[448] Flückiger’s Reactions, translated by Nagelvoort, Detroit, 1893.
Dragendorff was able to render evident ·025 mgrm. mixed with twenty times its weight of quin. sulphate; the same observer likewise recognised ·04 mgrm. of strychnine in thirty-three times its weight of caffeine. Veratrine is likewise not injurious.
The physiological test consists in administering the substance to some small animal (preferably to a frog), and inducing the ordinary tetanic symptoms. It may be at once observed that if definite chemical evidence of strychnine has been obtained, the physiological test is quite unnecessary; and, on the other hand, should the application of a liquid or substance to a frog induce tetanus, while chemical evidence of the presence of strychnine was wanting, it would be hazardous to assert that strychnine was present, seeing that caffeine, carbolic acid, picrotoxin, certain of the opium alkaloids, hypaphorine, some of the ptomaines, and many other substances induce similar symptoms. The best method (if the test is used at all) is to take two frogs,[449] and insert under the skin of the one the needle of a subcutaneous syringe, previously charged with a solution of the substance, injecting a moderate quantity. The other frog is treated similarly with a very dilute solution of strychnine, and the two are then placed under small glass shades, and the symptoms observed and compared. It is not absolutely necessary to inject the solution under the skin, for if applied to the surface the same effects are produced; but, if accustomed to manipulation, the operator will find the subcutaneous application more certain, especially in dealing with minute quantities of the alkaloid.[450]
[449] A very practical disadvantage of the physiological test is the great difficulty of obtaining frogs exactly when wanted.
[450] Methyl strychnine, as well as methyl brucine, has been shown by Brown and Fraser to have an effect exactly the opposite to that of strychnine, paralysing the muscles like curare. In the case, therefore, of the methyl compounds, a physiological test would be very valuable, since these compounds do not respond to the ordinary tests.
§ 399. Hypaphorine.—One substance is known which neither physiological test nor the colour reactions suffice to distinguish from strychnine, viz., hypaphorine,[451] the active matter of a papilionaceous tree growing in Java—the Hypaphorus subumbrans; a small quantity of the alkaloid is in the bark, a larger quantity is in the seed.
[451] Dr. C. Plugge, Arch. f. exp. Path. u. Ph., Bd. xxxii. 313.
Hypaphorine forms colourless crystals which brown, without melting, above 220°, and exhale a vapour smelling like napththylamine. The free alkaloid is soluble in water, but has no action on litmus. The salts are less soluble than the free alkaloid, so that acids, such as nitric or hydrochloric, produce in a short time precipitates on standing. Solutions of the salts are not precipitated by alkalies; chloroform, ether, benzene, all fail to extract it from either alkaline or acid solutions. It gives no precipitate with potassic chromate, but most general alkaloidal reagents precipitate.
It gives a precipitate with iodine trichloride, and has therefore probably a pyridine nucleus, it may be an acid anilide.[452] It gives the same colours as strychnine with sulphuric acid and potassic permanganate or potassic chromate; it causes in frogs tetanus, but the dose has to be much larger than that of strychnine. The duration of life in doses of 15 mgrms. may extend to five days, and frogs may even recover after 50 mgrms.
[452] Julius Tafel (Ber., 1890, 412) has shown that the colour reactions with H2SO4 and oxidising agents are the characteristic tests of an acid anilide.
The distinction between strychnine and hypaphorine is therefore easy; besides it will not occur in a chloroform extract, and it will not give a precipitate with potassic chromate.
§ 400. Quantitative Estimation of Strychnine.—The best process of estimating the proportion of each alkaloid in a mixture of strychnine and brucine, is to precipitate them as picrates, and to destroy the brucine picrate by nitric acid after obtaining the combined weight of the mixed picrates; then to weigh the undestroyed strychnine picrate.
To carry out the process, the solution of the mixed alkaloids must be as neutral as possible. A saturated solution of picric acid is added drop by drop to complete precipitation. A filter paper is dried and weighed, and the precipitate collected on to this filter paper; the precipitate is washed with cold water, dried at 105°, and weighed. This weight gives the combined weight of both strychnine and brucine picrates.
