Clinical pharmacology of calcium antagonists: a critical review

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.