Clinical pharmacokinetics of calcium antagonists. An update

Abstract

The calcium antagonists are valuable and widely used agents in the management of essential hypertension and angina. There is an increasing number of new agents to add to the 3 prototype substances nifedipine, diltiazem and verapamil. These new agents are dihydropyridines structurally related to nifedipine. However, they tend to have longer elimination half-lives (t 1/2 beta) and may be suitable for twice-daily administration. Amlodipine is an exception with a t 1/2 beta in excess of 30h. Apart from elimination rates, however, the pharmacokinetic characteristics of the newer agents have a notable tendency to resemble those of the established agents. They are highly cleared drugs, are relatively highly protein bound. As they are subject to significant first-pass metabolism, old age and hepatic impairment will increase their plasma concentrations due to a reduced first-pass effect. Renal impairment does little to their pharmacokinetics since the fraction eliminated unchanged by the kidney is small. For most agents, plasma concentration-response relationships have been described. Interesting areas for further research include chronopharmacokinetics, stereoselective pharmacokinetics and lipid solubility. Drugs affecting hepatic blood flow and drug metabolising capacity have predictable interaction potential. Some of the newer calcium antagonists will, like verapamil, increase plasma digoxin concentrations. Verapamil and diltiazem decrease phenazone (antipyrine) metabolism and therefore tend to decrease the metabolism of other drugs.