Epinephrine Structure, Function, Physiology, and Dysfunction

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Epinephrine

Epinephrine, also known as adrenaline is a neurotransmitter secreted by sympathetic fibers to respond to stress. In addition to acting as a neurotransmitter, adrenaline functions as a circulating hormone that is released directly into the blood stream from the adrenal medulla. Adrenergic receptors mediate the effects of epinephrine in response to stress and perceived threats or danger, eliciting the “fight-or-flight”, or freeze response of the sympathetic nervous system.

A sympathomimetic catecholamine, epinephrine stimulates the post-ganglionic nerves of the sympathetic nervous system. It is synthesized in neuroendocrine chromaffin cells in the brain and adrenal glands. Epinephrine forms an integral part of the behavioral and physiological “fight-or-flight” response to stress, and like glucocorticoids, it functions to increase the supply of oxygen and glucose to the brain and muscles, making these resources available to mount an effective response to the demands of the situation. The immediate release of epinephrine and norepinephrine in response to sympathetic stimulation prepares the body for challenging events by limiting non-vital physiological functions. These neurotransmitters, mandated with maintaining homeostasis, are released into the bloodstream from the adrenal medulla and affect the heart rate, perspiration, blood pressure, metabolism, among other effects

Epinephrine binds to the G-protein coupled alpha and beta-adrenergic receptors. The receptors differ in their physiological effects based on differences in their second messenger signaling mechanisms and have been further subdivided into several subtypes. Different types and levels of these receptors are expressed by all visceral organs, smooth muscle, and adipose tissue. Signaling through these receptors alters the function of and recruits these tissue and muscle during the “fight-or-flight” response to threatening situations, ensuring effective response and survival.

Binding of epinephrine to α1 adrenergic receptors induces contraction of the pupillary dilator muscle, vascular smooth muscle, and intestinal sphincter muscle; it's binding to β1 adrenergic receptors results in increased myocardial contraction, heart rate, and renin release; epinephrine acting via the β2 receptors is responsible for vasodilation, bronchodilation, increases aqueous humor levels in the eye, and enhances the sympathetic tone.

Due to its vasoconstrive effect, epinephrine along with phenylephrine can generally be added to local anesthetics to prolong and intensify the anesthetic effect in clinical settings.

Epinephrine plays an essential role in the process of nutrient absorption in the human body. Given intravenously, epinephrine produces a significant hyperglycemic effect through the activation of beta receptors. It elevates blood glucose levels by transiently increasing liver glucose production and by having a more sustained effect on preventing glucose uptake in the periphery. These effects of epinephrine has implications for stress-induced elevations in glucose and susceptibility to diabetes.

Epinephrine plays a role in ion transport in the intestines and influences the absorption of other drugs and molecules. The intestinal absorption of large molecules, like dextran, is facilitated by stimulation of alpha and beta receptors, which could prove to be attractive targets for enhancing the absorption of certain drugs. Catecholamines like epinephrine, norepinephrine, and dopamine are intimately associated with the enteric system. This interaction is mediated by postganglionic sympathetic neurons of the inferior and superior mesenteric and celiac ganglia. Located in the upper abdomen, the neurons from these ganglia innervate visceral organs, including the digestive tract and pelvis, and interact with the serosal surface to innervate the blood vessels. Additionally they send sympathetic projections to lymphoid tissue, regulating immune function and providing protection during times of inflammation.

Synthesis and Metabolism

Figure 1. Epinephrine chemical structure. (Public domain image accessed on August 17, 2022)

The catecholamine epinephrine (Figure 1), is released from the adrenomedullary chromaffin cells. The hatlike, small adrenal gland sits on top of and is connected to the kidneys. It functions essentially as a sympathetic ganglia of the autonomic nervous system, and receives neural inputs that stimulate the release of hormones from the gland. Intricacies of the molecular machinery of catecholamine biosynthesis and secretion by chromaffin cells of the normal adrenal medulla go awry in pheochromocytoma and paraganglioma—tumors of the chromaffin cells.

Epinephrine is generated from its precursor norepinephrine which is secreted in smaller quantities by the adrenal chromaffin cells.

