Chapter XXXVI: Part VI: Alkaloids and Poisonous Vegetable Principles Separated for the (10)

In cases of poisoning by colchicum at Berlin, Wittstock used the following process:--The contents of the stomach were mixed with a large amount of alcohol, a few drops of HCl added, and the whole well shaken; the fluid was then filtered, and the filtrate evaporated to a syrupy consistence at 37°. The resulting residue was dissolved in distilled water, the fat, &c., filtered off, and the liquid carefully evaporated. From the extract foreign matter was again separated by treatment with alcohol and filtration, and the last filtrate was evaporated to a syrupy consistence. The syrupy fluid was taken up by distilled water, filtered, evaporated to 30 grms., and 2 grms. of calcined magnesia with 90 grms. of ether were added. After a time, the ether was removed, and allowed to evaporate spontaneously. The residue was once more taken up with water, filtered from fat, &c., and evaporated. This final residue gave all the reactions of colchicine. In medico-legal researches, it must be remembered that colchicine is absorbed but slowly, a not insignificant portion remaining in the bowels, with the fæces.

XIII.--Muscarine and the Active Principles of Certain Fungi.

§ 516. =The Amanita Muscaria=, or fly-blown agaric, is a very conspicuous fungus, common in fir-plantations, about the size and shape of the common mushroom; but the external surface of the pileus is of a bright red, or sometimes of a yellowish cast, and studded over with warts. The common name of the fungus denotes that it was used in former times as a popular insecticide; the fungus was bruised, steeped in milk, and the milk exposed, in the same way as we now expose arsenical fly-papers.

Some peculiar properties of the agaric have long been known to the natives of Kamschatka, and of the north-eastern part of Asia generally. They collect the fungi in the hottest months, and hang them up to dry. The fungus is then rolled up in a kind of bolus, and swallowed without chewing. One large, or two small, fungi will produce a kind of intoxication, which lasts a whole day. It comes on in about two hours’ time, and is very similar to that of alcohol. There is a giddy feeling, the spirits are exalted, the countenance becomes flushed, involuntary actions and words follow, and sometimes loss of consciousness. It renders some persons remarkably active, and proves highly stimulant to muscular exertion; by too large a dose violent spasmodic effects are produced. “So very exciting to the nervous system in many individuals is this fungus, that the effects are often very ludicrous. If a person under its influence wishes to step over a straw or small stick, he takes a stride or a jump sufficient to clear the trunk of a tree. A talkative person cannot keep silence or secrets, and one fond of music is perpetually singing. The most singular effect of the amanita is the influence which it has over the urine. It is said that from time immemorial the inhabitants have known that the fungus imparts an intoxicating quality to that secretion, which continues for a considerable time after taking it. For instance, a man moderately intoxicated to-day will, by the next morning, have slept himself sober, but (as is the custom) by taking a teacup of his urine he will be more powerfully intoxicated than he was the preceding day. It is, therefore, not uncommon for confirmed drunkards to preserve their urine as a precious liquor against a scarcity of the fungus. The intoxicating property of the urine is capable of being propagated; for every one who partakes of it has his urine similarly affected. Thus, with a very few amanitas, a party of drunkards may keep up their debauch for a week. Dr. Langsdorf mentions that by means of the second person taking the urine of the first, the third of the second, and so on, the intoxication may be propagated through five individuals.”[553]

[553] Lindley’s _Vegetable Kingdom_.

§ 517. A few cases of poisoning by the fly-blown agaric from time to time have occurred in Europe, where it has been eaten in mistake for the edible fungi, or taken by children allured by the bright attractive colours. In these cases the poisonous symptoms noticed have been those of gastro-intestinal irritation, as shown by vomiting and diarrhœa, _dilated_[554] pupils, delirium, tetanic convulsions, slow pulse, stertorous breathing, collapse, and death. In a few cases epileptic attacks and trismus have been observed. The course is usually a rapid one, the death occurring within twelve hours. In cases of recovery, convalescence has been prolonged.

[554] This is the more curious, for muscarine strongly contracts the pupil. It, however, tends to prove what is stated in the text--viz., that there is more than one poisonous substance in _Amanita_.

=The post-mortem characteristics are not distinctive=, a fluid condition of the blood, hyperæmia of the brain, liver, and kidneys has been noticed.

§ 518. =Muscarine.=--These effects are partly due to an undiscovered, toxic substance--which seems to be destroyed at the temperature of boiling water, and is probably of rather easy destructibility--and of a very definite poisonous alkaloid (_muscarine_) first separated by a complex process by Schmiedeberg and Koppe in 1869.[555] It is a trimethylammonium base, and has lately been formed synthetically by Schmiedeberg and Harnack,[556] by treating cholin with nitric acid. Muscarine is isomeric with betain and oxycholin, from which it is separated by its fluorescence and poisonous properties.

[555] _Das Muscarin, das giftige Alkaloid des Fliegenpilzes._ Leipzig, 1869.

[556] _Arch. f. exper. Path._, Bd. 4 u. 5.

The structural formula of muscarine, and its connection with choline, is as follows:--

CH₂OH
|
CH₂
|
N(CH₃)₃OH

_Choline._

CH₂OH
|
CHOH
|
N(CH₃)₃OH

_Muscarine._

An atom of hydrogen from the choline, CH₂, group, being replaced by hydroxyl.

Muscarine is a colourless, strongly alkaline, syrupy fluid, which, if allowed to stand over sulphuric acid, becomes gradually crystalline, but liquefies again on exposure to the atmosphere. It dissolves in water in every proportion, and also in alcohol, but is very little soluble in chloroform, and insoluble in ether. It is not precipitated by tannin: it forms salts with acids, and gives precipitates with auric chloride, phosphotungstic, and phosphomolybdic acids, and also with potassio-mercuric iodide. The last precipitate is at first amorphous, but it gradually becomes crystalline. This was the compound used by the discoverers to separate the base. With many other general alkaloidal reagents muscarine forms no compound that is insoluble, and therefore gives no precipitate, such, _e.g._, as iodine with potassic iodide, picric acid, and platinic chloride. Muscarine is a stronger base than ammonia, and precipitates copper and iron oxides from solutions of their salts. Muscarine is very poisonous; 2 to 4 mgrms. are sufficient in subcutaneous injection to kill cats in from two to twelve hours--larger doses in a few minutes; but with rabbits the action is less intense. Cats become salivated, their pupils contract, they vomit, and are purged, the breathing becomes frequent, and there is marked dyspnœa. At a later stage the respirations are slower, and there are convulsions, and death.

