Mechanism of Action of Amiodarone
Amiodarone works through multiple electrophysiologic mechanisms across all four Vaughan Williams antiarrhythmic classes, primarily acting as a class III agent that prolongs cardiac action potential and refractoriness, while also blocking sodium, potassium, and calcium channels and exerting noncompetitive antisympathetic effects. 1
Primary Electrophysiologic Effects
- Class III effects: Prolongs cardiac action potential and refractoriness by blocking myocardial potassium channels 2, 1
- Class I effects: Blocks sodium channels at rapid pacing frequencies 1
- Class II effects: Exerts noncompetitive antisympathetic action (beta-blocking properties) 1
- Class IV effects: Blocks calcium channels, contributing to negative chronotropic effects in nodal tissues 1
Specific Cardiac Effects
Conduction System Effects
- Slows heart rate and atrioventricular nodal conduction through calcium channel and beta-receptor blockade 2
- Prolongs refractoriness through potassium and sodium channel blockade 2
- Slows intracardiac conduction through sodium channel blockade 2
- Prolongs intranodal conduction (Atrial-His) and refractoriness of the atrioventricular node 1
Vascular Effects
- Acts as a coronary and peripheral vasodilator 3
- Decreases cardiac workload and consequently myocardial oxygen consumption 1
Unique Pharmacokinetic Properties
- Highly lipid soluble, stored in high concentrations in fat, muscle, liver, lungs, and skin 2
- Extremely long elimination half-life (average 58 days) due to slow release from lipid-rich tissues 2
- Major active metabolite is desethylamiodarone (DEA), which also has antiarrhythmic properties 2, 1
- Metabolized primarily by cytochrome P450 enzymes (CYP3A4 and CYP2C8) 1
Clinical Implications of Mechanism
- The complex multi-channel blocking properties make amiodarone effective for both ventricular and supraventricular arrhythmias 3
- Unlike other class III agents, amiodarone rarely causes torsades de pointes despite QT prolongation 3
- Can be used in patients with left ventricular dysfunction due to minimal negative inotropic effects 3
- Initial acute effects after IV administration are predominantly focused on the AV node 1
Important Clinical Considerations
- The multiple mechanisms of action contribute to amiodarone's effectiveness but also explain its numerous drug interactions and side effects 4
- Routine monitoring of plasma levels is not recommended due to complex pharmacokinetics 2
- Drug interactions occur through inhibition of multiple cytochrome P450 pathways (including CYP2C9, CYP2D6, and CYP3A4) 2
- Despite QT interval prolongation, polymorphic ventricular tachycardia (torsades de pointes) is rare 2
Amiodarone's complex and multifaceted mechanism of action explains both its remarkable efficacy against a wide range of arrhythmias and its extensive side effect profile that requires careful monitoring during long-term therapy.