Esmolol, an ultrashort-acting, selective beta 1-adrenoceptor antagonist: pharmacodynamic and pharmacokinetic...

The effects of esmolol at different rates of infusion (100, 250 and 500 micrograms.kg-1 BW.min-1) were compared with beta-adrenoceptor occupancy (beta 1 and beta 2, estimated by a subtype selective radioreceptor assay) and plasma concentrations of esmolol and its acid metabolite were measured by HPLC. Up to a rate of infusion of esmolol of 500 micrograms.kg-1 BW.min-1 there was a maximal beta 1-receptor occupancy of 84.7% while beta 2-receptor occupancy was below the detection limit; confirming the beta 1 selectivity of esmolol. Exercise-induced increases in heart rate and systolic blood pressure were reduced by esmolol in a dose-dependent manner. The estimated EC50 values of rate of infusion for the reduction in heart rate and systolic blood pressure during exercise were 113 and 134 micrograms.kg-1 BW.min-1, respectively. Additionally, heart rate and systolic blood pressure were reduced moderately at rest. Because of the short elimination half-life of esmolol caused by the rapid hydrolysis to its acid metabolite, 45 min after end of infusion high plasma concentrations of the metabolite (maximally 80 micrograms.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 micrograms.kg-1 BW.min-1. The plasma concentrations of antagonist detected by radioreceptor assay and plasma concentrations of esmolol detected by HPLC showed a good correlation (r = 0.97).(ABSTRACT TRUNCATED AT 250 WORDS)