The alkaloid has also been tried on man. Doses of from 3 to 5 mgrms., injected subcutaneously, cause, after a few minutes’ profuse salivation, increased frequency of the pulse, nausea, giddiness, confusion of thought and myosis, but no vomiting, and no diarrhœa. Small quantities applied to the eye cause, after a few minutes, a derangement of the accommodation, but no change in the size, of the pupil; larger quantities cause also myosis, which depends upon an excitement of the sphincter iridis, or of the oculomotorius.

§ 519. The actions of muscarine and atropine are to a great extent antagonistic. This is especially and beautifully demonstrated by the effects of the two substances on the frog’s heart. The action of muscarine upon the heart is to excite the inhibitory nerve apparatus, while the action of atropine is to paralyse the same system. One mgrm. of muscarine, injected subcutaneously into a frog, arrests the heart _in diastole_, but if a suitable dose of atropine is applied to the heart thus arrested, it begins to beat again; or, if atropine is first given, and then muscarine, the heart does not stop. The muscarine heart, when it has ceased to beat, may be successfully stimulated by galvanism. Muscarine at first excites the respiratory centre, and then paralyses it.

§ 520. =Detection of Muscarine in the Body.=--Muscarine itself is not likely to be taken as a poison or administered; but if it is sought for in the fly-blown agaric, or in the tissues or organs of persons who have been poisoned by the fungus, the process of Brieger appears the best. The process depends upon the fact that muscarine gives a soluble mercuric chloride compound, and is not precipitated by chloride of platinum, whilst most other substances accompanying it give more or less insoluble precipitates. The substances are treated with water acidulated with hydrochloric acid, and the acidulated extract concentrated (best in a vacuum) to a syrup. The syrupy residue is now treated with water, and the solution precipitated by means of mercuric chloride solution and any precipitate filtered off; the filtrate is freed from mercury by SH₂, and evaporated to a syrup; the syrup is repeatedly extracted with alcohol, and the alcoholic solution precipitated with platinum chloride and any precipitate filtered off. The filtrate is freed from alcohol, and all the platinum thrown out of solution by SH₂; the aqueous filtrate is now concentrated to a small volume, and again platinum chloride added, any precipitate which forms is filtered off, and the final filtrate allowed to crystallise. If muscarine be present, a crystalline compound of muscarine platinum chloride will form.

The crystals are usually octahedral in form, and have the composition (C₅H₁₄NO₂Cl)₂PtCl₄; the percentage of platinum is 30·41.

It would probably be necessary to identify farther, by the action of the poison on a frog.

§ 521. =The Agaricus phalloides=, a common autumn fungus, has been several times mistaken for mushrooms, and has proved fatal; of some 53 cases collected by Falck, no less than 40, or 75 per cent., were fatal; the real mortality is much lower than this, for it is only such cases that are pronounced and severe which are likely to be recorded. The fungus contains a toxalbumin which has been named “phallin.” The action of this toxalbumin is to dissolve the blood corpuscles; according to Kobert, even one 250,000th dilution produces “polycholie,” with all its consequences, such as the escape of hæmoglobin and its decomposition products in the blood and urine, multiple blood coagulation through the fibrin ferment becoming free, and serious cerebral disturbance. If into a dog, cat, or rabbit, only 0·5 mgrm. of phallin be injected intravenously, within from twenty to thirty minutes blood from a vein shows that the serum has a red colour.

The symptoms in man first appear in from three to forty-eight hours; there is mostly diarrhœa, violent vomiting, with cramp in the legs, cyanosis, and collapse. There are also nervous phenomena, convulsions, trismus, and, in a few cases, tetanic spasms. The pulse, in seven cases described by Maschka, was very small, thready, and quick, but in others, again, small and slow. The pupils have in some cases been dilated, in others unchanged. Death is generally rapid. In two of Maschka’s cases from sixty to sixty-eight hours after the investigation, but in the rest from twelve to eighteen hours. Life may, however, be prolonged for several days. In a case recorded by Plowright,[557] in which a boy had eaten a piece of the pileus, death occurred on the fourth day.

[557] _Lancet_, 1879.

§ 522. =The post-mortem appearances= observed in Maschka’s seven cases were--absence of cadaveric rigidity, dilatation of the pupil, a dark red fluid condition of the blood, numerous ecchymoses in the pleura, in the substance of the lungs, the pericardium, the substance of the heart, the liver, kidneys, and spleen. The mucous membrane of the digestive canal presented nothing characteristic. In two cases there were a few ecchymoses, and in one the mucous membrane of the stomach was softened, red, and easily detached. In one case only were any remnants of the fungus found, by which the nature of the substance eaten could be determined. The bladder in each case was full. In three cases a fatty degeneration of the liver had commenced. The same appearance was met with in some of the older cases related by Orfila.

§ 523. =The Agaricus pantherinus= is said to be poisonous, although Hertwig found it to have no action when given to dogs.

=The Agaricus ruber=, a bright-hued fungus, growing profusely on the Hampshire coast, of a purple-red colour--the colouring-matter not only covering the pileus, but also extending down the stipe--is poisonous, and has recently been chemically investigated by Phipson,[558] who has identified a colouring-matter _ruberine_, and an alkaloid _agarythrine_. Agarythrine is separated by macerating the fungus (from which the skin containing the colouring-matter has been removed) as completely as possible in water acidulated with 8 per cent. of hydrochloric acid. The filtered solution is neutralised by sodic carbonate, and the alkaloid shaken up with ether. On evaporation the ether leaves a white, somewhat greasy-looking substance, having a bitter burning taste, and easily fusible into yellow globules, giving forth an odour like quinoleine; it is soluble in alcohol and ether. From Phipson’s observations it would appear probable that the red colouring-matter is derived from a decomposition of this alkaloidal substance. A rose-red colour is produced by the action of nitric acid, and chlorinated lime first reddens and then bleaches it. Buchwald[559] has recorded three cases of poisoning by this fungus; the patients were labourers, who, after eating the fungus, suffered from vomiting, thirst, a “drunken” condition, cramp, albuminuria, and disturbance of the sensory functions. The fungus causes in cats myosis, but is said not to affect rabbits.

