Cocaine

COCAINE, Cocainum (C₁₇H₂₁O₄N), an alkaloid obtained from the leaves of the shrubby plant Erythroxylon coca Lamarck (family Erythroxylaceae), which has been used since very ancient times in South America as a stimulant and folk remedy. Bolivia and Peru are considered the homeland of Erythroxylon coca, where the plant is now widely cultivated, as well as throughout South America and in Asia (in Java, Ceylon, and British India). The natives of South America from time immemorial acquired the habit of chewing Coca leaves, thereby moderating the feeling of hunger, maintaining muscular energy, and sustaining good spirits even during exhausting and prolonged marches in the Andes. The natives chew Coca leaves with the addition of burnt lime or the ash of the Chenopodium plant. The daily portion of leaves for an Indian reaches 30–45.0 g with an average cocaine content of 0.5% (0.2–0.8%); consequently, a person chewing Coca leaves consumes about 0.2 g of cocaine daily. However, in some cases the amount of leaves per person reaches 300–400 g. Reports on Erythroxylon coca reached Europe shortly after Columbus's discovery of America. In 1750, a specimen of Coca was delivered to the Paris Botanical Garden, and in 1842, dried Coca leaves were brought to Hamburg. The first attempts to isolate the active principle from Coca leaves were unsuccessful for a long time. Cocaine was isolated in a pure crystalline state by Lossen, who also established the correct empirical formula of cocaine: C₁₇H₂₁O₄N. Lossen also pointed out that upon boiling with a solution of mineral acids, cocaine breaks down into methyl alcohol, benzoic acid, and the base 'ecgonine'. Lossen's data were subsequently confirmed; the cleavage reaction of cocaine proceeds according to the formula C₁₇H₂₁O₄N + 2H₂O = C₉H₁₅O₃N + C₆H₅COOH + CH₃OH. Consequently, in composition cocaine is the methyl ester of benzoylecgonine; the structural formula of cocaine is: /^H CH₂-CH-C--COOCH₃ II

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_O.COS_vH_v . CH₂-CH-----CH₂ Ecgonine is chemically very close to tropine base, with which tropic acid is bound in atropine: ecgonine is regarded as carboxylic tropine. Thus, through ecgonine and tropine, a chemical affinity is established between cocaine and atropine, and thereby the common features in the pharmacological action of both just-named alkaloids become understandable. Pure cocaine is a colorless crystalline powder with a bitter taste; crystals in the form of large monoclinic prisms; melting point + 98°; cocaine has a bitter taste; solubility in water 1 : 600 at 25°, 1 : 260 at 80°; in alcohol 1 : 5 at 25°; in 12 parts of olive oil, in 4 parts of ether, in 0.5 parts of chloroform; cocaine solutions react alkaline and rotate the plane of polarization to the left. The stability of cocaine in aqueous solutions is not great, yet greater than previously thought, provided, however, that the cocaine is absolutely pure (Medvedkova): a 5-minute boiling of a cocaine solution or sterilization by water vapor at a temperature of + 100° for an hour does not cause any noticeable splitting of cocaine or weakening of the strength of action of its solution. Also, prolonged storage of sterilized cocaine solutions does not significantly affect the therapeutic activity of the solutions. For the stability of (neutral) cocaine solutions, the quality of the glass of the vessel into which the cocaine solution is poured is very important (Medvedkova). Cocaine can also be obtained synthetically from ecgonine. With acids, cocaine forms salts: citric, benzoic, hydrobromic, hydrochloric; the latter is used in medicine. The hydrochloride salt of cocaine, Cocainum hydrochloricum, s. Cocainum muriaticum C₁₇H₂₁O₄N + HCl (Ph VII) is a colorless crystalline powder with a bitter taste (crystals of prismatic or leaf-like form or in the form of broad tablets); melting point at 187-183°; readily soluble in water - 1 part in 0.5 part (Ph VII) of cold water, easily in aqueous alcohol, more difficultly in absolute alcohol. The medical use of cocaine is determined by its paralyzing effect on sensory nerves at the site of administration, as a result of which loss of sensitivity ensues. If a mixed nerve is subjected to the influence of cocaine, depression begins first in the sensory fibers and only later spreads to the motor fibers. This kind of sequence in the action of cocaine was discovered with respect to the n. ischiadicus (W. Kochs) and confirmed in studies in other cases of mixed nerves; on the basis of these experiments, it was concluded that cocaine has a special electivity for sensory nerves and especially for sensory nerve endings. However, cocaine cannot be regarded as a substance acting specifically only on sensory nerves, and cocaine cannot be considered a "sensory curare," as the early investigators of cocaine action did (Dastre). Cocaine affects not only sensory nerve endings or sensory nerve trunks, but also motor nerves, as well as the central nervous system. The latter reacts to cocaine with particular sensitivity. Very small doses of highly diluted cocaine solutions, entering the blood, affect only the central nervous system; further administration of somewhat larger doses is often also unable to cause a decrease in the excitability of sensory nerves. Gross points out that the central nervous system is approximately 6 times more sensitive to the action of local anesthetics than the peripheral nervous system, and thus explains the particular intensity of the action of cocaine on the central nervous system. Proceeding from this, the electivity of cocaine upon its local application must be accepted only conditionally, as relative and not brightly expressed. Sensory nerve endings in