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epinephrine

epinephriine

Mechanism of Action​

Epinephrine is a non-selective sympathomimetic catecholamine that acts as a potent agonist on both α- and β-adrenergic receptors.

It is the strongest activator of α receptors overall.

Key Effects by Receptor​

  • α-adrenergic (primarily α1): Causes vasoconstriction → counters vasodilation and vascular permeability in anaphylaxis, reduces fluid loss, and raises blood pressure to combat hypotension. Also contracts pupillary dilator muscle (mydriasis) and intestinal sphincters.
  • β-adrenergic:
    • β1: Increases heart rate, myocardial contractility, and renin release → boosts cardiac output.
    • β2: Relaxes bronchial smooth muscle (bronchodilation) to relieve bronchospasm, wheezing, and dyspnea in anaphylaxis or asthma; also causes some vasodilation (at low doses), tocolysis, and increased aqueous humor production.
  • Additional: Acts as a histamine antagonist; promotes glycogenolysis and raises blood sugar.

Dose-Dependent Effects​

Effects vary with dose:

  • Low doses — Predominantly β-receptor activation → greater bronchodilation, cardiac stimulation, and some β2-mediated vasodilation (may lower diastolic BP initially).
  • Higher doses — Shift toward stronger α-receptor effects → prominent vasoconstriction, increased vascular tone, and blood pressure elevation (overriding β2 vasodilation).

This makes epinephrine first-line for anaphylaxis (reverses hypotension and bronchospasm), cardiac arrest (improves perfusion via α effects), and adjunctive use in severe asthma or shock.

Absorption​

Following intravenous injection, epinephrine disappears rapidly from the blood stream.

Subcutaneously or intramuscular administered epinephrine has a rapid onset and short duration of action. Subcutaneous administration during asthmatic attacks may produce bronchodilation within 5 to 10 minutes, and maximal effects may occur within 20 minutes.

The drug becomes fixed in the tissues rapidly,.

Distribution​

Intravenous injection produces an immediate and intensified response and disappears rapidly from the blood stream.

Steady state typically reached within 10 to 15 minutes when administered as a continuous infusion

Metabolism​

Epinephrine is eliminated through metabolic pathways in the liver and is taken up into adrenergic neurons and metabolized by MAO and catechol-O-methyltransferase to metadrenaline, sulfate conjugates, and hydroxy derivatives of mandelic acid.

Excretion​

The majority of the dose of epinephrine is seen excreted in the urine,.

About 40% of a parenteral dose of epinephrine is excreted in urine as metanephrine, 40% as VMA, 7% as 3-methoxy-4-hydroxyphenoglycol, 2% as 3,4-dihydroxymandelic acid, and the rest as acetylated derivatives. These metabolites are excreted mainly as the sulfate conjugates and, to a lesser extent, the glucuronide conjugates. Only small amounts of the drug are excreted completely unchanged.

Indication(s)​

Epinephrine is FDA-approved for:

  • Emergency treatment of type I hypersensitivity reactions, including anaphylaxis (injection and nasal spray forms; first-line therapy).
  • Increasing mean arterial blood pressure in adults with hypotension associated with septic shock (often as add-on after norepinephrine ± vasopressin, per Surviving Sepsis Campaign guidelines).
  • Induction and maintenance of mydriasis during intraocular surgeries (in select formulations; note some newer ones exclude this due to excipients).

Key Clinical Guidance:

  • ACAAI recommends prescribing epinephrine auto-injectors (EAIs) for at-risk patients, with education on proper use and always carrying them.
  • In cardiac arrest, it's used in resuscitation protocols (e.g., ACLS) to restore rhythm/perfusion, but not for cardiac failure, hemorrhagic, traumatic, or cardiogenic shock.
  • Other uses (often off-label or historical): prolonging local anesthetics, hemostasis, bronchial asthma relief, mucosal decongestion (e.g., rhinitis), glaucoma, uterine relaxation, symptomatic relief of urticaria/angioedema/serum sickness, and OTC for intermittent asthma symptoms (wheezing, chest tightness).

