Pharmacologic Action

Local Action

Digitalis has no effect on the unbroken skin, but to mucous membranes and subcutaneous tissues is irritant. When administered hypodermati-cally, it causes pain at the site of injection, and through its irritant properties may cause destruction of tissue, with the formation of either a slough or a sterile abscess (sterile because not due to pathogenic bacteria). In a sick patient a number of such irritative areas are sufficient to cause fever and depressing reflexes, or at least much discomfort, so that the hypodermatic use of digitalis preparations is to be avoided when possible. Of the active principles, digitalein is the least irritating, digitoxin the most irritating.

Alimentary Tract

The taste is bitter and unpleasant. Because of the local irritant effect in the stomach, nausea or even vomiting may result. But in practice, this nausea and vomiting usually come on only after the patient has been taking digitalis for several days; and this is because their chief cause is not the irritation of the stomach, but stimulation of the vomiting center after the drug has become absorbed. This stimulation increases until the center becomes so sensitive that the slight irritation of each subsequent dose results in nausea or vomiting, and requires that the administration of the drug be stopped. This undesirable effect is thus largely central, and it occurs from doses administered intravenously, hypodermatically, or by rectum, as well as those administered by mouth. But a sensitive vomiting center makes the stomach highly susceptible to local irritants, hence doses by mouth are more prone to produce vomiting than doses administered in other ways.

Upon the intestines there is ordinarily no effect, but sometimes, probably either from the local irritation of unabsorbed drug or from stimulation of the motor nerves of the intestines (the vagus nerves), or perhaps from muscular stimulation, diarrhea is set up. Strophanthin has been shown to be a direct stimulant of intestinal muscle.

Fig. 5.

Fig. 5. - Tracings showing toxic effects of digitalis.

Digitalis, then, has decided effects upon the stomach and intestines, but they are undesirable ones. Worth Hale has determined that in a period of three hours the acid of the gastric juice invariably causes a diminution of from 25 to 35 per cent. in the activity of the digitalis and strophanthus glucosides. He recommends that to avoid this the official preparations should be neutral; and should be administered with an alkali, and not after meals, but later, when the gastric acidity is low.

Absorption takes place from the intestines, and since the drug penetrates the tissues very slowly, is uncertain in rate and degree. Thus twelve to thirty-six hours, and sometimes several days, elapse before the systemic action is manifest. Eggleston states that both digitalis and digitoxin are probably rapidly and fairly uniformly absorbed from the alimentary canal of man, but strophanthus, strophanthin, ouabain, and true digitalin are poorly or irregularly absorbed when given by mouth. After deep intramuscular injections the effects follow more rapidly; but even then, owing to the drug's slow diffusibility, may not appear for hours. In dogs, intravenous toxic doses will produce a prompt response, but in man even intravenous administration of therapeutic amounts may require one-half to several hours for measurable results.

Fig. 6.

Fig. 6. - Tracings showing toxic effects of digitalis.

Where the digitalis principles remain is not yet certain. Cloetta found no digitoxin in the heart muscle of rats and frogs.

Hatcher (1912) states that, after an intravenous injection of a fatal dose in cats, ouabain leaves the blood in about three minutes. After the injection of double the lethal dose of digi-toxin death takes place in five minutes; and from an overwhelming dose, may take place during the administration; from less than the fatal dose some of the effect may persist for three or four weeks.

Circulation

In a laboratory animal it is observed that a good-sized dose of digitalis has profound effects upon the circulation. The striking laboratory effects are given under Toxicology. In both the laboratory animal and in man the circulatory effects are known to be brought about through action upon five different structures. These structures are the sinus node, the cardiac muscle, the auriculoventricular bundle, the coronary arteries, and the systemic arteries. The effects are both nervous and muscular. The following are noted in man: