Epinephrine

Mechanism of Action

Epinephrine is a sympathomimetic catecholamine that exerts its pharmacological effects on α- and β-adrenergic receptors through a G-protein–linked second messenger system.[13] At small doses, epinephrine has a greater affinity for β-receptors. However, large doses produce selective action on α-receptors. Through its action on α1-receptors, epinephrine induces increased vascular smooth muscle contraction, pupillary dilator muscle contraction, and intestinal sphincter muscle contraction.

Other significant effects of epinephrine include increased heart rate, myocardial contractility, and renin release via β1 receptors. β2 receptor activation produces bronchodilation, which can be useful as an adjunct treatment for asthma exacerbations, as well as vasodilation, tocolysis, and increased aqueous humor production.

Pharmacokinetics

Absorption: When administered intravenously (IV), epinephrine is rapidly absorbed into the bloodstream. Due to its high water solubility, it is quickly distributed throughout the body's tissues. The plasma half-life of epinephrine is very short, typically less than 5 minutes, indicating its rapid elimination from circulation.

Distribution: After IV administration, epinephrine is rapidly distributed throughout the body. The pharmacokinetic profile reveals a rapid decline in plasma concentrations, with a steady state typically reached within 10 to 15 minutes when administered as a continuous infusion.

Metabolism: Epinephrine undergoes extensive biotransformation, primarily in the liver, kidneys, and other extraneuronal tissues. The primary metabolic enzymes involved in its metabolism are monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), which degrade epinephrine into inactive metabolites, most notably vanillylmandelic acid.[14]

Excretion: The majority of epinephrine is eliminated through metabolic pathways, with only an insignificant fraction excreted unchanged in the urine. The liver has a predominant role in the clearance of epinephrine, significantly contributing to its removal from the bloodstream. Additional contributions to the elimination process come from the kidneys, skeletal muscle, and mesenteric organs, all of which are vital in the drug's clearance from circulation.

Administration

Available Dosage Forms and Strengths

Epinephrine is available in various forms depending on the diagnosis. For the treatment of anaphylaxis, epinephrine is preferably injected intramuscularly into the anterolateral aspect of the thigh for rapid absorption, although subcutaneous injection is also an option. In advanced cardiovascular life support (ACLS), epinephrine can be administered IV or IO as needed.

Another route of administration is through an endotracheal tube, commonly used in neonatal resuscitation. Epinephrine is also available as a prefilled auto-injector or syringe for subcutaneous or intramuscular administration, typically with a concentration of 0.3 mg/0.3 mL. Additionally, it is available as an injectable solution with a concentration of 0.1 mg/mL (1 mg/10 mL).

Adult Dosage

Anaphylactic shock: For anaphylactic shock in adults and children with a body weight of 30 kg (66 lbs) or more, the recommended dose of epinephrine is 0.3 to 0.5 mg (0.3-0.5 mL), administered intramuscularly or subcutaneously into the anterolateral aspect of the thigh every 5 to 10 minutes as needed. For managing anaphylactic shock, a 0.1 mg/mL solution of epinephrine may be administered via IV route. The typical initial dose is 0.1 mg (1 mL), given at a rate of 1 to 4 mcg/min.

Alternatively, an infusion may be initiated at 5 to 15 mcg/min, with adjustments based on clinical response. When IV access is not readily available, intraosseous (IO) administration can be used, with dosing identical to the IV route. A single 2 mg spray should be administered into one nostril for intranasal administration. If the initial response is insufficient after 5 minutes, a second dose may be administered.

Hypotension associated with septic shock: Epinephrine injection (1 mg/mL) should be diluted in a dextrose solution before infusion. The infusion should be administered through a large vein at 0.05 to 2 mcg/kg/min, titrated to achieve the desired mean arterial pressure. Once the target hemodynamic status is reached, the infusion should be gradually tapered.

