Clinical Pharmacology of Calcium Antagonists

Abstract

Although diltiazem, nifedipine, and verapamil exhibit great diversity in chemical structure, they exhibit common pharmacokinetic properties. They are all highly cleared drugs and thus subject to a significant hepatic first-pass metabolism. Therefore, their bioavailability is low despite their almost complete absorption following oral administration. In addition, the bioavailability of these drugs is subject to inter- and intraindividual variations even in healthy subjects. In patients with liver disease, bioavailability increases substantially due to intra- and extrahepatic shunting. During multiple dosing, the oral clearance decreases and bioavailability increases, thus leading to higher steady-state concentrations than those predicted from single-dose studies. The interpretation of pharmacodynamic data in relation to plasma drug concentrations should consider the following points: presence of hysteresis effect and pharmacodynamic models employed for the analysis of the concentration-effect relationship (log-linear versus Emax model). The route of administration can influence the concentration-effect relationship due to the formation of active metabolites and/or stereoselective first-pass metabolism. The available pharmacokinetic data for the three calcium antagonists are discussed with special emphasis on their contribution to pharmacodynamic effects.