The precipitate is now detached from the filter, washed into a small flask, and heated on the water-bath for some time with nitric acid diluted to 1·056 gravity (about 11 per cent. HNO3). This process destroys the brucine picrate, but leaves the strychnine picrate untouched. The acid liquid is now neutralised with ammonia or soda, and a trace of acetic acid added; the precipitate of strychnine picrate is now collected and weighed. The weight of this subtracted from the first weight, of course, gives that of the brucine picrate.
One part of strychnine picrate is equal to 0·5932 strychnine; and one part of brucine picrate is equal to 0·6324 brucine.
From the strychnine picrate the picric acid may be recovered and weighed by dissolving the picrate in a mineral acid and shaking out with ether; from the acid liquid thus deprived of picric acid the alkaloid may be separated by alkalising with ammonia and shaking out with chloroform.
§ 401. Brucine (C23H26N2O4 + 4H2O)[453] occurs associated with strychnine in the plants already mentioned; its best source is the so-called false angustura bark, which contains but little strychnine. Its action is similar to that of strychnine. If crystallised out of dilute alcohol it contains 4 atoms of water, easily expelled either in a vacuum over sulphuric acid or by heat. Crystallised thus, it forms transparent four-sided prisms, or arborescent forms, like boric acid. If thrown down by ammonia from a solution of the acetate, it presents itself in needles or in tufts.
[453] Sonnenschein has asserted that brucine may be changed into strychnine by the action of NO3. This statement has been investigated by A. J. Cownley, but not confirmed.—Pharm. Journ. (3), vi. p. 841.
The recently-crystallised alkaloid has a solubility different from that which has effloresced, the former dissolving in 320 parts of cold, and 150 parts of boiling water; whilst the latter (according to Pelletier and Caventou) requires 500 of boiling, and 850 parts of cold water for solution. Brucine is easily soluble in absolute, as well as in ordinary alcohol; 1 part dissolves in 1·7 of chloroform, in 60·2 of benzene. Petroleum ether, the volatile and fatty oils and glycerine, dissolve the alkaloid slightly, amyl alcohol freely; it is insoluble in anhydrous ether. The behaviour of brucine in the subliming cell is described at p. 260. Anhydrous brucine melts in a tube at 178°. The alcoholic solution of brucine turns the plane of polarisation to the left [α]r = -11·27°. The taste is bitter and acrid. Soubeiran maintains that it can be recognised if 1 part is dissolved in 500,000 parts of water. If nitric trioxide be passed into an alcoholic solution of brucine, first brucine nitrate is formed; but this passes again into solution, from which, after a time, a heavy, granular, blood-red precipitate separates: it consists of dinitro-brucine (C23H24(NO2)2N2O4). Brucine fully neutralises acids, and forms salts, which are for the most part crystalline. The neutral sulphate (C23H25N2O4SH2O4 + 31⁄2H2O) is in long needles, easily soluble in water. The acetate is not crystalline, that of strychnine is so (p. 321).
Brucine is precipitated by ammonia, by the caustic and carbonated alkalies, and by most of the group reagents. Ammonia does not precipitate brucine, if in excess; on the other hand, strychnine comes down if excess of ammonia is added immediately. This has been proposed as a method of separation; if the two alkaloids are present in acid solution, ammonia in excess is added, and the solution is immediately filtered; the quantitative results are, however, not good, the strychnine precipitate being invariably contaminated by brucine.
Chromate and dichromate of potassium give no precipitate with neutral salts of brucine; on the other hand, strychnine chromate is at once formed if present. It might, therefore, be used to separate strychnine from brucine. The author has attempted this method, but the results were not satisfactory.
