Electropharmacology of amiodarone: absence of relationship to serum, myocardial, and cardiac sarcolemmal membrane drug concentrations.

Plasma concentrations are often of major consideration in the evaluation of therapeutic efficacy of cardiovascular drugs. This approach is based on the assumptions that the concentration of the drug in the cardiac muscle is in equilibrium with the plasma drug level and that pharmacologic efficacy is proportional to the myocardial drug concentration. The more pronounced pharmacologic efficacy of amiodarone following chronic administration, despite low plasma drug concentrations, and the lesser effects of the drug after acute intravenous administration, when drug levels are maximum, has not been explained on the basis of the pharmacokinetic behavior of the drug. Data obtained from the transmembrane action potential recordings from rabbit ventricular myocardium were therefore correlated with drug concentrations in the serum, myocardium, and myocardial sarcolemma following acute intravenous administration and after 4 weeks of oral administration of 20 mg/kg/day of amiodarone. Following 15 minutes of acute drug administration, when amiodarone concentrations were maximal in the serum (4.72 +/- 1.23 micrograms/ml), cardiac muscle (34.5 +/- 7.6 micrograms/gm), and sarcolemma (1.94 mg/gm protein), the electrophysiologic changes were insignificant. However, following chronic treatment, when levels of amiodarone were low in the serum (0.05 +/- 0.01 micrograms/ml amiodarone, 0.25 +/- 0.08 micrograms/ml desethylamiodarone), cardiac muscle (1.91 +/- 0.9 micrograms/gm amiodarone, 1.35 +/- 1.33 micrograms/gm desethylamiodarone), and myocardial membranes (0.043 mg/gm protein [amiodarone], 0.097 mg/gm protein [desethylamiodarone], there was a 54.3% increase in action potential duration at 90% repolarization (p less than 0.01) and 65% increase in the effective refractory period (p less than 0.01) of rabbit ventricular myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)