AHFS Class:

• Vasoconstrictors 52:32

Generic Name(s):

• EPINEPHrine Hydrochloride

• EPINEPHrine

Epinephrine, an endogenous catecholamine that is the active principle of the adrenal medulla, is a vasoconstrictor.

Epinephrine is used locally to control superficial bleeding from arterioles and capillaries in the skin and mucous membranes of the eye, nose, mouth, throat or larynx, mainly during surgery. Bleeding from larger vessels is not controllable by topical application of epinephrine. The drug is especially useful in dental surgery.

Epinephrine may be added to solutions of some local anesthetics such as procaine or lidocaine to decrease the rate of vascular absorption of the local anesthetic, thereby localizing anesthesia and prolonging the duration of anesthesia; the risk of systemic toxicity caused by the local anesthetic is also decreased, and bleeding in the operative field may be reduced.

Epinephrine may be applied topically to the nasal mucosa as a decongestant; however, the drug has a short duration of action and rebound congestion frequently occurs. Other longer acting sympathomimetic agents such as oxymetazoline are more commonly used for this purpose. Epinephrine has been used as a decongestant when applied topically to the conjunctiva in patients with conjunctivitis resulting from nonspecific chronic irritation or allergy. However, the drug's effects in such cases usually lasted less than 1 hour and may have been followed by reactive hyperemia.

For systemic uses of epinephrine, see Epinephrine 12:12.12. For uses of epinephrine in the treatment of glaucoma or as a mydriatic, see Epinephrine 52:24.

Administration

Epinephrine solutions are applied topically to mucous membranes. The drug may also be injected intracamerally (into the anterior chamber of the eye) or subconjunctivally (beneath Tenon's capsule) to control hemorrhage. Epinephrine nasal and topical solutions must not be injected.

Dosage

Dosage of epinephrine hydrochloride is expressed in terms of epinephrine.

As a vasoconstrictor to control bleeding in the mucosa or to produce nasal decongestion, a 0.1% (1:1000) solution of epinephrine is applied topically as drops or spray to mucosa as required. To control bleeding during ocular surgery or to produce conjunctival decongestion, 1 or more drops of a 0.1% (1:1000) solution of epinephrine (no longer commercially available in the US) has been applied topically to the conjunctiva 1-3 times or as necessary. To control ocular bleeding, the drug may be injected into the anterior chamber of the eye or subconjunctivally in concentrations of 0.01% (1:10,000) to 0.1% (1:1000). As a topical hemostatic, solutions containing epinephrine in concentrations of 0.002% (1:50,000) to 0.1% (1:1000) may be sprayed or applied with cotton or gauze to the skin, mucous membranes, or other tissues. In one study, 4 mL of a 0.0005% (1:200,000) solution of epinephrine was infiltrated into the buccal and labial vestibules of the maxilla and mandible in each quadrant as a hemostatic in oral surgery.

For use with local anesthetics, epinephrine may be used in concentrations of 0.0005% (1:200,000) to 0.002% (1:50,000).

Adverse Effects

Nasal Preparations

After intranasal application, epinephrine can cause CNS symptoms such as nervousness and restlessness. The drug, however, causes less CNS stimulation than does ephedrine, and the effects subside quickly when epinephrine is discontinued. Rebound nasal congestion occurs frequently. Epinephrine solutions may sting slightly after intranasal application because of the presence of the antioxidant, sodium bisulfite.

Parenteral Preparations

Intracameral injection (into the anterior chamber of the eye) of epinephrine 1:1000 has been associated with endothelial damage, irreversible edema, and opacification of the cornea. Results of one study indicate that these effects are caused by sodium bisulfite in concentrations of 0.1% which are present in most commercially available products.

