Epinephrine

Epinephrine is a very powerful hormone that affects many body systems, especially during exercise. Epinephrine, commonly called adrenaline, is responsible for the “adrenaline rush,” or “surge of adrenaline,” that is experienced during excitement, stress, and athletic competitions. In stressful or dangerous situations, epinephrine also functions as a neurotransmitter that conducts impulses across the synapses between nerve cells. Synthetic epinephrine is used to treat life-threat-ening conditions such as heart attacks and anaphylactic shock, including exercise-induced anaphylaxis.

Epinephrine was the first hormone ever discovered. By 1904, it had been synthesized in the laboratory. A small, water-soluble molecule called a catecholamine, epinephrine is produced and secreted by cells in the medulla, or inner portion, of the adrenal glands, along with two closely related catecholamine hormones and neurotransmitters, norepinephrine (previously called noradrenaline) and dopamine. The terms “epinephrine” and “adrenaline” come from Greek and Latin roots, respectively, that mean “on the kidneys.” The adrenal glands are located just above the kidneys and are important components of the endocrine system, releasing hormones that travel through the bloodstream to regulate and coordinate the metabolism of cells throughout the body. Epinephrine is synthesized in the adrenal medulla by a pathway that leads from the amino acid tyrosine to dopamine to norepinephrine and finally to epinephrine. Epinephrine is stored in and secreted from specialized cellular compartments called chromaffin vesicles. In addition to their roles in the normal functioning of the human body, all three catecholamines are involved in the alarm or fight-or-flight response that is fundamental to exercise physiology.

Epinephrine affects almost every system in the body, although its effects are very different in various tissues. It exerts its effects by binding to proteins called adrenergic receptors on the surfaces of cells. Different types of cells have different types of adrenergic receptors that bind epinephrine, including alpha-1 and -2 and beta-1, -2, and -3 receptors. Drugs that mimic the effects of epinephrine are called adrenergics. Epinephrine and drugs that mimic its effects are also referred to as sympathomimetic agents because they excite the sympathetic nervous system, the portion of the autonomic or involuntary nervous system that responds to stressful or emergency situations. Amphetamines and ephedrine (a common ingredient in over-the-counter and prescription decongestants and bronchodilators) are examples of adrenergics, or sympathomimetic agents that increase the heart rate, among other effects. Beta-blockers, which slow the heart rate, block the binding of epinephrine to beta-adrenergic receptors on cells of the heart and blood vessels.

Epinephrine and other hormones are sometimes called “primary messengers” because they are carried through the bloodstream to various cell types, where they bind to receptors and set off chain reactions inside the cells. These intracellular reactions involve “second messengers.” For example, epinephrine binding to beta-adrenergic receptors on liver cells sets off a chain of reactions that culminate with the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). cAMP is a second messenger that directly stimulates enzymes to carry out the metabolic effects of epinephrine.

The adrenal glands continuously produce and secrete small amounts of epinephrine. However, under non-stress conditions, blood levels of glucose are controlled primarily by the hormones insulin and glucagon, with epinephrine, norepinephrine, and growth hormone playing only minor roles. The normal level of total catecholamines in the blood is about 0.06 micrograms per liter (µg/L), with epinephrine levels in resting adults usually less than 0.01 µg/L. The onset of physical activity or a stress alarm, such as preparing to run a race, can increase the levels of epinephrine and other catecholamines in the blood 50-fold–1,000-fold in minutes or even seconds.

Catecholamines are usually measured with urine tests, although they also can be measured in the blood. Catecholamines and their breakdown products, vanillylmandelic acid (VMA) and metanephrine, are excreted in the urine. Over a 24-hour period, the usual amounts excreted in the urine are:

Epinephrine increases the blood and oxygen supply to muscles and major organs, especially the brain, heart, and kidneys, by increasing cardiac output and breathing rate. Epinephrine accomplishes this by causing some involuntary muscles to contract and others to relax.

Epinephrine increases cardiac output by binding to beta-1 adrenergic receptors in heart muscle, making the heart beat faster and stronger. Epinephrine binding to alpha-1 adrenergic receptors contracts the smooth muscles lining the arterioles or small arteries. This constriction increases the resistance in the peripheral blood vessels, raising blood pressure and restricting the flow of blood to the skin so that more blood flows to the internal organs. Epinephrine also slows down digestion.

