Amiodarone: Ionic and cellular mechanisms of action of the most promising class III agent

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 remain s to be clarified about its short- and long-term actions on multiple molecu lar targets, This article reviews electrophysiologic effects of amiodarone based on previous reports and our own experiments in single cells and multi cellular tissue preparations of mammalian hearts. As acute effects, amiodar one inhibits both inward and outward currents. The inhibition of inward sod ium and calcium currents (I-Na, I-Ca) is enhanced in a use- and voltage-dep endent manner, resulting in suppression of excitability and conductivity of cardiac tissues especially when stimulated at higher frequencies and in th ose with less-negative membrane potential. Both voltage- and ligand-gated p otassium channel currents (I-K, I-K,I-Na, I-K,I-ACh) are also inhibited at therapeutic levels of drug concentrations, Acutely-administered amiodarone has no consistent effect an 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 mast likely due to a decrease in the current density of I-K and I-to. Chronic amiodarone was s hown to cause a down-regulation of Kv1.5 messenger ribonucleic acid (mRNA) in rat hearts, suggesting a drug-induced modulation of potassium-channel ge ne expression. Tissue accumulation of amiodarone and its active metabolite (desethylamiodarone) may modulate the chronic effects, causing variable sup pression of excitability and conductivity of the heart through the direct e ffects of the compounds retained at the sites of action. Amiodarone and des ethylamiodarone could antagonize triiodothyronine (T-3) action on the heart at cellular or subcellular levels, leading to phenotypic resemblance of lo ng-term amiodarone treatment and hypothyroidism. (C)1999 by Excerpta Medica , Inc.