§ 402. Physiological Action.—The difference between the action of strychnine and that of brucine on man or animals is not great. Mays states that strychnine affects more the anterior, brucine the posterior extremities. In strychnine poisoning, convulsions occur early, and invariably take place before death; but death may occur from brucine without any convulsions, and in any case they develop late. Brucine diminishes local sensibility when applied to the skin; strychnine does not.[454] In a physiological sense, brucine may be considered a diluted strychnine. The lethality of brucine, especially as compared with strychnine, has been investigated by F. A. Falck.[455] He experimented on 11 rabbits, injecting subcutaneously brucine nitrate, in doses of varying magnitude, from 100 mgrms. down to 20 mgrms. per kilogram of body-weight. He found that brucine presented three stages of symptoms. In the first, the respiration is quickened; in 3 of the 11 cases a strange injection of the ear was noticed; during this period the pupils may be dilated. In the second stage, there are tetanic convulsions, trismus, opisthotonus, oppressed respiration, and dilated pupils. In the third stage, the animal is moribund. Falck puts the minimum lethal dose for rabbits at 23 mgrms. per kilo. Strychnine kills 3·06 times more quickly than brucine, the intensity of the action of strychnine relative to that of brucine being as 1 : 117·4. Falck has also compared the minimum lethal dose of strychnine and brucine with the tetanising opium alkaloids, as shown in the following table:—
[454] Journ. Physiol., viii. 391-403.
[455] Brucin u. Strychnin; eine toxikologische Parallele, von Dr. F. A. Falck. Vierteljahrsschr. f. gerichtl. Med., Band xxiii. p. 78.
TABLE SHOWING THE LETHAL DOSES OF VARIOUS TETANISING POISONS.
| Minimum Lethal Dose for every Kilogram Weight of Rabbit. |
Proportional Strength. |
||
|---|---|---|---|
| Mgrms. | |||
| Strychnine nitrate, | 0·6 | ... | |
| Thebaine nitrate, | 14·4 | 24 | ·0 |
| Brucine nitrate, | 23·0 | 38 | ·33 |
| Landanine nitrate, | 29·6 | 49 | ·33 |
| Codeine nitrate, | 51·2 | 85 | ·33 |
| Hydrocotarnine nitrate, | 203·8 | 339 | ·66 |
If these views are correct, it follows that the least fatal dose for an adult man would be 1·64 grm. (about 24·6 grains) of brucine nitrate.
§ 403. Tests.—If to a solution of brucine in strong alcohol a little methyl iodide is added, at the end of a few minutes circular rosettes of crystal groups appear (see fig.): they are composed of methyl brucine iodide (C23H25(CH3)N2O4HI). Crystals identical in shape are also obtained if an alcoholic solution of iodine, or hydriodic acid with iodine, is added to an alcoholic solution of brucine. A solution of strychnine gives with methyl iodide no similar reaction. Strychnine in alcoholic solution, mixed with, brucine in no way interferes with the test. The methyl iodide test may be confirmed by the action of nitric acid. With that reagent it produces a scarlet colour, passing into blood-red, into yellow-red, and finally ending in yellow. This can be made something more than a mere colour test, for it is possible to obtain a crystalline body from the action of nitric acid on brucine. If a little of the latter be put in a test-tube, and treated with nitric acid of 1·4 specific gravity (immersing the test-tube in cold water to moderate the action), the red colour is produced. On spectroscopic examination of the blood-red liquid a broad, well-marked absorption band is seen, the centre of which (see page 55) is between E. & F. [W. L. about 500]. There is also a development of nitric oxide and carbon dioxide, and the formation of methyl nitrite, oxalic acid, and kakotelin (C23H26N2O4 + 5NHO3 = C20H22N4O9 + N(CH3)O2 + C2H2O4 + 2NO + 2H2O). On diluting abundantly with water, the kakotelin separates in yellow flocks, and may be crystallised out of dilute hydrochloric or dilute nitric acid in the form of yellow or orange-red crystals, very insoluble in water, but dissolving readily in dilute acid. On removal by dilution of the product just named, neutralisation with ammonia, and addition of a solution of chloride of calcium, the oxalate of lime is thrown down. The nitric acid test is, therefore, a combined test, consisting of—the production by the action of nitric acid (1) of a red colour; (2) of yellow scales or crystals insoluble in water; (3) of oxalic acid. No alkaloid save brucine is known to give this reaction.
