Pilocarpine

Pilocarpine (Pilocarpinum), an alkaloid contained in the leaves of jaborandi (Folia Jaborandi, s. Folia Pilocarpi). Jaborandi is the native name in Brazil for various plants of the rue family (Rutaceae-Rutoideae-Cusparieae), namely: Pilocarpus Jaborandi Holmes (N. Brazil),?, pennatifolius Lemaire (S. Brazil and Paraguay), identical with P. Selloanus Engler; P. trachylophus Holmes (New Brazil), P. microphyllus Stapf (Marangam), P. spicatus St. Hilare (Sao Paulo), P. racemosus Vahl (Martinique, Guadeloupe). The plants are small (up to 4 m in height) shrubs with large dark, dark-green odd-pinnate leaves, with individual species having particular characteristics. The commercial varieties of jaborandi leaves are mostly leaves of several species. The first two species are accepted. The leaves contain the alkaloids: pilocarpine, isopilocarpine, pseudopilocarpine, pilocarpidine, jaborine, jaboridine (in the leaves of P. microphyllus also carpiline or pilozine), volatile essential oil (0.2-1.1%), resin and mineral substances. P. is the most important alkaloid in action and content in the leaves (0.15-1.9%). Discovered in 1875 by Gerrard and Hardy. Not obtained in crystalline form, but forms crystalline salts (of which the most important are hydrochloric and nitric acids). In pure form P. represents a thick, honey-like, colorless non-volatile liquid, bitter taste, difficult to dissolve in water and easily in alcohol, ether and chloroform. Chemically, P. has the composition CnH16O3N, its structural formula is not yet fully established. Pinner and Schwarz (1902) attribute to it the following structure: c2h5.ch-ch.ch2.c------n.ch3 OCH2

From this formula it is seen that the alkaloid consists of a methylated glyoxaline (imidazole) ring, connected with a homopilopine residue, or is a lactone of pilocarpinic acid. Upon addition of NaOH [or KOH, Ba(OH)₂] the lactone ring of the homopilopine group opens: C₂H₅.CH-CH.CH₂.C-------N.CH₃ NaOOC CH₂OH CH------N^'^CH and the alkaloid is converted into a salt of pilocarpinic acid; this salt does not possess the action of P.; Therefore it is assumed (Marshall) that the action of P. is closely connected with its lactone structure; while the influence of the glyoxaline part of the molecule has not yet been established. Isopilocarpine and pseudopilocarpine are stereoisomers of P.; isopilocarpine is obtained by the action of heat or alkali on P. and is converted into the latter upon heating with alcoholic solution of KOH. In the leaves of jaborandi it is present in smaller quantities and is weaker in action than P. In pure form it represents a syrup, forms crystalline salts. Experimental data show that isopilocarpine in small doses is 6-8 times, and in large doses 20 times weaker than P.--Pilocarpidine. (C₁₀H₁₄O₂N₂) differs from the preceding ones in its chemical composition. It is contained only in the leaves of jaborandi. It acts similarly to P., but is weaker than it and isopilocarpine. - Jaborine (C₂₂H₃₂0₄N4) according to many authors is a product of decomposition (condensation) of other alkaloids in the process of preparation of P. and acts in some respects analogously to atropine. The commercial preparation under the name jaborine (Merck's factory) was found to contain only P., isopilocarpine and pilocarpidine.-P. is absorbed very quickly by mucous membranes and especially by subcutaneous fatty tissue. It is excreted by the urine mostly unchanged, but in combination with other substances. The short duration of action of P. is explained by its inactivation in the tissues "due to adsorption. Pilocarpine does not pass into milk. Action on the organism. P. belongs to the group of poisons acting selectively on the endings of parasympathetic nerves (see Vagotropic substances); this action manifests itself as excitation, which with sufficient doses is replaced by inhibition and paralysis. This action is not of central origin, as it is observed in animals even after section of the corresponding secretory or motor parasympathetic nerves, likewise on isolated organs. It is also not the result of any influence of P. on the cells of vegetative ganglia, as it is observed also after their paralysis by nicotine. The action lies peripheral to the nerve endings, because it remains even after their complete degeneration, but is stopped by atropine; since the latter in the doses used in this case does not act on the cells of the organs themselves, the point of application of P.'s action is considered to be that intermediate substance which connects the nerve endings with the secretory or muscle cell (myoneural connection). It is usually assumed that P. by itself does not act on the endings of sympathetic nerves. In the whole organism the picture of P.'s action is considerably complicated due to the intensified secretion of adrenaline by the adrenal glands, the influence of P. on the central nervous system in connection with certain exceptions to the general rules presented by its action (sweat glands). Therefore some authors (especially clinicians) are inclined to consider P. an amphotropic poison, i.e. acting on both divisions of the autonomic nervous system. The main organs-executors, resp. objects of action of pilocarpine, are the glands, smooth musculature and heart. With subcutaneous administration of P. salts the action begins after 10-15 minutes and with therapeutic doses (0.005-0.01) lasts from 1/2 to 3 hours. Glands. P. causes a strong increase in the secretion