Basic and Clinical Pharmacology of Amiodarone: Relationship of Antiarrhythmic Effects, Dose and Drug Concentrations to Intracellular Inclusion Bodies

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Abstract
Amiodarone is a unique class III antiarrhythmic drug with several unusual pharmacokinetic, pharmacodynamic, and toxicological actions which are quite distinct from those of the standard antiarrhythmic drugs. Extensive animal and clinical studies have demonstrated that amiodarone and its major metabolite, desethylamiodarone, both produce a marked increase in the duration of transmembrane action potential which may be related to their antiarrhythmic as well as clinical electrophysiological activity. Unlike most other cardiovascular drugs, it has been recognized for more than 20 years that optimal antiarrhythmic effects may take several days to weeks after onset of oral therapy. Amiodarone is highly lipid soluble and exhibits at least three separate compartments of drug distribution, with a long elimination half‐life of 14–120 days after chronic therapy. The pharmacokinetic profile of desethylamiodarone is qualitatively similar to that of amiodarone, but its elimination half‐life is even longer and its tissue distribution may be slightly different. Although there may not be any correlation between serum drug levels and clinical toxicity of amiodarone during long‐term therapy, recent animal as well as clinical data suggest that multilamellar intracellular inclusions can be dissociated from cell death or clinical toxicity. Thus, it is possible that amiodarone toxicity can be minimized with low doses or low serum drug concentrations. The metabolite(s) of amiodarone may play a major role in its pharmacological and toxicological actions.