What is the mechanism of action of Amiodarone?

Mechanism of Action of Amiodarone

Amiodarone is a unique antiarrhythmic drug that exhibits properties of all four Vaughan Williams classes (I-IV), making it a broad-spectrum antiarrhythmic with multiple ion channel effects that collectively contribute to its potent antiarrhythmic efficacy. 1, 2

Primary Mechanisms

Amiodarone's complex mechanism of action includes:

1. Class I effects:

   • Blocks sodium channels, particularly at rapid pacing frequencies
   • Slows intracardiac conduction
   • Inhibits or terminates arrhythmias by influencing automaticity and re-entry 3

2. Class II effects:

   • Exerts noncompetitive antisympathetic action (beta-blocker-like effects)
   • Slows heart rate
   • Slows atrioventricular nodal conduction 1

3. Class III effects (predominant classification):

   • Blocks potassium channels that conduct repolarizing currents
   • Prolongs cardiac action potential duration and QT interval
   • Extends effective refractory period in cardiac tissues 3, 1

4. Class IV effects:

   • Blocks calcium channels
   • Further contributes to slowing of AV nodal conduction 1

Additional Mechanisms

• Vasodilatory effects: Decreases cardiac workload and myocardial oxygen consumption 1
• Thyroid effects: May antagonize triiodothyronine (T3) action on the heart at cellular levels, contributing to its long-term effects 4
• Genetic modulation: Chronic amiodarone may cause down-regulation of potassium channel gene expression (Kv1.5 mRNA) 4

Electrophysiological Impact

Amiodarone affects multiple cardiac parameters:

• Prolongs intranodal conduction (Atrial-His, AH)
• Increases refractoriness of the atrioventricular node (ERP AVN)
• At higher doses (>10 mg/kg), prolongs right ventricular effective refractory period (ERP RV)
• Causes modest QRS prolongation at higher doses 1

Acute vs. Chronic Effects

• Acute effects: Primarily focused on AV node, causing intranodal conduction delay and increased nodal refractoriness through calcium channel blockade and adrenergic antagonism 1
• Chronic effects: More pronounced class III effects with moderate action potential duration prolongation and minimal frequency dependence 4

Clinical Implications

• Despite QT interval prolongation, amiodarone rarely causes torsades de pointes compared to other class III antiarrhythmics 5
• Can be used safely in patients with left ventricular dysfunction, unlike many other antiarrhythmics 6
• Effective for both supraventricular and ventricular arrhythmias due to its broad spectrum of action 2

Important Considerations

• Amiodarone has extremely complex pharmacokinetics with a very long half-life (averaging 58 days) due to its high lipid solubility and extensive tissue distribution 3
• Its active metabolite, desethylamiodarone (DEA), also possesses antiarrhythmic properties similar to the parent compound 1
• Requires careful monitoring due to potential for serious adverse effects in multiple organ systems 6

Understanding amiodarone's complex mechanism of action explains both its remarkable efficacy against a wide range of arrhythmias and its unique safety profile compared to other antiarrhythmic agents.