Comparative effects of felodipine, nitrendipine and nifedipine in healthy subjects: concentration-effect relationships of racemic drugs and enantiomers.
The effects of racemic (rac) felodipine, rac-nitrendipine and nifedipine (all 20 mg solution p.o.) on non-invasively measured blood pressure and heart rate were investigated in a randomised, double-blind, cross-over study in 12 normotensive, young, healthy males. Compared to baseline values, heart rate increased more after rac-felodipine treatment (+47% at maximum) than rac-nitrendipine (+40%) and nifedipine (+38%); only small and variable changes in blood pressure were observed with any of the drugs. The baseline-corrected area under the heart rate-time curve up to 4 h after the administration of rac-felodipine was 197% and 180% larger than after nifedipine and rac-nitrendipine treatment, respectively. The effects on heart rate could be fitted individually to a sigmoidal Emax-model without hysteresis for all drugs under investigation. The relative potencies of the unbound drugs for their indirect effects on heart rate were 1:7:43 for nifedipine, rac-nitrendipine and rac-felodipine, respectively. The active (S)-enantiomers of felodipine and nitrendipine appeared to be 9- and 60-times as potent as nifedipine in this respect, assuming no (inter)activity of the (R)-enantiomers. Individual and mean changes in blood pressure were small, they were not related to plasma concentrations, and did not differ between treatments.
Soons
P A
PA
Center for Bio-Pharmaceutical Sciences, University of Leiden, The Netherlands.
Cohen
A F
AF
Breimer
D D
DD
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015736:Felodipine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D009543:Nifedipine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D009568:Nitrendipine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D013237:Stereoisomerism
D009568:Nitrendipine; D009543:Nifedipine; D015736:Felodipine