The salicylate of an alkaloid prepared from physostigma.

Characters. - Colourless, shining, acicular, or short, columnar crystals, gradually turning reddish when long exposed to air and light, odourless, having a bitter taste, and a neutral reaction.

Dose.- 1/16 to 1/12 gr.

Physiological Action. - Physostigma stimulates muscular fibre, both voluntary and involuntary, throughout the body, and paralyses the nerve-centres.

The alkaloids of Calabar bean have different actions, and different or even contradictory results may be obtained according to the amount of each present in the preparation of the bean employed. Physostigmine or eserine paralyses the nervous centres and stimulates muscular fibre, but calabarine causes convulsions like strychnine.

General Action. - A small dose of physostigma, from its action on the muscular fibres of the intestine, causes pain in the abdomen, with nausea and vomiting. From its action on the vagus and motor centres it causes a sense of oppression in the chest, and weakness. With larger doses these symptoms become worse; and, in addition, contraction of the pupil, salivation, slowness of the pulse, and spasmodic respiration occur. Death is due to paralysis of respiration.

The excitability of the muscles is increased, so that they contract on the application of a slighter stimulus than usual, but their actual working power is not increased. In the first stage of poisoning in frogs muscular tremors are often apparent, and are also seen on the local application of the drug to the muscle of frogs. They are due to the local action of the drug on the intramuscular end-plates, for they occur when the sciatic nerve has been divided before poisoning, but cease after the injection of curare.

The spinal cord is paralysed; the posterior columns first and then the anterior columns. This action on the cord is the cause of the general paralysis induced by the drug. Convulsions like those of strychnine-poisoning may occur. They are due to calabarine.

The medulla is paralysed, and respiratory movements cease before the reflex action of the spinal cord is destroyed.

The motor nerves in warm-blooded animals are not usually affected until very late, but in frogs they are paralysed gradually.

The sensory nerves are partially paralysed by the local application of physostigma in a concentrated form, but not when it is injected into the blood.

The brain in man seems not to be paralysed, for in a number of cases of poisoning which occurred among children in consequence of eating the beans, consciousness was not impaired at all, and neither convulsions nor anaesthesia occurred. Notwithstanding the absence of convulsions in these cases, however, physostigma appears to have an irritant action upon the brain, for when it is administered to epileptic patients, or to animals rendered epileptic by section of the sciatic nerve, it increases the number of fits (p. 188). Cats and guinea-pigs poisoned by it also show symptoms of great cerebral excitement, becoming very timid and running wildly about. This may be partly due to-interference with the respiration, but can hardly be the only cause, as this condition is not observed in the case of other drugs which paralyse the respiration. In frogs the brain appears to be paralysed before the spinal cord, so that voluntary motion ceases before reflex action.

Action on the Eye. - When locally applied, physostigma causes contraction of the pupil, diminishes intra-ocular tension, and causes spasm of accommodation, preceded by increased power of accommodation for near objects; often twitching of the eyelids and slight supra-orbital pain are observed. These effects are due either to stimulation of the fibres of the third nerve or of the circular muscular fibres of the iris; but are certainly not due to paralysis of the sympathetic, since stimulation of the sympathetic will, during the influence of the poison, cause dilatation of the pupil (p. 222).

Respiration is first quickened and then retarded. The acceleration is due to spasm of the bronchial tubes according to some observers; but others consider it to be caused by stimulation of the ends of the vagi in the lungs (p. 245); and it is certain that if the vagi are first divided, physostigma no longer causes acceleration of respiration, but slows it from the first. The slowing of respiration is due to paralysis of the respiratory centre in the medulla. Death is the result of this failure of respiration.

