Strychnine

STRYCHNINE, Strychninum, an alkaloid obtained from various species of the plant Strychnos, growing in tropical Asia, northern Australia, and on the islands of Ceylon, Java, and Timor: Strychnos nux vomica L., Strychnos Ignatii Berg., Strychnos colubrina L. From the fruits of these plants, 2–5% of alkaloids are extracted, the main part of which (about ¹/₂) is strychnine. Among other alkaloids obtained from these plants, one should mention the long-known brucine (see) and strychnicin (strychnicin). The chemical structure of strychnine has not been precisely established and can currently be represented in the following form: /CO C₂₀H₂₂NO\

; as a free base, strychnine is usually not used. Of its salts, the nitric acid and sulfuric acid salts are most frequently used. Methods for detecting S. can be divided into 2 groups: chemical and biological. The former include the colorimetric method described in the Pharmacopoeia VII and consisting of the following: to solutions of S. 1 : 10 is added a concentrated solution of KOH or NaOH—a white, insoluble precipitate of the base falls out. The precipitated sediment is filtered off, dissolved in H₂S0₄, and a crystal of potassium dichromate is added: bluish-violet bands appear around the crystal, disappearing upon movement of the liquid. This reaction can also be performed with minute quantities of S.; its sensitivity is about 0.001 mg. Another colorimetric reaction: concentrated sulfuric acid is poured into a test tube and an equal volume of an acidic solution of S. with the addition of a zinc salt and 1 drop of nitric acid is added: at the place of contact of the liquids, a characteristic red coloration appears, which does not disappear upon boiling, but disappears upon the addition of KSCN (Malaquin). Sensitivity is about 0.001 mg. S. is also determined by a reaction with vanillin and sulfuric acid; microchemically—with potassium ferricyanide, by the color change of iodine-containing gelatin, and others. Biological methods consist in obtaining an aqueous extract from organs or other objects of study and introducing it under the skin or directly into the spinal cord of white mice or frogs. A characteristic picture of poisoning is thus obtained (mice tremble sharply, reflexes are amplified). On young mice, the sensitivity is about 0.002 mg. A solution of S. applied to the mucosa of the tongue causes a sensation of sharply bitter taste. This bitter taste is well perceptible even at dilutions of 1 : 50,000 and is recommended by some authors as an auxiliary method for detecting S. when it is found in small quantities. Applied to the skin, S. has no local effect; when applied to places with a damaged epithelium, it causes a tingling sensation. S. is not absorbed through intact skin. If, however, the cathode is moistened with a solution of S., then upon passing a direct electric current, S. easily passes through the skin integuments (see Ionotherapy). Through all mucous membranes, as well as through exposed wound surfaces, S. is absorbed very intensively. Experiments on herbivorous animals show, however, that absorption from various mucous membranes can proceed at different rates: very slow absorption in the stomach and significantly more intensive absorption in the small intestines are observed. A portion of the dose introduced into the stomach and, when the exit from it was ligated, causing no poisoning within a day, causes death in a few minutes when introduced into the small intestine. In carnivores, no such sharp difference between absorption in the stomach and intestine was observed, although individual authors note a relatively more intensive absorption from the small intestines. Absorption from the large intestines proceeds somewhat slower than from the small ones. The alkaline reaction of solutions promotes the absorption of S., while an acidic reaction weakens it. The presence of gum arabic in solutions weakens the absorption of S., whereas the addition of egg white, according to Vasilyev, enhances the absorption of S. (Stepanov) (egg white has an alkaline reaction). The absorption of strychnine in birds is sharply slowed down when it is taken by mouth, and this deceleration is greater the fuller their crop. The excretion of S. from the organism occurs mainly by the kidneys (up to ¹/₃ of the total amount), and S. can be detected in the urine within a few minutes after intake. In addition, S. is excreted by the intestines, sweat, and glands (including the mammary and salivary glands). The complete excretion of S. proceeds slowly (3–4 days; upon intake of 7.5 mg—11 days; Hall), as a result of which cumulation is possible with repeated intakes. S. passes from mother to fetus, but does not pass into the egg when given to birds. Upon intake of therapeutic doses of S. in healthy people, saliva secretion is somewhat enhanced and the feeling of hunger increases. Upon intake of toxic doses, a sharply expressed feeling of hunger appears, and timidity and restlessness quickly develop. Respiration becomes deep and frequent, and a feeling of pain in the chest appears. Painful muscle twitching develops and, accompanied by visual sensations of flickering lightning, an attack of tetanic convulsions unfolds. These