CHRONOPHARMACOLOGY OF ENALAPRIL IN HYPERTENSIVE PATIENTS

The pharmacokinetics and pharmacodynamics of enalapril, an angiotensin converting enzyme inhibitor, are reported to vary with the time of ad ministration. The present study was undertaken to examine whether the effect of enalapril on plasma bradykinin (BK), substance P and prostag landin E(2) (PGE(2)), which are likely to be involved in the mechanism of enalapril-induced cough, might also be affected by its time of adm inistration. Enalapril 5 mg or placebo was given orally at 10:00 h (da y trial) or 22:00 h (night trial) to 12 patients with essential hypert ension. Serum concentrations of total drug (enalapril + enalaprilat, i ts active metabolite) during the day and night trials did not differ s ignificantly at any time. However, serum enalaprilat tended to be high er and its maximum concentration greater in the day trial than in the night trial. Blood pressure 24 h after administration of enalapril was reduced at 22:00 h, but not at 10:00 h. Plasma BK tended to increase following enalapril administration at 10:00 h, but not at 22:00 h. Rem arkable increases in plasma BK were observed in two patients in the da y trial and one of them also complained of cough. However, no such inc rease in plasma BK or subsequent adverse effect were recorded in the n ight trial. Plasma substance P and PGE(2) did not change significantly following enalapril administration either in the day or night trial. The results suggest that the response of BK to enalapril is affected b y the time of administration. In patients who complain of cough during treatment with enalapril during the daytime, this adverse effect migh t be diminished or eliminated by a switch to night-time administration .