Administration​

Epinephrine is available in various forms depending on the diagnosis.

For Anaphylaxis, intramuscular injection into the anterolateral aspect of the thigh is preferred for rapid absorption. Subcutaneous injection is also an option.

In Advanced Cardiovascular Life Support (ACLS), may be administered IV or IO as needed.

In neonatal resuscitation, administration via endotracheal tube is commonly used.

epinephrine is available as:

  • an injectable solution with a concentration of 0.1 mg/mL (1 mg/10 mL)
  • prefilled auto-injector or syringe for subcutaneous or intramuscular administration (Typically 0.3 mg/0.3 mL)

Dosing​

Anaphylactic Shock / Anaphylaxis​

  • Adults & children ≥30 kg (66 lbs): 0.3–0.5 mg (0.3–0.5 mL of 1:1000 solution) IM/SC into anterolateral thigh; repeat q5–10 min as needed.
  • IV/IO (if needed for shock): 0.1 mg (1 mL of 0.1 mg/mL solution) bolus, then infuse 1–4 mcg/min; or start infusion at 5–15 mcg/min, titrate to response.
  • Intranasal: Single 2 mg spray in one nostril; repeat after 5 min if inadequate response.

Hypotension in Septic Shock​

  • Infuse via large vein at 0.05–2 mcg/kg/min, titrate to target mean arterial pressure.
  • Taper gradually once hemodynamically stable.

Mydriasis During Intraocular Surgery​

  • Avoid tartaric acid formulations.
  • Dilute 1 mg/mL epinephrine in 100–1000 mL ophthalmic irrigation solution → concentration 1:100,000 to 1:1,000,000 (10–1 mcg/mL); irrigate as needed.
  • Intracameral bolus: 0.1 mL of 1:100,000 to 1:400,000 (10–2.5 mcg/mL).

Cardiac Arrest (off-label / ACLS protocol)​

  • IV/IO: 1 mg (using 0.1 mg/mL solution) q3–5 min until ROSC.
  • Endotracheal (if no IV/IO access): 2–2.5 mg q3–5 min until IV/IO established or ROSC achieved.

Always use weight-based adjustments in pediatrics, ensure proper dilution/route, and monitor closely for cardiovascular effects.

Adverse Effects​

Common adverse effects include tachycardia, hypertension, headache, anxiety, apprehension, palpitations, diaphoresis, nausea, vomiting, weakness, and tremors.

By System​

  • CNS: Anxiety, dizziness, nervousness, agitation, headache; may exacerbate Parkinson disease.
  • Cardiovascular: Arrhythmias, chest pain, hypertension, palpitations, tachycardia, cerebrovascular accidents, ventricular ectopy, vasospasm, tissue ischemia.
  • Dermatologic: Gangrene (especially buttocks injection site), skin necrosis/extravasation injury.
  • Endocrine/Metabolic: Hyperglycemia, hypokalemia, lactic acidosis.
  • Gastrointestinal: Nausea, vomiting, elevated AST/ALT.
  • Neuromuscular: Tremors, weakness.
  • Renal: Decreased renal perfusion.
  • Respiratory: Dyspnea, pulmonary edema.

Most effects are dose- and route-related (worse with IV); monitor closely in cardiac/vulnerable patients and avoid extravasation.

Drug-Drug Interactions​

Epinephrine Drug Interactions (Summary)

Antagonize Pressor Effects (↓ BP response)​

Drugs that blunt epinephrine's vasoconstriction and blood pressure elevation:

  • α-blockers
  • Vasodilators (e.g., nitrates)
  • Diuretics
  • Antihypertensives

Potentiate Effects (↑ vasoconstriction, inotropy, overall action)​

Drugs that enhance epinephrine's sympathetic effects:

  • Sympathomimetics
  • β-blockers
  • Tricyclic antidepressants
  • MAO inhibitors
  • COMT inhibitors
  • Clonidine
  • Doxapram
  • Oxytocin
  • Levothyroxine
  • Quinidine
  • Certain antihistamines

