Chapter 10. Cardiotonic Agents for the Treatment of Heart Failure

Publisher Summary Effective pharmacologic therapy of heart failure is brought about either by enhancing the contractile state of the failing pump with positive inotropic agents or by the adjustment of the peripheral circulatory state with peripheral vasodilators. The applications of agents that stimulate myocardial contractility are of major value in the treatment of heart failure. In heart failure, the fundamental defect is an impairment of ventricular myocardial contractility that results in an inadequate output to meet the metabolic and circulatory demands of the body. Subsequent to the depression of the contractile state of the heart, loading conditions on the heart become critical determinants of the output. Sympathomimetic amines are the other major class of cardiac stimulants that are used for the treatment of failure. The use of these agents is limited because of oral ineffectiveness, positive chronotropic activity, arrhythmogenic properties, and unwanted peripheral vasoconstrictor actions. Presently, Dobutamine (Dobutrex) and Dopamine (Intropin) are the predominantly used sympathomimetic agents for heart failure. Proposed models of the digital receptor have been suggested that consist of hydrophobic, electrostatic, and hydrogen bonding sites with the steroid, lactone, and sugar moieties of the cardiotonic steroids. One of the most promising positive inotropic agents under study is the bipyridyl analog amrinone. The ionophore monensin, which preferentially complexes sodium, has undergone study as a cardiotonic agent. The increase in heart rate was eliminated by reserpine pretreatment or β-adrenoceptor blockade, while the increase in contractility was only partially attenuated, indicating a direct inotropic effect of the ionophore. Three peptides with similar cardiotonic activity have been isolated from the sea anemone: Anthopleuran-A (AP-A) and AP-C have been sequenced, while AP-B has been partially sequenced.