Kinetic-dynamic relations and individual responses to enalapril.
Pharmacokinetic and pharmacodynamic variability largely account for interindividual differences in the response to antihypertensive drugs including angiotensin converting enzyme inhibitors. The factors determining the response to enalapril have been investigated in a placebo-controlled study in essential hypertension. The effects of placebo, the initial dose of enalapril, and long-term (1 and 6 weeks) treatment with enalapril were studied in 13 subjects. By using an integrated kinetic-dynamic model that incorporates a parameter for saturable protein binding, individual responses for blood pressure reduction and angiotensin converting enzyme inhibition were characterized in terms of the maximum effect (Emax) and the drug concentration required to produce 50% of Emax (Ce50). In individual subjects, plasma enalaprilat concentrations could be correlated with falls in blood pressure and changes in plasma angiotensin converting enzyme activity. For the group, Emax was -46.1 +/- 16.5 and -19.7 +/- 3.8 mm Hg for systolic and diastolic blood pressure, respectively, and the corresponding Ce50 values were 66.1 +/- 20.2 and 61.6 +/- 22.5 ng/ml. For angiotensin converting enzyme inhibition, Emax (%) and Ce50 (ng/ml) were, respectively, 102.4 +/- 5 and 19.8 +/- 13 after the first dose, 103 +/- 5 and 33.4 +/- 20.3 after 1 week, and 101.3 +/- 2.2 and 31.3 +/- 18.9 after 6 weeks. There was no relation between the responsiveness to enalapril (Emax or Ce50) and patient age or plasma renin activity, but there was a significant positive correlation between Emax and the pretreatment blood pressure. In individual subjects, Emax (first dose) was directly correlated with Emax after 1 and 6 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
Donnelly
R
R
University Department of Medicine and Therapeutics, Stobhill General Hospital, Glasgow, United Kingdom.
Meredith
P A
PA
Elliott
H L
HL
Reid
J L
JL
D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood; D000959:Antihypertensive Agents; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D012083:Renin / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004656:Enalapril; D007703:Peptidyl-Dipeptidase A; D012083:Renin