Mechanism of action
Adrenaline is a direct-acting sympathomimetic that binds to all adrenergic receptor subtypes—α1, α2, β1, and β2—with varying affinity depending on dose and site of action.
Receptor effects
α1-adrenergic activation causes vasoconstriction in the skin, mucosa, and splanchnic circulation, increasing systemic vascular resistance and blood pressure. This is the mechanism underlying its use in anaphylaxis and shock.
β1-adrenergic activation increases heart rate (positive chronotropy), contractility (positive inotropy), and conduction velocity (positive dromotropy), making adrenaline valuable in cardiac arrest and symptomatic bradycardia.
β2-adrenergic activation produces bronchodilation and inhibits mast cell degranulation, which is critical in anaphylaxis and severe asthma exacerbations. β2 effects also cause skeletal muscle vasodilation and inhibit uterine contractions.
α2-adrenergic activation decreases insulin secretion and inhibits noradrenaline release from presynaptic nerve terminals.
Dose-dependent effects
At low doses, β effects (especially β2 vasodilation) predominate; at higher doses, α-mediated vasoconstriction becomes dominant. This dose-response relationship is a classic exam concept.
- Adrenaline is the ONLY drug proven to reduce mortality in anaphylaxis; give IM into anterolateral thigh immediately.
- Non-selective β-blockers (propranolol) + adrenaline → unopposed α-stimulation → severe hypertension and bradycardia.
- 1:1000 concentration (1 mg/mL) is for IM use; 1:10,000 (0.1 mg/mL) is for IV cardiac arrest; confusing them is a fatal error.
- β2 effects: bronchodilation, vasodilation, hyperglycemia, hypokalemia, tocolysis, tremor.
- α1 effects: vasoconstriction (↑ SVR, ↑ BP), mydriasis, decreased GI motility.
- Adrenaline increases myocardial O₂ demand (β1) while potentially decreasing coronary flow (α1) → risk of MI in CAD.
- Extravasation → tissue necrosis; antidote is phentolamine (α-blocker) infiltrated locally.
- Volatile anesthetics (halothane) sensitize myocardium to adrenaline → ventricular arrhythmias.
- Epinephrine reversal: adrenaline + α-blocker → unopposed β2 vasodilation → profound hypotension (classic exam trap).
Indications
Adrenaline is used in acute, life-threatening conditions where rapid adrenergic stimulation is required.
- Anaphylaxis: First-line treatment; IM administration into the anterolateral thigh reverses bronchospasm, laryngeal edema, and cardiovascular collapse
- Cardiac arrest: Used in advanced cardiac life support (ACLS) for ventricular fibrillation, pulseless ventricular tachycardia, asystole, and pulseless electrical activity
- Severe bronchospasm: Adjunct in life-threatening asthma or status asthmaticus unresponsive to inhaled β2-agonists
- Distributive shock: Vasopressor support in septic, neurogenic, or anaphylactic shock
- Local anesthesia: Combined with local anesthetics to prolong duration and reduce systemic absorption via vasoconstriction
- Superficial bleeding: Topical hemostasis in mucosal bleeding (e.g., epistaxis, gastrointestinal endoscopy)
- Acute hypotension: Symptomatic bradycardia with hypotension unresponsive to atropine
- Glaucoma: Rarely used topically to lower intraocular pressure in open-angle glaucoma
Pharmacokinetics
Adrenaline is a catecholamine with rapid onset and short duration of action.
Absorption: Ineffective orally due to extensive first-pass metabolism. IM injection (preferred route in anaphylaxis) produces peak plasma levels in 5-10 minutes. IV infusion provides immediate effect. Subcutaneous absorption is slower and less predictable. Inhaled formulations are used for bronchospasm.
Distribution: Does not cross the blood-brain barrier in significant amounts. Distributes rapidly to highly perfused organs (heart, liver, kidneys).
Metabolism: Rapidly metabolized by catechol-O-methyltransferase (COMT) in the liver and monoamine oxidase (MAO) in neuronal tissue. Metabolites include metanephrine and vanillylmandelic acid (VMA), which are excreted renally. Plasma half-life is approximately 2-3 minutes after IV administration.
Excretion: Renal elimination of inactive metabolites. Duration of action after IM injection is 10-20 minutes; IV infusion effects cease within minutes of discontinuation.
Adverse effects
Adrenaline's adverse effects are extensions of its adrenergic activity and are dose-dependent.