Epinephrine relaxes smooth muscles of the bronchioles around the lungs and increases the breathing rate so that more oxygen is available. Epinephrine also acts as a natural decongestant. Thus, it has been shown that regular 30-minute workouts that increase the release of epinephrine can help relieve allergy symptoms.

Epinephrine increases the availability of glucose for energy in several ways. Glucose is stored as glycogen in the liver and muscles. Epinephrine binding to liver cells stimulates the formation of cAMP, which directly activates the enzyme glycogen phosphorylase to break down glycogen into individual glucose molecules that are released into the bloodstream. Epinephrine binding to beta-adrenergic receptors also stimulates the release of the hormone glucagon by the pancreas. Glucagon further increases the rate of glycogen breakdown by the liver, increasing blood glucose levels. By binding to alpha-adrenergic receptors, epinephrine inhibits insulin secretion by the pancreas, enabling blood glucose levels to rise further. Epinephrine stimulates the anaerobic breakdown of glycogen to pyruvate or lactate in skeletal muscle, via a process called glycolysis, with the formation of ATP as an energy source. Epinephrine also stimulates the breakdown of glycogen in heart muscle and inhibits the formation of glycogen from glucose in the liver via a cAMP-dependent process.

Synthetic epinephrine is the drug of choice for treating anaphylaxis or anaphylactic shock because it rapidly relaxes the muscles of the airways and constricts blood vessels to raise blood pressure. Anaphylaxis is a rare—but sudden, severe, and potentially lifethreatening—allergic reaction that can occur with exposure to an allergen to which the body has been previously sensitized. Histamine and other substances released from tissues and from cells in the blood dilate blood vessels, lowering blood pressure to a dangerous level, even to the point of unconsciousness. They also constrict the airways in the lungs, making it difficult to breath, and can cause fluid to leak from blood vessels, resulting in swelling and hives, especially around the face and throat, which further impedes breathing. Anaphylaxis can be fatal in as little as ten minutes. Symptoms also can disappear only to return later. An epinephrine injection quickly constricts blood vessels, opens the airways, and halts swelling.

Exercise-induced anaphylaxis (EIA) is an unpredictable allergic reaction that appears to be triggered by exposure to an allergen before or during physical exercise. Various allergens can trigger EIA, including foods, latex, medications, and insect bites. EIA most often occurs while running, swimming, or cycling, although even yard work has been known to trigger an attack. It is more common among people with a family history of EIA, under conditions of extreme temperature, and in menstruating women. EIA is a serious concern for children with severe allergies who play sports. People with a known susceptibility to EIA should always exercise with a partner and carry an auto-injection epinephrine pen. These are singledose, pre-filled, automatic devices for injecting epinephrine under the skin or into the muscle of the outer thigh. The proper dose is predetermined for each patient. For children weighing 33–66 lb. (15–30 kg), the average auto-injector dose is 0.15 mg. For those weighing over 66 lb. (30 kg), the average dose is 0.3 mg. Epinephrine injections do not cure anaphylaxis; rather, they relieve symptoms for 10–15 minutes until emergency help arrives.

Epinephrine is used as emergency treatment for cardiac arrest and other heart rhythm irregularities that reduce or stop the heartbeat. A 2016 study reported that a shot of epinephrine within five minutes of cardiac arrest increases the chance of survival by 20%. Epinephrine also is used to decrease bleeding during surgery and to prolong the effects of local anesthetics.

In the past, epinephrine was commonly used as a quick-relief bronchodilator for severe asthma attacks, as well as for obstructive lung diseases such as chronic bronchitis or emphysema. Because of its other effects, especially speeding up the heart and increasing oxygen demand, epinephrine is now only used when selective beta-2 adrenergics (agonists) are unavailable.

Certain medical conditions can cause excessive production and secretion of epinephrine and other catecholamines. These conditions include pheochromocytoma (a tumor of the epinephrine-producing chromaffin cells of the adrenal gland) and nervous system tumors that affect hormone production, including neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. Symptoms of excessive epinephrine may include constant or intermittent high blood pressure, which may be accompanied by headache, sweating, heart palpitations, and/or anxiety.

Margaret Alic, PhD