Description: Epinephrine is an endogenous catecholamine that has many therapeutic applications. Endogenous epinephrine is produced primarily from norepinephrine in the adrenal medulla. Epinephrine can be administered by injection, inhalation, or administered topically to the eye; the effects of exogenous epinephrine are identical to those of the endogenous hormone. Therapeutically, it can be administered IV for use as a cardiac stimulant and as a bronchodilator in cases of anaphylactic shock. Epinephrine is utilized during cardiopulmonary rescuscitation and is currently included within the Advanced Cardiac Life Support (ACLS) protocols for ventricular fibrillation, pulseless electrical activity, asystole, and bradycardia.[9190] High-dose epinephrine is is no longer recommended for routine use during the treatment of cardiac arrest, but may be considered as alternative therapy.[2999] [9190] The use of epinephrine as a bronchodilator in the treatment of asthma has largely been superceded by nebulized albuterol. It is administered topically to the eye as a diagnostic aid and is often combined with local anesthetics to prolong the duration of action of these agents. The discovery of epinephrine's pharmacologic effects and synthesis date back to the late 1800s. Epinephrine was approved by the FDA in 1939. Epinephrine administered by metered-dose inhaler is available without a prescription for treatment of asthma, however, in November 1994, the FDA expressed concern regarding OTC status for this dosage form.

Mechanism of Action: Epinephrine has complex target organ effects. It is a potent agonist at both alpha- and beta- receptors throughout the body except for the sweat glands and facial arteries. Epinephrine is a nonselective adrenergic agonist; it stimulates alpha1-, alpha2-, beta1-, and beta2-adrenergic receptors, although the degree of stimulation at these receptors may vary depending on the dose administered (i.e., the circulating concentration of epinephrine at the receptor). Stimulation of alpha1-receptors by epinephrine leads to arteriolar vasoconstriction. Stimulation of presynaptic alpha2-receptors inhibits norepinephrine release via negative feedback while stimulation of post-synaptic alpha2-receptors also leads to arteriolar vasoconstriction. Stimulation of beta1-receptors induces a positive chronotropic and inotropic response. Stimulation of beta2-receptors by epinephrine leads to arteriolar vasodilation, bronchial smooth muscle relaxation, and increased glycogenolysis. Subsequent to binding at the adrenergic receptor, the intracellular actions of epinephrine are mediated by cyclic adenosine monophosphate (cAMP). The production of cAMP is augmented by beta-stimulation and attenuated by alpha-stimulation.

The major therapeutic effects of systemic epinephrine include: bronchial smooth muscle relaxation, cardiac stimulation, vasodilation in skeletal muscle, and stimulation of glycogenolysis in the liver and other calorigenic mechanisms. The effects of epinephrine on smooth muscle are varied and determined by relative receptor density and hormonal effects. When used topically in the eye in patients with open-angle glaucoma, epinephrine lowers intraocular pressure, produces a brief mydriasis, and may improve the coefficient of aqueous outflow. When used topically on the skin or mucosal surfaces, epinephrine constricts arterioles, thus producing local vasoconstriction and hemostasis in small blood vessels.

Epinephrine primarily exerts its relaxant effect on bronchial smooth muscle via stimulation of beta2-receptors. Beta2-stimulation also prevents mast cell secretion of histamine and other autocoids, thus antagonizing its effect on end organs and reversing bronchoconstriction and edema. Furthermore, alpha-stimulation may decrease secretions from the bronchial mucosa, attenuating the development of edema. There is some evidence that epinephrine's alpha properties make it more effective than pure beta-agonists for the treatment of some pulmonary conditions such as bronchiolitis in children.[824]