convulsions are characterized by the simultaneous contraction of all skeletal musculature—both flexors and extensors—causing opisthotonos (since the group of back muscles is stronger than the abdominal ones). Pressure in the abdominal cavity increases sharply, respiration ceases due to the tetanus of the chest muscles, the face, red at first, becomes cyanotic, veins become engorged, and eyes bulge from the orbits. Due to the contraction of facial muscles, an expression of a smile appears on the face (sardonic smile). Consciousness is preserved. Due to the simultaneous contraction of flexors and extensors, a sensation of sharp pain appears. The attack lasts a few seconds or minutes and is replaced by a state of extreme general weakness. After a short interval, a new attack of tetanus develops. In humans, more than 3–5 attacks are rarely observed, because death occurs as a result of changes in a number of functions during the attack and, above all, the absence of respiration. Death usually occurs not during the attack itself, but somewhat later from respiratory depression. Rigor mortis sets in very rapidly, in the very first minutes after death. In the case of survival, a state of sharp weakness develops, and deafness, psychic disorders, and prolonged blindness may be observed. In experiments on frogs, the stage of tetanus is always followed by the next stage of relaxation of the skeletal musculature, and with large doses, death occurs with phenomena of paralysis of the central nervous system. The main role in S. poisoning is played by excitation of the central nervous system, predominantly the spinal cord and medulla oblongata. Removal of the brain and medulla oblongata does not eliminate the developed tetanus and does not prevent its appearance, from which it can be concluded that the main role in the development of tetanus belongs to the action of S. on the spinal cord. Tetanus can be provoked by touching the skin of a frog; it does not develop after cocainization, consequently, the convulsions in S. poisoning are of reflex origin. Strychnine convulsion differs from a normal reflex in the following: 1) In an ordinary reflex, only a specific group of muscles contracts, and the reflex often has a protective character. In S. poisoning, in response to irritation, all muscles contract, and the reflex loses its protective character. 2) In an ordinary reflex, the degree of its expression depends on the strength of the irritation; upon repeated irritation, summation of the effect is observed. In S. poisoning, there is no such dependence: the response is immediately maximal ("all or nothing"). Numerous studies have been devoted to the question of which elements of the spinal cord S. acts upon. On the basis of experiments, it becomes probable that strychnine acts mainly on the internuncial neurons (Schaltneuron) of the spinal cord, exciting them, as a result of which an irritation coming from outside is easily transmitted to various segments of the spinal cord and leads to the appearance of tetanus. S. also has an exciting effect on the medulla oblongata. Respiration quickens and becomes deeper long before the onset of tetanus. As a result of excitation of the vasomotor center, blood pressure rises. As a result of excitation of the vagus nerve center, the heart rhythm slows down. Barath showed in humans that even with 2–3 mg of S., blood pressure can rise by 18–35 mm with a simultaneous slowing of the rhythm. In experiments on curarized animals, every irritation of sensory pathways leads to a significant rise in blood pressure and a slowing of the pulse. In non-curarized animals, tetanic muscle contraction additionally contributes to this. The effect on the brain in humans is expressed in a feeling of fear, timidity in animals. In experiments by Sollmann, stroking an animal (a rabbit) delayed the appearance of convulsions, from which it can be concluded that the feeling of fear can provoke and accelerate the onset of tetanus. Consciousness in humans in S. poisoning is preserved until the end. According to some studies (Baglioni, Amantea, and others), S. leads to an increase in the excitability of the motor regions of the cerebral cortex. S., even in therapeutic doses, causes an aggravation of the sense organs. An aggravation of taste, tactile sensations, smell, hearing, and vision is observed. Under the influence of S. injection, in about 15 minutes visual acuity increases from ²⁰/₂₀ to ²⁰/₅; the visual field increases. The opinion is widespread that the improvement of vision is the result of the action of S. on the retina of the eye, and therefore injections for therapeutic purposes were made into the temple of the affected side. However, there is reason to believe that the improvement of vision is the result of the action of S. on the central nervous system, since the outflow of lymph does not go from the temporal region to the retina, but vice versa, and the improvement of vision occurs independently of the injection site (Fellenberg). S. produces a greater effect on an eye with weakened vision than on a healthy one; apparently, this is connected with the usual rule of a greater effect of poison on organs located under conditions of pathobiosis.

