The ripe seed of Physostigma venenosum (Fam. Leguminosce), yielding, when assayed, not less than 0.15 per cent. of alkaloid soluble in ether. The plant is a woody twiner of western Africa, and the calabar beans were used by the native medicine men for "trial by ordeal." The person accused of a crime was given a paste made of the seeds; if he recovered, he was declared innocent; if he died, he was guilty. It is said that if enough cattle were made over to the priests they were prone to mistake harmless seeds for the calabar in making the paste.

Constituents

The alkaloid physostigmine or eserine is the essential ingredient. There are also minute quantities of two or three other alkaloids, of which eseridine or isophysostigmine has the action of physostigmine, and calabarine that of strychnine. Physostigmine in solution is decomposed by light or heat, and a reddish color indicates diminished activity. Preparations and Doses. -

Physostigma, 0.15 per cent. of alkaloid; dose, 1 1/2 grains

(0.1 gm.). Extract, 1.7 to 2.3 per cent. of alkaloid; dose, 1/8 grain

(0.008 gm.). Tincture, 10 per cent., 15 minims (1 c.c.).

Physostigmine salicylate, soluble in 75 parts of water and 16 of alcohol, is given in dose of 1/60-1/30 grain (0.001-0.002 gm.).

Pharmacologic Action

Physostigmine stimulates the secretory nerve-endings of glands and the nerve-endings of striated and smooth muscle. It therefore antagonizes the effects of atropine upon secretion, upon the action of smooth muscle, and upon the eye; and antagonizes curare in its effects upon striated muscle. It has no effect on sensory nerve-endings.

Secretion

Physostigmine is not employed in medicine to increase secretions, for by arteriole constriction and the cutting off of the blood-supply of the glands the amount of the secretion is limited.

Muscle

Its effect upon the action of smooth muscle is strongest in the alimentary tract, so that it may be employed, either by mouth or hypodermatically, as a cathartic. It also tends to cause contraction of the bladder, ureters, bronchi and spleen, and perhaps also of the uterus.

Fig. 52.

Fig. 52. - Longitudinal muscle of small intestine immersed in saline. Tone waves make their appearance. At A, physostigmine sulphate, 0.1 mg., was added; at B, atropine sulphate, 1 mg. The powerful muscle contraction from physostigmine is abolished by atropine, but normal peristalsis is permitted. (Tracing made by Dr. C. C. Lieb.)

Its effect upon the action of striated muscle is shown in the isolated gastrocnemius by increased irritability and increased power to lift a load. Irregular stimulation in man is also indicated by peculiar fascicular spasms or twitchings of the muscle, as in the temporal or orbital muscles when the drug is used in the eye, or in the muscles of the limbs in poisoning. It is directly antidotal to the peripheral action of curare, and presumably acts upon the same structures.

The Pupil

If a drop of 1: 200 aqueous solution of eserine is placed in the eye, contraction of the pupil begins in one or two minutes and reaches its maximum in one-half to one hour. The marked contraction lasts from twelve to thirty-six hours, and the normal size of the pupil is regained in from two to four days. The contraction is due to stimulation of the ends of the third nerves, physostigmine not contracting the pupil after degeneration of the nerve (Anderson).

Accommodation

Through similar action on the ends of the third nerve, the ciliary muscle contracts like the circular muscle of the iris, and allows the lens to bulge forward. This causes the sight to be fixed in accommodation for near objects, while objects more than a few feet away are out of focus. There is sometimes supra-orbital or eyeball pain from continued overaction of this muscle. The accommodation returns to normal somewhat more quickly than the pupil.

Intra-ocular tension is much lowered, without any essential preliminary rise in tension. This lowering is usually considered due to the increased escape of fluid through the spaces of Fontana, which are promptly opened up by the contraction of the pupil; but Gronholm attributes much of the fall of tension to contraction of the vessels and the resulting diminished secretion.

The use of the drug in the eye may be followed by disagreeable or painful twitchings of the eyelid, or fascicular spasms of the adjoining face or temporal muscles. Physostigmine is much more powerful than pilocarpine as an antagonist of atropine.

Circulation

The effect upon the heart and arteries is but poorly understood. Small doses slow the heart, and as this effect follows large doses of atropine, it cannot be due to vagus center stimulation. Some authors believe there is a stimulation of the vagus nerve-endings. In the frog there are direct muscle stimulation and increased irritability, but in mammals strengthening is not usually seen. The arterioles are contracted from peripheral stimulation, probably chiefly of the ends of the vasoconstrictor nerves, for Dixon says there is no contraction after apocodeine. Arterial pressure is raised. There is apparently no effect upon the vasoconstrictor center. In poisoning, both heart muscle and vasoconstrictor mechanism are depressed so that the arterial pressure falls.

Respiration is at first quickened and deepened, from stimulation of the center and probably of the afferent vagus endings in the bronchi. In poisoning there is depression of the center, and there may be asthmatic breathing from contraction of the bronchial muscles. Death is due to failure of the respiratory center.

Nervous System

The cerebrum is little affected, consciousness in fatal poisoning remaining until near the end. The vital medullary centers are at first stimulated, then depressed. The reflexes are depressed, and in poisoning there may be an ascending paralysis, beginning in the legs. The effect on peripheral nerves has been spoken of; there is no effect on sensory nerves.

Excretion is rapid by the urine. A slight amount appears in the saliva and bile.

Toxicology

Noteworthy are the marked muscular weakness without loss of consciousness. The pupils are markedly contracted, the skin covered with sweat, there are vomiting, diarrhea, and cramps in the abdomen. The loss of muscular power begins in the legs and ascends, and is accompanied by twitching or tremor. The heart is at first slow and the arterial pressure good; later the heart becomes weak and slow, and the blood-pressure is lowered. The respiration is at first rapid and deep, then becomes shallow and labored or perhaps asthmatic. Death occurs from paralysis of respiration. The antidote is atropine for the asthma, the diarrhea, and the intestinal cramps; if necessary, the patient must be treated for collapse, bearing in mind that the heart itself is very weak. Joseph and Meltzer recommend magnesium sulphate as partly antidotal. It can be used subcutaneously or in the spinal canal, the dose being 1 dram (4 c.c.) of a 25 per cent. solution.

Therapeutics

The extract in pills, and the salts of physostig-mine hypodermatically, are used as cathartics. Since not many drugs will act as cathartics when administered hypodermatically, a knowledge of this power of physostigmine may be of value in some severe illnesses or postoperative conditions.

The physostigmine salts, usually in a solution of 1: 200, are much employed in the eye to lessen the high intraocular tension of glaucoma, and, after drugs of the atropine class, to hasten the return of the pupil, accommodation and intraocular tension to normal. They are preferred to pilocarpine because their action lasts longer and is more complete, and there is no noteworthy preliminary rise of intraocular tension. A disadvantage is the nervous spasm of the eyelid and temporal muscles, which may occur frequently during several hours; and the contraction of the ciliary muscles, which may cause a blurring of the vision.

Physostigmine is employed as an antidote in magnesium sulphate poisoning.