Amrinone, Forerunner of Novel Cardiotonic Agents, Caused Paradigm Shift of Heart Failure Pharmacotherapy

Abstract

Amrinone has been a great forerunner of noncatechol and nonglycoside novel cardiotonic agents and given an extraordinary strong impact in the development of novel cardiotonic agents. Unexpectedly, amrinone failed to rescue the patients with chronic heart failure, thereby produced a prominent paradigm shift from inotropic to cardioprotective therapy, and contributed to advances in the current pharmacotherapy of chronic heart failure. In this study, Alousi et al showed that amrinone is a potent, long-acting positive inotropic agent when given orally or intravenously to either anesthetized or unanesthetized dogs. Amrinone was orally active with a rapid onset of action and duration of >5 hours and showed a wide separation between the positive inotropic and chronotropic effect. Amrinone increased contractile force and the rate of force development without changes in duration of the contractile cycle or time-to-peak tension, and in action potential or excitability even when it was given in relatively high concentrations. The toxicological studies attested to a low toxicity of amrinone ≤10 mg/kg, with less serious side effects such as lowering in blood pressure and an increase in heart rate compared with cardiac glycosides and catecholamines. The therapeutic index of amrinone was wide in contrast to that of cardiac glycosides that have a therapeutic index of ≈2 to 3, with life-threatening arrhythmias. Of greater interest was that amrinone did not increase cardiac output of the normal (nonfailing), but increased that of the failing heart model. The mechanism of action of amrinone, however, was shown only by exclusion criteria. Amrinone did not seem to act via a catecholamine mechanism because its inotropic effect was not blocked by the β-receptor blocking agent propranolol or by depletion of cardiac norepinephrine with reserpine. It was reported that there were no significant changes in the level of cardiac cAMP or phosphodiesterase (PDE) that could be responsible …