Original Articles
Amiodarone: ionic and cellular mechanisms of action of the most promising class III agent

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Abstract

Amiodarone is the most promising drug in the treatment of life-threatening ventricular tachyarrhythmias in patients with significant structural heart disease. The pharmacologic profile of amiodarone is complex and much remains to be clarified about its short- and long-term actions on multiple molecular targets. This article reviews electrophysiologic effects of amiodarone based on previous reports and our own experiments in single cells and multicellular tissue preparations of mammalian hearts. As acute effects, amiodarone inhibits both inward and outward currents. The inhibition of inward sodium and calcium currents (INa, ICa) is enhanced in a use- and voltage-dependent manner, resulting in suppression of excitability and conductivity of cardiac tissues especially when stimulated at higher frequencies and in those with less-negative membrane potential. Both voltage- and ligand-gated potassium channel currents (IK, IK,Na, IK,ACh) are also inhibited at therapeutic levels of drug concentrations. Acutely-administered amiodarone has no consistent effect on the action potential duration (APD). The major and consistent long-term effect of the drug is a moderate APD prolongation with minimal frequency dependence. This prolongation is most likely due to a decrease in the current density of IK and Ito. Chronic amiodarone was shown to cause a down-regulation of Kv1.5 messenger ribonucleic acid (mRNA) in rat hearts, suggesting a drug-induced modulation of potassium-channel gene expression. Tissue accumulation of amiodarone and its active metabolite (desethylamiodarone) may modulate the chronic effects, causing variable suppression of excitability and conductivity of the heart through the direct effects of the compounds retained at the sites of action. Amiodarone and desethylamiodarone could antagonize triiodothyronine (T3) action on the heart at cellular or subcellular levels, leading to phenotypic resemblance of long-term amiodarone treatment and hypothyroidism.

Section snippets

Acute effects of amiodarone

In cardiac cells or tissues whose excitation depends on activation of fast sodium channels, the most consistent change of action potential configuration elicited by acute application of amiodarone is a decrease of the maximum upstroke velocity (Vmax). This Vmax inhibition is enhanced in a frequency- or use-dependent manner like class I antiarrhythmic drugs.24, 25, 26, 27, 28, 29 Onset and offset kinetics of the use-dependent Vmax inhibition are relatively rapid. The recovery time constant (tR)

Chronic effects of amiodarone

The most prominent effect of chronic amiodarone on action potentials of cardiac cells is the prolongation of APD (class III action). This has been confirmed in the working myocardium (atrial and ventricular muscles) as well as in specialized conducting systems (sinoatrial node, atrioventricular nodes, and Purkinje fibers) in a variety of animal species.18 Regarding the class I action of chronic amiodarone, there is a considerable controversy among investigators. Some studies showed

Amiodarone and thyroid hormones

One molecule of amiodarone contains 2 iodine atoms comprising 37% of total molecular weight, and it shares some structural analogies with thyroid hormones.21, 61 Cardiac effects of amiodarone are similar to those seen in hypothyroidism in many aspects22, 61: a prolongation of APD and the refractory period of all cardiac tissues, bradycardia, reduced myocardial oxygen consumption, reduced myocardial β-adrenergic receptor density, prolonged systolic interval, decreased Ca2+-ATPase activity,

Conclusions

This review has pointed out fundamental differences between acute and chronic effects of amiodarone on the electrophysiologic properties of cardiac cells. As an acute effect, amiodarone inhibits both inward and outward currents. The inhibition of inward sodium and calcium currents is enhanced in a use- and voltage-dependent manner, resulting in the suppression of excitability and conductivity in both INa- and ICa-dependent cardiac tissues. The inhibition is greater in the tissues stimulated at

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