The potent cardiac effects of epinephrine are primarily mediated via stimulation of beta1-receptors on the myocardium and conducting system of the heart. The stimulation of these receptors results in both increased inotropic and chronotropic effects. Systolic blood pressure is usually elevated as a result of increased inotropy, although diastolic blood pressure is decreased secondary to epinephrine-induced vasodilation. As a result, pulse pressure is increased. Epinephrine indirectly causes coronary artery vasodilation, particularly during cardiac arrest. Epinephrine can simultaneously increase myocardial oxygen supply (secondary to coronary vasodilation) and increase oxygen demand (secondary to a positive inotropic and chronotropic effect on the heart). Increased myocardial excitability and automaticity markedly increase the potential for developing dysrhythmias. Nonspecific beta-stimulation by epinephrine, combined with moderate alpha agonism, results in inotropic effects equal to those of dopamine and dobutamine but greater chronotropic effects than either agent.

Blood flow to skeletal muscles is augmented by epinephrine via beta2-stimulation, resulting in vasodilation. Stimulation of alpha1-receptors by epinephrine leads to arteriolar vasoconstriction while stimulation of beta2-receptors by epinephrine leads to arteriolar vasodilation. At normal therapeutic doses, this effect is only mildly countered by the vasoconstriction caused by alpha-stimulation. At higher doses, however, vasoconstriction and elevation of both peripheral vascular resistance and blood pressure can occur.

The metabolic effects of epinephrine relate primarily to the regulatory processes that control glucose concentration in the plasma. Beta2-stimulation of the skeletal muscle and liver increases glycogenolysis. Alpha-stimulation of the liver increases gluconeogenesis and inhibits insulin release by the pancreatic islet cells. Furthermore, in adipose cells, beta-stimulation will induce the catabolism of triglycerides, therefore increasing plasma free fatty acids. Serum potassium concentrations fluctuate after administration of epinephrine. Initially, hyperkalemia occurs secondary to release of potassium ions from hepatocytes. Hypokalemia quickly follows as potassium ions are taken up by the skeletal muscle.

Pharmacokinetics: Epinephrine is administered either by injection, by inhalation, or topically to the eye. The oral bioavailability of epinephrine is poor, owing to its rapid and extensive metabolism in the gut and liver; as a result, epinephrine is not administered orally. Epinephrine is, however, well absorbed systemically when administered by intramuscular (IM) or subcutaneous (SQ) routes. Subcutaneous administration is favored over intramuscular. Onset of action after subcutaneous administration is 5—15 minutes, and the duration of action is 1—4 hours. The onset of action after IM administration is variable, and the duration of action is 1—4 hours. Absorption of an IM dose may be increased both quantitatively and qualitatively by massaging the area of injection, which increases local blood flow. After inhalation of a normal dose, the drug is only slightly absorbed systemically, and its effects are limited primarily to the respiratory tract. The onset of action after an inhaled dose is 1—5 minutes, and the duration of action is 1—3 hours. The onset of action of various effects of an intraocular dose range from minutes to 1 hour, and the duration of these actions are from less than 1 hour to 24 hours.

Epinephrine is distributed throughout the body. Epinephrine crosses the placenta but does not penetrate the blood-brain barrier to a great extent. Epinephrine will distribute into breast milk.

The pharmacologic activity of epinephrine is rapidly terminated by uptake and metabolism in the synaptic cleft. Circulating drug is metabolized by the enzymes catechol-O-methyltransferase and monoamine oxidase in the liver and in other tissues. These inactive metabolites are then conjugated to either sulfates or glucuronides and renally excreted. Minimal amounts of the drug are excreted unchanged in the urine.

References
824. Menon K et al. A randomized trial comparing the efficacy of epinephrine with salbutamol in the treatment of acute bronchiolitis. J Pediatr 1995;126:1004—7.

2999. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: advanced cardiovascular life support. Circulation 2000;102(8 Suppl):112—165.

9190. ECC Committee, Subcommittees and Task Forces of the American Heart Association. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Advanced Cardiac Life Support Part 7.2: management of cardiac arrest. Circulation 2005;112:58—66.



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