ESMOLOL, AN ULTRASHORT-ACTING, SELECTIVE BETA(1)-ADRENOCEPTOR ANTAGONIST - PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES

The effects of esmolol at different rates of infusion (100, 250 and 50 0 mu g.kg(-1) BW.min(-1)) were compared with beta-adrenoceptor occupan cy (beta(1) and beta(2), estimated by a subtype selective radiorecepto r assay) and plasma concentrations of esmolol and its acid metabolite were measured by HPLC. Up to a rate of infusion of esmolol of 500 mu g .kg(-1) BW.min(-1) there was a maximal beta(1)-receptor occupancy of 8 4.7 % while beta(2)-receptor occupancy was below the detection limit; confirming the beta(1) selectivity of esmolol. Exercise-induced increa ses in heart rate and systolic blood pressure were reduced by esmolol in a dose-dependent manner. The estimated EC(50) values of rate of inf usion for the reduction in heart rate and systolic blood pressure duri ng exercise were 113 and 134 mu g.kg(-1) BW.min(-1), respectively. Add itionally, heart rate and systolic blood pressure were reduced moderat ely at rest. Because of the short elimination half-life of esmolol cau sed by the rapid hydrolysis to its acid metabolite, 45 min after end o f infusion high plasma concentrations of the metabolite (maximally 80 mu g.ml(-1)) but no esmolol were detectable. Since no in vivo effects have been observed, despite the presence of high plasma concentrations of the metabolite, the metabolite did not participate in the observed effects up to an infusion rate of esmolol of 500 mu g.kg(-1) BW.min(- 1). The plasma concentrations of antagonist detected by radioreceptor assay and plasma concentrations of esmolol detected by HPLC showed a g ood correlation (r=0.97). Since the cardiovascular effects, determined before and 45 min after termination of infusion of esmolol were simil ar, it can be concluded that the observed effects on heart rate and sy stolic blood pressure are exclusively mediated by esmolol.