Secretion

The sweat, tears, saliva, bile, and mucus are increased by stimulation of the sympathetic nerve-endings in the glands.

Glands

There is a distinct relation between the thyroid and adrenal glands. Increased thyroid secretion as in exophthalmic goitre, or the administration of thyroid appears to sensitize the sympathetic nervous system to epinephrine. Hoskins states that feeding adrenal to young male animals leads to hypertrophy of the testes.

Uterus

Epinephrine causes constriction of the uterine arteries and of the uterus itself. The latter effect also follows local application (as in an intra-uterine douche).

Bladder

Local application produces an astringent effect upon the bladder wall. Intravenous administration results in stimulation of the ends of the sympathetic or inhibitory nerves of the bladder, with the effect of relaxation of the bladder muscles. The ureter shows increase in tone and rate of contraction.

Urine

Houghton states that the secretion of urine is increased synchronously with the rise in arterial pressure, and continues above normal for several minutes after blood-pressure falls. He believes that the kidney arteries are passively dilated. In five experiments the arterial pressure showed a rise of from 56 to 88 mm. Hg, and the urine an increase of from 8 to 30 minims. But the arterial pressure averaged six minutes for its return to normal, while the urine secretion did not get back to normal until fifteen minutes. Some observers note a decrease or even cessation of the urine production during the epinephrine vasoconstriction. It is an interesting observation that the urine may be found to contain sugar, and this has been proved to be due to an excessive amount of sugar in the blood from lack of dextrose destruction. It is an artificial diabetes, which occurs even if the rise in blood-pressure is prevented. It does not occur if the animal is first starved until its stored glycogen is all used up. Herter and his associates have found that the same effect follows when the pancreas is painted with epinephrine. Kleimer and Meltzer find the increased urination and glycosuria more readily produced by subcutaneous than by intramuscular injections. It would seem that the diuretic and sugar-producing actions are quite independent. (See "pupil reaction" above.)

Metabolism

Lusk and Richet say, "the theory that epinephrine causes a production of sugar from fat, decreases the power of the organism to oxidize glucose through inhibition of pancreatic function, and stimulates the thyroid so that protein metabolism is increased is untenable in every particular."

Elimination

The fate of epinephrine is not certainly known. Falta says that when it is injected subcutaneously or into the peritoneal cavity, none appears in the urine, while when given by mouth, though it has no systemic effects, it is eliminated in the urine.

Toxicology

From the local use of the drug, there have been reports of overacting heart, palpitation, and vomiting. These must be due to idiosyncrasy, for they are unusual. After the hypodermatic or intravenous doses there is frequently excitement, with tremor, and in some cases much anxiety. Cushny says that the hypodermatic injection of very large doses in mammals results in excitement, tremors, and paralysis of the hind limbs, and, in addition, sometimes vomiting, increased urination, or hemorrhages from various mucous membranes or from the kidneys. Death occurs either from paralysis of the respiratory center or from heart failure, due to back pressure from the constricted systemic arteries. There is no doubt that some post-operative cases of pulmonary edema are due to the use of this drug with saline infusion.

Epinephrine And Chloroform

Levy and Lewis (1912) report a research on cats, regarding the simultaneous use of these two drugs. They found that - (1) Small intravenous injections of epinephrine chloride, given to an animal under high percentages of chloroform vapor, produce a condition of irritability of the ventricle, with irregular and rapid heart; and that (2) low tensions of chloroform vapor with small intravenous injections of epinephrine chloride ultimately produce the highest grade of ventricular disorder, viz., ventricular fibrillation, which means death. Levy's later studies corroborate these findings.

Therapeutics

A. For local effect it is employed - 1. To cause shrinkage of mucous membrane, whether the membrane is normal, or swollen and hyperemic. In the nose such shrinkage gives a clearer view for examinations, and more room for the passage of instruments, such as a Eustachian catheter. In hay-fever or acute catarrh, i. e., a fresh cold in the head, the application of an epinephrine solution on a cotton probe almost instantly shrinks the tissues and frees the stuffed-up air-passages. This effect may last half an hour or more, and if the patient then remains quiet and in a warm room, may persist for hours after the adrenaline action is over. In hay-fever the adrenaline solution diluted with normal saline is often used as a spray; but it might be noted that there are some reports of chronic turgescence or hyperemia following its frequent use in this condition. In some operations, as for adenoids and hypertrophies, the shrinkage of tissue may be undesirable. Dropped in the eye, it may lessen a conjunctival swelling, and so favor the finding and removal of a foreign body. In prolapse of the rectum, or hemorrhoids, the shrinkage may enable the protruding mass to be replaced.