Cardiovascular
- Tachycardia and palpitations (β1 stimulation)
- Hypertension (α1 vasoconstriction); may precipitate hypertensive crisis
- Arrhythmias: Ventricular ectopy, ventricular tachycardia, atrial fibrillation (especially with hypoxia or volatile anesthetics)
- Myocardial ischemia or infarction: Increased myocardial oxygen demand (β1) plus coronary vasoconstriction (α1) in patients with coronary artery disease
- Pulmonary edema: Rare, from acute left ventricular dysfunction
Neurological
- Anxiety, tremor, headache, dizziness (central and peripheral β stimulation)
- Cerebral hemorrhage: Reported with severe hypertension
Metabolic
- Hyperglycemia: Increased glycogenolysis and gluconeogenesis, decreased insulin secretion (α2)
- Hypokalemia: β2-mediated intracellular potassium shift
- Lactic acidosis: From β2-mediated increased glycolysis
Local
- Tissue necrosis: If extravasation occurs during IV infusion (α1 vasoconstriction); phentolamine is the antidote
- Prolonged vasoconstriction: Avoid in digits, penis, nose, and ears when used with local anesthetics
Other
- Acute angle-closure glaucoma: Risk with ophthalmic use in susceptible patients
- Rebound nasal congestion: With prolonged topical nasal use
Contraindications and warnings
Absolute contraindications
There are no absolute contraindications to adrenaline in life-threatening emergencies such as anaphylaxis or cardiac arrest. The benefit outweighs all risks.
Relative contraindications and cautions
Outside of emergencies, use with caution in:
- Coronary artery disease: Risk of myocardial ischemia or infarction from increased oxygen demand and potential coronary vasoconstriction
- Uncontrolled hypertension: May precipitate hypertensive crisis or cerebrovascular accident
- Hyperthyroidism: Enhanced sensitivity to catecholamines
- Pheochromocytoma: May trigger severe hypertension (although adrenaline may be used diagnostically)
- Angle-closure glaucoma: Ophthalmic use may increase intraocular pressure
- Cerebrovascular disease: Risk of hemorrhagic stroke with acute hypertension
- Elderly patients: Increased cardiovascular sensitivity
- Pregnancy: Not contraindicated in anaphylaxis, but may delay second stage of labor (β2 tocolysis) and reduce placental blood flow (α1 vasoconstriction)
Drug-specific warnings
- Volatile anesthetics (halothane, isoflurane) sensitize the myocardium to catecholamine-induced arrhythmias
- Sulfite sensitivity: Some formulations contain sodium metabisulfite as a preservative, which may cause allergic reactions in susceptible individuals
- Ensure correct concentration and route; dosing errors (especially confusing 1:1000 and 1:10,000 concentrations) can be fatal
Drug interactions
Major interactions
Non-selective β-blockers (propranolol, nadolol): Unopposed α-adrenergic stimulation leads to severe hypertension, reflex bradycardia, and possible coronary vasospasm. Paradoxical hypertensive response is a classic exam scenario. Cardioselective β-blockers (metoprolol, atenolol) carry lower but still significant risk.
Monoamine oxidase inhibitors (MAOIs): Inhibit metabolism of catecholamines, prolonging and intensifying adrenaline's effects. Risk of hypertensive crisis. Allow 14 days washout after MAOI discontinuation.
Tricyclic antidepressants (TCAs): Potentiate pressor response by blocking neuronal reuptake of catecholamines. Risk of severe hypertension and arrhythmias.
Volatile anesthetics: Halogenated hydrocarbons (halothane, enflurane, isoflurane) sensitize the myocardium to catecholamines, increasing arrhythmia risk.
Cocaine and amphetamines: Potentiate sympathomimetic effects; risk of severe hypertension, myocardial ischemia, and arrhythmias.
Moderate interactions
α-adrenergic blockers (phentolamine, prazosin): Antagonize α-mediated vasoconstriction, reducing adrenaline's pressor effect and unmasking β2 vasodilation. This is the mechanism of epinephrine reversal: when adrenaline is given to a patient on an α-blocker, unopposed β2-mediated vasodilation causes profound hypotension instead of the expected rise in blood pressure.
Antimuscarinics (atropine): Additive tachycardia.
Thyroid hormones: Enhance cardiovascular sensitivity to catecholamines.
Ergot alkaloids: Risk of severe peripheral vasoconstriction and gangrene.
Diuretics and antihypertensives: Adrenaline may antagonize their blood pressure-lowering effects.
Insulin and oral hypoglycemics: Adrenaline increases blood glucose (α2 and β2 effects), potentially requiring dose adjustment.
Clinical pearls
- IM injection into the anterolateral thigh is the preferred route in anaphylaxis; absorption is more rapid and reliable than subcutaneous or deltoid injection. Delayed administration is the leading cause of anaphylaxis fatalities.
- Adrenaline auto-injectors (e.g., EpiPen) deliver 0.3 mg (0.15 mg for children <25 kg). A second dose may be given after 5-15 minutes if symptoms persist. Advise patients to activate emergency services immediately after use.
- Concentrations: 1:1000 (1 mg/mL) is used for IM injection; 1:10,000 (0.1 mg/mL) is used for IV bolus in cardiac arrest. Confusion between these concentrations is a common medication error.
