ALKALOIDAL POISONS.

ALKALOIDS are the main poisonous principles of plants. They include a large proportion of the known nerve poisons, and they act directly upon the nervous system, many of them acting through nerves upon certain muscles of the body. The several alkaloids are distinguished by the physiologic effect of each in its individual power upon different parts of the nervous system. The physiologic effects as obtained upon animals are limited according to the nervous organization in each species, and are more fully and surely obtained upon the developed nervous system of man.

The Chemical Character and Constitution of the Alkaloids. In classification the alkaloids are basal, electropositive in their ability to unite with acids and produce salts. Strictly speaking, an "organic base" may be a union of carbon with any element of the nitrogen family and with hydrogen preponderating over oxygen, if the latter be present. Ammonia is the inorganic type of the organic nitrogen bases, as phosphin and arsin are types of like organic bases formed by phosphorus and by arsenic. Pyridin is the structural type of the principal poisonous vegetable alkaloids and of the alkaloids which have the most marked chemical character. The pyridin nucleus, holding an atom of nitrogen with five of carbon in a closed chain, has all the stability of the fundamental benzene type, and has, besides, a special capability of additive combination. However complex the alkaloid, its electropositive polarity centers in the pyridin-like ring and in its nitrogen member. In the solanaceous alkaloids and in those of coca the structure is simply that of pyridin extended in side or cross chains of carbon. In the quinolin nucleus, which enters into the strychnos alkaloids, the pyridin is reinforced by a conjoined benzene ring. In some of the opium alkaloids the three-ring structure of phenanthren is united to the nitrogen nucleus, which differs from that of pyridin in the admission of oxygen instead of carbon in one of the six positions of the cycle. These closed chains are all of the six-membered type. Vegetable alkaloids are their highly complex derivatives. Such are the deductions drawn from the actual data of synthesis and of analysis, and they accord with the obvious character of these alkaloids, their clearly marked properties, and the distinctness of their deportment in analysis. Molecular individuality appears alike in their physiologic power and in their chemical activities.

The chief alkaloids of the fungi and the animal alkaloids or leukomains, as well as the ptomains or bases due to bacteria, are for the most part constituted with open chains of carbon as nitrogen bases. In some of these bases, however, nitrogen is found in closed chains of other than the regular type of six-membered rings, such as indol, which is of the type of pyrról joined to benzene. Numbers of alkaloids, ptomains, and leukomains are as yet undetermined in chemical structure. Guareschi enumerates seventy ptomains and leukomains, among which twenty-six have been found to have open structure, and but seven have been found to agree with the simple closed chain structures of the pyridin type. Of the latter, an example is the dihydrotoluidin, secondary base, obtained by Gautier and Mourgues from cod-liver oil. Putrescin and cadaverin are open-chain diamins of very simple constitution. The alkaloids of tea and the other beverage plants are diureids, now represented as derivatives of purin.

2

1

The element oxygen is found in the non-volatile alkaloids, and the structural relations of this element give the key to several peculiarities. Hydroxyl, especially if phenolic, gives solubility in the alkaloids. Ester formations, as in atropin and in a two-fold way in cocain, render an alkaloid saponifiable as truly as a fat.

3

Identification in Analysis. In respect to the bearing of structural chemistry upon fallacies of analysis in identification of the poisonous vegetable alkaloids, it is a reasonable conclusion that compounds of such remarkable chemical individuality ought to be identified by the analyst, and that he ought to be able to distinguish a vegetable alkaloid from a ptomain, at all events quite as surely as he can distinguish one vegetable alkaloid from another. Now when greater numbers of bases of vegetable and of putrefactive origin are becoming known, the danger of mistaking one for another is seen to have been greater than has been realized. But in this advance of chemical knowledge the resources of analysis are being enlarged and enriched as well. With these resources, when they are faithfully employed, greater precision is attainable in the determination of minute quantities. of poisons, such as are recovered in postmortem analysis. Meanwhile the inherent limitations upon this recovery are more definitely understood. The new light shed upon the constitution of the organic bases reveals new means of identification and gives meaning to the detail of chemical

tests.