of a number of glands, so that after a single therapeutic dose the total loss in body weight can reach 2-4 kg. Usually the action first manifests itself on the salivary glands, followed by the sweat glands and others. The amount of saliva sharply increases, so that from 0.01 hydrochloric P. in man is secreted in 2-3 hours on average 550-750 cm³ of viscous saliva. The total amount of solid constituents in it is increased, but their percentage content either does not change or even somewhat increases; the increase especially refers to the organic constituents. The amylolytic power of such saliva is noticeably lowered, but the total amount of ptyalin excreted is greater than in normal conditions (Ewing). The intensified secretion is accompanied by dilation of the blood vessels of the gland, but this is a secondary phenomenon due not to pilocarpine but to the influence on the vessel wall of metabolic products formed or liberated during the intensified work of the organ. It is possible that the intensified secretion of glands also has a central origin, as it is observed also in the case if P. is not allowed to the periphery (when all vessels of the gland are ligated), but the connection with the central nervous system is maintained by means of the sympathetic nerve. In very large doses P. does not cause intensified secretion and even prevents the onset of secretion which is observed from irritation of the secretory nerve by electricity; these doses also diminish the blood flow. This action is the result of paralysis of the endings of the secretory nerves, not of the cells, as after irritation of the sympathetic nerve the secretory activity of the cells increases.- The mucous membranes (of the nose, mouth, pharynx, larynx, bronchi), lacrimal and sebaceous glands (of the external auditory canal, skin) also increase their secretion with therapeutic doses of P., which leads to an increase in sputum, cough movements, etc. In pulmonary diseases caution is required in the use of P., because due to the intensified secretion of bronchial glands, dilation of pulmonary vessels and spasm of bronchioles from P. cases of pulmonary edema have sometimes been observed. A particularly noted intensification of the secretion of the skin's sebaceous glands in the clinical use of P. to stimulate hair growth; in successful cases it has been noted that the new hairs are darker than the previous ones. Perspiration is sharply intensified, so that in 2-3 hours 500-700 cm³ of very watery sweat of neutral or weakly alkaline reaction, without odor, is excreted. Perspiration is accompanied by dilation of the skin vessels and an increase (by 1/4-1°) in skin temperature, sensation of warmth and pulsation of the temporal and carotid arteries, acceleration of respiration and pulse. The dilation of skin vessels sometimes begins from the site of P. injection and then spreads further, which may also indicate a peripheral (along with central) origin of this action; the same is evidenced by the dilation of vessels of isolated organs (Kravkov). With the sweat a considerable amount of nitrogenous substances is excreted, which has particular clinical significance in kidney diseases: thus, in 3 liters of sweat in a healthy person 2.5 g of nitrogen is excreted, while in nephritics up to 8.0 g. The peripheral nature of P.'s action is proved by the fact that perspiration is observed also after section and degeneration of the nerves of a cat's paw. The sweat-inducing action of P. is destroyed by atropine, although the secretory nerves of the sweat glands in all other respects behave like sympathetic nerves. The ability of the endings of the sympathetic nerves of sweat glands to respond to parasympathicotropic poisons (P., atropine) has not yet received a satisfactory explanation. Besides peripheral P. apparently also has a central action, as in traumatic transverse lesions of the spinal cord perspiration after P. is observed only in those areas of skin which remained in connection with the gray matter of the brain, from which the sweat nerves emerge, while in areas of skin where this connection is interrupted by trauma, perspiration is not observed (sometimes this reaction is used for diagnosis of the level of spinal cord lesion). However, the possibility is not excluded that here not sweat, but sensory and vasodilator nerves play a role, the interruption of which leads to disorders of blood circulation and cessation of perspiration (Cushny). The latter circumstance perhaps explains the fact that in man after section of a limb nerve small doses of pilocarpine no longer cause perspiration. P. exerts less influence on the glands of the stomach-intestinal canal. In small doses in dogs an abundant jerky secretion of the stomach was observed, but apparently here mainly abundant secretion of mucus, not gastric juice, is present, as the secret at this time has much solid residue (up to 6.4%) and weakly digests proteins; it is often of alkaline reaction and contains amylase, which may also indicate its intestinal origin, all the more so that at the same time anti-peristaltic movements of the intestine are observed, which may lead to the throwing back of intestinal juice and bile into the stomach (Dixon). Increased secretion of gastric juice can be observed only from large doses of P. (Sollmann). It is possible that the secretion of intestinal glands is increased by P. (Savich). The secretion of pancreatic juice is increased to a slight degree.