Increase Arrhythmogenic Risk (↑ risk of arrhythmias)​

Drugs that heighten epinephrine-induced cardiac irritability:

  • β-blockers
  • Cyclopropane & halogenated hydrocarbon anesthetics
  • Antihistamines
  • Exogenous thyroid hormones
  • Diuretics
  • Cardiac glycosides (e.g., digoxin)

Exacerbate Hypokalemia​

Drugs that worsen epinephrine-induced potassium loss:

  • Potassium-depleting agents: corticosteroids, diuretics, theophylline

Key Clinical Note: Monitor closely for arrhythmias, blood pressure changes, and electrolytes in patients on multiple interacting drugs. Adjust epinephrine dosing or timing as needed, and prioritize vital sign/arrhythmia surveillance.

Contraindications & Warnings​

Epinephrine has no absolute contraindications — administration is guided by clinical judgment, weighing life-saving benefits against potential risks in every case.

Relative Contraindications​

  • Hypersensitivity to sympathomimetic drugs
  • Closed-angle (narrow-angle) glaucoma
  • Anesthesia with halothane (or similar halogenated hydrocarbons)
  • Catecholaminergic polymorphic ventricular tachycardia (CPVT) — unique risk due to potential for life-threatening arrhythmias

Administration Warnings​

  • Avoid injection sites: Digits (fingers/toes), nose, penis, ears, or any tissues supplied by end arteries — high risk of ischemia and necrosis.
  • Extravasation: Closely monitor IV administration; extravasation can cause severe local tissue necrosis and sloughing.
  • Cardiovascular risks: May induce or worsen vasospasm, angina pectoris, or ischemia — use with extreme caution and close monitoring in patients with preexisting heart disease, coronary artery disease, or arrhythmias.

Special Guidance​

  • Allergen immunotherapy (per 2024 AAO-HNS guidelines): Do not initiate in patients who are:
    • Pregnant
    • Have uncontrolled asthma
    • Cannot tolerate injectable epinephrine

Always prioritize prompt use in true emergencies (e.g., anaphylaxis, cardiac arrest) despite these precautions, as withholding can be fatal. Monitor vital signs, ECG (if possible), and injection sites rigorously.

Special Considerations​

Hepatic Impairment​

No specific dosage adjustments recommended in product labeling.

Renal Impairment​

No specific dosage adjustments recommended in product labeling.

Pregnancy​

  • Standard ACLS dosing (1 mg IV/IO q3–5 min) generally applies during cardiac arrest; no routine adjustment needed despite physiologic changes.
  • Epinephrine preferred over vasopressin (Class IIb, Level C evidence).
  • β2-mediated tocolysis may oppose oxytocin and delay labor.
  • Caution in anaphylaxis-induced hypotension: potential uterine vasoconstriction may reduce fetal oxygen delivery.
  • Previous FDA category C — animal studies show possible teratogenic risk during organogenesis; crosses placenta.
  • Do not withhold life-saving treatment due to fetal concerns.
  • Caution if maternal BP ≥130/80 mm Hg.

Breastfeeding​

  • Poor oral bioavailability and short half-life → minimal infant exposure via breast milk.
  • High IV doses may reduce milk production or inhibit letdown.
  • Low-dose IM (e.g., EpiPen), epidural, topical, inhaled, or ophthalmic use unlikely to interfere.
  • For ophthalmic: apply nasolacrimal duct pressure for ≥1 min and wipe excess to minimize absorption.
  • Safe and first-line for anaphylaxis in breastfeeding individuals (same as non-breastfeeding).

Pediatric Patients​

  • Anaphylaxis (EAI dosing): ACAAI recommends 0.1 mg or 0.15 mg auto-injector for less than 15 kg (infants/young children).
  • Cardiac arrest (IV/IO): 0.01 mg/kg (0.1 mL/kg of 0.1 mg/mL solution); max 1 mg per dose; repeat q3–5 min as needed.