[558] _Chem. News_, p. 199, 1882.

[559] _Industr. Bl._, 1876.

§ 524. =The Soletus satanas, or luridus= (=Lenz=), is poisonous; very small quantities of the uncooked fungus caused in Lenz, who experimented upon its properties, violent vomiting. In cases in which this fungus has been eaten accidentally, the symptoms have been very similar to cholera.

§ 525. =The Common Morelle= seems under certain conditions to be poisonous. From six to ten hours after ingestion there have appeared depression, nausea, jaundice, dilated pupils, and in the worst cases at the end of the first day, delirium, somnolence, and muscular cramps, followed by collapse and death. In a case observed by Kromholz, the _post-mortem_ appearances were jaundice, a dark fluid state of the blood, and hyperæmia of the brain and liver. Boström fed a dog with 100 grms. of the fresh young morelle; the animal died on the third day, and the canaliculi of the kidney were found filled with hæmoglobin, partly amorphous, and partly crystalline.[560]

[560] See Casper’s _Viertelj._, 1844; Keber, _Preuss. Vereinszeitg._ 1846; Boström, _Ber. d. Phys. Med. Soc._, Erlangen, 1880; Schauenstein, “Giftige Schwämme” in Maschka’s _Handbuch_, &c.

DIVISION II.--GLUCOSIDES.

I.--Digitalis Group.

§ 526. =The Digitalis purpurea=, or foxglove, is a plant extremely common in most parts of England, and poisoning may occur from the accidental use of the root, leaves, or seeds. The seeds are very small and pitted; they weigh 1126 to a grain (_Guy_), are of a light brown colour, and in form somewhat egg-shaped. The leaves are large, ovate, crenate, narrowed at the base, rugous, veined, and downy, especially on the under surface. Their colour is a dull green, and they have a faint odour and a bitter, nauseous taste. The leaf is best examined in section. Its epidermis, when fresh, is seen to consist of transparent, hexagonal, colourless cells, beneath which, either singly or in groups, there are round cells of a magenta tint, and beneath these again a layer of columnar cells, and near the lower surface a loose parenchyma. The hairs are simple, appearing scantily on the upper, but profusely on the lower, surface; each is composed of from four to five joints or cells, and has at its base a magenta-coloured cell. The small leaves just below the seed-case, and the latter itself, are studded with glandular hairs. The root consists of numerous long slender fibres.

§ 527. =Chemical Composition.=--It is now generally accepted that there exist in the foxglove, at least, four distinct principles--_digitalin_, _digitonin_, _digitoxin_, and _digitalein_. Besides these there are several others of more or less definite composition, which are all closely related, and may be derived from a complex glucoside by successive removals of hydrogen in the form of water.

The following is the theoretical percentage composition of the digitalins, the identity of which has been fairly established. They are arranged according to their percentage in carbon:--

TABLE SHOWING THE COMPOSITION OF THE DIGITALINS.

+------------------+--------+-------------------------------------+
| Name. |Formula.| Percentage Composition. |
+------------------+--------+-------------------------------------+
| Digitalein, | C₂₁H₄₆O₁₁ | C. 53·16 per cent. H. 8·08 per cent.|
| Digitonin,[561] | C₃₁H₅₂O₁₇ | C. 53·44 „ H. 7·46 „ |
| Digitalin, | C₅₄H₈₄O₂₇ | C. 58·16 „ H. 3·65 „ |
| Digitaletin, | C₄₄H₃₀O₁₈ | C. 62·41 „ H. 3·54 „ |
| Digitoxin, | C₂₁H₃₂O₇ | C. 63·63 „ H. 8·08 „ |
| Digitaleretin, | C₄₄H₃₈O₁₈ | C. 66·05 „ H. 4·58 „ |
| Paradigitaletin, | C₄₄H₃₄O₁₄ | C. 67·17 „ H. 4·3 „ |
+------------------+--------+-------------------------------------+

[561] According to Kiliani, digitonin has the composition of C₂₇H₄₄O₁₃, and it breaks up, when heated with hydrochloric acid, as follows:--

C₂₇H₄₄O₁₃ + 2H₂O = C₁₆H₂₄O₃ + 2C₆H₁₂O₆.
Digitonin. Digitogenin. Dextrose.

--_Ber._, xxiii. 1555-1568.

§ 528. =Digitalein= is a colourless, amorphous body, easily soluble
in water and in cold absolute alcohol. It may be precipitated from
an alcoholic solution by the addition of much ether. It is with
difficulty soluble in chloroform, and insoluble in ether. It is
precipitated from a watery solution by tannin, or by basic lead
acetate; saponification by dilute acids splits it up into glucose
and digitaleretin. It has a sharp, acrid taste, and the watery
solution froths on shaking.

§ 529, =Digitonin=, a white amorphous body, has many of the
characters of saponin. Like saponin, it is easily soluble in water,
and the solution froths, and, like saponin again, it is precipitated
by absolute alcohol, by baryta water, and by basic lead acetate. It
may be readily distinguished from saponin by treating a watery
solution with sulphuric or hydrochloric acid. On saponifying, it is
split up into digitogenin, galactose, and dextrose. On heating, a
beautiful red colour develops. It does not give the bromine
reaction.

=Digitogenin= is insoluble in water and aqueous alkalies; it is somewhat soluble in alcohol, chloroform, and glacial acetic acid; it forms a crystalline compound with alcoholic potash, which is strongly alkaline, and not very soluble in alcohol.

§ 530. =Digitalin=, when perfectly pure, forms fine, white, glittering, hygroscopic needles, or groups of crystalline tufts; it is without smell, but possesses a bitter taste, which is at once of slow development and of long endurance. On warming, it becomes soft under 100°, and, above that temperature, is readily decomposed with evolution of white vapours. It is insoluble in water, in dilute soda solution, in ether, and in benzene. It is soluble in chloroform, especially in chloroform and alcohol, and dissolves easily in warm acetic acid; twelve parts of cold and six of boiling alcohol of 90 per cent. dissolve one of digitalin. Dilute hydrochloric or sulphuric acid decompose it into glucose and digitaletin (C₄₄H₃₀O₁₈); if the action is prolonged, digitaleretin (C₄₄H₃₈O₁₈), and finally dehydrated digitaleretin, are formed. Concentrated sulphuric acid dissolves it with the production of a green colour, which by bromine passes into violet-red, but on the addition of water becomes green again. Hydrochloric acid dissolves it with the production of a greyish-yellow colour, passing gradually into emerald green; water precipitates from this solution a resinous mass.