Epinephrine is produced as the final step in the chain of a common catecholamine biosynthetic pathway in which the essential amino acid L-tyrosine is  hydroxylated in an initial reaction by the rate-limiting enzyme tyrosine hydroxylase, to form L-dihydroxyphenylalanine (L-DOPA). Tyrosine hydroxylase is present in all catecholaminergic cells. L-DOPA is decarboxylated by the catalytic activity of aromatic L-amino acid decarboxylase (AADC) to produce dopamine, which is further converted to norepinephrine in a hydroxylation reaction catalyzed by dopamine beta-hydroxylase. The final step in the biosynthesis of epinephrine is the conversion of norepinephrine to epinephrine by the enzyme, phenylethanolamine N-methyltransferase (PNMT), with the methyl group supplied by S-adenosyl-methionine. This final conversion process occurs in cells that use epinephrine as a hormone and neurotransmitter in the adrenal medulla and a small subset of neurons in the brain.

Epinephrine turnover and metabolism is under the dynamic control of two enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). Internal stores of epinephrine in the adrenal chromaffin cells are O-methylated by COMT to produce the principal metabolite, metanephrine.

The epinephrine secreted by sympathetic nerves, and the circulating epinephrine is taken up and cleared by the liver and kidney. Oxidative deamination of epinephrine by MAO, results in an aldehyde that is further processed to form alcohol or acid metabolites, specifically 3,4-dihydrophenylglycol (DHPG).

Disorders of the Adrenergic System

Several diseases are associated with epinephrine. Absence or severe deficiency of adrenal gland hormones such as epinephrine cause Addison's disease, a condition that presents with non-specific symptoms such as dizziness when standing, fatigue, nausea, and darkening of the skin. On the other hand, excessive secretion of epinephrine and noradrenaline can lead to a rare adrenal tumor or pheochromocytoma, that can trigger a severe and dangerous increase in blood pressure. These tumors usually occur in men and women aged 30 to 50 years. Non-typical symptoms are vomiting and chest pain, and in some instances pheochromocytoma patients experience episodes of orthostatic hypotension.

Another disorder associated with epinephrine is lactic acidosis that results from the formation of pyruvate and induction of glycolysis, an effect mediated by beta adrenergic receptors. Results of a cardiopulmonary bypass study showed that administration of epinephrine after bypass surgery, increased the likelihood of lactic acidosis in some patients, and is associated with a decrease in oxygen extraction and increased blood flow. Another endocrine disorder ascribed to epinephrine is hyperglycemia. The transient response of hepatic glucose production to epinephrine is converted to a sustained response accompanied by increases in cortisol and glucagon. Apart from increased glucose production associated with epinephrine, there is also reduced glucose uptake leading to elevated glucose levels responsible for hyperglycemia.

Epinephrine has been used extensively to reduce bleeding by increasing localized constriction of blood vessels. Epinephrine reduces the systemic toxic effects of certain local anesthetics. However, excessive intravenous injection of epinephrine can cause headaches, cerebral hemorrhage, cardiac arrest, and ventricular arrhythmias. Epinephrine like other medications can enhance physiological tremors and the pathophysiology of epinephrine induced tremors includes its acting on beta-adrenergic receptors peripherally, in the muscles. Several clinical studies have shown that excessive epinephrine can reach toxic levels in the circulation that can have severe consequences such as tachycardia, collapse, and even death. Excess adrenal hormones, including epinephrine can trigger systemic resistance causing pulmonary edema and congestion.

Clinical studies

Medically, epinephrine belongs to a class of drugs known as alpha/beta adrenergic agonists and is administered to treat anaphalaxis, cardiac arrest, septic shock induced hypotension, ventricular fibrillation, mydriasis, amongst other conditions.

Various clinical studies have tested epinephrine as a pharmacological agent to treat various diseases. The injectable solution of epinephrine has a dosage of 0.1mg/mL (1:10,000) and 1mg/mL (1:1000). The dose of epinephrine for cardiac arrest is 0.5–1.0 mg (5-10 mL). The normal value of epinephrine in the urine is 0.5–20 mcg/24 hours. A randomized clinical trial analyzed the cardiac life-supporting effects of standard and high doses of epinephrine, and found that the higher dose significantly improved spontaneous cardiac circulation without increasing complications.

Another clinical study showed that epinephrine combined with steroids and the peptide vasopressin had a beneficial effect on the return of spontaneous circulation in patients suffering from cardiac arrest, without complications of bleeding and renal failure. In addition to treating cardiac arrest, epinephrine is the mainstay of anaphylaxis as it is a vasoconstrictor. Epinephrine can reduce hypotension, shock, and upper airway edema. Systemic reactions and anaphylaxis are known to occur as a result of administration of allergy immunotherapy tablets in allergic immunotherapy treatment. However, taken concurrently with epinephrine, these tablets have been shown to avert these serious side effects.