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

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.

Comparison of posttransplant outcomes in patients with no, acute, or chronic amiodarone use before heart transplantation

“…Also, the duration of amiodarone use before HTX might have an impact on posttransplant survival as the duration of amiodarone intake can influence the achievement of steady state as well as its half-life 12,13…”

“…Amiodarone is a very lipophilic drug with an extended volume of distribution and a slow clearance rate 2,13–15. Its half-life ranges from only a few hours in patients with a single dose, over a half-life of ~2 months in patients with short-term use, to a half-life of ~4 months in patients with long-term use 13–15.…”

“…Its half-life ranges from only a few hours in patients with a single dose, over a half-life of ~2 months in patients with short-term use, to a half-life of ~4 months in patients with long-term use 13–15. Therefore, even with initial oral loading doses of ~1,000 mg per day and/or intravenous administration, amiodarone may take several weeks to exert its optimal antiarrhythmic effects 9,12,13. Therefore, in patients with pretransplant amiodarone use, the cardiac allograft is exposed to amiodarone to a certain degree due to the above-mentioned properties 1,2.…”

“…Due to its slow distribution to tissue, amiodarone may take several weeks to months to reach steady-state tissue concentrations and exert optimal antiarrhythmic effects 12,13. Additionally, the reported half-life of amiodarone varies extremely, starting with a half-life of only a few hours in patients with a single dose, going up to a half-life of ~2 months in patients with short-term amiodarone use, and having the longest half-life of ~4 months in patients with long-term use of amiodarone 13–15.…”

“…Additionally, the reported half-life of amiodarone varies extremely, starting with a half-life of only a few hours in patients with a single dose, going up to a half-life of ~2 months in patients with short-term amiodarone use, and having the longest half-life of ~4 months in patients with long-term use of amiodarone 13–15. Therefore, meticulous differentiation between acute and chronic amiodarone use seems essential.…”