Precautions and Contraindications

Use of epinephrine in the mucosa occasionally causes systemic sympathomimetic effects such as palpitation, tachycardia, extrasystoles, premature ventricular contractions, hypertension, occipital headaches, pallor, trembling, faintness, and increased perspiration. If epinephrine is used prior to ocular surgery, especially for injection with a local anesthetic, the patient should be warned of the possibility of systemic sympathomimetic effects; surgery should not be started until restlessness has subsided. Overdosage or inadvertent IV injection of epinephrine may result in cerebrovascular hemorrhage because of a marked increase in blood pressure.

Patients should be instructed to discontinue using epinephrine and consult their physicians if signs of sensitivity develop or if irritation persists or increases during therapy with the drug.

Some commercially available formulations of epinephrine hydrochloride contain sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

The cardiovascular status of the patient should be considered before initiating epinephrine therapy. The drug should be used with caution in patients with vascular hypertension or cardiac disorders, including arrhythmias and cardiovascular disease. Epinephrine should also be used with caution in diabetic, hyperthyroid, aphakic, psychoneurotic, or geriatric patients or those with cerebral arteriosclerosis, long-standing bronchial asthma, or a history of bronchial asthma. Epinephrine should be used with extreme caution in patients with long-standing bronchial asthma or emphysema who have developed degenerative heart disease.

Epinephrine must be used cautiously, if at all, prior to or during surgery with cyclopropane or halogenated hydrocarbon anesthetics such as halothane. The danger of ventricular arrhythmias such as ventricular premature contractions, tachycardia, or fibrillation may be increased.

Epinephrine is contraindicated in patients with angle-closure glaucoma or those predisposed to angle closure. Epinephrine is also contraindicated in patients with known sensitivity to the drug or to other components in the commercially available preparations and in individuals with organic brain syndrome or cardiac dilatation and coronary insufficiency. In conjunction with local anesthetics, epinephrine is contraindicated for use in ears, nose, fingers, toes, or genitalia.

Pregnancy

Pregnancy

Although there are no adequate and controlled studies to date in humans, epinephrine has been shown to be teratogenic in rats when given at dosages 25 times the usual human dosage. Parenterally administered epinephrine in late pregnancy or labor may cause fetal anoxia. (See Cautions: Pregnancy, in Epinephrine 12:12.12.) Epinephrine should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

General Anesthetics

Absorption of epinephrine in patients receiving cyclopropane or halogenated hydrocarbon general anesthetics may result in arrhythmias including ventricular premature contractions, tachycardia, or fibrillation. Epinephrine may not be absorbed rapidly enough to cause serious adverse effects when applied topically as a hemostatic in patients undergoing short surgical procedures such as tonsillectomy and adenoidectomy using halothane anesthesia. Epinephrine is contraindicated for use with chloroform, trichloroethylene, or cyclopropane and should be used cautiously, if at all, with other halogenated hydrocarbon anesthetics such as halothane. Prophylactic administration of lidocaine or prophylactic IV administration of propranolol 0.05 mg/kg may protect against ventricular irritability if epinephrine is used during anesthesia with a halogenated hydrocarbon anesthetic. In one study, arrhythmias occurring after parenteral use of epinephrine during general anesthesia responded promptly to IV propranolol 0.05 mg/kg.

Other Drugs

Epinephrine should not be used in patients receiving high dosage of other drugs such as cardiac glycosides which can sensitize the heart to arrhythmias.

Tricyclic antidepressants such as imipramine, some antihistamines (especially diphenhydramine, tripelennamine, and dexchlorpheniramine) and thyroid hormones may potentiate the effects of epinephrine, especially on heart rhythm and rate. Potentiation by tricyclic antidepressants or antihistamines may result from inhibition of tissue uptake of epinephrine or norepinephrine or by increased adrenoreceptor sensitivity to epinephrine. Although monoamine oxidase (MAO) is one of the enzymes responsible for epinephrine metabolism, MAO inhibitors do not markedly potentiate the effects of epinephrine.