Most authors believe that P. has no effect on bile secretion, while the appearance of a larger amount of bile in the intestine noted by some authors can be explained by the increased motor activity of the gallbladder and duct muscles. P. also has no effect on milk secretion. The absence of P.'s effect on bile and milk secretion is consistent with the fact that the secretory nerves for both processes are still unknown. P. apparently has no direct effect on diuresis, while the decrease in urine and chlorides in it is explained by the large loss of fluid through other glands, as well as by the contraction of the smooth muscles of the ureters. With regular administration of P. to animals for several days, hyperglycemia and glycosuria are observed. Some authors attribute their origin to the enhanced secretion of adrenaline by the adrenal glands under the influence of P., however, in experiments on rabbits, this was observed even after bilateral removal of the adrenal glands (Bornstein and Holm), as well as after complete splanchnicotomy (Farber); thus, the mechanism of this action of P. has not been clarified. Smooth muscle. The tone and contraction of almost all organs' smooth muscle are significantly enhanced under the influence of P.; with sufficient doses, spasm is observed. When applied to the eye, as well as after large doses of P. orally or subcutaneously, pupil constriction occurs, which with sufficient doses can become the size of a pinhead. The action begins with local application in about 15 minutes, reaches its maximum in 1/2 to 1 hour, and disappears only after 3-5 hours; after this, some pupil dilation may be observed, which is attributed to the subsequent paralysis of the oculomotor nerve or excitation of the sympathetic nerve. The constriction of the pupil is due to excitation of the endings of the oculomotor nerve; Dixon believes that P. also excites sympathetic ganglion cells, as before pupil constriction, its dilation can often be noticed (in cats with intravenous administration of P.). Due to excitation of the endings of the oculomotor nerve, contractions of the ciliary muscle occur, as a result of which the Zinn's ligament relaxes, the curvature of the lens increases, and accommodation is established for near vision (so-called spasm of accommodation). This action begins about 15 minutes after applying P. to the eye and lasts for about 2.5 hours; in humans, it has been observed that this action may occur before the size of the pupil changes, although usually it happens later. Intraocular pressure first slightly increases, but soon this increase passes and gives way to a significant and prolonged decrease, which is explained by the outflow of intraocular fluid through the Fontana spaces, expanded due to the contraction of the iris (pupil constriction). The initial increase in pressure has no satisfactory explanation. Due to excitation of the endings of the pulmonary branches of the vagus nerve, contractions of the bronchiole muscles occur, the lumen of which can reach complete spasm. Very often before this, there is a well-expressed dilation of the bronchioles, which is attributed (Dixon) to earlier and stronger excitation of bronchodilating fibers. Enhanced movements of the stomach can cause severe pain under the xiphoid process, as well as nausea, rarely vomiting; some authors (Eggleston, Hatcher) attribute these phenomena to a central origin, while most believe that their basis is sensory irritation of the stomach due to its enhanced contractions. Enhanced peristalsis of the intestine leads to repeated emptying with noisy gas discharge. The stool is initially of solid consistency, but later, due to insufficient time for fluid absorption, it becomes liquid. The liquid consistency of the stool may also depend on the enhanced secretion of intestinal glands. When the intestine is completely emptied, continuing peristalsis manifests as painful tenesmus or colic. With large doses of P., it can cause spasm of the intestine, and the intestines may take the form of beads; atropine eliminates this spasm. It is possible that in addition to excitation of the endings of the vagus nerves, the enhancement of peristalsis from pilocarpine is also due to its toning and exciting effect on the Meissner's plexus of the intestine. The gallbladder performs rhythmic contractions with increased tone, which promotes the rhythmic outflow of bile into the duodenum. The contractions of the smooth muscles of the spleen and ureters are expressed to a weak degree. Rhythmic contractions are noted in the urinary bladder, which sometimes leads to painful urges and repeated emptying of the bladder. P. either has no effect on the sphincter or causes its relaxation; the detrusor muscle and trigone