The alkaloid of Amanita muscaria, the fly-fungus.

Properties

Muscarine is an alkaloid with strong basic properties, and combines with acids to form salts. It has the consistence of sirup, is without odor, free from taste, and is readily soluble in water and in alcohol, but is insoluble in ether and in chloroform.

As muscarine is but slightly irritating to the tissues, it may be used subcutaneously. The dose ranges from one eighth of a grain to two grains.

Antagonists

The actions of muscarine are antagonized by atropine (Schmiedeberg and Koppe), by digitaline (Böhm), and by eserine (Prevost). By atropine it is antagonized at all points. When the heart is arrested by muscarine, it possesses the capability of again renewing its action under the influence of a large number of agents, but atropine possesses this property in the highest degree (Alison). Muscarine arrests the heart in diastole by stimulating the intracardiac inhibition apparatus—atropine paralyzes this apparatus (Prevost); muscarine causes intense dyspnoea by inducing strong contraction of the pulmonary arteries—atropine relaxes this spasm, unloads the right cavities of the heart, and respiration is resumed; muscarine lowers, atropine raises the blood-pressure; muscarine tetanizes the muscular layer of the intestine—atropine induces a paresis of the same; muscarine increases the secretions of liver, pancreas, and intestinal mucous membrane—atropine arrests these secretions; muscarine stops the renal secretion—atropine restores it; muscarine causes sweating, salivation, and lachrymation—atropine dries them all; muscarine contracts the pupil—atropine dilates the pupil. For the quantity producing a given physiological effect, the power of the two agents is very unequal, atropine being much stronger. An atropinized eye dilated to a certain point will not be contracted by the quantity of muscarine sufficient when unopposed to induce a marked degree of myosis; but a much larger quantity may overcome the atropine. The same fact is true throughout the whole range of their antagonistic action.

In frogs poisoned by digitaline, the cardiac movements recommence and are maintained for hours by the application of a solution of muscarine. The same fact is true of tobacco and physostigma: the heart arrested by these agents recommences movements when muscarine is applied, and vice versa.

Synergists

The motor depressants synergize some of the actions of muscarine. A close correspondence exists between pilocarpine and muscarine. They both cause nausea, diarrhoea; muscarine at first quickens then slows, and pilocarpine quickens the pulse; they both flush the face and produce free perspiration and salivation; they both cause frontal headache; both contract the pupil; and both diminish the urinary secretion. They differ in some respects, but chiefly in the extent of their action, or quantitatively. Pilocarpine causes more perspiration and salivation; muscarine produces decidedly more active intestinal movements. Pilocarpine diminishes the urinary secretion, but muscarine may arrest it entirely. Pilocarpine slightly contracts the pupil; muscarine contracts the pupil more decidedly, but when applied to the eye directly, dilates the pupil. Pilocarpine always quickens the pulse, muscarine slows the pulse.

Physiological Actions

The salivary secretion in a large proportion of subjects is much increased. A feeling of constriction of the neck, nausea, and vomiting, and more or less abdominal pain, are produced by it, whether administered by the stomach or subcutane-ously (Brunton). The pancreatic and biliary secretions are notably increased after the injection of some milligrammes into a vein (Prevost). This increase of these secretions took place as well between as during digestion. The intestinal mucus is also greater in quantity than normal, and it may be streaked with blood (Schiff). The intestines are thrown into active contractions, tetanized, rather than merely stimulated into more frequent vermicular movements. Under ordinary medicinal doses in man, the bowels are relaxed and the character of the evacuations altered, doubtless, because of the much greater quantity of the biliary and pancreatic secretions poured out. The increased movement of the intestines is accompanied by considerable colic-like pain.

Muscarine enters the blood promptly, whether introduced through the stomach or subcutaneously. It is a cardiac poison. A very minute quantity—a mere trace—applied to the frog's heart, arrests its movements. As Schmiedeberg and Koppe first demonstrated, it arrests the heart in the diastole, and does not impair the irritability of the heart-muscle, for, on irritation of the heart by mechanical, chemical, or electrical means, it again contracts. If the dose is short of lethal, the heart is merely slowed, the number of pulsations being reduced ten, twenty, or even forty beats per minute. Section of the vagi does not affect this result. The action is due to stimulation of the intracardiac inhibitory apparatus. By Alison it is referred to overexcitation of the cardiac terminals of the vagus, and coincident diminution in the activity of the sympathetic fibers. When the effects of muscarine are manifested by a diminution of the pulse-rate, the blood-pressure begins to decline. At first the vessels contract, but this is soon succeeded by dilatation (Bogosslowsky). With the slowing of the heart and dilatation of the vessels, the blood accumulates in the periphery, and the blood-pressure is consequently reduced one half.