There are other methods of producing the colour test. If a few drops of nitric acid are mixed with the substance in a test-tube, and then sulphuric acid cautiously added, so as to form a layer at the bottom, at the junction of the liquids a red zone, passing into yellow, is seen.
A solution of brucine is also coloured red by chlorine gas, ammonia changing the colour into yellow.
Flückiger[456] has proposed as a test mercurous nitrate, in aqueous solution with a little free nitric acid. On adding this reagent to a solution of brucine salt, and gently warming, a fine carmine colour is developed.
[456] Archiv f. Pharm. (3), vi. 404.
In regard to the separation of brucine from organic fluids or tissues, the process already detailed for strychnine suffices. It is of very great importance to ascertain whether both strychnine and brucine are present or not—the presence of both pointing to nux vomica or one of its preparations. The presence of brucine may, of course, be owing to impure strychnine; but if found in the tissues, that solution of the question is improbable, the commercial strychnine of the present day being usually pure, or at the most containing so small a quantity of brucine as would hardly be separated from the tissues.
§ 404. Igasurine is an alkaloid as yet but little studied; it appears that it can be obtained from the boiling-hot watery extract of nux vomica seeds, through precipitating the strychnine and brucine by lime, and evaporation of the filtrate. According to Desnoix,[457] it forms white crystals containing 10 per cent. of water of crystallisation.
[457] Journ. Pharm. (3), xxv. 202.
It is said to be poisonous, its action being similar to that of strychnine and brucine, and in activity standing midway between the two.
§ 405. Strychnic Acid.—Pelletier and Caventou obtained by boiling with spirit small, hard, warty crystals of an organic acid, from S. ignatius, as well as from nux vomica seeds. The seeds were first exhausted by ether, the alcohol solution was filtered and evaporated, and the extract treated with water and magnesia, filtered, and the residue first washed with cold water, then with hot spirit, and boiled lastly with a considerable quantity of water. The solution thus obtained was precipitated with acetate of lead, the lead thrown out by SH2, and the solution evaporated, the acid crystallising out. It is a substance as yet imperfectly studied, and probably identical with malic acid.
§ 406. The bark of the Quebracho Blanco[458] (Aspidosperma quebracho) contains, according to Hesse’s researches, no fewer than six alkaloids—Quebrachine, Aspidospermine, Aspidospermatine, Aspidosamine, and Hypoquebrachine. The more important of these are Aspidospermine and Quebrachine.
[458] See Liebig’s Annal., 211, 249-282; Ber. der deutsch. Chem. Gesellsch., 11, 2189; 12, 1560.
Aspidospermine (C22H30N2O2) forms colourless needles which melt at 206°. They dissolve in about 6000 parts of water at 14°—48 parts of 90 per cent. alcohol, and 106 parts of pure ether. The alkaloid gives a fine magenta colour with perchloric acid.
Quebrachine (C21H26N2O3) crystallises in colourless needles, melting-point (with partial decomposition) 215°. The crystals are soluble in chloroform, with difficulty soluble in cold alcohol, but easily in hot. The alkaloid, treated with sulphuric acid, and peroxide of lead, strikes a beautiful blue colour. It also gives with sulphuric acid and potassic chromate the strychnine colours. Quebrachine, dissolved in sulphuric acid containing iron, becomes violet-blue, passing into brown. The alkaloid, treated with strong sulphuric acid, becomes brown; on adding a crystal of potassic nitrate, a blue colour is developed; on now neutralising with caustic soda no red coloration is perceived. Dragendorff has recently studied the best method of extracting these alkaloids for toxicological purposes. He recommends extraction of the substances with sulphuric acid holding water, and shaking up with solvents. Aspidospermine is not extracted by petroleum ether or benzene from an acid watery extract, but readily by chloroform or by amyl alcohol. It is also separated from the same solution, alkalised by ammonia, by either amyl alcohol or chloroform; with difficulty by petroleum ether; some is dissolved by benzene. Quebrachine may be extracted from an acid solution by chloroform, but not by petroleum ether. Alkalised by ammonia, it dissolves freely in chloroform and in amyl alcohol. Traces are taken up by petroleum, somewhat more by benzene. Aspidospermine is gradually decomposed in the body, but Quebrachine is more resistant, and has been found in the stomach, intestines, blood, and urine. The toxicological action of the bark ranks it with the tetanic class of poisons. In this country it does not seem likely to attain any importance as a poison.
