments of the central nervous system, primarily subject to the depressing action of N. v. 3) Direct exciting action of N. v. on the central nervous system, especially on its motor functions. The possibility of such action of N. d., especially for a long time subject to doubt, has been proven for the most diverse objects (nerve, muscle, ciliated epithelium, heart, etc.). Specifically for the central nervous system, the stage of increase in motor function of the brain (with simultaneous inhibition of its sensory function) has been clearly detected in the case of administration of small doses of alcohol and paraldehyde (Kraepelin). Although in the experiments of Kraepelin the second of the named factors may also have played a role, however, a complete denial of the direct exciting action of N. v. on the central nervous system is hardly possible (N. Meyer). From the experiments of Kraepelin it clearly follows that inhibition of sensory function precedes inhibition of motor function. Due to this, in that stage of narcosis in which all reflexes have already been lost, the excitability of motor neurons remains still preserved (experiments with electrical irritation of the cerebral cortex of Hitzig; experiments on the spinal cord of Bernstein and others). The study of various reflex arcs shows that, the more neurons (resp. synapses) participate in one function or another, the more easily and earlier it is affected by N. v. Since spinal cord reflexes have a simpler reflex arc, they are affected later than brain reflexes (exceptions are those reflexes that, having their center in the brain, are built according to the type of spinal cord, for example, the corneal reflex). Those functions of the central nervous system that possess the ability to automatism, i.e., in addition to reflex excitability, have a pronounced humoral excitability, are affected later than reflex functions. Therefore, the respiratory center functions in that stage of narcosis in which all reflexes are lost. The circumstance that more complex nervous mechanisms are phylogenetically (and ontogenetically) younger gives reason to consider phylogenetically older functions of the central nervous system as more stable and to consider the sequence in the damage of individual functions from this point of view. The greater stability of the respiratory center to the depressing action of indifferent N. v. makes it possible to use them to obtain the so-called general anesthesia, in which both pain and reflex sensitivity are completely lost. The greatest importance as general anaesthetica to the present time belongs to volatile N. v., which include 1) unsaturated hydrocarbons (acetylene, resp. nar pylene, ethylene, propylene) and close to them in type of action nitrous oxide; 2) ethyl ether and 3) halogen-substituted hydrocarbons (chloroform, chloroethyl, bromoethyl). The volatility of these substances makes it possible to introduce them through the respiratory tract; due to the large surface of absorption, they quickly enter the blood. Since the excretion of these substances from the body occurs through the same respiratory tract and again with sufficient speed, it becomes possible to constantly regulate the concentration of N. v. in the body. Only with this method of anesthesia is physiological dosing of the substance sufficiently achievable. The listed substances differ both in the strength of action and in their toxicity. By toxicity here is meant the closeness of the narcotic and dangerous for life concentration of it (i.e., the small zone of tolerance), insufficient reversibility of its action, the presence of side effects on the heart and parenchymal organs. Unsaturated hydrocarbons are the most typical indifferent N. v. and the least toxic; due to the relatively small narcotic strength, they are used in high concentrations in a mixture with oxygen; it should be noted that substances of higher molecular weight, such as propylene and trimethylethylene (so-called pental), already have a toxic effect. Ethyl ether, being a significantly stronger anesthetic, at the same time is relatively non-toxic. Halogen-substituted hydrocarbons, surpassing the previous substances in their narcotic action, turn out to be significantly more toxic. Since the toxicity of the substance is significantly less manifested with a short time of narcosis and its lesser depth, substances of the type of chloroethyl (very volatile, rapidly acting substance, with a small "zone of tolerance") are used for the purpose of short-term stunning of the central nervous system for the time of short operations, etc. (so-called Rauschnarcose). For the purpose of anesthesia, non-volatile N. v. of the fatty series are also used (for example, urethane, hedonal, avertin, pernokton). Thus, only N. v. of the fatty series belong to the group of general anaesthetica. The only exception is nitrous oxide, an inorganic substance, which, however, in terms of its action type, completely belongs to indifferent narcotics and, like them, is characterized by the absence of selective (resp. specific) action on individual functions of the central nervous system, due to which more stable central mechanisms (respiratory center) are affected last. Narcotic substances of another type of action, such as morphine, scopolamine, etc., which, as will be noted below, have a high selectivity of narcotic action, precisely because of these properties cannot be used for the purpose of obtaining deep narcosis; these substances in doses that have not yet led to the loss of reflex sensitivity, already lead to paralysis of respiration. Not having a selective action on individual functions of the central nervous system, magnesium salts also cannot be used for these purposes, as they give a picture of rapid paralysis of the entire central nervous system, including the respiratory center. All these preparations, however, find their application as synergists of general anaesthetica from among the N. v. of the fatty series (see below). The next pharmacotherapeutic group of N. v. are hypnotics (hypnotica) (see Hypnotics). Even weaker in intensity of narcotic effect is the pharmacological effect when prescribing sedatives (sedativa). An indisputable narcotic effect is obtained from the action of those substances of the aromatic series that usually bear the name of antipyretics and which, due to their inherent narcotic properties, were called by Schmiedeberg "antipyretic narcotics." Such is the action of pyramidon, phenacetin, lactophenin, aspirin and many others. In the narcotic action of these compounds, in addition to the presence of a benzene ring, the presence in the side chain of radicals of the fatty series (methyl and especially ethyl groups, as well as radicals of fatty acids - acetic and lactic) also plays a role. However, this action is particularly significantly expressed on the general well-being in morphine, which is a typical "euphoricum." With any sedative action, there is always one degree or another of effect on the centers of vegetative innervation; especially pronounced it is precisely in those preparations that are now called.

