Acute haemodynamic effects and pharmacokinetics of ramipril in patients with heart failure. A placebo controlled three-dose study.
The aim of the present study was primarily to evaluate the haemodynamic effects of the ACE-inhibitor ramipril which is active via its metabolite ramiprilat. Ramipril 1.25, 2.5 and 5 mg and placebo was administered orally to 4 groups of 12 patients with heart failure (NYHA III) in a double-blind randomised, parallel study. Haemodynamics were monitored for 24 h and blood was sampled and urine collected for up to 96 h. In the placebo-treated group the cardiac index (CI) was significantly increased (15.8%) and right atrial pressure decreased (26.6%). Ramipril 1.25 mg had insignificant haemodynamic effects compared to placebo and the 2.5 mg dose had significant effects on some haemodynamic variables. Ramipril 5 mg had pronounced and sustained effects on pulmonary artery pressure, which fell by 43.7%, and pulmonary capillary wedge pressure (PCWP; -59.1%); systemic vascular resistance was also decreased 21%. A significant effect on CI was only seen after 2.5 mg ramipril (+7.4%). The mean maximal degree of ACE inhibition was 73.2, 90.4 and 98.5%, respectively, after the three doses of ramipril. Complete inhibition of ACE-activity was seen at a mean plasma concentration of ramiprilat of 4.7 ng.ml-1. The degree of inhibition declined with a half life of about 75 h. There was a significant relation between the degree of ACE-inhibition and change in PCWP but not with the change in SVR. Ramipril was mainly eliminated in the form of ramiprilat and inactive metabolites.
Beermann
B
B
Medical Products Agency, Uppsala, Sweden.
Nyquist
O
O
Höglund
C
C
Jacobsson
K A
KA
Näslund
U
U
Jensen-Urstad
M
M
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D017257:Ramipril / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; C052549:ramiprilat; D017257:Ramipril