This section is from the book "Materia Medica: Pharmacology: Therapeutics Prescription Writing For Students and Practitioners", by Walter A. Bastedo. Also available from Amazon: Materia Medica: Pharmacology: Therapeutics: Prescription Writing for Students and Practitioners.
Fig. 25. - Adrenaline chloride solution. At a, 2 c.c. subcutaneously. No effect on blood-pressure. At b, 2 c.c. deep in thigh muscles. At c, 0.1 c.c. by vein; prompt rise in blood-pressure (lower tracing) from 107 to 190, loss of tone and contractility of the ventricle (middle tracing), and increase in contractility of the auricle (upper tracing). The down-stroke of auricle and ventricle is systole. Marked vagus effects are present. (Tracing made by Dr. C. C. Lieb.)
2. From subcutaneous injection there may be a slight rise in arterial pressure, but almost always there is no measurable effect. This is the author's experience in tests with students and asthmatics. There is, however, a fairly prompt effect upon contracted bronchi, even though the arteries are unaffected.
3. From deep intramuscular injection enough seems to get into the blood-stream to induce quite frequently a distinct though comparatively small rise in arterial pressure and a relaxation of the bronchi. These effects are most noticeable when the arteries are relaxed or the bronchi strongly contracted.
The effect of an intravenous dose upon the circulation is a marked rise in arterial pressure and a momentary increase in rate, followed by strengthened and slowed heart. The rise in pressure is only momentary, but may be maintained by repeating the dose or by continuous slow infusion. A graduated rise in pressure may be obtained by intravenous injection of increasingly large doses.
The most marked constriction is in the arteries of the splanchnic area, where it may be so great that the intestines are almost bloodless. It is produced if the splanchnic nerves are cut, or if the central nervous system is destroyed; therefore it is due to a peripheral action and not to a central one. The peripheral effect is well shown in an isolated viscus or an isolated limb, by measuring the venous outflow before and after epinephrine. In perfusing a dog's leg, for example, the outflow may be almost entirely stopped by the addition of a few minims of epinephrine solution to the perfusion fluid, but no such action occurs if apocodeine or ergotoxine has previously been used to paralyze the ends of the vasoconstrictor nerves. Therefore the site of the stimulation by epinephrine is the vasoconstrictor nerve-endings or the myoneural junctions (Elliott). After ergotoxine, which paralyzes the vasoconstrictor endings but not the vasodilators, epinephrine is regularly followed by vasodilation, an effect known as the "vasomotor reversal" of Dale. Hart-mann, and also Haskins, have shown that after intravenous administration there is vasodilation in the skeletal muscles, i. e., the blood is shifted from the splanchnic area to the active muscles, a valuable effect in shock. The coronary arteries, having no vasoconstrictor nerves, are dilated, or at least their tone diminished so that they become dilated (Janeway and Park). Macht obtained powerful constriction of the pulmonary artery. There is some evidence that the cerebral arteries tend to be dilated.
Janeway and Park (1912) have shown that "the effect of epinephrine on an excised artery in a physiologically inert solution is in inverse ratio to the degree of tonus possessed by that artery." In other words, it is to be expected that general arterial relaxation with low arterial pressure, as in Addison's disease, will give a greater proportionate response to the drug than would a normal state of the arteries and normal arterial pressure. In a case of Addison's disease at St. Luke's Hospital, 15 minims slowly administered intravenously caused the pressure to rise from 90 to 160 mm. Haskins and Moore have established the fact that normally when there is enough epinephrine in the blood to give a pressor effect, the intestines become paralyzed.
Cameron (1906) determined that 1/100 grain (0.6 gm.) of nitroglycerin was just enough to neutralize the pressure-raising power of 0.0075 mg. of epinephrine hydrochloride, i. e., about 8 minims (0.5 c.c.) of the 1:1000 solution.
If the vagus nerves are cut, there is no slowing of the heart, or at least if there is slight slowing, it is abolished by atropine; therefore the slowing must be due to stimulation of the vagus, and essentially of the vagus center. But if the arterial pressure is kept low by bleeding or by paralysis of the vasoconstrictor endings by apocodeine or ergotoxine, there is no slowing. It has been shown also that the slowing always follows the rise in arterial pressure. Thus it is evidently due to the reflex stimulation of the vagus which regularly occurs when the arterial pressure rises, and not to direct stimulation of the vagus center by the drug. Therefore the slowing is reflex, and is dependent upon the rise in arterial pressure, and not upon direct vagus stimulation.
When epinephrine is slowly added to the perfusion fluid for an isolated heart, a myocardiograph tracing shows increased systolic contraction and lessened diastolic relaxation. In other words, there are increased contractility and increased tonicity. Atropine to paralyze the vagus endings does not change the effect, but apocodeine and ergotoxine, which paralyze the accelerator endings, abolish it. Therefore the accelerator endings must be the site of stimulation by the drug. Some investigators believe that there is a slight muscular stimulation in addition.
Thus, in an intact mammal, epinephrine slows the heart, increases its tone, strengthens its beat, and dilates its coronary arteries. It also constricts the systemic arterioles. The manner in which these effects are brought about, and the rapidity of action, are entirely different from those of digitalis. The rise in arterial pressure is very great and very prompt, epinephrine being the most powerful blood-pressure-raising drug that we employ in medicine. As the effect is peripheral and not central, the rise occurs even when the vasoconstrictor center is paralyzed or exhausted, but it lasts only from one to five minutes. It may be kept up for a long time without apparent harm by frequently repeated doses, or by the very slow administration intravenously of a dilution in normal saline solution.