What is the mechanism of action (MOA) of Amiodarone?

Mechanism of Action of Amiodarone

Amiodarone has a broad spectrum of action that includes blockade of depolarizing sodium currents and potassium channels that conduct repolarizing currents, which inhibits or terminates ventricular arrhythmias by influencing automaticity and re-entry. 1

Comprehensive Electrophysiologic Effects

Amiodarone is classified as a class III antiarrhythmic drug according to the Vaughan Williams classification, but it uniquely possesses electrophysiologic characteristics of all four classes:

1. Class I effects:

   • Blocks sodium channels at rapid pacing frequencies
   • Slows intracardiac conduction

2. Class II effects:

   • Exerts noncompetitive antisympathetic action (beta-blocking effects)
   • Contributes to slowing of heart rate

3. Class III effects:

   • Blocks myocardial potassium channels
   • Lengthens cardiac action potential (main effect with prolonged administration)
   • Prolongs refractoriness in all cardiac tissues

4. Class IV effects:

   • Produces negative chronotropic effects in nodal tissues similar to calcium channel blockers
   • Slows conduction in the AV node 2

Specific Cellular and Tissue Effects

Amiodarone's actions at the cellular level include:

• Prolongation of the duration of action potential in all cardiac fibers with minimal reduction of maximal upstroke velocity
• Prolongation of the refractory period in all cardiac tissues
• Increasing cardiac refractory period without influencing resting membrane potential (except in automatic cells)
• Reduction of the slope of prepotential in automatic cells, generally reducing automaticity 2

These electrophysiologic effects manifest clinically as:

• Decreased sinus rate by 15-20%
• Increased PR and QT intervals by about 10%
• Development of U-waves
• Changes in T-wave contour 2

Hemodynamic Effects

Unlike many other antiarrhythmic drugs, amiodarone has unique hemodynamic properties:

• Relaxes vascular smooth muscle
• Reduces peripheral vascular resistance (afterload)
• Slightly increases cardiac index after intravenous administration
• Can be used without increasing mortality in patients with heart failure, unlike sodium channel blockers 1, 2
• Produces no significant change in left ventricular ejection fraction after oral dosing, even in patients with depressed LVEF 2

Clinical Implications of MOA

The complex mechanism of action explains why amiodarone:

• Is effective against a wide range of arrhythmias (both ventricular and atrial)
• Has a delayed onset of action (effects on abnormal rhythms typically not seen before 2-3 days and usually require 1-3 weeks)
• Demonstrates persistent antiarrhythmic effects for weeks or months after discontinuation 2

Important Considerations

• Despite QT interval prolongation, amiodarone rarely causes torsades de pointes compared to other QT-prolonging antiarrhythmics
• The drug has a very long half-life (averaging about 58 days) due to its high lipid solubility and slow release from tissue stores 2
• Amiodarone's vasodilatory action can decrease cardiac workload and consequently myocardial oxygen consumption 2

Understanding amiodarone's complex mechanism of action is essential for appropriate clinical use and explains both its remarkable efficacy and unique side effect profile in the management of cardiac arrhythmias.