ACUTE HEMODYNAMIC-EFFECTS AND PHARMACOKINETICS OF RAMIPRIL IN PATIENTS WITH HEART-FAILURE - A PLACEBO-CONTROLLED 3-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.