§ 407. Pereirine—an alkaloid from pereira bark—gives a play of colours with sulphuric acid and potassic bichromate similar to but not identical with that of strychnine. Fröhde’s reagent strikes with it a blue colour. On dissolving pereirine in dilute sulphuric acid, and precipitating by gold chloride, the precipitate is a beautiful red, which, on standing and warming, is deepened. Pereirine may be extracted from an acid solution, after alkalising with ammonia, by ether or benzene.
§ 408. Gelsemine (C22H28N2O4) is an alkaloid[459] which has been separated from Gelsemium sempervirens, the Carolina jessamine, a plant having affinities with several natural orders, and placed by De Candolle among the Loganiaceæ, by Chapman among the Rubiaceæ and by Decaisne among the Apocynaceæ. It grows wild in Virginia and Florida.[460] Gelsemine is a strong base; it is yellowish when impure, but a white amorphous powder when pure. It fuses below 100° into a transparent vitreous mass, at higher temperatures it condenses on glass in minute drops; its taste is extremely bitter; it is soluble in 25 parts of ether, in chloroform, bisulphide of carbon, benzene, and in turpentine; it is not very soluble in alcohol, and still less soluble in water, but it freely dissolves in acidulated water. The caustic alkalies precipitate it, the precipitate being insoluble in excess; it is first white, but afterwards brick-red. Tannin, picric acid, iodised potassic iodide, platinic chloride, potassio-mercuric iodide, and mercuric chloride all give precipitates. Fröhde’s reagent gives with gelsemine a brown changing to green.
[459] Dr. T. G. Wormley separated, in 1870, a non-nitrogenised remarkably fluorescent body, which he named gelsemic acid (Amer. Journ. of Pharm., 1870), but Sonnenschein and C. Robbins afterwards found gelsemic acid to be identical with æsculin (Ber. der deutsch. Chem. Ges., 1876, 1182). Dr. Wormley has, however, contested this, stating that there are differences. (Amer. Journ. of Pharm., 1882, p. 337. Yearbook of Pharmacy, 1882, p. 169.)
[460] The following are its botanical characters:—Calyx five-parted, corolla funnel-shaped, five-lobed, somewhat oblique, the lobes almost equal, the posterior being innermost in bud; stamens five; anthers oblong sagittate, style long and slender; stigmas two, each two-parted, the divisions being linear; fruit elliptical, flattened contrary to the narrow partition, two-celled, septicidally two-valved, the valves keeled; seeds five to six in each cell, large, flat, and winged; embryo straight in fleshy albumen; the ovate flat, cotyledons much shorter than the slender radicle; stem smooth, twining and shrubby; leaves opposite, entire, ovate, or lanceolate, shining on short petioles, nearly persistent; flowers large, showy, very fragrant, yellow, one to five in the axil of the leaves.
Sulphuric acid dissolves gelsemine with a reddish or brownish colour; after a time it assumes a pinkish hue, and if warmed on the water-bath, a more or less purple colour; if a small crystal of potassic bichromate be slowly stirred in the sulphuric acid solution, reddish purple streaks are produced along the path of the crystal; ceric oxide exhibits this better and more promptly, so small a quantity as ·001 grain showing the reaction. This reaction is something like that of strychnine, but nitric acid causes gelsemine to assume a brownish-green, quickly changing to a deep green—a reaction which readily distinguishes gelsemine from strychnine and other alkaloids.
§ 409. Fatal Dose.—10 mgrms. killed a frog within four hours, and 8 mgrms. a cat within fifteen minutes. A healthy woman took an amount of concentrated tincture, which was equivalent to 11 mgrms. (1⁄6 grain), and died in seven and a half hours.