of the bladder are in a state of contraction. If contractions of the bladder existed before the administration of P., after it they become more prolonged, and the tone of the muscles increases. The action of P. lasts 5-10 minutes, after which gradual relaxation of the bladder occurs. The tone of the uterine muscle and the amplitude of its spontaneous contractions increase; the action of pilocarpine is not long-lasting. The point of application of P.'s action here has not yet been finally clarified. Although atropine completely eliminates this action, thereby showing that it was due to excitation of the pelvic parasympathetic nerve, nevertheless, there are experimental data speaking in favor of excitation of the sympathetic hypogastric nerve (having motor and inhibitory fibers for the uterus). Thus, after paralysis of the motor fibers of the hypogastric nerve by ergotoxin, pilocarpine causes relaxation of the uterus instead of contraction. Clark (Clark) believes that P. excites all sympathetic endings in the uterus. Dixon, however, considers the action of P. as the algebraic sum of 3 factors: excitation by it of sympathetic ganglia, increased secretion of adrenaline, and the direct motor action of P. on the uterine muscle cells: The enhancement of contractions of the guinea pig's uterus and the uterus of a pregnant cat, along with the relaxation of the non-pregnant uterus in a cat, Dixon explains by the fact that here there is only an expression of the difference in the relative strength of the direct exciting action on the muscle and the indirect inhibitory action; the latter takes precedence in the pregnant cat. This question requires further clarification on human material. With large doses of P. in humans, enhanced contractions of the uterus (cases of abortion) have been observed. Cardiovascular system. Excitation of the endings of the vagus nerve in the heart is expressed by slowing of its rhythm (especially pronounced in the atria), significant increase in diastolic relaxation and decrease in the force of heart contractions; blood pressure decreases at the same time; with large doses, heartbeats can completely cease, but there is no paralysis of the muscles, as the heart responds to chemical or mechanical irritation with contraction. Quite often in dogs and humans, slowing of the heart rate is preceded by an initial increase in it (by 10-20 beats per minute), accompanied by an increase in blood pressure. In humans, unpleasant sensations in the heart area (palpitations) and dilation of skin vessels, mainly of the face, are noted at this time. The increase is observed together with the beginning of abundant gland secretion. It is considered as an indirect phenomenon, occurring either due to dilation of the vessels (from transient paralysis of the vasomotor center) as a compensatory phenomenon or as a reflex effect from the frequent nausea (see above) under the action of pilocarpine. Dixon also allows for excitation of the endings of the sympathetic nerves of the heart (direct or indirect through enhanced secretion of adrenaline by the adrenal glands); under certain conditions (e.g., when P. is administered orally), it can prevail. The stage of slowing of the heart rate in humans and mammals is usually very short, followed by a secondary increase in heart rate, explained by excitation of the endings of the sympathetic accelerating nerves and possibly of the heart nodes, and not by paralysis of the vagus nerves, as it is observed even after turning off the vagus nerve with atropine; blood pressure increases at this time. With large doses, gradual depression of the heart muscle and vasomotor center occurs, due to which the pulse becomes rare and weak, and blood pressure drops sharply. Changes in the lumen of blood vessels under the action of P. depend mainly on its effect on the vasomotor center, since parasympathetic innervation of the vessels is poorly developed (see Autonomic nervous system); some role in vasodilation (of the skin, lungs, etc.) can be played by P.'s excitation of vasodilator endings in the vascular wall (Jaffe). Blood. The number of erythrocytes, leukocytes (especially many-nucleated) and the percentage content of Hb in the blood increase due to some thickening of the blood (loss of fluid due to enhanced secretion of glands, especially sweat glands, and increased insensible perspiration); in addition, leukocytosis also depends on the squeezing out of leukocytes from the spleen and lymph glands due to contraction of their smooth muscles (Harvey). This action is eliminated by atropine. The concentration of chlorides does not change significantly, the amount of sugar in the blood increases to a greater extent than could be explained by fluid loss (see above).