Older Adults (Geriatric)​

  • Start at the lower end of dosing range due to age-related declines in renal, hepatic, and cardiac function.
  • Titrate carefully based on clinical response and monitor closely for adverse effects (e.g., arrhythmias, hypertension).

Monitoring​

Epinephrine is a potent hormone requiring vigilant monitoring due to its broad physiological effects.

IV Administration​

  • Expect tachycardia and hypertension — titrate precisely with continuous hemodynamic monitoring (BP, HR, ECG).
  • Often combined with local anesthetics to prolong duration and enhance analgesia.

Extravasation Management​

  • Prevent ischemia/necrosis by careful IV technique.
  • If extravasation occurs: Immediately infiltrate the area with 10–15 mL saline containing 5–10 mg phentolamine (α-blocker) to reverse vasoconstriction.
  • Note: Vasopressor use (including epinephrine) in ICU settings is linked to finger ischemia in some hospitalized patients.

Renal Considerations​

  • Can cause renal vasoconstriction → reduced renal blood flow and urine output.
  • Use clinical judgment in patients with chronic kidney disease (CKD) or other renal pathologies; monitor closely for oliguria or worsening function.
  • Renalase (a kidney-produced enzyme) metabolizes epinephrine; deficiency in CKD may lead to prolonged/elevated epinephrine levels.

Intraocular Use​

  • Always dilute epinephrine before use to avoid corneal endothelial damage (risk from undiluted sodium bisulfite-containing formulations).

Other Effects​

  • Stimulates β2 receptors in skeletal muscle → increases lactate production; this can complicate interpretation of serum lactate in septic shock (may elevate lactate independently of tissue hypoperfusion).

In all scenarios, balance benefits against risks, monitor vital signs/labs closely, and intervene promptly for complications.

Toxicity​

Signs & Symptoms of Overdose​

Patients may experience severe pallor, cold skin, and metabolic acidosis due to elevated blood lactic acid levels. Complications are more likely in individuals with preexisting conditions.

Epinephrine overdose may lead to myocardial ischemia, infarction, renal insufficiency, and cardiomyopathy. Pulmonary edema may occur as a result of peripheral vasoconstriction and myocardial stimulation. Due to its strong β1-adrenergic effects on cardiac tissues toxicity can result in potentially fatal cardiac arrhythmias or ischemia due to its strong β1-adrenergic effects on cardiac tissue.

Epinephrine toxicity may also lead to fatal dysrhythmias, cardiac arrest, and significant cardiac morbidity.

Case reports have associated epinephrine toxicity with Takotsubo cardiomyopathy (Broken Heart Syndrome), causing the left ventricle to weaken and balloon.

Management of Overdose​

Respiratory support, α-adrenergic blockers, or vasodilators such as nitrites may be used to minimize to reduce vasoconstriction and improve vascular flow.

For potentially fatal cardiac arrhythmias or ischemia, β-adrenergic blocking agents should be administered.

Clinical Pearls​

The 'Drity Epi Drip'​

In an Emergency Code situation, the 'Dirty Epi Drip' may be used as a temporizing measure until your team can appropriately setup the infusion pump with a Pharmacy-made drip.

warning

Follow hospital protocols, and perform double-checks with another staff member.

  • Step 1: Grab your code-cart epinephrine. (Typically 1mg/10mL Syringe)

epinephriine_Syringe

  • Step 2: Inject the full 1 mg into a 1,000 mL Normal Saline Bag

epinephriine_DirtyEpiDrip

note

Final concentration 1 mcg/mL

  • Step 3: Run wide open in your peripheral IV or IO until the patient’s hemodynamics stabilize. Check pressures frequently and titrate (squeeze the bag, or roller-clamp the line) based on patient’s response.

The maximum rate of infusion will vary with catheter size, IV bag height, and squeeze on the bag. With a wide-open 18-gauge IV, the patient will receive ~20-30 mL/min (20-30 mcg/min) of epinephrine. This is similar to the recommended push-dose epinephrine (0.1 mg or 100 mcg over 5 minutes = 20 mcg per minute).