§ 410. Effects on Animals—Physiological Action.—Gelsemine acts powerfully on the respiration; for example, Drs. Sydney Ringer and Murrell[461] found, on operating on the frog, that in two minutes the breathing had become distinctly slower; in three and a half minutes, it had been reduced by one-third; and in six minutes, by one-half; at the expiration of a quarter of an hour, it was only one-third of its original frequency; and in twenty minutes, it was so shallow and irregular that it could no longer be counted with accuracy. In all their experiments they found that the respiratory function was abolished before reflex and voluntary motion had become extinct. In several instances the animals could withdraw their legs when their toes were pinched, days after the most careful observations had failed to detect the existence of any respiratory movement. The heart was seen beating through the chest wall long after the complete abolition of respiration.
[461] Lancet, vol. i., 1876, p. 415.
In their experiments on warm-blooded animals (cats), they noticed that in a few minutes the respirations were slowed down to 12 and even to 8, and there was loss of power of the posterior extremities, while at short intervals the upper half of the body was convulsed. In about half an hour paralysis of the hind limbs was almost complete, and the respiratory movements so shallow that they could not be counted. In the case of a dog, after all respiration had ceased tracheotomy was performed, and air pumped in: the animal recovered.
Ringer and Murrell consider that gelsemine produces no primary quickening of the respiration, that it has no direct action on either the diaphragm or intercostal muscles, that it paralyses neither the phrenic nor the intercostal nerves, and that it diminishes the rate of respiration after both vagi have been divided. They do not consider that gelsemine acts on the cord through Setschenow’s inhibitory centre, but that it destroys reflex power by its direct action on the cord, and that probably it has no influence on the motor nerves. Dr. Burdon Sanderson has also investigated the action of gelsemine on the respiration, more especially in relation to the movements of the diaphragm. He operated upon rabbits; the animal being narcotised by chloral, a small spatula, shaped like a teaspoon, was introduced into the peritoneal cavity through an opening in the linea alba, and passed upwards in front of the liver until its convex surface rested against the under side of the centrum tendineum. The stem of the spatula was brought into connection with a lever, by means of which its to-and-fro movements (and consequently that of the diaphragm) were inscribed. The first effect is to augment the depth but not the frequency of the respiratory movements; the next is to diminish the action of the diaphragm both in extent and frequency. This happens in accordance with the general principle applicable to most cases of toxic action—viz., that paresis of a central organ is preceded by over-action. The diminution of movement upon the whole is progressive, but this progression is interrupted, because the blood is becoming more and more venous, and, therefore, the phenomena of asphyxia are mixed up with the toxical effects. Dr. Sanderson concludes that the drug acts by paralysing the automatic respiratory centre; the process of extinction, which might be otherwise expected to be gradual and progressive, is prevented from being so by the intervention of disturbances of which the explanation is to be found in the imperfect arterialisation of the circulating blood. Ringer and Murrell have also experimented upon the action of gelsemine on the frog’s heart. In all cases it decreased the number of beats; a small fatal dose produced a white contracted heart, a large fatal dose, a dark dilated heart; in either case arrest of the circulation of course followed.
§ 411. Effects on Man.—The preparations used in medicine are the fluid extract and the tincture of gelsemine; the latter appears to contain the resin of the root as well as the active principle. There are several cases on record of gelsemine, or the plant itself, having been taken with fatal effect.[462] Besides a marked effect on the respiration, there is an effect upon the eye, better seen in man than in the lower animals; the motor nerves of the eye are attacked first, objects cannot be fixed, apparently dodging their position, the eyelids become paralysed, droop, and cannot be raised by an effort of the will; the pupils are largely dilated, and at the same time a feeling of lightness has been complained of in the tongue; it ascends gradually to the roof of the mouth, and the pronunciation is slurred. There is some paresis of the extremities, and they refuse to support the body; the respiration becomes laboured, and the pulse rises in frequency to 120 or 130 beats per minute, but the mind remains clear. The symptoms occur in about an hour and a half after taking an overdose of the drug, and, if not excessive, soon disappear, leaving no unpleasantness behind. If, on the other hand, the case proceeds to a fatal end, the respiratory trouble increases, and there may be convulsions, and a course very similar to that seen in experimenting on animals. Large doses are especially likely to produce tetanus, which presents some clinical differences distinguishing it from strychnine tetanus. Gelsemine tetanus is always preceded by a loss of voluntary reflex power, respiration ceases before the onset of convulsions, the posterior extremities are most affected, and irritation fails to excite another paroxysm till the lapse of some seconds, as if the exhausted cord required time to renew its energy; finally, the convulsions only last a short time.