Action on the Circulation. - Small doses sometimes cause a slight fall in blood-pressure, larger ones always cause a rise. This rise is chiefly due to the increased contractile power of the heart, but it is not improbable that it is aided by a contraction of the arterioles, the muscular fibres of which, like all other involuntary muscles in the body, are stimulated by the action of physostigma upon them. According to Von Bezold and Goetz the rise is also partly due to tetanic contraction of the intestinal walls, which drives the blood out of them. The irritability of the vagus appears to be increased, as a slighter stimulus applied to its trunk will stop the heart after its administration. We should therefore expect the normal stimuli passing to the vagus centre along sensory nerves from various parts of the body to have a greater effect upon the heart than usual, and thus render its beats slower. This seems to be the case, for physostigma causes slowness of the pulse, which does not appear to depend upon direct stimulation of the vagus roots, as it is absent in animals which have been deeply chloralised before the administration of physostigma. In such animals physostigma, on the contrary, quickens the pulse and raises the blood-pressure.

Muscle. - When applied to the frog's heart it renders the pulsations slower and more powerful. Its stimulant action on the cardiac muscular fibre is so great that neither irritation of the vagus nor of the venous sinus can stop the heart. That the vagus is not paralysed is shown by the fact, that when the stimulant action of the physostigma on the muscular fibre is counteracted by a poison having a paralysing action on the muscle, such as a double salt of copper, stimulation of the vagus will again produce the stillstand in diastole.1 In larger doses physostigma produces the staircase phenomenon (p. 312, and Fig. 30, p. 110), and finally imperfect stillstand in systole. The contracted ventricle still continues to pulsate slightly, and when it is distended by increasing the pressure of the fluid within it the pulsations become vigorous, and there is no tendency, as in the case of digitalis, to rapid paralysis of the cardiac muscle.

The action of physostigma on the heart is counteracted by atropine, and, though to a less extent, the action of atropine is counteracted by physostigma (p. 493).

From its action on involuntary muscle it causes contraction of the stomach, retching and vomiting. It causes also diarrhoea and increased peristaltic movements of the intestines, which finally end in tetanic contraction, so that the lumen of the intestine is almost obliterated, and it appears like a hard cord. It causes contraction of the spleen, bladder, and uterus: these contractions are not prevented by a dose of atropine sufficient to paralyse the nerves. The difference between the action of muscarine, which causes tetanic contraction of the intestine by acting on the nerves, and of physostigma, which produces a similar effect by acting on the muscular fibre, is seen when muscarine, atropine, and physostigma are administered successively to an animal.2 The muscarine first causes tetanic contraction. Atropine causes this to disappear, and produces complete relaxation, which is succeeded by a second tetanic contraction after the administration of physostigma. In consequence of its action on the bladder it causes urination.

Secretion is increased by physostigma not only in the salivary, but in the sweat, lacrimal, and mucous glands. It seems probable that the secretion is not due, like that produced by muscarine, nicotine, or pilocarpine, to an action on the ends of the secreting nerves, but rather to the action of physostigma on the secreting cells themselves, because, unlike the secretion produced by the three drugs already mentioned, it still persists after the administration of atropine. Physostigma restores its excitability to the chorda tympani after its secretory fibres have been paralysed by atropine. When the dose of physostigma is large, the secretion of saliva which it occasions lasts only for a short time, because the vessels of the gland become so much contracted through the action of the drug that the circulation is insufficient to maintain the secretion (p. 358).

1 Harnack, Buchheim's Arzneimittellehre, 3te Aufl, p. 712.

2 Schmiedeberg, Arzneimittellehre, p. 70.

Uses. - It is used in certain diseases of the eye, e.g. wounds and ulcers of the cornea, and from its lessening intra-ocular tension it is used in glaucoma and staphyloma (p. 224). It removes dilatation of the pupil and paralysis of accommodation after the use of atropine, and, used alternately with atropine, breaks down adhesions after iritis (p. 226).

It is used in tetanus, strychnine-poisoning, general paralysis of the insane, and mania, in paraplegia and in locomotor ataxy.

It is also useful in constipation due to atony of the intestinal walls.

It has been recommended in bronchitis, catarrh, and dyspnoea when due to weakness of the bronchial muscles (Ringer).

It is used as an antidote to atropine and also to strychnine.

Treatment in Poisoning by Physostigma. - Evacuate the stomach by an emetic, and inject atropine (4 minims of the liquor every 1/4 hour) until the pulse quickens or the symptoms pass off. If the dose of atropine be too great, it seems to intensify the lethal action of the physostigma.