Ruzicka asserts that P. increases the number of Malpighian corpuscles in the spleen. Small doses of P. decrease, while large doses increase the rate of lymph flow in the thoracic duct, which Camus and Gley explain by excitation of the motor nerves of the thoracic duct. General phenomena. The temperature of the skin slightly (by 0.5-1.5°) rises (vasodilation), and to a small degree an increase in internal temperature may also be observed (increased glandular work); however, if heat loss becomes great (perspiration, insensible respiration), then the internal temperature falls, especially during fever. Metabolism somewhat increases; increased excretion of CO₂ and uric acid has been noted. In cases of poisoning, symptoms of action on the central nervous system are observed. At the same time, weakly expressed symptoms of psychic excitation and more distinct motor phenomena (muscle twitching, trembling, mild convulsive movements, such as hiccups) are observed. Convulsions sometimes observed in humans can be explained by anemia of the brain due to heart weakness. More distinct symptoms of excitation of the centers of the medulla oblongata (vasomotor, vomiting, respiratory) with their subsequent paralysis are observed. Depression of individual parts of the vasomotor center (controlling the innervation of the skin and brain vessels) begins quite early, but complete paralysis occurs only from large doses. The initial excitation of the respiratory center manifests as increased and intensified breathing; with large doses, however, slowing of respiration and asphyxial dyspnea with convulsions follow. Suffocation depends, in addition to paralysis of the respiratory center, on spasm of the bronchi, accumulation of abundant mucus in the bronchi, and slowing of pulmonary circulation due to paralysis of the heart muscle. All these phenomena form the basis of pulmonary edema from P. Fatal outcome in severe cases has been observed from collapse due to paralysis of the heart muscle. Symptoms of acute poisoning: profuse salivation, profuse sweating, pupil constriction, visual disturbances, nausea, vomiting, diarrhea, marked slowing of the pulse, sometimes significant depression of the psyche, collapse, pulmonary edema. Treatment of poisoning. Frequent mild cases of poisoning pass without special treatment. In more severe cases, atropine is administered subcutaneously (0.005 in a 1:1,000 solution up to 3 times) as an antagonist of P. in relation to its peripheral action. In other respects, treatment is purely symptomatic (cardiac and central nervous system stimulants, etc.). Application. Of the salts of P., P. hydrochloricum is most widely used in the USSR; in Anglo-Saxon countries, P. nitricum; their dosage is the same. Externally, P. is used in ophthalmic practice (¹/₄-4% solutions) in glaucoma, corneal ulcers, etc., as a means of reducing intraocular pressure and constricting the pupil; its action is weaker than that of physostigmine, but due to its lower toxicity, it is less dangerous. Externally, P. has been proposed in alopecia and some dermatoses as a means of increasing the secretion of skin glands, dilating skin vessels, enhancing skin nutrition, and promoting hair growth. Tappeiner, however, found that local application of P. does not cause increased glandular secretion. For resorptive action, P. is administered mainly subcutaneously, less often per os. It is recommended (Trendelenburg) to avoid poisoning symptoms by first testing the patient's sensitivity to P. by administering a dose of 0.005, i.e., 0.5 cm³ of a 1% solution; in a normal person, this dose usually has no effect. The main application of pilocarpine is based on its diaphoretic and salivary effects, whereby a large amount of fluid and with it products of metabolism, toxins, etc., are removed from the body. Subcutaneously, 0.01-0.015 P. or repeated doses (every 7 hours) of 0.005 are administered, and per os, 0.01 three to four times a day in renal dropsy, nephritis, and other kidney diseases (especially favorable effect from early administration of P. in uremia), in poisoning by heavy metals (mercury, lead), meat poison, and other poisons that limit secretion (in atropine poisoning, P., as a weaker antagonist, is unlikely to be successful; as for its action on the central nervous system, P. is not an antagonist of atropine), in various types of exudates and transudates (pleurisy, pericarditis, otitis media, iritis, choroiditis, retinal detachment, retrobulbar neuritis, etc.). The effect on exudates of large serous cavities (e.g., pleura) is insignificant. Subcutaneous administration in skin edema