What is the mechanism of action of adrenaline (epinephrine)?

Mechanism of Action of Adrenaline (Epinephrine)

Adrenaline acts on both alpha and beta-adrenergic receptors throughout the body, producing dose-dependent cardiovascular, respiratory, and metabolic effects that are critical for treating life-threatening conditions like anaphylaxis and cardiac arrest. 1

Receptor Binding and Primary Actions

Adrenaline is a non-selective adrenergic agonist that binds to multiple receptor subtypes with varying affinities 1, 2:

• Alpha-1 adrenergic receptors: Causes vasoconstriction, increases peripheral vascular resistance, and decreases mucosal edema 3, 1
• Beta-1 adrenergic receptors: Increases heart rate (chronotropic effect), enhances cardiac contractility (inotropic effect), improves cardiac conduction, and increases cardiac output 3, 4, 5
• Beta-2 adrenergic receptors: Produces bronchodilation through relaxation of bronchial smooth muscle, causes vasodilation in skeletal muscle and coronary vessels, and decreases release of inflammatory mediators from mast cells and basophils 3, 4

Dose-Dependent Receptor Effects

The clinical effects of adrenaline vary dramatically based on dosing, creating a biphasic hemodynamic response 4, 6:

Low-Dose Effects (<0.3 mcg/kg/min)

• Predominantly beta-adrenergic activity with beta-2 effects being most prominent 4, 6
• Decreases systolic and diastolic blood pressure through beta-2 mediated vasodilation 4, 6
• Increases heart rate and cardiac output 4
• Decreases systemic vascular resistance 4, 6

High-Dose Effects (>0.3 mcg/kg/min)

• Alpha-adrenergic effects become dominant 4, 6
• Causes significant vasoconstriction and increased blood pressure 4, 6
• May trigger DNA damage and suppress p53 levels through β-arrestin-mediated pathways, leading to inflammation 3
• Can cause calcium overload and bioenergetic compromise with persistent sympathoexcitation 3

Specific Organ System Effects

Cardiovascular System

• Increases myocardial oxygen demand through enhanced heart rate and contractility 5
• Improves coronary blood flow through beta-2 mediated coronary vasodilation 4
• Increases both inotropy and chronotropy via beta-1 receptor stimulation 3, 4

Respiratory System

• Relaxes bronchial smooth muscle, alleviating bronchospasm, wheezing, and dyspnea 1
• This beta-2 effect is critical in anaphylaxis management 3

Metabolic Effects

• Increases glycogenolysis and reduces glucose uptake by tissues 1
• Inhibits insulin release from the pancreas, resulting in hyperglycemia 1
• Increases blood lactic acid levels 1

Other Smooth Muscle Effects

• Relaxes smooth muscle of the stomach, intestine, uterus, and urinary bladder 1
• Alleviates pruritus, urticaria, and angioedema in anaphylaxis 1
• Causes mydriasis when administered parenterally 1

Critical Clinical Considerations

Pharmacokinetics

• Rapid onset of action within minutes but is rapidly metabolized, resulting in short duration of effect 3, 1
• Repeated dosing may be necessary every 5-15 minutes for ongoing symptoms 3
• 10-20% of patients receiving epinephrine for anaphylaxis require more than one dose 3

Potential Adverse Effects from Mechanism

• Beta-adrenergic stimulation through β-arrestin pathways can trigger DNA damage and inflammation with prolonged use 3
• High-dose administration may cause immunosuppression and promote bacterial outgrowth 3
• Can induce contraction band necrosis in the myocardium, particularly post-resuscitation 3
• May increase myocardial oxygen consumption adversely in the post-resuscitation period 3

Drug Interactions Affecting Mechanism

• Beta-blockers significantly alter epinephrine's effects: Non-selective beta-blockers block both beta-1 and beta-2 receptors, potentially leaving alpha effects unopposed and causing paradoxical hypertension 4
• Epinephrine should be used with extreme caution in patients taking beta-blockers, particularly in anaphylaxis 4
• Risks are heightened when administering adrenaline to patients with cardiac arrest provoked by cocaine or other sympathomimetic drugs 3

Mechanism-Based Therapeutic Rationale

• Epinephrine is the only first-line treatment for anaphylaxis because its broad receptor activity addresses multiple pathophysiologic mechanisms simultaneously 3
• No other single drug provides the combination of vasoconstriction, bronchodilation, cardiac support, and mast cell stabilization 3
• Antihistamines and corticosteroids are adjunctive only, with little data supporting their effectiveness in anaphylaxis 3