Classification of positive inotropic actions based on electrophysiologic characteristics: where should calcium sensitizers be placed?

A number of new positive inotropic agents with diverse mechanisms of action have been discovered over the past 20 years. Most of these cardiotonic drugs exhibit characteristic electrophysiologic profiles. This prompted us to propose a classification scheme based on electrophysiologic principles, modifying the categories recently suggested by another author. Class I actions designate positive inotropic mechanisms that enhance the transmembrane calcium current by various means, such as beta-receptor stimulation (dobutamine, class I/A), phosphodiesterase inhibition (milrinone, class I/B), direct stimulation of adenylate cyclase (forskolin, class I/C), or direct modulation of calcium channel gating (BAY K 8644, class I/D). Class II action includes mechanisms that lead to elevation of intracellular sodium activity either by inhibiting the Na,K pump (digitalis, class II/A) or by increasing transmembrane sodium influx (DPI 201-106, class II/B). Class III action involves a mechanism by which sensitivity of the myofilaments to calcium increases (EMD 53998, levosimendan). This mechanism is not associated with apparent electrophysiologic manifestations. Positive inotropism due to lengthening of the cardiac repolarization (almokalant) is considered as class IV action. The possible clinical implications of the various positive inotropic mechanisms are also discussed.