Enoximone

Abstract

Synopsis

Enoximone is an imidazolone derivative currently undergoing trials in patients with congestive heart failure refractory to conventional therapy. It is a phosphodiesterase inhibitor with both positive inotropic and vasodilator properties, and is active by both oral and intravenous routes of administration. While pharmacodynamic studies have documented beneficial haemodynamic effects after short term oral administration, and objective and subjective improvement relative to placebo during some short term trials, its clinical efficacy during continuous longer term therapy remains uncertain. Enoximone is of potential benefit as an adjunct in short term management of patients with end-stage cardiac failure awaiting cardiac transplantation. In the usually small studies reported to date enoximone was generally better tolerated at oral dosages of less than 2 mg/ kg than at higher dosages.

Thus, while its pharmacodynamic profile holds potential promise in a difficult therapeutic area, the long term clinical efficacy and tolerability of enoximone remain yet to be determined in controlled trials of adequate size and duration.

Pharmacodynamic Properties

Enoximone administered as an intravenous infusion markedly improved left ventricular pump performance in patients with moderate to severe congestive heart failure (CHF) with no significant alteration in heart rate or arterial pressure. The positive inotropic effect was accompanied by vasodilation, evidenced by reductions in systemic vascular resistance and pulmonary capillary wedge pressure. Peak haemodynamic effects occur within 4 hours of intravenous drug administration with effects persisting up to 14 hours. The haemodynamic effects of oral enoximone are similar to those occurring after intravenous administration. Exercise duration has been shown to improve with enoximone. The amplitude and duration of effect of intravenous enoximone have been shown to be dose dependent.

In electrophysiological studies during acute administration enoximone did not appear to be arrhythmogenic. Peak cumulative doses of 1 to 3 mg/kg intravenously resulted in variable effects on myocardial oxygen consumption. A reduction in myocardial lactate extraction has been observed after enoximone administration.

Plasma renin activity tended to increase in response to intravenous enoximone administration, with no change in norepinephrine and arginine vasopressin levels. Significant reductions in glomerular filtration rate and renal plasma flow were observed after intravenous, but not with chronic oral administration of enoximone. Limb vascular resistance decreased and limb blood flow increased in response to single dose oral enoximone, compared with placebo.

Compared with nitroprusside, enoximone produced a greater increase in cardiac index and stroke volume index. Enoximone has been shown to produce a greater reduction in left ventricular filling pressure than that produced by dobutamine, without increasing heart rate or mean arterial pressure.

The mechanism of action of enoximone is not completely clear but it appears to act by selective inhibition of cardiac phosphodiesterase, resulting in elevated cyclic AMP levels in cardiac muscle tissue, which in turn leads to increased contractile force and rate of relaxation of the heart. Elevated levels of cyclic AMP in vascular smooth muscle may also be responsible for the vasodilatory properties of enoximone.

Pharmacokinetic Properties

Following a single oral dose of enoximone 150mg as a soft gelatin capsule in fasting healthy volunteers, peak plasma enoximone concentrations were reached within 2.5 hours. It has been shown that presence of food may affect the rate of absorption, with peak plasma concentrations of enoximone being higher and attained earlier in nonfasting volunteers. In patients with congestive heart failure, oral clearance appears to be reduced. The mean bioavailability in healthy volunteers is between 53 and 60%.

Enoximone is extensively metabolised in the liver to the corresponding sulphoxide, AUCs of which are substantially higher than those of enoximone following oral administration. The metabolite is excreted in the urine, and elimination by this route accounts for about 65 to 80% of the administered dose. Elimination half-life of enoximone is about 1 to 2 hours in healthy volunteers and shows large interindividual variation in patients with CHF, with estimates ranging from about 3 to 20 hours.

Therapeutic Efficacy

In most studies of orally administered enoximone in the treatment of moderate to severe CHF the drug has been added to existing therapy with diuretics and cardiac glycosides and, in some patients, vasodilators. Most controlled clinical trials of oral enoximone involved small groups of patients treated for short periods of 3 to 6 weeks, although follow-up has been longer in uncontrolled studies and findings were mixed. Similarly, results of double-blind comparisons with placebo were not consistent, with shorter studies showing convincing evidence of efficacy while in longer trials of up to 16 weeks’ duration statistically significant differences between enoximone and placebo were sometimes, but not always, apparent; the effect of enoximone on survival also remains unclear. A few small comparative studies suggest similar efficacy for oral enoximone and captopril, but these preliminary findings require confirmation. Haemodynamic benefit in some studies however, suggested the usefulness of enoximone in reducing the need for mechanical interventions in patients awaiting cardiac transplantation.

Tolerability

The most common adverse effects reported during enoximone treatment are gastrointestinal in origin, including nausea, dyspepsia and diarrhoea with the incidence of such effects being dose-related. Most of these are resolved by decreasing the enoximone dosage. Enoximone does not appear to be arrhythmogenic in clinically administered dosages.

Dosage and Administration

Although the manufacturer’s recommendations are unavailable, in therapeutic or haemodynamic trials in patients with congestive heart failure enoximone has been given orally in a dosage of 150 to 450mg daily, and intravenously in cumulative dosages of 0.5 to 10 mg/kg.