[462] See Lancet, 1873, vol. ii. p. 475; Brit. Med. and Surg. Journ., April 1869; Phil. Med. and Surg. Reporter, 1861.
§ 412. Extraction from Organic Matters, or the Tissues of the Body.—Dragendorff states that, from as little as half a grain of the root, both gelsemine and gelsemic acid may be extracted with acid water, and identified. On extracting with water acidified with sulphuric acid, and shaking up the acid liquid with chloroform, the gelsemic acid (æsculin?) is dissolved, and the gelsemine left in the liquid. The chloroform on evaporation leaves gelsemic acid in little micro-crystals; it may be identified by (1) its crystallising in little tufts of crystals; (2) its strong fluorescent properties, one part dissolved in 15,000,000 parts of water showing a marked fluorescence, which is increased by the addition of an alkali; and (3) by splitting up into sugar and another body on boiling with a mineral acid. After separation of gelsemic acid, the gelsemine is obtained by alkalising the liquid, and shaking up with fresh chloroform; on separation of the chloroform, gelsemine may be identified by means of the reaction with nitric acid, and also the reaction with potassic bichromate and sulphuric acid.
§ 413. Cocaine (C17H21NO4).—There are two cocaines—the one rotating a ray of polarised light to the left, the other to the right. The left cocaine is contained in the leaves of Erythroxylon coca with other alkaloids, and is in commerce.
Cocaine has been used most extensively in medicine since the year 1884—its chief use being as a local anæsthetic. Chemically cocaine is a derivative of ecgonin, being ecgonin-methyl-ester. It has a pyridine nucleus, and may be written C5H4N(CH3)—H3CHO—(COC6H5)—CH2COOCH3, or expressed graphically as follows:—
Properties.—Cocaine is in the form of four- to six-sided prisms of the monoclinic system. It is one of the few alkaloids which melt under the temperature of boiling water, the melting-point being as low as 85° in water. It readily furnishes a sublimate at 100°, partially decomposing. On boiling with hydrochloric acid cocaine is decomposed into methyl alcohol, ecgonin, and benzoic acid, according to the following reaction:—
| Cocaine. | Benzoic acid. |
Ecgonin. | Alcohol. | |||||
| C17H21NO4 | + | 2H2O | = | C6H5COOH | + | C9H15NO3 | + | CH3OH. |
Cocaine is but little soluble in water, but easily dissolves in ether, alcohol, benzene, chloroform, and carbon disulphide; an aqueous solution is alkaline to methyl-orange, but not to phenol-phthalein. It can be made synthetically by the reaction of ecgonin-methyl-ester with benzoyl chloride.
§ 414. Cocaine Hydrochlorate (C17H21NO4HCl).—Crystallised from alcohol, cocaine hydrochlorate appears in prismatic crystals; these crystals, according to Hesse,[463] when perfectly pure, should melt at 186°, although the melting-point is generally given as 200° or even 202°. Cocaine hydrochlorate is soluble in half its weight of water, insoluble in dry ether, but readily soluble in alcohol, amyl alcohol, or chloroform.
[463] O. Hesse, Annalen, 276, 342-344.
