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Kinetics and dynamics of calcium entry antagonists in systemic hypertension
Insights
Long-term use of calcium-entry antagonists like verapamil, diltiazem, and nifedipine prolongs their elimination half-life due to altered liver blood flow. Plasma levels are not reliable for guiding long-term antihypertensive therapy.
Area of Science:
- Pharmacology
- Clinical Pharmacy
- Drug Metabolism
Background:
- Calcium-entry antagonists (verapamil, diltiazem, nifedipine) are metabolized hepatically, with elimination rates dependent on liver blood flow.
- Hemodynamic effects of these drugs during long-term use alter liver blood flow, impacting drug delivery and clearance.
- Initial pharmacokinetic data may not accurately predict drug behavior during chronic administration.
Purpose of the Study:
- To investigate the pharmacokinetic changes of calcium-entry antagonists during long-term administration.
- To assess the influence of altered liver blood flow on the elimination half-life of these drugs.
- To evaluate the correlation between plasma concentrations and therapeutic effects with chronic use.
Main Methods:
- Review of pharmacokinetic data for verapamil, diltiazem, and nifedipine.
- Analysis of the relationship between drug effects, liver blood flow, and pharmacokinetic parameters.
- Comparison of short-term versus long-term administration profiles.
Main Results:
- Long-term administration of calcium-entry antagonists likely prolongs elimination half-life due to sustained effects on liver blood flow.
- Hepatic disorders affecting liver blood flow significantly alter drug pharmacokinetics.
- Correlations between plasma concentrations and hemodynamic effects are less reliable with long-term use compared to short-term administration.
Conclusions:
- The elimination half-life of verapamil, diltiazem, and nifedipine is probably significantly prolonged during long-term therapy.
- Plasma drug level monitoring is generally not clinically useful for guiding antihypertensive therapy, except for assessing compliance or abnormal drug handling.
Abstract:
The calcium-entry antagonists verapamil, diltiazem and nifedipine (and their analogs) are all eliminated by hepatic metabolism and the rate of disposition is dependent on the rate of liver blood flow. During long-term administration, the profound hemodynamic effects of these agents result in changes in hepatic blood flow in association with decreases in arterial pressure, and either increases or decreases in measured cardiac output. This alters the drug's rate of delivery to the site of elimination, with concomitant changes in systemic clearance and a prolongation in elimination half-life. The pharmacokinetic data determined after initial single doses, therefore, only suggest the kinetic characteristics during long-term administration, because this profile depends on the drugs' sustained effects on liver blood flow. The elimination half-life of all 3 prototypical calcium antagonists is probably significantly prolonged during long-term dosing with clinically effective regimens. Patients with hepatic disorders in which liver blood flow is altered, such as cirrhosis, have profound changes in pharmacokinetics with both short- and long-term administration of verapamil and are likely to have similar changes with other calcium antagonists. During short-term administration, the plasma concentrations of verapamil and other calcium antagonists relate closely to the observed hemodynamic (and electrophysiologic) effects. With long-term administration, however, these correlations are much less impressive. When given in tablet form, nifedipine lowers blood pressure roughly in proportion to plasma levels between 20 and 200 ng/ml; verapamil plasma levels between 80 and 800 ng/ml are associated with antihypertensive efficacy. Plasma level measurements, therefore, are not of clinical importance as guides to antihypertensive therapy, except to identify noncompliance or abnormal patterns of drug handling.