humans upon local application of cocaine according to the method of Schleich cease to respond to painful stimuli when using solutions of cocaine hydrochloride at a concentration of 1 : 20,000 (Braun). However, in the case just cited, the loss of excitability of sensory nerve endings occurs in connection not only with the specific action of cocaine on nerve elements, but also depending on the technique of injecting solutions (see Local anesthesia). The concentration of cocaine solutions plays an essential role in the duration of anesthesia. A 1:20,000 cocaine solution causes a transient anesthesia; with a cocaine solution of 1:1,000 strength, anesthesia lasts about 15 minutes, and from 1% cocaine solutions anesthesia is prolonged up to 25 minutes. Before the loss of sensitivity from cocaine occurs, the nerve or its endings undergo some excitation; the nerve also reacts with increased irritation at the moment when the anesthesia passes and the nerve sensitivity is restored. Anesthesia of the skin occurs from cocaine 2 - 3 - 5 minutes after the introduction of its solution by means of a syringe, wherein first the sensation of itching and temperature sensation disappear, and then the pain sensation; while the tactile sensation and the sensation of pressure are almost unaffected. When the tongue is stroked with a cocaine solution, the taste sensation is lost first for bitter, then for sweet, then for salty, and finally for sour. Pain sensations in the tongue disappear under the influence of cocaine in the first place, and tactile ones in the last. Olfaction is also lowered and disappears from cocaine, but this is preceded by an aggravation of smell. Upon local action of cocaine on mucous membranes, apart from the loss of sensitivity, a well-noticeable vasoconstriction occurs: the mucosa turns pale, becomes almost white in color, dries up, shrinks; mucus secretion stops; channels lined with mucous membranes become wider and more accessible for manipulations. One can also clearly see the constriction of vessels in the eye if a few drops of a 2-3% solution of cocaine are dropped into the eye. At first, the superficial small vessels narrow, then the larger and deeper-lying ones, the iris becomes noticeably anaemic, the cornea becomes dry on the surface and therefore matte-transparent; the vessels of the conjunctiva also narrow. The constriction of vessels by cocaine is of great practical importance because, as a result of vasoconstriction, the absorption of cocaine is hindered and it is retained at the site of administration, which is why its local action is intensified, while on the other hand less cocaine enters the general bloodstream and poisoning does not occur. When cocaine is used in eye practice, right at the beginning of the action, simultaneously with the constriction of vessels, a short-lived burning sensation appears in the eye, quickly replaced by a feeling of coldness; this latter sensation also quickly disappears, and 3-5 minutes after the introduction of cocaine into the eye, the cornea and conjunctiva lose their sensitivity. After 10-15-20 minutes, pupil dilation sets in, reaching its greatest magnitude after 30-40 minutes, and after an hour the pupil begins to decrease again and finally returns to normal size after 6-8 hours. Pupil dilation from cocaine is not maximal, as with atropine. A solution of cocaine introduced into the eye causes protrusion of the eyeball and widening of the palpebral fissure, as a result of which the eye appears as if bulging, and the gaze somewhat immobile, fixed. Such changes in the eye until recently were explained by irritation of the endings of the sympathetic nerve in the eye, and an analogy was drawn with the same phenomena occurring in animals upon electrical stimulation of the cervical sympathetic nerve. However, Fröhlich and Loewi believe that the action of cocaine consists not in the irritation of sympathetic nerve endings, but in the depression of the inhibitory nerve apparatus in the eye, which is why pupil dilation occurs, for example, from such small doses of adrenaline that before the introduction of cocaine did not cause any action. Such studies establish, among other things, the sensitizing significance of cocaine with respect to adrenaline. As a pupil-dilating agent, cocaine causes an increase in intraocular pressure; therefore, in glaucoma and a tendency to glaucoma, cocaine is contraindicated. The accommodative capacity of the eye under the influence of cocaine also changes, which is associated with irritation of the sympathetic nerve, changes in blood vessels and intraocular pressure, under the influence of which protrusion of the cornea occurs with a change in curvature and an increase in refractive properties. When using cocaine on the eye, one's attention is drawn to the property of cocaine to penetrate tissues unusually quickly and to facilitate the penetration of other substances into the eye. Cocaine is easily absorbed, which causes very rapid onset of signs of general action or poisoning from cocaine in animals and humans. Gross established by his studies that in tissue cells the action of cocaine occurs after cocaine is released as a free base; the faster the hydrolytic cleavage of the cocaine salt occurs, the sooner and more intensely the administered solution acts. In humans, as in higher animals, cocaine does not penetrate through intact skin. However, if the epidermis is removed, anesthesia occurs upon exposure of such skin to cocaine. However, loss of sensitivity can also be achieved in intact skin if cataphoresis is used. Local anesthesia of the skin in humans and higher animals is induced by injecting cocaine solutions with a syringe into the skin to an appropriate depth.

