EFFECTS OF NONSEDATING ANTIHISTAMINE, ASTEMIZOLE, ON THE IN-SITU CANINE HEART ASSESSED BY CARDIOHEMODYNAMIC AND MONOPHASIC ACTION-POTENTIALMONITORING

The possible mechanisms of cardiac adverse effects of astemizole were studied using a halothane-anesthetized in vivo canine model under the cardiohemodynamic and monophasic action potential monitoring. A dose o f 0.3 mg/kg of iv astemizole (n = 7), which is close to the recommende d dose for clinical use, showed a bradycardic effect and a reversed us e-dependent lengthening of repolarization. The increase in the repolar ization was greater than in the effective refractory period. These eff ects persisted even when the plasma drug concentration became undetect able. Additional administration of 3.0 mg/kg of iv astemizole (n = 7) decreased the mean blood pressure, suppressed the cardiac contraction and conduction, and induced early after depolarization-like potential in addition to the qualitatively similar effects compared to those obs erved by the lower dose. The decrease of the plasma concentration of a stemizole followed the pattern predicted by the two-compartment theory of pharmacokinetics, but the drug concentration in the cardiac muscle was estimated to be more than 100 times greater than that in plasma. Our study emphasizes that each cardiac consequence of astemizole overd ose may be related to proarrhythmic effects and the monitoring of plas ma drug concentration will be less helpful in predicting the cardiac a dverse effects of astemizole. The results provide some insights into t he clinical cardiotoxicity of astemizole. Drugs or interventions induc ing positive chronotropic, inotropic, and dromotropic effects can beco me good candidates for the treatment of astemizole intoxication, which may attenuate the cardiac effects of astemizole including the lengthe ning of repolarization. (C) 1997 Academic Press.