In a number of cases, they are used to affect special functions. Thus, 'antipyretics' are used to calm the excitation of temperature-regulating centers (in this complex effect, the vasomotor and sweat gland innervation participates) and to eliminate restlessness and poor well-being in feverish patients; morphine is used to calm the central innervation of respiration (in shortness of breath, cough), to suppress a number of pathological reflexes of the autonomic nervous system, in states of fear and mental agitation in the mentally ill. These substances also possess the ability to calm 'pain centers,' which is why so-called analgesic substances (analgetica, or anodyna) sometimes coincide with sedativa. Morphine and its substitutes act particularly specifically in this regard; the substances of the aromatic series mentioned earlier act more weakly. Obviously, the analgesic and euphoric effects of these preparations are related to each other. In therapy, only the first effect is usually consciously used, while the second effect in the case of morphine is avoided due to the great danger of addiction, and in the case of 'antipyretics' it is usually used only indirectly, although for eliminating restlessness and poor well-being in feverish patients this effect has great importance even at doses that little lower the temperature. The therapeutic significance of the synergism of narcotic substances is great, especially when synergists of different types of action are used. In the latter case, according to Burgi's rule, potentiation takes place, i.e., the enhancement of the effect of one synergist by another. This synergism is applied in general anesthesia, when with the help of morphine as well as scopolamine, they seek to prevent or weaken the stage of reflex action of volatile narcotics and the stage of excitement, and also to facilitate the further management of anesthesia. Synergism is also used in a number of other mixed anesthesias, for example, in magnesium-ether anesthesia. Synergism is used comparatively rarely in hypnotic preparations (e.g., the combination of veronal with Indian hemp in indonal). Its use is significantly more common in sedative and analgesic preparations (compare the ready-made combinations produced: veramon=veronal+pyramidon; codeonal=codeine+veronal; somnacetine=veronal+phenacetin+codeine and many others). In addition, when synthesizing a number of new substances, they often seek to combine in one molecule the action of different preparations (see the numerous organic compounds of bromine and others).-All narcotic substances are capable to a greater or lesser degree of causing habituation (see Morphine-morphinism, Cocainism. Narcotism). By habituation should be understood, on the one hand, the development of tolerance to the narcotic (resp. depressing) effect, and on the other hand, the development of craving for the narcotic (narcotism). In acute poisoning by narcotic substances, the following general measures are necessary: 1) removal of the unabsorbed poison, if it was introduced into the digestive tract, by inducing vomiting and washing the stomach; 2) acceleration of the excretion of the absorbed poison by prescribing diuretics, and in case of poisoning by volatile narcotic substances-by artificial respiration; 3) prevention and combating of the cooling of the body, occurring due to increased heat loss, by means of hot-water bottles; 4) combating the oxygen starvation occurring due to depression of the respiratory center, by administering oxygen (better in a mixture with 5% CO₂ to stimulate the respiratory center); 5) stimulation of the central innervation of respiration and the cardiovascular system by means of caffeine, camphor, atropine, lobeline, cardiazol, hexeton; 6) combating those symptoms of poisoning that are characteristic of individual narcotic substances (see the respective articles).- On chronic poisonings - see also Narcotism.

V. Karasiv.