§ 415. Pharmaceutical Preparations.—Cocaine hydrochlorate is officinal. Gelatine discs, weighing 1·31 mgrms. (1⁄50 grain), and each containing 0·33 mgrm. (1⁄200 grain) of the salt are officinal, and used by ophthalmic surgeons. A solution of the hydrochlorate, containing 10 per cent. of cocaine hydrochlorate and (for the purposes of preserving the solution) 0·15 per cent. of salicylic acid is also officinal. Stronger solutions may also be met with; for instance, a 20 per cent. solution in oil of cloves for external application in cases of neuralgia.
§ 416. Separation of Cocaine and Tests.—Cocaine may be shaken out of solutions made slightly alkaline by ammonia by treatment with benzene; it also passes into petroleum ether under the same circumstances. The best method is to extract a solution, made feebly alkaline, thoroughly by ether, and then shake it out by benzene and evaporate the separated benzene at the ordinary air temperature. The property of the alkaloid to melt at or below the temperature of boiling water, and the ready decomposition into benzoic acid and other products, render cocaine easy of identification. If, for instance, a small particle of cocaine is put in a tube, a drop of strong sulphuric acid added and warmed by the water-bath, colourless crystals of benzoic acid sublime along the tube, and an aromatic odour is produced.
Flückiger has recommended the production of benzoate of iron as a useful test both for cocaine and for cocaine hydrochlorate.
One drop of a dilute solution of ferric chloride added to a solution of 20 mgrms. of cocaine hydrochlorate in 2 c.c. of water, gives a yellow fluid, which becomes red on boiling from the production of iron benzoate. This reaction is of little use unless a solution of the same strength of ferric chloride, but to which the substance to be tested has not been added, is boiled at the same time for comparison, because all solutions of ferric chloride deepen in colour on heating.
A solution of the alkaloid evaporated to dryness on the water-bath, after being acidulated with nitric acid, and then a few drops of alcoholic solution of potash or soda added, develops an odour of benzoic ethyl-ester. Cocaine hydrochlorate, when triturated with calomel, blackens by the slightest humidity or by moistening it with alcohol. Cocaine in solution is precipitated by most of the group reagents, but is not affected by mercuric chloride, picric acid, nor potassic bichromate.
Added to the tests above mentioned, there is the physiological action; cocaine dilates the pupil, tastes bitter, and, for the time, arrests sensation; hence the after-effect on the tongue is a sensation of numbness.
§ 417. Symptoms.—A large number of accidents occur each year from the external application of cocaine; few, however, end fatally. Cocaine has thus produced poisonous symptoms when applied to the eye, to the rectum, to the gums, to the urethra, and to various other parts. There have been a few fatal cases, both from its external and internal administration; Mannheim, for example, has collected eleven of such instances.
The action of cocaine is twofold; there is an action on the central and the peripheral nervous system. In small doses cocaine excites the spinal cord and the brain; in large it may produce convulsions and then paralysis. The peripheral action is seen in the numbing of sensation. There is always interference with the accommodation of vision, and dilatation of the pupil. The eyelids are wider apart than normal, and there may be some protrusion of the eyeball.
The usual course of an acute case of poisoning is a feeling of dryness in the nose and throat, difficulty of swallowing, faintness, and there is often vomiting; the pulse is quickened; there is first cerebral excitement, followed usually by great mental depression. Occasionally there is an eruption on the skin. Hyperæsthesia of the skin is followed by great diminution of sensation, the pupils, as before stated, are dilated, the eyes protruding, the eyelids wide open, the face is pale, and the perspiration profuse. Convulsions and paralysis may terminate the scene. Death takes place from paralysis of the breathing centre; therefore the heart beats after the cessation of respiration. As an antidote, nitrite of amyl has apparently been used with success.
There is a form of chronic poisoning produced from the taking of small doses of cocaine daily. The symptoms are very various, and are referable to disturbance of the digestive organs, and to the effect on the nervous system. The patients become extremely emaciated, and it seems to produce a special form of mania.
§ 418. Post-mortem Appearances.—The appearances found in acute cases of poisoning have been hyperæmia of the liver, spleen, and kidneys, as well as of the brain and spinal cord.
In the experimental poisoning of mice with cocaine Ehrlich[464] found a considerable enlargement of the liver.