Phosphodiesterase Inhibitors

The cyclic AMP—phosphodiesterase (PDE) inhibitors reduce the degradation of cellular cyclic AMP; the consequences are generally those of elevated cyclic AMP, much as would occur in response to a stimulator of adenylyl cyclase activity. In the heart, the result is positive inotropism. In the peripheral vasculature, the result is dilation of both resistance and capacitance vessels, leading to reduction of both afterload and preload. These combined effects on the myocardium and in the periphery underlie the classification of these drugs as "inodilators".

INAMRINONE AND MILRINONE Parenteral formulations of inamrinone (previous name: amrinone) and milrinone are approved for short-term support of the circulation in advanced heart failure. Both drugs are bipyridine derivatives and relatively selective inhibitors of PDE3, the cyclic GMP-inhibited cyclic AMP PDE. These drugs cause direct stimulation of myocardial contractility and acceleration of myocardial relaxation. In addition, they cause balanced arterial and venous dilation with a consequent fall in systemic and pulmonary vascular resistances, and left and right heart filling pressures. Cardiac output increases due to the stimulation of myocardial contractility and the decrease in left ventricular afterload. As a result of this dual mechanism of action, the increase in cardiac output with milrinone is greater than that seen with nitroprusside at doses that comparably reduce systemic resistance. Conversely, the arterial and venous dilator effects of milri-none are greater than those of dobutamine at doses that produce comparable increases in cardiac output.

Intravenous infusions of either drug should be initiated with a loading dose followed by a continuous infusion. For inamrinone, a 0.75-mg/kg bolus injection administered over 2-3 minutes is followed by a 2- to 20-ig/kg/min infusion. The loading dose of milrinone is usually 50 ig/kg, and the continuous infusion rate ranges from 0.25-1 [g/kg/min. The elimination half-lives of inamrinone and milrinone in healthy subjects are 2-3 hours and 0.5-1 hour, respectively, and are approximately doubled in patients with severe heart failure. Clinically significant thrombocytopenia occurs in 10% of patients receiving inamrinone but is rare with milrinone. Because of its greater selectivity for PDE3 isoenzymes, shorter t122, and more favorable side-effect profile, mil-rinone is preferred among currently available PDE inhibitors for short-term, parenteral inotropic support. The vasodilating effects of the drug and its relatively protracted t1/2 limit use in patients with low systemic arterial pressure.

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