The sharpening of the organs of taste is also of central origin. The effect of strychnine on the peripheral somatic nervous system, even at toxic doses, is of negligible significance. The conductivity of motor nerves under the influence of strychnine doses significantly exceeding those necessary for the development of convulsions increases; under the influence of normal doses, the conductivity of motor nerves does not change. Strychnine has no effect on the muscle itself in tolerated doses; upon direct action in large doses, a slight depression of striated muscle is observed, as well as depression of the endings of motor nerves. The observed improvement in performance under the influence of small doses of strychnine must be explained by central causes (Varrier-Jones experiments on himself). Of organs with smooth musculature, contractions of the uterus and intestines are possible under the influence of strychnine. These contractions can also be recorded on isolated organs (5 mg of strychnine per 200 cm³ of Ringer's solution). Vascular contractions are observed mainly due to reflex causes and excitation of the vasomotor center. An increase in the tone of the heart muscle is noted; an increase in the pendular movements (Pendelbewegung) of the intestine. With the development of convulsions, the amount of Ca in the blood increases, the number of young forms of red blood cells in the blood increases, and the blood formula shifts to the left. Basal metabolism changes little with the administration of doses that do not cause convulsions under strychnine: some authors find that it does not change, others that it increases slightly. With the development of tetanus, oxygen consumption and carbon dioxide output are increased. Body temperature may rise, but since heat dissipation usually increases as well, the temperature most often remains unchanged. In experiments on winter frogs, it was established that strychnine causes glycosuria. In summer frogs, glycosuria is obtained if they are placed on ice; glycogen reserves in the liver are necessary for the development of glycosuria. In warm-blooded animals, glycosuria was obtained by authors only in young animals. Strychnine in doses that do not cause convulsions increases the excretion of adrenaline, thereby contributing to the elevation of the tone of the sympathetic nervous system. This in turn can contribute to hyperglycemia. Therapeutic application. Strychnine is prescribed: 1) For digestive disorders. Due to its bitter taste, strychnine improves the secretion of gastric juice. The motor ability of the stomach improves. The acidity of the gastric juice under the influence of strychnine approaches normal. In case of its insufficiency, it increases. In pylorospasm, increased acidity after treatment with strychnine decreases. 2) For stomach ulcers. A decrease in pain, improvement in general well-being and appetite, disappearance of blood in the stool, and a decrease in constipation are observed. For indications 1 and 2, salts are often not used, but tincture of nux vomica containing strychnine. 3) For poisoning with chloroform, chloral hydrate, veronal, etc., strychnine excites the respiratory center depressed by these poisons. 4) For cardiac weakness. Strychnine helps in cases where the insufficiency of cardiac activity is caused by insufficient vascular tone: strychnine, by exciting the vasomotor center and increasing vascular tone, improves blood circulation. Recently, strychnine has also been recommended for extrasystoles. 5) In shock, strychnine, by exciting the vasomotor center, causes a rise in blood pressure. 6) For various kinds of motor paralysis with the aim of increasing the tone of weakened centers. In acute inflammatory processes, deterioration was observed, and strychnine should not be prescribed. 7) For incomplete atrophy of the optic nerve, amblyopia, amaurosis—in these cases, strychnine is traditionally injected into the temporal region of the affected side. Apparently, however, the site of injection does not play a significant role. The effect reduces to the sharpening of the senses due to the excitation of the corresponding parts of the central nervous system. 8) For the weakening of the tone of the sphincters of the rectum, urinary bladder, and for nocturnal enuresis. For paresis of the vocal cords after diphtheria, etc. 9) In the treatment of chronic alcoholism. The phenomena of depression of the central nervous system in this condition greatly complicate the fight against the disease. The therapeutic significance of strychnine lies in increasing the tone of the central nervous system and improving general well-being. 