§ 531. =Digitaletin.=--A substance obtained by Walz on treating his
digitalin by dilute acids. It is crystalline, and its watery
solution tastes bitter. It melts at 175°, and decomposes, evolving
an acid vapour at about 206°. It dissolves in 848 parts of cold, and
222 of boiling, water; in 3·5 parts of cold, and in from 2 to 4 of
boiling, alcohol. It is with difficulty soluble in ether. It
dissolves in concentrated sulphuric acid, developing a red-brown
colour, which, on the addition of water, changes to olive-green. On
boiling with dilute acids, it splits up into sugar and
digitaleretin.

§ 532. =Digitoxin= always accompanies digitalin in the plant, and may by suitable treatment be obtained in glittering needles and tabular crystals. It is insoluble in water and in benzene. It dissolves with some difficulty in ether, and is readily dissolved by alcohol or by chloroform. On boiling with dilute acids, it is decomposed into an amorphous, readily soluble body,--_Toxiresin_. Digitoxin, according to Schmiedeberg, only exists in the leaves of the digitalis plant, and that in the proportion of 1 part in 10,000. Digitalin and digitoxin are _par excellence_ the poisonous principles of the plant. Toxiresin is also intensely poisonous. It may be obtained in crystals by extracting the dry exhausted leaves with alcohol of 50 per cent., precipitating with lead acetate, and washing the precipitate first with a dilute solution of sodium carbonate (to remove colouring-matter), and then with ether, benzene, and carbon disulphide, in all of which it is insoluble; on decomposing the lead compound, digitoxin may be obtained in colourless scales or needle-shaped crystals.

§ 533. =Digitaleretin=, the origin of which has been already alluded
to, is a yellowish-white, amorphous powder, possessing no bitter
taste, melting at 60°, soluble in ether or in alcohol, but insoluble
in water.

=Paradigitaletin= is very similar to the above, but it melts at
100°, and is insoluble in ether.

§ 534. Several other derivatives have been obtained and described, such as the inert _digitin_, _digitalacrin_, _digitalein_, and others, but their properties are, as yet, insufficiently studied. Digitalin, as well as digitoxin, may now be obtained pure from certain firms, but the ordinary digitalin of commerce is, for the most part, of two kinds, which may be distinguished as French and German digitalin. The French digitalin, or the digitalin of Homolle, is prepared by treating an aqueous extract of the digitalis plant with lead acetate, and freeing the filtrate from lead, lime, and magnesia, by successive additions of alkaline carbonate, oxalate, and phosphate, and then precipitating with tannin. The tannin precipitate is treated with litharge, and the digitalins boiled and extracted from the mass by means of alcohol, and lastly, purifying with animal charcoal. Crystals are in this way obtained, and by removing all substances soluble in ether by that solvent, digitalin may be separated. The German digitalin is prepared according to the process of Walz, and is extracted from the plant by treatment with alcohol of ·852. The alcohol is removed by evaporation, and the alcoholic extract taken up with water; the watery extract is treated with lead acetate and litharge, filtered, the filtrate freed from lead by hydric sulphate, and the excess of acid neutralised by ammonia, and then tannin added to complete precipitation. The precipitate is collected and rubbed with hydrated oxide of lead, and the raw digitalin extracted by hot alcohol. The alcohol, on evaporation, leaves a mixture of digitalin mixed with other principles and fatty matter. If sold in this state, it may contain from 2 to 3 per cent. of digitalein and digitonin. On treating the mixture with ether, digitalin with some digitaletin is left behind, being almost insoluble in ether. Since, however, digitaletin is very insoluble in cold water, by treating the mixture with eight parts of its weight of cold water, digitalin is dissolved out in nearly a pure state. It may be further purified by treating the solution with animal charcoal, recrystallisation from spirit, &c.

§ 535. =Reactions of the Digitalins.=--Digitonin is dissolved by dilute sulphuric acid (1 : 3) without colour, and the same remark applies to hydrochloric acid; on warming with either of these acids, a violet-red colour appears; this reaction thus serves to distinguish digitonin from the three other constituents, as well as from saponin.

Sulphuric and gallic acids colour the glucosides of digitalin, digitalein, and digitonin, red, but not digitoxin, which can be identified in this way.

Sulphuric acid and bromine give with digitalin a red, and with digitalein a violet coloration, which, on the addition of water, change respectively into emerald and light green. This, the most important chemical test we possess, is sometimes called _Grandeau’s test_; it is not of great delicacy, the limit being about ·1 mgrm.

§ 536. =Pharmaceutical Preparations of Digitalin.=--Digitalin itself is officinal in the French, Belgium, Portuguese, Russian, Spanish, and Austrian pharmacopœias. It is prepared in our own by making a strong tincture of the leaves at 120° F.; the spirit is then evaporated off, and the extract heated with acetic acid, decolorised by animal charcoal, and filtered. After neutralisation with ammonia, the digitalin is precipitated with tannin, and the tannate of digitalin resolved into tannate of lead and free digitalin, by rubbing it with oxide of lead and spirit.

Digitalis leaf is officinal in most of the pharmacopœias.

Tincture of digitalis is officinal in our own and all the Continental pharmacopœias, and an ethereal tincture is used in France and Germany.

An _Acetum digitalis_ is officinal in the Netherlands and Germany; an extract and infusion are also used to some extent.

With regard to the nature of the active principle in these different preparations, according to Dragendorff, digitonin and digitalein are most plentiful in the acetic and aqueous preparations; whilst in the alcoholic, digitalin, digitoxin, and digitalein are present.

According to Schmiedeberg, commercial digitalin contains, in addition to digitoxin, digitonin, digitalin, and digitalein; of these, digitonin is greatest in amount.[562]

[562] H. Kiliani, _Ber._, xxiii.

§ 537. =Fatal Dose.=--The circumstance of commercial digitalin consisting of varying mixtures of digitoxin, digitalin, and digitalein, renders it difficult to be dogmatic about the dose likely to destroy life. Besides, with all heart-poisons, surprises take place; and very minute quantities have a fatal result when administered to persons with disease of the heart, or to such as, owing to some constitutional peculiarity, have a heart easily affected by toxic agents. Digitoxin, according to Kopp’s[563] experiments, is from six to ten times stronger than digitalin or digitalein. Two mgrms. caused intense poisonous symptoms. Digitoxin is contained in larger proportions in Nativelle’s digitalin than in Homolle’s, or in the German digitalin. The digitalin of Homolle is prescribed in 1 mgrm. (·015 grain) doses, and it is thought dangerous to exceed 6 mgrms.

[563] _Archiv f. exp. Pathol. u. Pharm._, vol. iii. p. 284, 1875.

Lemaistre has, indeed, seen dangerous symptoms arise from 2 mgrms. (·03 grain), when administered to a boy fifteen years old. It may be predicated from recorded cases and from experiment, that digitoxin would probably be fatal to an adult man in doses of 4 mgrms. (1/16 grain), and digitalin, or digitalein, in doses of 20 mgrms. (·3 grain). With regard to commercial digitalin, as much as from 10 to 12 mgrms. (·15 to ·18 grain) have been taken without a fatal result; on the other hand, 2 mgrms. gave rise to poisonous symptoms in a woman (Battaille). Such discrepancies are to be explained on the grounds already mentioned. It is, however, probable that 4 mgrms. (or 1/16 grain) of ordinary commercial digitalin would be very dangerous to an adult.

It must also, in considering the dose of digitalin, be ever remembered that it is a cumulative poison, and that the same dose--harmless if taken once--yet, frequently repeated, becomes deadly: this peculiarity is shared by all poisons affecting the heart. When it is desired to settle the maximum safe dose for the various tinctures, extracts, and infusions of digitalis used in pharmacy, there is still greater difficulty, a difficulty not arising merely from the varying strength of the preparations, but also from the fact of the vomiting almost invariably excited by large doses. Individuals swallow quantities without death resulting, simply because the poison is rapidly expelled; whereas, if the œsophagus was ligatured (as in the experiments on the lower animals formerly favoured by the French school of toxicologists), death must rapidly ensue. The following table is a guide to the maximum single dose, and also the amount safe to administer in the twenty-four hours in divided doses. As a general rule, it may be laid down that double the maximum dose is likely to be dangerous:--

TABLE SHOWING THE MAXIMUM SINGLE DOSE, AND MAXIMUM QUANTITY OF THE DIFFERENT PREPARATIONS OF DIGITALIS, WHICH CAN BE ADMINISTERED IN A DAY.

+----------------+----------------------+--------------------------+
| | Single Dose. | Per Day. |
| +----------+-----------+-------------+------------+
| | Grains or| Grammes | Grains or |Grammes |
| | Minims. | or c.c’s. | Minims. |or c.c’s. |
+----------------+----------+-----------+-------------+------------+
|Powdered Leaves,| 4½ grns. | ·3 grm. | 15·4 grns. | 1·0 grm. |
|Infusion, | 480 m. |28·3 c.c. | 1440 m. | 84·9 c.c. |
|Tincture, | 45 m. | 3 c.c. | 135 m. | 9 c.c. |
|Digitalin, | ·03 grn. | ·002 grm.| ·09 grn. | ·006 grm. |
|Extract, |3·0 „ | ·2 „ | 12·0 „ | ·8 „ |
+----------------+----------+-----------+-------------+------------+

§ 538. =Statistics.=--The main knowledge which we possess of the action of digitalis is derived from experiments on animals, and from occasional accidents in the taking of medicines; but in comparison with certain toxic agents more commonly known, the number of cases of death from digitalis is very insignificant. Of 42 cases of digitalis-poisoning collected by Husemann, 1 was criminal (murder); 1 the result of mistaking the leaves for those of borage; 42 were caused in medicinal use--in 33 of these last too large a dose had been given, in 3 the drug was used as a domestic remedy, in 2 of the cases the prescription was wrongly read, and in 1 digitalis was used as a secret remedy. Twenty-two per cent. of the 45 were fatal.

§ 539. =Effects on Man.=--It was first distinctly pointed out by Tardieu that toxic doses of digitalis, or its active principles, produced not only symptoms referable to an action on the heart, but also, in no small degree, gastric and intestinal irritation, similar to that produced by arsenic. Tardieu also attempted to distinguish the symptoms produced by the pharmaceutical preparations of digitalis (the tincture, extract, &c.), and the glucoside digitalin; but there does not appear a sufficient basis for this distinction. The symptoms vary in a considerable degree in different persons, and are more or less tardy or rapid in their development, according to the dose. Moderate doses continued for some time (as, for example, in the persistent use of a digitalis medicine) may produce their first toxic effects even at the end of many days; but when a single large dose is taken, the symptoms are rarely delayed more than three hours. They may commence, indeed, in half an hour, but have been known to be retarded for more than twenty-four hours, and the longer periods may be expected if digitalis is given in hard, not easily soluble pills. There is commonly a feeling of general _malaise_, and then violent retching and vomiting. The pulse at first may be accelerated, but it soon is remarkably slowed--it sinks commonly down to 50, to 40, and has even been known as low as 25. To these symptoms, referable to the heart and to the digestive tract, are added nervous troubles; there are noises in the ears, and disturbances of vision. In a case related by Taylor, a red-coal fire seemed to the patient to be of a blue colour; in another, related by Lersch,[564] there was blindness for eighteen hours, and for some time a confusion in the discrimination in colours; quiet delirium has also been noticed. As the case proceeds, the gastric symptoms also increase in severity; the tongue Christison, in one case, noticed to be enormously swollen, and the breath fœtid. Diarrhœa is commonly present, although also sometimes absent. The action of the kidneys is suppressed. Hiccough and convulsions close the scene.

[564] _Rhen. West. Corr. Bl._, 15, 1848; Husemann in Maschka’s _Handbuch_.

In the cumulative form, the symptoms may suddenly burst out, and the person pass into death in a fainting-fit without any warning. As a rare effect, hemiplegia may be mentioned.