Pharmacology

Topically applied epinephrine constricts arterioles in the skin and mucous membranes by its effect on α-adrenergic receptors. The drug produces local vasoconstriction and hemostasis in bleeding from small vessels but does not control bleeding from larger vessels. Topical application of the drug to the nasal mucosa results in constriction of dilated arterioles and reduction in blood flow and nasal congestion. Nasal ventilation and aeration are improved temporarily; however, rebound vasodilation and nasal congestion frequently occur. Conjunctival congestion is temporarily relieved following topical application of epinephrine to the conjunctiva or subconjunctival injection, but reactive hyperemia may occur.

In normal eyes, epinephrine is a poor mydriatic. However, the drug may produce effective mydriasis when the permeability of the eye is increased during surgery or trauma, after postganglionic sympathetic denervation (as in Horner's syndrome or Raeder's syndrome), and in patients with chronic renal hypertension, hyperthyroidism, or certain cases of glaucoma.

Pharmacokinetics

Absorption

Local vasoconstriction usually occurs within 5 minutes after topical administration or intraocular injection of epinephrine and generally lasts less than 1 hour.

Occasionally, enough epinephrine may be absorbed following topical application to the conjunctiva or mucosa or intraocular injection to cause systemic sympathomimetic effects.

Distribution

Following topical application of radiolabeled epinephrine to the eye in rabbits, highest concentrations of the drug in tissues and fluids other than the eye occurred in the pituitary gland, with lower concentrations in the intestine, fat, adrenal gland, kidney, heart, lung, spleen, ovary, pancreas, liver, uterus, muscle, brain, and serum. In humans, systemically absorbed epinephrine crosses the placenta but not the blood-brain barrier. Systemically absorbed epinephrine distributes into milk.

Elimination

The pharmacologic actions of epinephrine are terminated mainly by uptake and metabolism in sympathetic nerve endings. Circulating drug is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol- O -methyltransferase (COMT) and monoamine oxidase (MAO). The major metabolites are metanephrine and 3-methoxy-4-hydroxy-mandelic acid (vanillylmandelic acid, VMA), both of which are inactive. Epinephrine and its metabolites are excreted by the kidneys.

Chemistry and Stability

Chemistry

Epinephrine is an endogenous catecholamine which is the active principle of the adrenal medulla. Both the endogenous substance and the official preparation are the levorotatory isomer which is 15 times more active than the dextrorotatory isomer.

Epinephrine may be obtained from the adrenal glands of animals or prepared synthetically; drug obtained from animals may contain up to 4% norepinephrine. Epinephrine occurs as a white to nearly white, microcrystalline powder or granules. Epinephrine is only very slightly soluble in water but readily forms water soluble salts (such as the hydrochloride) with acids. Epinephrine injection is a nearly colorless, slightly acidic aqueous solution prepared with the aid of hydrochloric acid and contains the drug as the hydrochloride salt. The injection has a pH of 2.5-5. Nasal solutions of epinephrine hydrochloride also are acidic.

Stability

Epinephrine, epinephrine salts, and solutions containing the drugs gradually darken on exposure to light and air and must be stored in tight, light-resistant containers. In some commercially available injections, air has been replaced with nitrogen to avoid oxidation. Withdrawal of doses from multiple-dose vials introduces air into the vials, subjecting the remaining epinephrine to oxidation. Oxidation of the drug imparts first a pink, then a brown color. Epinephrine preparations must not be used if they are discolored or contain a precipitate. Commercially available epinephrine preparations contain a variety of preservatives including antioxidants, bacteriostatic agents, and chelating agents. These preparations vary in stability, depending on the preservatives used. The manufacturer's directions should be followed with respect to storage requirements for each product.

Epinephrine is readily destroyed by oxidizing agents or alkalies, including sodium bicarbonate, halogens, permanganates, chromates, nitrates, nitrites, and salts of easily reducible metals such as iron, copper, and zinc. Epinephrine solutions have been reported to be physically incompatible with many drugs, but the compatibility depends on several factors (e.g., the concentration of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information. Epinephrine may be mixed with 0.9% sodium chloride injection but is incompatible with 5% sodium chloride injection.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.