Calcium antagonists. Pharmacokinetic properties.

Area of Science:

• Pharmacology
• Clinical Therapeutics
• Drug Metabolism

Background:

• Calcium antagonists (slow-channel blockers) are vital cardiovascular drugs.
• Optimizing dosage regimens requires understanding drug pharmacokinetics.
• Verapamil, diltiazem, and nifedipine are widely used cardiovascular calcium antagonists.

Purpose of the Study:

• To review and evaluate the pharmacokinetic properties of verapamil, diltiazem, and nifedipine.
• To summarize current knowledge on the absorption and disposition of these agents.
• To highlight gaps in understanding, especially for diltiazem and nifedipine.

Main Methods:

• Literature review of pharmacokinetic studies.
• Analysis of absorption, distribution, metabolism, and excretion (ADME) data.
• Evaluation of drug interactions and factors influencing disposition.

Main Results:

• Verapamil has extensive pharmacokinetic data; diltiazem and nifedipine have limited data due to analytical challenges.
• All three drugs undergo extensive hepatic metabolism; active metabolites accumulate.
• Verapamil exhibits stereoselective first-pass metabolism; bioavailability is around 22% and affected by liver function.
• Elimination half-lives: verapamil ~8 hours, diltiazem ~5 hours.
• High protein binding; potential interactions exist but clinical significance is often doubtful.
• Age and hepatic cirrhosis affect drug clearance.
• Verapamil increases digoxin levels; diazepam may decrease diltiazem levels.

Conclusions:

• Pharmacokinetic variability necessitates plasma level monitoring for verapamil and diltiazem, despite undefined therapeutic ranges.
• Low and variable systemic availability of these agents complicates prediction of plasma concentrations after oral administration.
• Further research is needed to fully elucidate the pharmacokinetics of diltiazem and nifedipine.