2. To arrest a small hemorrhage - at any place where the bleeding point is accessible, as in the nose, stomach, bladder, etc. In nose-bleed the hemorrhage may often be checked by a pledget of cotton soaked in epinephrine solution and applied to the bleeding spot. In postpartum hemorrhage the liquid may be added to a hot intra-uterine injection to favor uterine contraction and perhaps to constrict the uterine arteries.

3. To prolong local anesthesia and to prevent local hemorrhage - it is added to solutions of cocaine and other local anesthetics. It acts by vasoconstriction, which checks the rapid removal of the anesthetic by the blood-stream. Berry (1905) showed that the toxic action of cocaine is increased when it is administered with epinephrine.

4. To allay itching of vulva and anus it may be applied on cotton. It acts on the moist parts of the vulva, whether mucous membrane or not.

5. In anterior poliomyelitis, in the ascending paralysis types, spinal injection of 15 minims (1 c.c.) has seemed to check the progress of the paralysis.

B. For systemic effect - it is administered hypodermatically or intravenously, according to the condition to be treated.

1. Hypodermatically - (a) to overcome bronchial asthma, a single dose of 15 minims (1 c.c.), (b) to check anaphylactic shock, and (c) in Addison's disease, 5 minims (0.3 c.c.), three times a day. This latter is a condition of weakness and wasting, with pigmentation of the skin and low blood-pressure, and it results from destruction of the suprarenal glands. It was thought that doses of epinephrine might take the place of the natural secretion of these glands, but reports from its use hypodermatically or by mouth are not encouraging, and intravenous administration several times a day in chronic disease is obviously impossible. Loewi found 2 cases of Addison's disease so sensitive to epinephrine that dangerous symptoms followed its intravenous use. In our own experience there has been no effect on the course of the disease, though in one case 15 minims (1 c.c.) administered slowly intravenously caused a temporary rise in systolic pressure from 90 to 160 mm. Others report temporary improvement. Osborne recommends the whole gland in the form of tablets which are allowed to disintegrate slowly in the mouth. As a matter of fact, recent research would seem to indicate that the manifestations of Addison's disease are not due merely to absence of epinephrine, but also to the loss of one or more elements from the cortex of the gland; and this would account in part for the lack of benefit from the administration of epinephrine. Epinephrine will not prolong life after the removal of the adrenals.

2. Intravenously - it is employed as a rapidly acting circulatory stimulant of great power in collapse or shock. Owing to its ephemeral action and to the impracticability of frequent intravenous doses, it is suitable only in emergencies, and is not employed in ordinary conditions of failure of compensation. It should not be given in chloroform collapse (see above). For administration, it may be diluted with normal saline and injected into the vein by a syringe; if there has been loss of blood, it may be added to a saline infusion. If given rapidly with a saline infusion when there has been no loss of blood, it increases the chances of pulmonary edema and heart failure, but a good-sized dose may be given with saline if the infusion is carried on very slowly. T. C. Janeway states that he has seen "the most amazing restoration from apparent imminent death follow the intravenous injection of epinephrine in large doses, in one case over 1 dram (4 c.c.) of the 1: 1000 solution in a little more than an hour."

Dangers

A. From Local Use

1. After operations (upon the nose, urethra, etc.) there is risk of late hemorrhage from secondary vasodilatation.

2. In hay-fever there is risk of a chronic state of vascular dilatation following the frequent use of the drug.

B. From Intravenous Administration

1. In cerebral arteriosclerosis there is risk of rupture of a cerebral artery from any sudden great rise in general blood-pressure.

2. In internal hemorrhage, especially cerebral or pulmonary, there is risk of increasing the hemorrhage.

3. In pulmonary edema there is risk of increasing the edema.

4. In emergencies there is risk of precipitating heart failure and producing pulmonary edema or general edema.