From quickly repeated large doses the very great constriction of the arteries may result in failure of the left ventricle with dilatation and weakness, at a time when the right heart is pumping more blood into the pulmonary arteries. The result is pulmonary edema. This effect has frequently occurred in rabbits from 1 or 2 c.c. of the solution. It is especially likely to occur when the heart is already impaired, or if the epinephrine is given rapidly with a large saline infusion, for the saline liquid adds to the diffusible fluid in the lung capillaries.

Blood

Wiggers was unable to corroborate the finding of Richards and Vosburgh that epinephrine increases the coagulability of the blood, but Cannon and Gray show that small doses, 0.0001 mg. per kilo intravenously, and larger amounts subcu-taneously, shorten the coagulation time to one-half or even one-third, though when added to drawn blood it has no effect. Grabfield finds that it increases the prothrombin.

Connective-Tissue Changes In The Heart And Arteries

In 1903 Josue described sclerotic lesions of the aorta in rabbits to which epinephrine had been administered intravenously for long periods. In 1906 Pearce and Stanton injected 3 minims of the 1: 1000 solution every day for two months, and obtained not only these aortic changes, which they observed to be due to degeneration and calcification in the muscular tissue of the media, but noted also bulging of these weakened areas, the mechanical breaking of the elastic fibers, and the actual formation of aneurysmal dilatations. Pearce noted, also, some connective-tissue changes in the myocardium, but none in the peripheral arteries, while Erb found arteriosclerotic changes in the other arteries as well as the aorta. Erb attributes the effects to a toxic action rather than to the heightened blood-pressure, for he obtained them by intraperitoneal injections which did not raise blood-pressure. The lesions in epinephrine-produced arterioscleroses differ pathologically from the lesions of arteriosclerosis in human beings, but furnish valuable material for study. Pearce and Hill have later questioned the role of epinephrine in the production of some of these results, as they found arteriosclerotic changes quite common in supposedly normal rabbits.

The fear of producing any such changes by the therapeutic use of the drug need not be great, for we never administer epinephrine repeatedly for long periods except in two conditions, viz., disease of the suprarenal glands and bronchial asthma. The former is so regularly fatal that any risk may be taken for the chance of helping; moreover, the theory upon which epinephrine is given is that it may make up for a pathologic deficiency of the natural epinephrine of the patient, and, therefore, cannot be present in the system in excess. This theory is believed to be incorrect. (See Therapeutics.) In intractable bronchial asthma the drug may be used repeatedly by hypodermatic injection during long periods, and it is well in these cases to think of the possibility of harm to the arteries and heart, and to the nervous system.

Respiratory System

Used hypodermatically in small quantities, epinephrine causes increased depth of respiration; while if it is used intravenously it quickens respiration, the inspirations being shallower. Park (1912) found that when it was applied to excised rings of the bronchi of the ox, even in a concentration as low as1 : 10,000,000, it regularly caused relaxation without primary constriction. And it may be presumed that this effect is due to stimulation of the bronchodilator (sympathetic) nerve-endings. In man, when it is given hypodermatically, it produces a decided relaxation of contracted bronchi. The rule that the drug acts best where the condition it is opposing is extreme, makes it peculiarly valuable in spasmodic asthma due to excessive bronchial contraction, for the effect on the bronchi is out of proportion to the effect elsewhere, and is often evident even when the arterial pressure is not affected in measurable degree.

Nervous System

Following a hypodermatic dose, as for asthma, there is frequently an immediate onset of nervous excitement and agitation which may last as much as an hour or two.

Alimentary Tract

The local astringent effects may be obtained in mouth, esophagus, stomach, and rectum. On intravenous injection the drug stimulates the ends of the splanchnic or inhibitory nerves (which belong to the sympathetic system), and so lessens peristalsis of stomach and bowels. The contractions of the gall-bladder are said to be inhibited in the same way. The mucous secretions, the saliva, and the bile are increased, as mentioned below. Pemberton and Sweet (1912) have shown that intravenous injections of epinephrine inhibit the flow of pancreatic juice; and Herter found that painting the pancreas with epinephrine resulted in glycosuria.

The Eye

A drop of epinephrine solution in the eye causes the conjunctiva to become shrunken and pale, the eyelids to become retracted, and the eyeball to appear more prominent.

The drug, if in strong solution, also penetrates to the internal eye, and by stimulation of the sympathetic nerve-endings in the fibers of its radial muscles dilates the pupil. A solution of 1: 1000 ordinarily does not dilate the pupil; but Loewi and Rosenberg demonstrated that it does so in pancreatic disease, and in any condition with hyperglycemia, such as hyperthyroidism, diabetes, and after glucose intravenously or freely taken by mouth. Pratt failed to obtain the reaction in three dogs with extreme atrophy of the pancreas. As a test for epinephrine in a liquid, Meltzer and Auer make use of the extirpated frog's eye, which regularly reacts to a strength of 1: 1000, or even of 0: 10,000.

Muscle

The contraction of striped muscle is not affected, but its relaxation is greatly slowed, as with veratrine. Smooth muscle shows the effects of stimulation of sympathetic nerve-endings. Hoskins claims a vasodilator effect in the skeletal muscles with increased efficiency.