This brief _résumé_ of the symptoms may be further illustrated by the following typical cases:--A recruit, aged 22, desiring to escape from military service, went to a so-called “_Freimacher_” who gave him 100 pills, of which he was to take eight in two doses daily. Eleven days after the use of the pills, he became ill, and was received into hospital, where he suddenly died after three weeks’ treatment. His malady was at first ascribed to gastric catarrh; for he suffered from loss of appetite, nausea, and constipation. He complained of pain in the head, and giddiness. His breath smelled badly, and the region of the stomach was painful on pressure. The pulse was slow (56), the temperature of the body normal. Towards the end, the pulse sank to 52; he suffered from vomiting, noise in the ears, troubles of vision, great weakness, and later, hiccough and swelling in the neck. The mere act of standing up in order to show his throat caused him to faint; on the same day on which this occurrence took place, he suddenly died on the way to the nightstool. Thirteen of the pills were found in the patient’s clothes, and from a chemical and microscopical examination it was found that they contained digitalis leaf in fine powder. The quantity which the unfortunate man took in the four weeks was estimated at 13·7 grms. (= about 211 grains).

Two of his comrades had also been to the “_Freimacher_,” and had suffered from the same symptoms, but they had left off the use of the medicine before any very serious effect was produced.[565][566]

[565] Köhnhorn, _Vierteljahrsschr. f. ger. Med._, 1876, n. F. xxiv. p. 402.

[566] There is an interesting case on record, in which a woman died from the expressed juice of digitalis. She was twenty-seven years of age, and took a large unknown quantity of the freshly expressed juice for the purpose of relieving a swelling of the limbs. The symptoms came on almost immediately, she was very sick, and was attacked by a menorrhagia. These symptoms continued for several days with increasing severity, but it was not until the fifth day that she obtained medical assistance. She was then found semi-comatose, the face pale, pulse slow, epigastrium painful on pressure, diarrhœa, and hiccough were frequent. She died on the twelfth day. The _post-mortem_ appearances showed nothing referable to digitalis save a few spots of inflammation on the stomach.--Caussé, _Bull. de Thérapeutique_, vol. lvi. p. 100; _Brit. and For. Med. Chir. Review_, vol. xxvi., 1860, p. 523.

An instructive case of poisoning by digitoxin occurred in the person of Dr. Koppe, in the course of some experiments on the drug. He had taken 1·5 mgrm. in alcohol without result; on the following day (May 14) he took 1 mgrm. at 9 A.M., but again without appreciable symptoms. Four days later he took 2 mgrms. in alcoholic solution, and an hour afterwards felt faint and ill, with a feeling of giddiness; the pulse was irregular, of normal frequency, 80 to 84. About three hours after taking the digitoxin, Dr. Koppe attempted to take a walk, but the nausea, accompanied with a feeling of weakness, became so intense that he was obliged to return to the house. Five hours after the dose, his pulse was 58, intermittent after about every 30 to 50 beats. Vomiting set in, the matters he threw up were of a dark green colour; after vomiting he felt better for a quarter of an hour, then he again vomited much bilious matter; the pulse sank to 40, and was very intermittent, stopping after every 2 or 3 beats. Every time there was an intermission, he felt a feeling of constriction and uneasiness in the chest. Six and a quarter hours after the dose there was again violent vomiting and retching, with paleness of the face. The muscular weakness was so great that he could not go to bed without assistance. He had a disorder of vision, so that the traits of persons well-known to him were changed, and objects had a yellow tint. He had a sleepless night, the nausea and vomiting continuing. During the following day the symptoms were very similar, and the pulse intermittent, 54 per minute. He passed another restless night, his short sleep being disturbed by terrible dreams. On the third day he was somewhat better, the pulse was 60, but irregular and still intermittent; the nausea was also a little abated. The night was similar in its disturbed sleep to the preceding. He did not regain his full health for several days.[567]

[567] _Arch. f. exp. Path. u. Pharm._, vol. iii. p. 289, 1875.

A third case may be quoted, which differs very markedly from the preceding, and shows what a protean aspect digitalin poisoning may assume. A woman, twenty-three years old, took on June 26th, at 7 A.M., for the purpose of suicide, 16 granules of digitalin. Two hours later there was shivering and giddiness, so that she was obliged to go to bed. In the course of the day she had hallucinations. In the evening at 8 P.M., after eating a little food, she had a shivering fit so violent that her teeth chattered; there was cold sweat, and difficulty in breathing; she became gradually again warm, but could not sleep. At 1 A.M. the difficulty of breathing was so great that she dragged herself to the window, and there remained until 3 A.M., when she again went back to bed, slept until 7 A.M., and woke tolerably well. Since this attempt of self-destruction had failed, she took 40 granules. After one hour she became giddy, had hallucinations, chilliness, cold sweats, copious vomiting, and colicky pains; there was great muscular weakness, but no diarrhœa. Towards evening the vomiting became worse. There was no action of the bowels, nor was any urine passed; she felt as if her eyes were prominent and large. The sufferings described lasted during the whole night until five o’clock the following day, when the vomiting ceased, whilst the hallucinations, chilliness, and cold sweat continued; and the thirst, sick feeling, and weakness increased. The next morning, a physician found her motionless in bed, with pale face, notable double exophthalmus, dilated pupils, and cold skin, covered with sweat; the pulse was small and intermittent, sometimes scarcely to be felt (46 to 48 per minute); the epigastrium was painful on pressure. She passed this second night without sleep, and in the morning the pulse had risen from 56 to 58 beats, but was not quite so intermittent. There was some action of the bowels, but no urine was passed, nor had any been voided from the commencement; the bladder was not distended. The following (third) day some red-coloured, offensive urine was passed; the skin was warmer, and the pulse from 60 to 64, still somewhat intermittent--from this time she began to improve, and made a good recovery.[568]

[568] Related by Ducroix: _De l’Empoisonnement par la Digitale et la Digitaline._ Paris, 1864.

§ 540. =Physiological Action of the Digitalins.=--Whatever other physiological action this group may have, its effect on the heart’s action is so prominent and decided, that the digitalins stand as a type of _heart poisons_. The group of heart poisons has been much extended of late years, and has been found to include the following:--Antiarin, an arrow poison; helleborin, a glucoside contained in the hellebore family; a glucoside found in the _Apocynaceæ_, _Thevatii neriifolia_, and _Thevatia iccotli_; the poisonous principle of the _Nerium oleander_ and _N. odorum_; the glucoside of _Tanghinia venenifera_; convallamarin, derived from the species of _Convallaria_; scillotoxin, from the squill; superbin, from the Indian lily; and the alkaloid erythrophlœin from the _Erythrophlœum judiciale_ (see p. 432 _et seq._). This list is yearly increasing.