- Cardiac arrest dosing: IV/IO bolus every 3-5 minutes during ACLS; no maximum dose. Early defibrillation and high-quality CPR are more important than drug therapy in shockable rhythms.
- β-blocker interaction: If a patient on a non-selective β-blocker develops anaphylaxis, adrenaline may be less effective. Consider glucagon (activates adenylyl cyclase independently of β-receptors) as an alternative inotrope and bronchodilator.
- Extravasation management: If IV adrenaline extravasates, infiltrate the area with phentolamine (α-antagonist) diluted in saline to reverse local vasoconstriction and prevent necrosis.
- Epinephrine reversal: A classic exam concept where adrenaline given to a patient on an α-blocker (e.g., phenoxybenzamine, phentolamine) causes profound hypotension rather than hypertension. With α-receptors blocked, unopposed β2-mediated vasodilation predominates, leading to a paradoxical drop in blood pressure.
- Racemic adrenaline (nebulized) is used off-label for croup (laryngotracheobronchitis) to reduce subglottic edema, but effects are temporary and rebound edema may occur.
- End-tidal CO₂ monitoring during cardiac arrest: A sudden rise in ETCO₂ during CPR may indicate return of spontaneous circulation and is a more reliable sign than pulse checks alone.
- Avoid in digital nerve blocks: Never use adrenaline-containing local anesthetics in areas with end-arterial blood supply (fingers, toes, penis, nose, ears) due to risk of ischemic necrosis.
β2 effects = 2 B's: Bronchodilation, Blood sugar ↑ (and hypokalemia, tremor, vasodilation). The rest are β1 (heart) and α1 (vasoconstriction).
Practice questions
1. A 28-year-old woman develops facial swelling, urticaria, and wheezing 5 minutes after eating shellfish at a restaurant. Her blood pressure is 85/50 mmHg, heart rate is 120/min, and respiratory rate is 28/min. Auscultation reveals bilateral wheezing. Which of the following is the most appropriate initial pharmacologic treatment?
2. A 65-year-old man with a history of hypertension treated with propranolol is stung by a bee and develops generalized urticaria, throat tightness, and hypotension. Paramedics administer IM adrenaline, but his blood pressure increases to 210/110 mmHg and heart rate decreases to 48/min. Which of the following best explains the hemodynamic response?
3. A 45-year-old woman undergoing general anesthesia with isoflurane develops ventricular tachycardia shortly after the surgeon infiltrates the surgical site with lidocaine containing adrenaline. Which of the following best explains the mechanism of this arrhythmia?
Frequently asked questions
How does adrenaline work?
Adrenaline is a non-selective adrenergic agonist that activates α1, α2, β1, and β2 receptors. α1 activation causes vasoconstriction and increased blood pressure. β1 activation increases heart rate and contractility. β2 activation produces bronchodilation and vasodilation in skeletal muscle, and also inhibits mast cell degranulation. These combined effects make it life-saving in anaphylaxis and cardiac arrest.
What are the side effects of adrenaline?
Common side effects include tachycardia, palpitations, hypertension, anxiety, tremor, and headache. Serious adverse effects include ventricular arrhythmias, myocardial ischemia or infarction (especially in patients with coronary artery disease), hypertensive crisis, cerebral hemorrhage, pulmonary edema, hyperglycemia, and hypokalemia. Extravasation during IV infusion can cause tissue necrosis. In life-threatening emergencies like anaphylaxis, the benefits far outweigh these risks.
Is adrenaline a controlled substance?
No, adrenaline (epinephrine) is not a controlled substance in the United States or most other countries. It is available by prescription as auto-injectors, vials for injection, and nebulizer solutions. Some jurisdictions allow limited over-the-counter access to adrenaline auto-injectors. It is considered an essential emergency medication and is included on the WHO Model List of Essential Medicines.
Adrenaline vs noradrenaline — what is the difference?
Adrenaline (epinephrine) is a non-selective agonist at α1, α2, β1, and β2 receptors, causing vasoconstriction, increased cardiac output, and bronchodilation. Noradrenaline (norepinephrine) is primarily an α1 and β1 agonist with minimal β2 activity, producing potent vasoconstriction and increased blood pressure with less chronotropy and no bronchodilation. Clinically, adrenaline is preferred in anaphylaxis and cardiac arrest, while noradrenaline is the first-line vasopressor in septic shock.
Why is adrenaline given in the thigh for anaphylaxis?
Intramuscular injection into the anterolateral thigh (vastus lateralis muscle) provides rapid and reliable absorption compared to subcutaneous or deltoid injection. The thigh has greater muscle mass and blood flow, leading to faster drug delivery and onset of action. This route is critical because delayed adrenaline administration is the leading cause of anaphylaxis deaths. The dose can be repeated every 5-15 minutes if needed.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: C01CA24WHO ATC/DDD index: A01AD01
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.