Correlation between pharmacological response, kinetics of plasma concentration and in vitro receptor affinities exemplified with beta-adrenoceptor blocking drugs.

: The clinical effect of beta-adrenoceptor blocking drugs lasts longer than the respective half lives in plasma will suggest. This apparent discrepancy is easily explained by a superposition of the function of plasma concentration kinetics and the function for competitive antagonism at beta-adrenoceptors according to the law of mass action. By taking clinical data from the literature and by using results from ligand binding studies simultaneously, this was confirmed. Furthermore, it can be stated: 1) The plasma concentrations are representative for the drug concentration at the beta-adrenoceptor sites: Dissociation of beta-blockers from the receptor site is a much faster process than elimination from plasma and thus does not prolong effects. 2) Extent of beta-adrenoceptor blocking effect in vivo can be predicted from ligand binding studies based on the respective drug concentration in plasma. If the kinetics of the drug in plasma is known, the time course of effect can be delineated. 3) Only deviations from the above function describing the time course of effect may be indicative for active metabolites or additional compartments of drug distribution. Furthermore, deviations should occur if additional drug effects (e.g. partial agonist activity) are present. In general, any drug acting on the basis of the law of mass action should obey the described relation between the time course of plasma concentration and clinical effect (e.g. cardiac glycosides).