CLINICAL PHARMACOLOGICAL ASPECTS OF THERA PY WITH ENOXIMONE

Enoximone is an imidazole derivative which proved to be a selective in hibitor of the isoenzymes III/IV of the cAMP-specific phosphodiesteras e. It has been shown in various experimental models that the drug exer ts both positive inotropic and vasodilating properties which can be at tributed to the proposed mode of action. A marked dose-dependent impro vement in left ventricular pump performance was observed, with only mi nor changes in heart rate or systemic blood pressure, if enoximone was administered as i.v.-bolus to patients with moderate to severe conges tive heart failure. These effects coincided with vasodilatory effects as determined by decreases in systemic vascular resistance and pulmona ry capillary wedge pressure. Enoximone is eliminated by intensive meta bolism, predominantly in the liver, with enoximone sulfoxide being the major metabolite in man. Enoximone exhibits a marked first-pass metab olism following oral administration. There is evidence in the literatu re that the metabolism can be saturated either during long-term admini stration or by increasing the dose of enoximone. In experimental setti ngs, the metabolite exerts weak positive inotropic effects, too, and r econversion to the parent compound enoximone has been demonstrated in addition. The half-life of elimination of enoximone seems to be about 1 h in healthy volunteers and approximately 3 to 7 h in patients with congestive heart failure, with marked inter-individual differences. In patients with renal failure mainly enoximone sulfoxide accumulates in plasma depending on the degree of renal impairment. The elimination o f enoximone seems to be impaired in these patients, too, which might b e caused by enhanced reconversion due to the high plasma concentration s of the metabolite. Thus, the dose of enoximone should be reduced in patients with severe renal insufficiency. Although only limited inform ation on the kinetics of enoximone in patients with chronic liver dise ase is available, the pharmacokinetic profile of the compound suggests that the dose has to be reduced in these patients also. No clinically significant drug interactions have been demonstrated in man so far.