Mydriasis during intraocular surgery: Tartaric acid-containing formulations should be avoided. Epinephrine requires dilution before use for the induction and maintenance of mydriasis during intraocular surgery. A dilution of 1 mL of epinephrine (1 mg/mL, 1:1000) in 100 to 1000 mL of ophthalmic irrigation solution achieves a concentration of 1:100,000 to 1:1,000,000 (from 10 mcg/mL to 1 mcg/mL) and may be used as needed during the surgical procedure. Additionally, epinephrine can be administered intracamerally as a 0.1 mL bolus at a concentration of 1:100,000 to 1:400,000 (from 10 mcg/mL to 2.5 mcg/mL).

Cardiac arrest: In cases of sudden cardiac arrest due to asystole, ventricular fibrillation, pulseless electrical activity, or pulseless ventricular tachycardia (off-label use), the recommended IV or IO dose of epinephrine is 1 mg (using the 0.1 mg/mL solution) administered every 3 to 5 minutes until the return of spontaneous circulation (ROSC) is achieved. Alternatively, epinephrine may be administered via the endotracheal route at a dosage of 2 to 2.5 mg every 3 to 5 minutes until IV or IO access is established or ROSC.[15][16][17]

Specific Patient Populations

Hepatic impairment: The product labeling does not specify dosage adjustments for patients with hepatic impairment.

Renal impairment: The product labeling does not provide dosage adjustments for patients with renal impairment.

Pregnancy considerations: According to AHA guidelines, medication doses generally do not require adjustment for the physiological changes of pregnancy during cardiac arrest. Although pregnancy can alter the volume of distribution and medication clearance, current data do not support modifying standard dosing recommendations. For cardiac arrest in adults, the guideline recommends administering 1 mg of epinephrine IV or IO every 3 to 5 minutes. Due to potential uterine effects, and because epinephrine and vasopressin are considered equally effective, epinephrine is preferred (class IIb; Level of Evidence C).[18] 

Current ACLS guidelines recommend standard medication doses during pregnancy unless clinical circumstances necessitate adjustments. Due to its effect on β2-adrenergic receptors, which causes tocolysis, epinephrine opposes oxytocin’s actions on the uterus and may delay labor. Caution is also needed during anaphylaxis-induced hypotension in pregnancy, as it may cause uterine vasoconstriction, reducing oxygen delivery to the fetus.[19] However, life-saving interventions should not be withheld solely because of concerns about potential fetal teratogenicity or adverse outcomes.

Under the previous FDA categorization system, epinephrine is classified as a pregnancy category C drug. While well-controlled studies in humans are lacking, animal studies have indicated a potential teratogenic risk during organogenesis. Epinephrine is capable of crossing the placenta. Caution is advised when maternal blood pressure is ≥ 130/80 mm Hg.

Breastfeeding considerations: Limited data exist on the use of epinephrine during breastfeeding. Due to its poor oral bioavailability and short half-life, epinephrine in breast milk is unlikely to affect the infant. However, high IV doses may reduce milk production or inhibit letdown. Low-dose intramuscular epinephrine (eg, EpiPen) and epidural, topical, inhaled, or ophthalmic formulations are not expected to interfere with breastfeeding. To minimize absorption after using ophthalmic epinephrine, pressure must be applied to the nasolacrimal duct for at least 1 minute, and the excess solution must be removed. Epinephrine is the first-line treatment for anaphylaxis and can be safely administered to breastfeeding individuals in the same manner as non-breastfeeding patients.[20]

Pediatric patients: The ACAAI recommends prescribing either the 0.1 mg or 0.15 mg EAI dose for infants and patients with a body weight of less than 15 kg.[6] For infants, children, and adolescents in systole or pulseless arrest, the recommended IV or IO dosage is 0.01 mg/kg (0.1 mL/kg of a 0.1 mg/mL solution), with a maximum dose of 1 mg per administration. This dose may be repeated every 3 to 5 minutes as needed.[21][22]

Older patients: Due to the expected decline in renal, hepatic, and cardiac function in geriatric patients, epinephrine should be initiated at the lower end of the dosing range and titrated based on clinical response.