§ 541. =Local Action.=--The digitalins have an exciting or stimulating action if applied to mucous membranes--_e.g._, if laid upon the nasal mucous surface, sneezing is excited; if applied to the eye, there is redness of the conjunctivæ with smarting; if to the tongue, there is much irritation and a bitter taste. The leaves, the extract, and the tincture all have this directly irritating action, for they all redden and inflame mucous membranes.

§ 542. =Action on the Heart.=--The earlier experimenters on the influence of digitalis on the heart were Stannius and Traube. Stannius[569] experimented on cats, and found strong irregularity, and, lastly, cessation in diastole, in which state it responded no longer to stimuli. Rabbits and birds--especially those birds which lived on plants--were not so susceptible, nor were frogs.

[569] _Arch. f. Physiol._

Traube[570] made his researches on dogs, using an extract, and administering doses which corresponded to from ·5 to 4·0 grms. He divided the symptoms witnessed into four stages:--

[570] _Ann. d. Charité-Krankenhauses_, vol. ii. p. 785.

_1st Stage._--The pulse frequently diminishes, while the pressure of the blood rises.

_2nd Stage._--Not seen when large doses are employed; pulse frequency, as well as blood pressure, abnormally low.

_3rd Stage._--Pressure low, pulse beats above the normal frequency.

The slowing of the heart[571] is attributed to the stimulus of the inhibitory nerves, but the later condition of frequency to their paralysis. After the section of the vagi the slow pulse frequently remains, and this is explained by the inhibitory action of the cardiac centre. The vagus, in point of time, is paralysed earlier than the muscular substance of the heart.

[571] Slowing of the pulse was mentioned first by Withering (_An Account of the Foxglove_, Lond., 1785). Beddoes afterwards observed that digitalis increased the force of the circulation, the slowing of the pulse not being always observed; according to Ackermann, if the inhibitory apparatus is affected by atropine, or if the patient is under deep narcosis, the slowing is absent.

The increased blood pressure Traube attributed to increased energy of the heart’s contraction, through the motor centre being stimulated later; the commencing paralysis explains the abnormally low pressure.

There is, however, also an influence on vaso-motor nerves. What Dr. Johnson has described as the “stop-cock” action of the small arteries comes into play, the small arteries contract and attempt, as it were, to limit the supply of poisoned blood. Ackermann,[572] indeed, witnessed this phenomenon in a rabbit’s mesentery, distinctly seeing the arteries contract, and the blood pressure rise after section of the spinal cord. This observation, therefore, of Ackermann’s (together with experiments of Böhm[573] and L. Brunton[574]) somewhat modifies Traube’s explanation, and the views generally accepted respecting the cause of the increased blood pressure may be stated thus:--The pressure is due to prolongation of the systolic stroke of the cardiac pump, and to the “stop-cock” action of the arteries; in other words, there is an increase of force from behind (_vis a tergo_), and an increased resistance in front (_vis a fronte_).

[572] _Deutsch. Arch. f. klin. Med._, vol. xix. p. 125.

[573] _Archiv f. d. Ges. Phys._, vol. v. p. 153.

[574] _On Digitalis, with Some Observations on the Urine_, Lond., 1868.

§ 543. =Action of the Digitalins on the Muco-Intestinal Tract and other Organs.=--In addition to that on the heart, there are other actions of the digitalins; for example, by whatever channel the poison is introduced, vomiting has been observed. Even in frogs this, in a rudimentary manner, occurs. The diuretic action which has been noticed in man is wanting in animals, nor has a lessened diminution of urea been confirmed.

Ackermann found the temperature during the period of increased blood pressure raised superficially, but lowered internally. According to Boeck[575] there is no increase in the decomposition of the albuminoids.

[575] _Intoxication_, p. 404.

§ 544. =The Action of Digitalin on the Common Blow-fly.=--The author
has studied the effects of digitalin, made up into a thin paste with
water, and applied to the head of the common blow-fly. There are at
once great signs of irritation, the sucker is extruded to its full
length, and the fly works its fore feet, attempting to brush or
remove the irritating agent. The next symptom is a difficulty in
walking up a perpendicular glass surface. This difficulty increases,
but it is distinctly observed that weakness and paralysis occur in
the legs before they are seen in the wings. Within an hour the wings
become paralysed also, and the fly, if jerked from its support,
falls like a stone. The insect becomes dull and motionless, and
ultimately dies in from ten to twenty-four hours. A dose, in itself
insufficient to destroy life, does so on repetition at intervals of
a couple of hours. The observation is not without interest, inasmuch
as it shows that the digitalins are toxic substances to the muscular
substance of even those life-forms which do not possess a heart.

§ 545. =Action of the Digitalins on the Frog’s Heart.=--The general action of the digitalins is best studied on the heart of the frog. Drs. Fagge and Stevenson have shown[576] that, under the influence of digitalin, there is a peculiar form of irregularity in the beats of the heart of the frog; the ventricle ultimately stops in the white contracted state, the voluntary power being retained for fifteen to twenty minutes afterwards; in very large doses there is, however, at once paralysis. Lauder Brunton[577] considers the action on the heart to essentially consist in the prolongation of the systole.

[576] _Guy’s Hospl. Reports_, 3rd ver., vol. xii. p. 37.

[577] _On Digitalis, with Some Observations on the Urine_, Lond., 1868.

Atropine or curare have no influence on the heart thus poisoned. If the animal under the influence of digitalin be treated with muscarine, it stops in diastole instead of systole. On the other hand, the heart poisoned by muscarine is relieved by digitalin, and a similar influence appears to be exercised by atropine. The systolic stillness of the heart is also removed by substances which paralyse the heart, as delphinin, saponin, and apomorphin.

Large doses of digitalin, thrown suddenly on the circulation by intravenous injection, cause convulsions and sudden death, from quick palsy of the heart. With frogs under these circumstances there are no convulsions, but a reflex depression, which, according to Weil[578] and Meihuizen,[579] disappears on decapitation. The central cerebral symptoms are without doubt partly due to the disturbance of the circulation, and there is good ground for attributing them also to a toxic action on the nervous substance. The arteries are affected as well as the heart, and are reduced in calibre; the blood pressure is also increased.[580] This is essentially due to the firm, strong contraction of the heart, and also to the “stop-cock” action of the small arteries.[581]

[578] _Archiv f. Anat. u. Physiol._, 1871, p. 282.

