Pharmacokinetics and plasma-concentration-effect relationships of prenalterol in cardiac failure

Abstract

Prenalterol was administered as an intravenous infusion at three incremental rates (60, 120 and 240 nmol/min) to five patients with severe cardiac failure. Haemodynamic, hormonal and metabolic variables were measured at the same time as plasma prenalterol concentrations, and the pharmacokinetics of the drug were studied by following plasma concentrations and urinary excretion during and after the infusion. Concentration-dependent increases in cardiac index, stroke index and stroke work index were observed without increases in arterial pressure, heart rate or myocardial oxygen demand. The reninangiotensin-aldosterone system was stimulated, although the extent of stimulation varied among patients. No strong correlations were found between the logarithm of the plasma prenalterol concentration and effect. Plasma clearance of the drug was lower in cardiac patients than in normal volunteers, but a large decrease in renal clearance was partially balanced by an increase in nonrenal clearance. Over the observed range of concentrations, no deviation from linearity was evident, and plasma concentrations of about 150 nmol/l were effective in improving cardiac function without significant side-effects.

Effects of cardiovascular disease on pharmacokinetics

“…In patients with cardiac failure (NYHA class II and III) and impaired renal function given a 72-hour infusion (60 nmol/min for 24 hours and 240 nmol/min for 24 hours) at steady state, there was a prolongation of half-life (3.7 vs. 2.1 hours in normals) and a reduction of renal and plasma clearance (Clr, 0.17 vs. 0.93 1/min in normals; Clp, 1.14 vs. 1.47 1/min), drug renal clearance being linearly related to creatinine clearance [84]. In patients with cardiac failure (NYHA class II and III) and impaired renal function given a 72-hour infusion (60 nmol/min for 24 hours and 240 nmol/min for 24 hours) at steady state, there was a prolongation of half-life (3.7 vs. 2.1 hours in normals) and a reduction of renal and plasma clearance (Clr, 0.17 vs. 0.93 1/min in normals; Clp, 1.14 vs. 1.47 1/min), drug renal clearance being linearly related to creatinine clearance [84].…”