QUANTIFICATION OF METOPROLOL BETA-2-ADRENOCEPTOR ANTAGONISM IN ASTHMATIC-PATIENTS BY PHARMACOKINETIC PHARMACODYNAMIC MODELING

An integrated pharmacokinetic-pharmacodynamic model was used to quantify the β2-blocking activity of metoprolol in seven asthmatic patients. The patients received a subcutaneous dose of terbutaline on two consecutive days. On day 1 they were pretreated with placebo and on day 2 with metoprolol 150 mg orally. Beta2-adrenoceptor mediated changes of plasma potassium and FEV1 were related to plasma concentrations of terbutaline and racemic metoprolol. Metoprolol activity was measured as the competitive (blocking) interaction of racemic metoprolol on the terbutaline response. Plasma concentrations and effects were monitored over 7 h following terbutaline administration. Despite the relative β1-selectivity of metoprolol, the effects of terbutaline were considerably attenuated. The mean (racemic) metoprolol concentration that corresponds to 50% maximum metoprolol receptor occupancy (IC50) for the effects on FEV1 and hypokalemia were, respectively, 17 (±8) and 22 (±12)ng/ml and were not statistically discernible. We conclude that individual integrated pharmacokinetic-pharntacodynamic modelling of the concentration-effect relations of agonist and antagonist is a feasible and direct method of quantifying β2-blocker effects in asthmatic patients. In stable asthma patients receiving therapeutic doses of metoprolol, the terbutaline plasma concentration needs to be increased two- to four-fold to obtain the same effect on FEV1. Plasma potassium may be considered an appropriate alternative parameter to predict the effect on FEV1. © 1992.