Upon the important question of mistaking ptomains for vegetable alkaloids the conclusions of Guareschi, as given in his admirable work on this subject, are presented in full in the following paragraphs :

1 Compt. rend., 1888, pp. 107, 110, 254.

2 Vaughan and Novy, Cellular Toxins, 1902, pp. 267-273.

3 Prescott, Organic Analysis, 1888, p. 170.

Alkaloids mit besonderer Berücksichtigung der vegetabilischen Alkaloide und der Ptomaine, von Dr. Icilio Guareschi, Professor an der königl. Universität Turin. Dr. Hermann Kunz-Krause, Berlin, 1896. See pages 597 and 600. Guareschi and Mosso, "Les Ptomaines, Recherches chimique, physiologiques et médico-légales," Arch. Ital. de Biologie. Guareschi, 1887, Gaz. chim. ital., vol xvii.,

p. 503.

Similarities of ptomains to plant bases make it very probable that before the researches of Selmi ptomains have been frequently mistaken for alkaloids in medicolegal cases. This conjecture increases in probability from the fact that formerly many chemists considered it to be sufficiently conclusive of poisoning to have extracted from the already putrefied intestines a poisonous alkaline-reacting substance giving all the general reactions of the alkaloids. To-day it is not so difficult to avoid that fallacy, although the discovery of cadaver alkaloids places a considerably higher responsibility not only upon the judgment but also on the knowledge and experience, of the chemist. On the other hand, the chemist of to-day must guard against the other extreme, that of allowing the vegetable alkaloids to leave the field altogether to the ptomains attributing to the presence of the latter observed reactions which really are those of plant alkaloids present in the organism. All vegetable alkaloids, with a few exceptions, can be characterized as such by their chemical and physiologic behavior, so as to be recognized in the presence of ptomains. A careful and experienced worker of to-day will not confound a vegetable alkaloid with a ptomain that is known and worked out, since, in spite of the great number of the ptomains, none has been observed to give reactions uniform in all points with any plant base.

An exception to this general statement may perhaps be made in case of poisoning occasioned by muscarin, and certain actively poisonous bases of the pyridin and hydropyridin series, as the last-named bases also occur among products of putrefaction. In these cases the proof of the occurrence of poisoning from analytic results alone is not only very difficult, but in the majority of cases impossible.

Moreover, special caution in expression of opinion is needful in all cases where the amount of the vegetable alkaloid extracted from portions of the body is too small to yield all the characteristic chemical and physiologic reactions. The same is true when the alkaloid cannot be obtained in purity, but remains mixed with ptomains and extractive matters. In all these cases it is practically impossible to draw definite and unobjectionable conclusions from analytic results.

Another consideration especially important from a chemicolegal point of view is the possibility of changes taking place in the composition of alkaloids under analytic treatment, such as those resulting in so-called amorphous alkaloids, some of which are insufficiently examined. The possibility of such changes makes it the strongest duty of the chemist fully to find his bearings upon the properties and reactions of all such plant-bases as colchicin, delphinin, cannabin, oleandrin, pseudo-curarin, lobelin, the alkaloids of hops, and others which are known only in the amorphous condition (Guareschi).

Perhaps a not unseasonable illustration of what has been said is given in the following: In a chemicolegal investigation Brouardel, Ogier, and Pouchet apparently isolated a basic compound which fully agreed with colchicin in all its reactions, and besides its action seemed

VOL II.-29

to be indicated by the observed symptoms of poisoning and the postmortem appearances. Nevertheless the chemists did not think these results sufficient to establish its identity, since there was the possibility that in the course of time ptomains as yet unknown would be discovered which in their chemical reactions agree with colchicin. The testimony furnished by the defendant, and brought out by Schutzenberger and Vulpian, partially corroborated the results of the first investigation. The last-named experts, in similar analytic work upon two cadavers in which the possibility of poisoning by colchicin was precluded, succeeded in isolating a ptomain which coincided in its reactions with the base isolated from the suspected organs, and also showed reactions very similar if not identical with colchicin. The outcome of these statements was the acquittal of the defendant. But if the research of Zeisel (unfolding the constitution of colchicin) had been known at the time, perhaps the result of that forensic inquiry might have been reversed.