in nephritis does not always produce a diaphoretic effect, as the conditions for absorption of P. are impaired and the function of the sweat glands may be altered. P. has also been proposed (but is less suitable) as a diaphoretic in colds (e.g., in acute laryngitis, bronchitis) and in rheumatic diseases (e.g., in muscular rheumatism). Increased mucus secretion can be utilized in dry cough: some recommend P. to clear the respiratory tract of croupous membranes. Small diaphoretic doses of pilocarpine (subcutaneously in adults, per os in children) sometimes have a beneficial effect in pruritus and skin itching without clear causes and in the absence of anatomical skin changes. According to some authors, the increased excretion of biliary mucus from P. facilitates the passage of gallstones (benefit is doubtful). As a poison that selectively excites the endings of the parasympathetic nerves, pilocarpine is used to investigate the state of tone of the vagus nerve. In acute and chronic cases of persistent atony of the intestine, P. is sometimes given subcutaneously or in microclysis instead of physostigmine or pituitrin. A tincture of jaborandi leaves is sometimes used in anorexia (e.g., in tuberculosis), atony of the stomach and intestine, chronic constipation, sexual neuroses. At present, jaborandi leaves are almost not used, as P. has several advantages over them. P. is contraindicated (or its use should be extremely cautious) in weak, cachectic individuals, in diseases of the heart and blood vessels (danger of collapse), in diseases of the respiratory tract (danger of pulmonary edema), during pregnancy (possibility of abortion), in cardiac dropsy. Preparations. 1. Pilocarpinum hydrochloricum (E.VII), C₁₁H₁₆N₂O₂.HCl, molecular weight 244.5, colorless, transparent, extremely hygroscopic, deliquescent in air, slightly bitter crystals with a melting point of about 200°. Very easily soluble in water and alcohol; difficult to dissolve in ether and chloroform; aqueous solutions have a weakly acidic reaction. Maximum doses-0.02 pro dosi and 0.04 pro die. - 2. Pilocarpinum nitricum, C₁₁H₁₆N₂O₂.HNO₃, molecular weight 271.4, colorless, non-hygroscopic, slightly bitter crystals, easily soluble (1:8-9) in water, difficult to dissolve in cold and absolute alcohol, more easily in hot alcohol; melting point 177°. Average doses (according to American and English pharmacopoeias) from 0.003 to 0.012, maximum single dose-0.03 g. - 3. P. hydrobromicum, C₁₁H₁₆N₂O₂.HBr, molecular weight 289, colorless, transparent crystals, somewhat less soluble in water and alcohol than P. hydrochloricum, and less hygroscopic than the latter. - 4. P. phenylicum, C₁₁H₁₆N₂O₂.C₆H₅OH, molecular weight 302, a colorless oily liquid soluble in water and alcohol. - 5. P. salicylicum, C₁₁H₁₆N₂O₂.C₇H₆O₃, molecular weight 346, colorless crystals or a white crystalline powder of slightly bitter taste, easily soluble in water, less soluble in alcohol. - 6. Eserin-Pilocarpin; the commercial preparation consists of a mixture obtained by joint crystallization of 1 part Physostigmini salicylici with 2 parts Pilocarpini hydrochlorici. A white crystalline powder easily soluble in water. Used in veterinary medicine instead of physostigmine for colic in horses. - 7. Folia Jaborandi are sometimes administered internally instead of P. in the form of a 1-3% aqueous infusion by tablespoon, externally for washing hair (to promote their growth); Extractum, Tinctura, and Oleum Jaborandi are used even less frequently. - As a substitute for P. as a specific salivary agent, the synthetic preparation Neu-Cesol, bromomethylate of the methyl ester of methylhexahydro-pyridine-carboxylic acid, has been proposed. White, water-soluble crystals. In tablets of 0.05-0.1 (2-3 times a day) subcutaneously or intramuscularly 0.025-0.05, the effect lasts 4-6 hours. Indicated in agonizing thirst in diabetics, botulism, postoperative renal edema and other diseases requiring restriction of fluid intake, in poisoning with scopolamine and atropine. It has similarity in action with P. only in relation to salivary secretion.

M. Nikolaev. Discovery in forensic medical cases. The usual reactions for the discovery of alkaloids, based on the appearance of colored products when acted upon by known oxidizers or reducers, cannot serve for the detection of P., since other alkaloids also give the reactions proposed for P. For detection, P. is extracted from an alkaline solution with chloroform (see Alkaloids, Poisons-isolation). It is made alkaline with sodium bicarbonate, avoiding caustic alkalis. For detection, only physiological testing can be used.