Calcium antagonists. Pharmacokinetic properties.

Abstract

An understanding of the pharmacokinetics of the calcium antagonists (slow-channel blocking drugs) is essential in order to design appropriate dosage regimens which will provide optimum therapeutic efficacy with these agents. This review summarises and evaluates the current state of knowledge of the absorption and disposition characteristics of the 3 most extensively used calcium antagonists in cardiovascular therapeutics: verapamil, diltiazem and nifedipine. While an extensive literature regarding the kinetics of verapamil exists, reports dealing with diltiazem and nifedipine are limited. This is, in part, due to difficulties in developing simple, specific and sensitive analytical procedures. All 3 drugs undergo extensive metabolism in the liver. Metabolites of verapamil (norverapamil) and diltiazem (desacetyldiltiazem) accumulate in the plasma of patients and have been shown to produce some effects similar to those of their parent compounds. The bioavailability of diltiazem and nifedipine has not been well studied, and no investigations of the absolute bioavailability of these compounds have been reported. However, the bioavailability of verapamil has been studied extensively; about 22% of an orally administered dose of verapamil is systemically available. Bioavailability is increased when liver function is impaired, such as in patients with hepatic cirrhosis. The high first-pass extraction of verapamil has been suggested to be stereoselective, with preferential elimination of the (-) isomer. The plasma concentration-time curves of verapamil and diltiazem have been studied following oral administration. The elimination half-lives of verapamil and diltiazem are about 8 and 5 hours, respectively. All 3 drugs are highly protein-bound in the plasma. Several other drugs have the ability to displace verapamil from plasma protein binding sites, but the clinical significance of this interaction is doubtful. Other drug interactions have been investigated with these agents. Verapamil causes digoxin plasma levels to rise during concomitant administration, but no drugs have been shown to alter the disposition of verapamil. Diazepam affects the plasma levels of diltiazem leading to a decrease. The mechanism of this interaction has not been reported, but an effect on bioavailability has been suggested. Age has been shown to be a factor in the disposition of both diltiazem and verapamil. Older patients tend to have lower clearances of these 2 drugs than do younger patients. It has also been shown that hepatic cirrhosis leads to a decreased clearance of verapamil. Plasma level monitoring may be helpful for adjusting doses of both verapamil and diltiazem, despite the absence of a definition of therapeutic plasma concentrations. These agents all have low, and highly variable, systemic availability, and plasma concentrations cannot be predicted after oral administration.