Once in the organism, cocaine is rapidly destroyed at the site of its administration, and after absorption, in the blood and tissues of various parts of the body. Wiechowski found in the urine of dogs poisoned with large doses of cocaine (0.09–0.312) an average of only 5% of the administered amount, and in rabbits he did not discover cocaine in the urine at all. However, some researchers believe that cocaine is not destroyed in the organism, but is strongly adsorbed by the tissues and only slowly released by them, which explains cases where even large doses of cocaine do not lead to poisoning. To reduce the danger of cocaine poisoning or eliminate it altogether, in patients a constriction or ligation of the limb is applied above the site of cocaine administration, and where this cannot be done due to local conditions, the administration of cocaine is combined with the injection of adrenaline for the maximum constriction of blood vessels at the injection site. By both methods, cocaine is prevented from entering the general bloodstream for a certain time; during this period, cocaine in the tissues at the site of its administration manages to be destroyed to a significant degree, and its remaining amount will no longer be sufficient for poisoning. The resorptive action of cocaine is directed primarily at the central and vegetative nervous system. In humans, from 0.01–0.02–0.03 of cocaine, the picture of general action can be twofold. If the sympathetic system reacts very strongly to cocaine, the action manifests itself predominantly on the part of the vasomotor system: pallor of the face, mucous membranes, integuments, dizziness, general weakness, chills, tremor, increased pulse rate, precordial distress, accelerated and weakened breathing, nausea, semi-fainting state, loss of muscular sense, difficulty in swallowing. In others, the effect of cocaine affects predominantly the psychic sphere (see Cocainism). The attack usually ends within 20–30 minutes, and the patient recovers, feeling, however, somewhat tired and sluggish. When the general action of cocaine occurs from large doses or a given person is particularly sensitive to cocaine, which often happens, the poisoning proceeds violently, with the irritation of the motor sphere of the central nervous system standing out particularly sharply: convulsive contractions begin, very diverse in their type: either choreiform movements, or convulsive contractions, or epileptiform or tetanic convulsions very frequently with phenomena of opisthotonos, or a cataleptic state. The eyes are protruded, pupils dilated; salivation is either abundant or very scanty. The pulse is either small and accelerated or slowed and intermittent; breathing is often slowed down to 8 per minute, but is also irregularly accelerated, often of the Cheyne-Stokes type. Urine output is either decreased or increased. Subsequently, excitation in severe cocaine poisoning is replaced by phenomena of general depression and paralysis, the patient loses consciousness, and death ensues from respiratory arrest. Solutions of cocaine cause poisoning all the faster the more concentrated they are. The danger from cocaine also increases if the injection site is the head or areas close to it: the neck, the upper part of the trunk. The magnitude of the fatal dose of cocaine for humans cannot be stated precisely, because there is a very large individual difference in relation to this poison on the part of various persons, and the conditions under which cocaine is introduced into the organism are also very diverse. Authors indicate as a lethal dose both 0.003 of cocaine hydrochloride and 0.015 per 1 kg of weight. In some cases, death in humans occurs almost instantaneously following a cocaine injection. The antidote for acute cocaine poisoning is amyl nitrite, with the help of which blood circulation in the brain and coronary vessels is restored. If cocaine poisoning is expressed by convulsive contractions, chloroform is a very useful antidote (Dogel). Subcutaneous injection of caffeine is also indicated in order to restore cardiac activity, subcutaneous injection of alcohol or, better, cognac for a reflex effect on the heart and respiratory center, as well as to cause some dilation of capillary vessels in the brain and heart. The lethal dose of cocaine for a dog is taken to be a dose of 0.03 per 1 kg of the animal's weight. With such an amount of subcutaneously administered cocaine, convulsions develop very rapidly and occur almost continuously until death itself, which occurs within 1–1.5 hours.