Adverse Effects

Common adverse effects of epinephrine include tachycardia, hypertension, headache, anxiety, apprehension, palpitations, diaphoresis, nausea, vomiting, weakness, and tremors. The adverse effects are listed by system as follows:

• Central nervous system: Anxiety, dizziness, nervousness, agitation, headache, and exacerbation of Parkinson disease. 
• Cardiovascular: Arrhythmias, chest pain, hypertension, palpitations, tachycardia, cerebrovascular accidents, ventricular ectopy, vasospasm, and tissue ischemia.
• Dermatologic: Gangrene at the injection site (especially in the buttocks) and skin necrosis with extravasation.
• Endocrine: Hyperglycemia, hypokalemia, and lactic acidosis.
• Gastrointestinal: Nausea, vomiting, and increase in aspartate transaminase and alanine transaminase.
• Neuromuscular: Tremors and weakness.
• Renal: Decreased renal perfusion.
• Respiratory: Dyspnea and pulmonary edema.

Drug-Drug Interactions

• Drugs that can antagonize the pressor effects of epinephrine include α-blockers, vasodilators such as nitrates, diuretics, and antihypertensives. These medications can reduce the vasoconstrictor effects of epinephrine, potentially diminishing its ability to raise blood pressure.

• Drugs that can potentiate the effects of epinephrine include sympathomimetics, β-blockers, tricyclic antidepressants, MAO inhibitors, COMT inhibitors, clonidine, doxapram, oxytocin, levothyroxine sodium, quinidine, and certain antihistamines. These drugs may enhance the effects of epinephrine, particularly its vasoconstrictive and inotropic actions.

• Drugs that can increase the arrhythmogenic potential of epinephrine include β-blockers, cyclopropane, halogenated hydrocarbon anesthetics, antihistamines, exogenous thyroid hormones, diuretics, and cardiac glycosides. These drugs may increase the arrhythmogenic potential of epinephrine, requiring close monitoring for the development of cardiac arrhythmias.

• Drugs that may exacerbate hypokalemia induced by epinephrine include potassium-depleting drugs such as corticosteroids, diuretics, and theophylline. These drugs may potentiate the hypokalemic effects of epinephrine, increasing the risk of significant electrolyte disturbances. Careful monitoring of vital signs is crucial, especially in patients with polypharmacy.

Contraindications

Epinephrine has no absolute contraindications. Practitioners should exercise clinical judgment and carefully weigh the benefits against potential risks before administration.

Warning and Precautions

Relative contraindications: Relative contraindications include hypersensitivity to sympathomimetic drugs, closed-angle glaucoma, and anesthesia with halothane. Catecholaminergic polymorphic ventricular tachycardia is another unique relative contraindication that warrants attention.[23] 

Location: Certain locations should be avoided when administering epinephrine, including the digits, nose, penis, and toes, due to the increased risk of ischemia. Epinephrine should not be used in tissues supplied by end arteries.[24] 

Extravasation risk: The administration of epinephrine should be closely monitored to prevent extravasation into surrounding tissues, as it may result in local tissue necrosis and other complications.

Cardiovascular effects: Epinephrine can exacerbate or induce vasospasm and angina pectoris, especially in patients with preexisting cardiovascular conditions.[25] Close monitoring is essential during administration in these cases.

Allergen immunotherapy: The 2024 guidelines from the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) advise against initiating allergen immunotherapy in patients who are pregnant, have uncontrolled asthma, or cannot tolerate injectable epinephrine.[26]

Monitoring

Epinephrine is a hormone with widespread physiological effects, requiring careful monitoring during use. When administered intravenously, tachycardia and hypertension are common and expected, making precise titration and hemodynamic monitoring essential. Additionally, epinephrine is often combined with anesthetic agents to enhance analgesia. In cases of epinephrine extravasation, prompt prevention and treatment of ischemia-induced necrosis are critical. The infiltrated area should be treated with a 10 to 15 mL saline solution containing 5 to 10 mg of phentolamine—an α-adrenergic blocking agent.[27] A study showed how hospitalized patients in the ICU with finger ischemia were associated with the use of vasopressors, including epinephrine.[28]

