From the Guidelines
Amiodarone works primarily as a class III antiarrhythmic drug that blocks potassium channels, prolonging cardiac action potential duration and effective refractory period, and also exhibits properties of all four Vaughan Williams antiarrhythmic classes, including blocking sodium channels, having beta-blocking properties, blocking calcium channels, and inhibiting adrenergic stimulation 1.
Mechanism of Action
The mechanism of action of amiodarone is complex and involves multiple effects on the heart, including:
- Blocking potassium channels, which prolongs cardiac action potential duration and effective refractory period
- Blocking sodium channels (class I effect)
- Having beta-blocking properties (class II)
- Blocking calcium channels (class IV)
- Inhibiting adrenergic stimulation (non-competitive alpha and beta blockade) This multifaceted mechanism of action makes amiodarone effective for various arrhythmias, including both supraventricular and ventricular arrhythmias.
Pharmacokinetics
Amiodarone accumulates in tissues due to its high lipophilicity, creating a large volume of distribution and extremely long half-life (25-100 days) 1. This explains its delayed onset of action and persistent effects after discontinuation.
Dosage and Administration
Amiodarone is typically initiated with a loading dose of 800-1600 mg daily for 1-3 weeks, followed by maintenance doses of 200-400 mg daily 1. The dosage should be kept at the lowest effective level to minimize side effects.
Side Effects and Monitoring
Due to its multiple mechanisms and broad spectrum of activity, amiodarone carries significant side effect risks, including:
- Thyroid dysfunction
- Pulmonary fibrosis
- Liver toxicity
- Corneal deposits
- Photosensitivity Regular monitoring of thyroid, liver, and pulmonary function is necessary to minimize the risk of these side effects 1.
Clinical Use
Amiodarone is effective for various arrhythmias, but its use should be carefully considered due to its potential side effects and interactions with other medications 1. It is often used as a second-line treatment for patients who are suitable for other antiarrhythmic drugs.
From the FDA Drug Label
CLINICAL PHARMACOLOGY Mechanisms of Action Amiodarone is generally considered a class III antiarrhythmic drug, but it possesses electrophysiologic characteristics of all four Vaughan Williams classes. Like class I drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like class II drugs, it exerts a noncompetitive antisympathetic action One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, a class III effect. The negative chronotropic effect of amiodarone in nodal tissues is similar to the effect of class IV drugs. In addition to blocking sodium channels, amiodarone blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness The antisympathetic action and the block of calcium and potassium channels are responsible for the negative dromotropic effects on the sinus node and for the slowing of conduction and prolongation of refractoriness in the atrioventricular (AV) node.
The mechanism of action of amiodarone is multifaceted and can be classified into several categories:
- Class I effect: blocks sodium channels at rapid pacing frequencies
- Class II effect: exerts a noncompetitive antisympathetic action
- Class III effect: lengthens the cardiac action potential with prolonged administration
- Class IV effect: negative chronotropic effect in nodal tissues, similar to class IV drugs Amiodarone also blocks myocardial potassium channels, contributing to slowing of conduction and prolongation of refractoriness, and has a vasodilatory action that can decrease cardiac workload and myocardial oxygen consumption 2
From the Research
Mechanism of Action of Amiodarone
The mechanism of action of amiodarone is complex and involves multiple effects on the cardiac action potential. Some key aspects of its mechanism include:
- Inhibition of inward and outward currents, including sodium and calcium currents (I(Na), I(Ca)) 3
- Inhibition of voltage- and ligand-gated potassium channel currents (I(K), I(K,Na), I(K,ACh)) 3
- Prolongation of the action potential duration (APD) with minimal frequency dependence 3
- Decrease in the current density of I(K) and I(to) 3
- Down-regulation of Kv1.5 messenger ribonucleic acid (mRNA) in rat hearts 3
Ion Channel Basis of Amiodarone's Effects
Amiodarone's effects on myocardial electrophysiological properties are primarily due to its blockade of the rapidly activating delayed rectifier potassium current (IKr) 4. This blockade delays the repolarization phase of the action potential and extends the effective refractory period. However, unlike other class III antiarrhythmic drugs, amiodarone has a lower risk of inducing long QT syndrome (LQTS) and torsade de pointes 4.
Frequency-Dependent Effects of Amiodarone
Amiodarone's effects on atrioventricular nodal function and slow-channel action potentials are frequency-dependent 5. The drug increases atrioventricular conduction time (AVCT) and refractory period (AVERP) in a use- and voltage-dependent manner, resulting in suppression of excitability and conductivity of cardiac tissues especially when stimulated at higher frequencies [(3,5)]. This frequency dependence is thought to be due to amiodarone's calcium channel-blocking activity 5.