Current status of non-digitalis positive inotropic drugs

Abstract

Considerable effort and resources have been directed at the development and study of positive inotropic drugs over the past 10–15 years. Much has been learned about the physiology and pharmacology of myocardial contraction, the application of agents to augment contractility, and, importantly, the general and specific limitations of positive inotropic therapy. Studies on acute inotropic intervention have now shown that a drug's ability to augment overall cardiac performance is heavily dependent on its effects on vasculature, vascular control, and ventricular-vascular coupling. The clinical research on new agents has served to remind us how difficult it is to formulate the “ideal” positive inotropic or cardiovascular support drug for the critical care setting. The vast effort to develop a chronically and orally administrate drug to replace or even supplement digitalis has generally been disappointing. The dopaminergic agents (e.g., ibopamine, levodopa) act primarily via vasodilation and their effectiveness and role in managing heart failure remain unresolved. The initial excitement about the phosphodiesterase III inhibitors (e.g., amrinone, milrinone, enoximone) has been tempered by the results of large well-designed trials indicating variable effectiveness and a prominent adverse effect profile. During long-term oral administration none of these agents has been shown to improve clinical status or exercise capacity beyond that achieved by digoxin, when administered either separately or in combination with digoxin. The Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial, showing that repeated oral administration of milrinone can increase mortality in heart failure, is having a devastating effect on the further development of this class of drugs. Investigation is proceeding at basic levels to unravel the intricate mechanisms of myocardial contraction and we are beginning to see the results of this research. Agents have been developed to “sensitize” the contractile apparatus to calcium and to act in very precise locations. We are hopeful that some of these agents will have a favorable benefit to adverse effect ratio and earn a position in the clinical therapeutics of heart failure.