- In cocaine poisoning, no changes occur in the blood of either humans or animals; in vitro, however, large amounts of cocaine can produce hemolytic changes in red blood cells and paralysis of leukocytes. In experiments with toxic doses of cocaine in animals, disturbances in the activity of the gastrointestinal tract were discovered due to the effect of cocaine on the sympathetic nervous system; initially, strong peristalsis is noted, followed by a quiescent state of the intestine, and the secretion of gastric juice almost ceases due to anesthesia of the gastric mucosa. The disorder of gastric digestion entails a disturbance of intestinal activity (constipation). In acute cocaine poisoning in mice and rabbits, enlargement of the liver and vacuolar degeneration of its cells have been observed. At toxic doses, muscular work is decreased, whereas from single moderate doses of cocaine, muscle fatigue is reduced and the strength of contractions is increased, such that muscular work under the influence of small doses of cocaine is unusually increased, which is used in practice in the use of so-called doping—a liquid injected into horses at races and trotting events. The mechanism of cocaine's effect on increasing working capacity is explained by a change in central innervation, and not by a direct effect of cocaine on muscles. In cocaine poisoning, oxidative processes proceed more intensively in the organism, dissimilation processes are increased, metabolism is enhanced, and temperature rises by 1–3–5°. Cocaine has found its application in medical practice in minor and major operations, and it is used in solutions of various concentrations—0.01–0.02–1% and 20%—depending on how it is applied: in the form of lubrications, injections, or instillation drop by drop (see Local anesthesia). Following the introduction into medical practice of new locally anesthetic agents, much less toxic than cocaine, the use of cocaine has declined sharply, although its importance still remains very high. The use of cocaine internally for the relief of the stomach is not recommended due to the danger of accustoming the patient to this remedy, and for seasickness—due to the groundlessness of such an application. In the elderly, in very weak and exhausted individuals, and in those suffering from heart diseases, cocaine is contraindicated. Idiosyncrasy to cocaine is a fairly frequent phenomenon. Cocaine may fail to produce a locally anesthetic effect altogether if it is injected into the area of an acute inflammatory process (panaritium, periostitis, etc.), which is explained perhaps by the rapid washing out of cocaine from the area of inflamed tissues, since blood vessels in such cases are dilated; besides, one can think that cocaine at the site of injection, encountering a huge number of phagocytes accumulating in the inflammatory focus, is rapidly destroyed by them (Nikolayev). Cocaini hydrochloricum is used in medicine, the maximum single dose of which according to Pharmacopoeia VII is 0.03, and the daily dose is 0.12. V. Nikolayev. Cocaine poisoning in forensic-medical terms. Patho-anatomical changes in acute cocaine poisoning are not very characteristic: in general, signs of death from asphyxiation are observed. Hyperemia of the internal organs, especially the brain, is fairly constant. When the poison is administered per os, there may be ecchymoses on the gastric mucosa. The urinary bladder is sometimes overfilled. Under the microscope, despite the short duration of the poisoning, hemorrhages throughout the organs and degenerative changes predominantly in the nervous elements can be detected. During a forensic-medical investigation of a corpse in cases of cocaine poisoning, the viscera are sent for chemical examination; in addition, for the same purpose, the skin, adipose tissue, and muscles from the site of the presumed administration of the poison are taken. Since cocaine decomposes easily in a corpse, the chemical examination should be carried out as soon as possible: according to Proels, in the first 2 weeks after death, and in general—no later than a month. Detection of cocaine in forensic-medical cases. Objects of study, besides the viscera, vomit, etc., can be various kinds of powders and drinks to which cocaine is added for various criminal purposes. In examining viscera and so forth for alkaloids (see Poisons, isolation), cocaine passes into chloroform from an alkaline solution. The chloroform extract is evaporated at room temperature. Part of the residue is tested with general reactions for alkaloids (see). Part of the residue is dissolved in a few drops of water with the addition of a drop of very diluted hydrochloric acid; the solution is evaporated at room temperature. The residue is dissolved in a drop of water, potassium permanganate is added, and the resulting crystals are compared under the microscope with a preparation obtained from Cocainum muriaticum. In the case of cocaine, purple plates or clusters of potassium permanganate are characteristic. The presence of reducing substances, as happens when examining viscera, interferes with the reaction with potassium permanganate. With sufficient amounts of cocaine, which occurs when examining powders, drinks, etc., cocaine is dissolved in alcohol and carefully, after adding an excess of concentrated sulfuric acid, heated for 5 minutes on a boiling water bath, cooled, and carefully diluted with water; in this case, the characteristic odor of benzyl ethyl ether is sensed. The reaction consists in the detection of benzoic acid cleaved from cocaine. Of great importance in the detection of cocaine is the physiological test: a part of the residue is dissolved in water using the smallest possible amount of hydrochloric acid (1%), the solution is evaporated at room temperature, and the residue is dissolved in the smallest possible amount of water: 1) when introducing the solution onto the mucous membrane of a cat's eye, dilation of the pupil is observed; 2) when extracting cocaine from pills, drinks, etc., an experiment on oneself can be performed: when applying a drop of solution to the tip of the tongue, a characteristic numbness is felt.