Pharmacokinetics and Hemodynamic Effects of Long-Term Nifedipine Treatment in Hypertensive Patients

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Abstract
In six patients with essential hypertension, pharmacokinetics and pharmacodynamics of nifedipine were investigated during 6 weeks of treatment. On day 1 nifedipine was infused intravenously (6.0 mg within 60 min), and on day 2 oral nifedipine treatment (20-mg tablets, twice daily) was started. Patients came to the hospital once weekly, when blood samples were taken and blood pressure and heart rate were assessed prior to tablet intake and 3 h later. After 6 weeks of oral treatment the intravenous infusion experiment was repeated. At the first intravenous nifedipine infusion a total systemic plasma clearance of 671 .+-. 240 ml/min (mean .+-. SD), an elimination half-life of 95 .+-. 36 min, and a volume of distribution of 60.2 .+-. 11.9 L were found. Protein unbound fraction of nifedipine amounted to 4.6 .+-. 0.3%. After 6 weeks of oral treatment half-life was almost doubled (p < 0.05), whereas in most patients the volume of distribution had slightly increased and systemic plasma clearance was decreased. Using a sigmoidal model, hemodynamic effects were fitted to nifedipine plasma concentrations. After 6 weeks the maximal effect of intravenous nifedipine on both systolic and diastolic blood pressures had significantly decreased. In four patients the potency had decreased considerably. During oral nifedipine treatment the mean plasma half-life was 5.8 .+-. 1.0 h; trough concentration was 11.3 .+-. 4.1 ng/ml and peak concentrations were 36.8 .+-. 14.3 ng/ml. During chronic treatment heart rate was not significantly changed, whereas systolic and diastolic blood pressures were significantly reduced (p < 0.02 and < 0.01, respectively). However, there were still relatively large differences in diastolic blood pressure before and 3 h after dosing, indicating insufficient drug concentration at the end of the dosage interval. It can be concluded from the results of the present study that intravenous pharmacokinetics and dynamics of nifedipine are altered after 6 weeks of chronic treatment in comparison with the acute situation. During oral nifedipine treatment blood pressure is significantly and permanently reduced. The differences in diastolic blood pressure, as found before and 3 h after oral dosage, indicate that a twice-daily 20-mg nifedipine regimen may not be optimal for each patient.