[579] _Archiv f. d. Ges. Physiol._, vol. vii. p. 201.

[580] The following is a brief summary of observations on the blood pressure; four stages may be noticed--(1) Rise of normal blood pressure, not necessarily accompanied with a diminution of pulse frequency; (2) continuation of heightened blood pressure, the pulse being raised beyond the normal rate; (3) continued high pressure, with great irregularity of the heart and intermittent pulse; (4) quick depression of pressure, sudden stopping of the heart, and death.

[581] According to Boehm (_Arch. f. d. Ges. Physiol._, Bd. v. S. 189) and to Williams (_Arch. f. exper. Pathol._, Bd. xiii. S. 2), the rise of pressure is due entirely to the heart, and not to the contractions of the small arteries; but I fail to see how the small arteries can contract, and yet not heighten the pressure.

§ 546. =Post-mortem Appearances.=--In the case of the recruit poisoned by digitalis leaf (p. 425), the blood was found dark and fluid; the right ventricle and auricle of the heart were filled with blood, the left empty; the brain and its membranes were anæmic; the stomach and mucous membrane of the intestines were in parts ecchymosed, and there were patches of injection. In the case of the widow De Pauw, poisoned with digitalin by the homœopath (Conty de la Pommerais), the only abnormality discovered was a few hyperæmic points in the mucous membrane of the stomach and small intestines. It is then certain that although more or less redness of the lining membrane of the intestine track may be present, yet, on the other hand, the active principle of the digitalis may destroy life, and leave no appreciable sign.

§ 547. =Separation of the Digitalins from Animal Tissues, &c.=--It is best to make an alcoholic extract after the method of Stas, the alcohol being feebly acidulated by acetic acid, and all operations being carried on at a temperature below 60°. The alcoholic extract is dissolved in water feebly acidulated by acetic acid, and shaken up, first with petroleum ether to remove impurities (the ether will not dissolve any of the digitalins), then with benzene, and, lastly, with chloroform. The benzene dissolves digitalein, and the chloroform, digitalin and digitoxin. On allowing these solvents to evaporate spontaneously, residues are obtained which will give the reactions already detailed. Neither the bromine nor any other chemical test is sufficient to identify the digitalins; it is absolutely necessary to have resource to physiological experiment. The method used by Tardieu in the classical Pommerais case may serve as a model, more especially the experiments on frogs. Three frogs were properly secured, the hearts exposed, and the beats counted. The number of beats was found to be fairly equal. Frog No. 1 was placed under such conditions that the heart was constantly moist. Frog No. 2 was poisoned by injecting into the pleura 6 drops of a solution in which 10 mgrms. of digitalin were dissolved in 5 c.c. of water. The third frog was poisoned by a solution of the suspected extract. The number of beats per minute were now counted at definite intervals of time as follows:--

TABLE SHOWING THE ACTION OF DIGITALIN ON THE FROG’S HEART.

+----------------------+--------------------+----------------------+
| Frog No. 1. | Frog No. 2. | Frog No. 3. |
| Unpoisoned. | Poisoned by a | Poisoned by the |
| | known quantity | suspected |
| | of digitalin. | extract. |
+----------------------+--------------------+----------------------+
| No. of beats | No. of beats | No. of beats |
| per minute. | per minute. | per minute. |
+----------------------+--------------------+----------------------+
| After 6 minutes, 42 | 20 | 26 |
| „ 10 „ 40 | 16 irregular. | 24 irregular. |
| „ 20 „ 40 | 15 | 20 „ |
| „ 28 „ 38 | 0 | 12 very irregular. |
| „ 31 „ 36 | 0 | 0 |
+----------------------+--------------------+----------------------+

In operating in this way--which is strictly comparative, and, with care, has few sources of error--if the heart of the frog poisoned with the unknown extract behaves in the number and irregularity of its contractions similarly to that of the digitalin-poisoned heart, it is a fair inference that, at all events, a “heart-poison” has been separated; but it is, of course, open to question whether this is a digitalin or one of the numerous groups of glucosides acting in the same way. If sufficient quantity has been separated, chemical reactions, especially the bromine test (Grandeau’s test), may decide, but with the larger number (yearly increasing) of substances acting similarly on the heart, great caution in giving an opinion will be necessary.

II.--Other Poisonous Glucosides Acting on the Heart.

§ 548. Several members of these glucosides have been studied by Schmiedeberg,[582] and his convenient divisions will be followed here:--

[582] _Beiträge zur Kentniss der pharmakol. Gruppe des Digitalins._

1. CRYSTALLISABLE GLUCOSIDES.

=Antiarin= (C₁₄H₂₀O₅).--Antiarin is an arrow poison obtained from
the milky juice of the _Antiaris toxicaria_ growing in Java.
Antiarin is obtained in crystals, by first treating the inspissated
milky juice with petroleum ether to remove fatty and other matters,
and then dissolving the active principle out with absolute alcohol.
The alcoholic extract is taken up with water, precipitated with lead
acetate, filtered, and from the filtrate antiarin obtained by
freeing the solution from lead, and then evaporating. De Vry and
Ludwig obtained about 4 per cent. from the juice. Antiarin is
crystalline, the crystals containing 2 atoms of water. Its
melting-point is given as 220·6°; the crystals are soluble in water
(254 parts cold, 27·4 parts boiling), they are not soluble in
benzene, and with difficulty in ether; 1 part of antiarin requiring
2792 parts of ether.

The watery solution is not precipitated by metallic salts. On
warming with dilute mineral acids, antiarin splits up into a resin
and sugar. Concentrated sulphuric acid gives with antiarin a
yellow-brown solution, hydrochloric and nitric acids strike no
distinctive colours.

§ 549. =Effects.=--Antiarin is essentially a muscular and a heart
poison. When given in a sufficient dose, it kills a frog in from
half an hour to an hour. Its most marked effect is on the cardiac
muscle, the heart beats more and more slowly, and at last stops, the
ventricle being firmly contracted. As with digitalin, there is a
very marked prolongation of the systole, and as with digitalin,
after the beats have ceased, a forcible dilatation of the ventricle
will restore them (Schmiedeberg). It is doubtful whether by
physiological experiment antiarin could be differentiated from
digitalin.