Non-receptor-mediated inotropic drugs

There has been an active search recently for non-glycoside, non-sympathomimetic positive inotropic agents. Phosphodiesterase inhibitors inhibit the breakdown of cyclic AMP, leading to an increase in intracellular cAMP concentration, and can be expected to enhance the force of myocardial contraction. The methylxanthines exert such an action in vitro; the situation in vivo is more complex, due to their manyfold actions. Phosphodiesterase F-III is relatively specific for cAMP degradation; the new phosphodiesterase inhibitors may act specifically by inhibiting this enzyme. Phosphodiesterase inhibitors with combined inotropic and vasodilatory action include amrinone, which is no longer in widespread use due to its pronounced side-effects, milrinone, which is much better tolerated and has shown promising results in recent large-scale trials, and sulmazole which has been withdrawn due to toxic effects in rodents. Other drugs are still under investigation. Of importance is the relative role of the inotropic versus dilatory action of these drugs. A salutory effect on resting haemodynamics, does not necessarily imply improved exercise haemodynamics. The pharmacokinetic profile of these drugs is also of interest. The clinical benefits should be sustained and the side-effects should not outweigh the beneficial actions of these drugs.