Receptor binding characteristics and pharmacokinetic properties as a tool for the prediction of clinical effects of beta-blockers.

The clinical effects of a single dose of beta-adrenoceptor antagonists (beta-blockers) lasts longer than the respective half-lives in plasma will suggest. This apparent discrepancy is easily explained by a superimposition 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 data from literature as well as those from receptor binding studies and clinical investigations from our laboratories this model was confirmed. Furthermore it can be stated: The plasma concentrations of beta-blockers are representative for the drug concentration at the beta-adrenoceptor in human. "Tight" receptor binding is not the reason for the prolonged effects, but rather the relation between drug concentration and the resp. EC50-value at the respective time of measurement. The extent of antagonism of beta-blockers in vivo can be predicted from ligand binding studies in vitro. Using the time-concentration profile in plasma in addition, the time course of clinical effects can be delineated. This holds true for the non-selective beta-blocker propranolol as well as atenolol, which shows selectively higher affinity at the beta 1-subpopulation. Deviations from the model suggested for the correlation between plasma concentration kinetics, time course of clinical effects and interaction between drug and receptor for beta-blockers may be indicative of additional compartments, active metabolites, partial agonist activity, counterregulatory processes, adaptive mechanisms and must be verified if taken for modelling. In general, any drug acting on the basis of the law of mass action should obey to the described relation between the time course of plasma concentrations and clinical effect (e.g. cardiac glycosides).