Disturbances of respiration occur with the other defined symptoms. The breathing grows more labored with the increasing effects of the agent, and presently an intense dyspnoea supervenes (Schmiedeberg). The mechanism of the labored respiration is obvious enough. Such a strong contraction of the pulmonary vessels ensues as to greatly diminish the quantity of blood circulating in the lungs, with the result of over-distention of the right cavities of the heart. Hence it follows that the state of the blood is impaired by the lack of oxygen and the retention of carbonic acid, and to these factors must be attributed in part the cyanosis and asphyxia. These modifications of the respiration occur after preliminary section of the vagi. The almost arrested oxygenation of the blood, the languid circulation, and the profuse perspiration, are the factors which cause a lowering of the temperature. By Schmiedeberg and Koppe there are recognized three conditions of the body-heat: 1. A slight elevation, which is by no means constant, and very transient, coming on in about two hours after the dose—a small one—has been taken; 2. A depression of one or two degrees, succeeded presently by the normal temperature, produced by a full medicinal dose; and, 3. A very pronounced lowering of the temperature from a fatal dose.

By the internal administration of muscarine the pupil contracts, and, singularly enough, by direct application, dilates. There are other examples of this paradox. Vision is disturbed by alteration of the accommodation apparatus by spasm. The myosis depends on stimulation of the circular fibers of the iris or of the third nerve, and not on paralysis of the radiating fibers, or of the sympathetic filaments.

Muscarine produces abundant perspiration, and, indeed, stimulates this function only less powerfully than pilocarpine. In most cases the saliva is correspondingly increased. The two functions do not always act together with the maximum energy, and one may be powerfully affected, while the other is quiescent. Lachrymation is nearly constant, and the nasal mucus is more abundant than in the normal state. Thus, while all other secretions and excretions are increased by muscarine, it is remarkable that the urine should be decidedly lessened in amount, even suppressed. In eight experiments made with great care, Prevost found that the injection of muscarine into a vein diminished the urinary secretion, and, indeed, almost stopped it when the dose was large. The elimination of muscarine takes place by the kidneys. The best evidence that it is excreted unchanged is the physiological action of the urine. The urinary secretion of an animal poisoned by muscarine will poison another animal to whom it is administered, and its powers are transmitted with little diminution through several.

Therapy

The applications of muscarine to the treatment of disease are yet in their infancy. The physiological effects indicate the direction of the remedial applications. As muscarine stimulates so powerfully the muscular fiber of the intestine, and the secretions of the pancreas, liver, and intestinal mucous membrane, it ought to be very serviceable in cases of constipation with torpor of the organs concerned in digestion. When constipation is due to paresis of the muscular layer of the bowel and to deficient secretion, this remedy will probably relieve it. In the treatment of intestinal torpor and deficient secretion, muscarine may be combined with other remedies, as atropine and strychnine, which act on the organs concerned, or with cathartics and cholagogues: Rx Muscarinae, gr. iv; ext. belladonnae, ext. nucis vomicae, āā gr. iij; euonymin, 3 ss. M. Ft. pil. no. xij. Sig.: One pill morning and evening. When the digestion of the starches and fats is imperfect, it is strongly indicated. In catarrh of the duodenum, and in catarrhal jaundice, it ought to be very efficient. In these maladies, the remedy should be administered frequently and in small doses: Rx Muscarinae, gr. j; aquae, oz j. M. Sig.: A tea-spoonful every three hours. It is probable, also, that it will prove useful in recent haemorrhoids due to congestion of the portal circulation. It promises well as a remedy for the removal of inflammatory effusions and exudations. It ought to afford prompt relief at the onset of a common cold, an acute bronchitis, hay-asthma, etc. As muscarine produces strong contraction of the pulmonary capillaries, it ought to be useful in pulmonary haemorrhage, in incipient congestion of the lungs, etc. Under such circumstances the combination with digitalis ought to be especially effective, for, while digitalis will aid the curative action on the pulmonary vessels, it will, at the same time, antagonize the cardiac depression caused by muscarine. It is contra-indicated in affections of the air-passages when secretion is in excess. For the night-sweats of phthisis fly-fungus has long been used, and a similar fungus is commended by Trousseau; but it has not been as successful in the hands of Murrell as some other agents, although capable, sometimes, of very good results. Muscarine is of doubtful propriety, if not positively contra-indicated, in renal affections characterized by deficiency in the excretion. On the other hand, it ought to be of signal service in diabetes insipidus and in saccharine diabetes. It has been used successfully to arrest the secretion of milk.

Authorities referred to:

Alison, Dr. Bouchardat's Annuaire de Thérapeutique, etc., for 1877, p. 47; also, Gaz. Méd. de Paris, February 20, 1877. The Action of Atropine and Muscarine on the Heart.

Bogosslowskt, Dr. Centralblatt für die med. Wissenschaften, No. 97, 1870.

Brunton, T. Lauder. Journal of Anatomy and Physiology, 1876, p. 342.

Harnack, Dr. Erich. Archiv für ezperimentelle Pathol, und Pharmakol., Band iv, p. 168. Unicrsuchunyen über Pflegenpilzalkaloide.

Prevost, Dr. J. L. Bull. Gén. de Thérap., vol. xciii, p. 371. Note relative á l'Antagonisme mutuel de l'Atropine et de la Muscarine.

Ringer and Mosshead. Ringer's Hand-Book of Therapeutics, eighth edition, article Muscarine.

Schiff, Prof. Lo Sperimentale, abstracted in the London Medical Record, vol. iv, 1876, p. 339.

Schmiedeberg und Koppe. Das Muscarin, das giftige Alkaloid des Fliegenpilzes., etc. Leipsic, 1869. Vogel.