Pharmacokinetics and pharmacodynamics of enalapril in patients with congestive heart failure and patients with hypertension.
The clinical pharmacokinetics and pharmacodynamics of enalapril and its de-esterified active metabolite, MK 422, were determined in eight patients with congestive cardiomyopathy and five patients with hypertension. After administration of single doses of 2.5, 5, and 10 mg enalapril in the congestive heart failure patients and 20 or 40 mg in the hypertensive patients, serum levels and urine elimination of enalapril and MK 422 were determined. Standing and supine heart rate and blood pressure were measured as was ejection fraction in the congestive heart failure group and renin activity, aldosterone levels, and converting enzyme activity in the hypertensive group. Apparent oral clearance after administration of 5 and 10 mg enalapril was lower in the congestive heart failure patients (0.6 +/- 0.2 and 0.7 +/- 0.4 L/min) than after 20 and 40 mg given to hypertensive patients (2.5 +/- 1.3 and 2.7 +/- 2.7 L/min). The elimination of MK 422 was also slower in the congestive heart failure patients (7.8 +/- 5.0 and 6.8 +/- 2.5 h after 5 and 10 mg enalapril, respectively, vs. 4.6 +/- 2.0 and 5.3 +/- 1.1 h after 20 and 40 mg, respectively, in the hypertension group). The enalapril area under the concentration-time curve increased disproportionately to dose increments in both groups, but was more pronounced in congestive heart failure. Twenty and 40 mg enalapril lowered the blood pressure by 2 h after dosing in the hypertension group, and peak effects were seen 4-5 h after dosing. Peak effects correlated with peak serum MK 422 concentrations but not with enalapril (MK 421) levels. Supine heart rates were unchanged after 20 mg, but increased after 40 mg; standing heart rates were transiently increased after 20 and 40 mg enalapril. Blood pressure was not significantly changed in the congestive heart failure group, and cardiac ejection fraction was unchanged. In the hypertension group, renin stimulation and converting enzyme activity inhibition were seen at 4 h and persisted for at least 24 h after administration of 40 mg enalapril. In summary, the clearance of enalapril and elimination of MK 422 was slower in congestive heart failure patients versus hypertensive patients. Therefore, slower onset and longer duration of drug effect might be anticipated in patients with congestive heart failure versus patients with hypertension during enalapril administration.
Schwartz
J B
JB
Taylor
A
A
Abernethy
D
D
O'Meara
M
M
Farmer
J
J
Young
J
J
Nelson
E
E
Pool
J
J
Mitchell
J R
JR
D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000097:blood; D000959:Antihypertensive Agents / Q000378:metabolism* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004151:Dipeptides / Q000378:metabolism* / Q000494:pharmacology; D004656:Enalapril; D015773:Enalaprilat; D005260:Female; D006207:Half-Life; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007208:Indocyanine Green; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000097:blood
D000959:Antihypertensive Agents; D004151:Dipeptides; D000450:Aldosterone; D004656:Enalapril; D012083:Renin; D015773:Enalaprilat; D007208:Indocyanine Green