Properties of Vegetable Alkaloids.—In respect to physical state these substances may be divided into: (1) Non-volatile alkaloids : very numerous, composed of carbon, hydrogen, nitrogen, and oxygen, colorless or white solids, melting when heated and usually subliming with partial decomposition, but inodorous and incapable of distillation unchanged. (2) Volatile alkaloids: comparatively few in number, composed of carbon, hydrogen, and nitrogen, without oxygen, for the most part liquid when free as bases, abundantly odorous and capable of distillation unchanged, even at ordinary atmospheric pressures. Nicotin, the odorous and poisonous principle of tobacco, is an example of the second division, as quinin is of the first division.

Both classes are capable of neutralizing ordinary acids, with the production of salts of the alkaloids, such as a sulphate or hydrochlorid.

Solubilities. In Water.-When free from combination with acids, the greater number of vegetable alkaloids are counted as insoluble in water—that is, their solubility in water is very slight. Thus, it is stated that strychnin is soluble in 6700 parts of water at 15° C. (59° F.) or in 2500 parts of boiling water. Cocain is reported to dissolve in 1300 parts of cold water. On the other hand, the ordinary salts of alkaloids, such as the sulphate, nitrate, acetate, or hydrochlorid, dissolve quite freely in water. The solutions are neutral to litmus and most other testpapers. Strychnin sulphate requires but about 40 times its weight of cold water to dissolve it; morphin sulphate requiring about half as much of the same solvent. It is in correspondence with the facts just stated that in ordinary aqueous solutions of the salts of the alkaloids the addition of any caustic alkali (short of excess) will cause an immediate precipitation of the uncombined alkaloid. Excess of the caustic alkali will redissolve such precipitates of alkaloids in some instances, but not in others, so that the effect of an excess of alkali is a means of distinguishing alkaloids from each other, a reaction seldom delicate enough to be useful with very small quantities. The effect of alkalis upon the ester

like composition of the so-called saponifiable alkaloids is not an immediate effect, and, though a reaction to be regarded, it is one likely to escape observation unless made a subject of inquiry.

Solubility in Alcohol.-In general, both the free alkaloids and their salts are soluble in ordinary alcohol with considerable abundance, and in proportions varying with the strength of the alcohol. Alkaloidal salts usually dissolve in alcohol more abundantly than do the free alkaloids; therefore a partial precipitation of alkaloid is obtained in some cases by adding alkali to alcoholic concentrated solution of alkaloidal salt, but this reaction is uncertain. Absolute alcohol is valuable as a This

solvent to separate alkaloids from various tissue-substances. separation from proteid and other matters requires to be made gradually with increasing strengths of the alcohol, or else very thorough washing of the finely divided precipitate, to avoid waste of the alkaloid by its retention in the matters coagulated by the alcohol.

Ether and Chloroform as Solvents.-These are the best known of the so-called immiscible solvents, those not miscible with water and separating from aqueous solutions in which they have been mixed by shaking. Neither chloroform nor ether, however, is entirely immiscible with water. The free alkaloids differ from each other as to solubility in ether and in chloroform, and these solvents have been somewhat used as a means of separating alkaloids from each other. The scheme introduced by Dragendorff in 1867 is the most elaborate plan for such separation, five or six immiscible solvents being used. But these solvents are more in use to effect a separation of whatever alkaloid be in hand from matter other than alkaloids, which is also done in Dragendorff's process; and in this use the analyst avails himself especially of this fact, that the sulphates, hydrochlorids, and other salts of the alkaloids refuse to dissolve in the immiscible solvents with a very few well-known exceptions. This fact was first made available by Otto in 1856, in his modification of the method of Stas for the extraction of alkaloids in toxicology. For example, from an acidulous aqueous solution containing strychnin, chloroform will dissolve out and remove whatever matters are soluble in this solvent, leaving the alkaloid as a salt in the watery solution. Now the liquid is made alkaline and treated with the chloroform, in which the free alkaloid dissolves, and a distinct step in purification is taken. By the repetition of these, stages of treatment the alkaloid is gradually purified. In the complex scheme of Dragendorff, already mentioned, all his immiscible solvents are employed successively in acid and then in alkaline solution, the aqueous liquid being shaken out with each solvent, which is left to separate and then drawn or siphoned off. Ether and chloroform are used also upon solid residues, stirring to dissolve, as well as in an "extraction apparatus" and in other ways in the course of analytic work.

Other Immiscible Solvents.-The benzene (benzol) of coal-tar distillation, petroleum ether, amyl-alcohol, acetic ether, acetone, are used in the 1 For description of the Dragendorff process see p. 331.