10) With lumbar anesthesia by stovaine. ¹/₃–¹/₂ mg of strychnine is added to the stovaine solution in order to reduce the depressing effect of stovaine on the respiratory center. 11) For sexual impotence. Help in poisoning. First of all, it is necessary to remove the amount of poison that has not yet been absorbed. When taking strychnine per os, it is necessary to wash out the stomach thoroughly, preferably with tannin solutions (strong tea can be taken). Strychnine forms an insoluble compound with tannin, which, however, disintegrates under the action of gastric juice, so the resulting compound must be removed. Since reflexes are increased in strychnine poisoning, it is often necessary to preliminarily chloroform the patient before introducing the stomach tube. The absorption of strychnine can be reduced by giving crushed charcoal, preferably activated, since strychnine is well adsorbed on its surface. For threatening convulsions, narcotics are used, preferably chloroform. Hypnotics of the sulfonal type are not used, since with the duration of their action, summation with subsequent depression from strychnine may result. All kinds of irritations, including light and sound irritations, must be eliminated as much as possible (maximum rest). Preparations. 1) Strychninum nitricum, strychnine nitrate. Colorless needle crystals, bitter taste. Soluble in 90 parts of cold and in 3 parts of boiling water; in 3 parts of alcohol. Prescribed in pills, drops, powders, and subcutaneously. Dose (Pharmacopoeia) 0.001 (0.003). 2) Strychninum hydrochloricum, strychnine hydrochloride, and 3) Strychninum sulfuricum, strychnine sulfate—similar to the previous one. In addition, preparations obtained directly from various parts of Strychnos are used: 1) Tinctura Strychni, s. Tinctura Nucis vomicae, nux vomica tincture. Prepared from 10 parts of nux vomica seeds in a sufficient amount of 70% alcohol so that the tincture contains 0.25% alkaloids. Prescribed internally 5–10 drops several times a day. Doses 1.0 (3.0) (Pharmacopoeia). 2) Alcoholic extract from nux vomica seeds. Brown coarse powder. Contains 16% alkaloids. Prescribed internally in powders, pills, 0.01 (0.03). Sugar can be added. Higher doses 0.03 (0.12) (Pharmacopoeia). A. Vasilyev. Detection in forensic medical cases. Like other alkaloids, strychnine is extracted from parts of a corpse with acidified alcohol (see Poisons, isolation). Upon evaporation of the alcoholic extract to the consistency of syrup, the liquid is treated with absolute alcohol, filtered, and the filtrate is evaporated again. The operation is repeated until alcohol ceases to precipitate protein bodies. The syrup is diluted with water to a small volume, and the acidic liquid is repeatedly extracted with chloroform; then the liquid is saturated with ammonia and again repeatedly extracted with chloroform. Chloroform extracts from the alkaline solution, combined together and washed with water, are evaporated. The residue is subjected to purification by dissolving it in water using the smallest possible amount of very dilute hydrochloric acid, extracting with chloroform from an acidic and caustic alkaline solution. The residue upon evaporation of chloroform from the alkaline extract is dissolved in the smallest possible amount of dilute hydrochloric acid (1%), and the solution is evaporated at room temperature on several watch glasses. In case general reagents for alkaloids (e.g., iodine solution in the presence of potassium iodide, bismuth iodide solution in potassium iodide, etc., see Alkaloids) give precipitates in a part of the residue solution, reactions for strychnine are performed. 1. A part of the residue is dissolved with sulfuric acid (5 parts of concentrated sulfuric acid and 1 part of water) and a crystal of potassium dichromate is added: a blue coloration appears (streaks), turning to violet, red, and then disappearing. 2. A solution of vanadic acid in concentrated sulfuric acid gives the same, but more permanent coloration. 3. Physiological testing is necessary: a part of the residue is dissolved with the aid of 1% hydrochloric acid, and the solution is evaporated to dryness on a water bath. The residue is dissolved in 1 cm³ of water. Two as identical as possible frogs are placed in identical beakers lightly covered with paper. Then, drawing the test solution into a pipette, it is carefully dropped onto the back of one frog. The next drop is released when the first is absorbed. This continues until the entire solution is absorbed by the frog's skin. Then the appearance of tetanic convulsions is observed, which is preceded by an increase in reflexes compared to the other frog.