Renal impairment requires careful monitoring, as epinephrine can constrict renal blood vessels and decrease urine output. In patients with chronic kidney disease (CKD) and various other renal pathologies, clinical judgment is necessary. In patients with CKD or other renal pathologies, clinical judgment is essential. Researchers have identified a new enzyme—renalase—which is produced by the kidneys and is responsible for metabolizing epinephrine. Some studies have shown that renalase is deficient in CKD, leading to elevated epinephrine levels in these patients.[29] During intraocular use, epinephrine requires dilution to prevent corneal endothelial damage, which can occur with undiluted concentrations of sodium bisulfite. Additionally, epinephrine may increase lactate production by stimulating skeletal muscle β2-adrenergic receptors, making the interpretation of serum lactate levels more challenging in cases of septic shock.[7]

Toxicity

Signs and Symptoms of Overdose

Epinephrine overdose may lead to myocardial ischemia, infarction, renal insufficiency, and cardiomyopathy. Patients may also experience severe pallor, cold skin, and metabolic acidosis due to elevated blood lactic acid levels. These complications are more likely in individuals with preexisting conditions or when epinephrine is administered in high doses. Pulmonary edema may also occur as a result of peripheral vasoconstriction and myocardial stimulation.[30] Due to its strong β1-adrenergic effects on cardiac tissue, epinephrine toxicity can result in potentially fatal cardiac arrhythmias or ischemia. Epinephrine toxicity may also lead to fatal dysrhythmias, cardiac arrest, and significant cardiac morbidity. Case reports have also associated epinephrine toxicity with Takotsubo cardiomyopathy.[31]

Management of Overdose

Excessive epinephrine administration, leading to supra-therapeutic levels, may cause predictable adverse effects requiring supportive treatment. An α-adrenergic blocker or vasodilators such as nitrites may be used to minimize pressor effects. Respiratory support and an α-adrenergic blocking agent might be necessary to reduce vasoconstriction and improve vascular flow. For potentially fatal cardiac arrhythmias or ischemia, β-adrenergic blocking agents should be administered.

Enhancing Healthcare Team Outcomes

Although numerous medications are readily available for various medical conditions in both inpatient and outpatient settings, epinephrine is not often discussed until a patient experiences severe medical deterioration. Due to its physiological effects, epinephrine is commonly used in "code" situations, such as ventricular fibrillation and pulseless electrical activity. These situations demand the expertise and collaboration of an interprofessional healthcare team, including physicians, nurses, pharmacists, emergency medical technicians (EMTs), and other healthcare professionals. During such critical circumstances, the team leader—usually the attending physician—oversees and makes medical decisions.

The clinician, supported by other healthcare professionals and students, interprets electrocardiography (ECG) findings and determines when epinephrine is necessary. From an EMT perspective, epinephrine is usually pre-prepared for immediate administration in prehospital settings, allowing for rapid intervention. In contrast, hospital-based providers may need to draw epinephrine from a vial using a syringe, which can introduce time delays. Effective interprofessional communication is crucial in these critical situations to ensure all healthcare team members are informed and aligned on the necessary steps for timely and accurate administration, optimizing patient resuscitation outcomes.

The proper medication dosage must be administered within an appropriate timeframe to minimize the risk of toxicity. Thus, a pharmaceutical consultation is recommended in these cases. Effective communication among all healthcare team members is essential, as everyone functions as part of an interprofessional team rather than as individuals working in isolation. Recently, researchers conducted a randomized, double-blind trial in the United Kingdom, with the primary end point being the survival rate at 30 days for out-of-hospital cardiac arrests. Secondary outcomes focused on survival rates until hospital discharge with favorable neurological outcomes.

The study included over 8000 patients, with roughly half receiving parenteral epinephrine or a saline placebo, along with standard care. The results indicated that epinephrine was associated with a higher 30-day survival rate compared to saline (placebo). However, there was no improvement in neurological outcomes.[32] The ACAAI recommends that clinicians counsel patients at high risk for anaphylaxis always to carry a self-injectable epinephrine device and ensure that patients are adequately educated on its indications and correct use.[6]

An interprofessional approach to managing epinephrine therapy leads to the best patient outcomes with the fewest adverse effects. Effective communication and collaboration among clinicians, pharmacists, and nurses are essential to minimizing potential adverse effects and enhancing patient outcomes related to epinephrine use.