The failing left ventricle is characterized by depression of myocardial contractility and increased sensitivity to alterations of left ventricular afterload. This latter attribute of the failing ventricle is manifest by a greater proportional reduction of stroke volume as the impedance to ejection is increased. Conversely, afterload reduction in this setting can be associated with substantial increases in stroke volume. This increased afterload dependence underlies the beneficial effects of load reduction therapy in patients with heart failure due to systolic dysfunction.
SODIUM NITROPRUSSIDE Sodium nitroprusside (nitropress) is a prodrug and potent vasodilator that reduces both ventricular filling pressures and systemic vascular resistance. It has a rapid onset (2-5 minutes) and offset (quickly metabolized to cyanide and NO, the active vasodilator) of action and its dose can be titrated expeditiously to achieve the desired hemodynamic effect. For these reasons, nitroprusside is commonly used in intensive-care settings for rapid control of severe hypertension and for the management of decompensated heart failure. The basic pharmaco-logic properties of this drug are described in Chapter 32.
Several mechanisms contribute to the reduction of ventricular filling pressures after treatment with nitroprusside. This agent directly increases venous capacitance, redistributing blood volume from the central to the peripheral venous circulation. Nitroprusside also causes a fall in peripheral vascular resistance as well as an increase in aortic wall compliance and improves ventricular-vascular coupling; left ventricular afterload is decreased and cardiac output is thereby increased. This combination of preload and afterload reduction improves myocardial energetics by reducing wall stress. This improvement in myocardial energetics is contingent upon maintenance of a mean arterial pressure sufficient to drive coronary perfusion during diastole. Following the rapid withdrawal of nitroprusside, a transient deterioration in ventricular function associated with a rebound increase in systemic vascular resistance occurs. Nitroprusside is particularly effective in patients with CHF due to elevations of systemic vascular resistance and/or mechanical complications that follow acute myocardial infarction (such as mitral regurgitation or left-to-right shunts through a ventricular septal defect).
The most common adverse effect of nitroprusside is hypotension. In general, nitroprusside initiation in patients with severe heart failure results in increased cardiac output and a parallel increase in renal blood flow, improving both glomerular filtration and diuretic effectiveness. However, excessive reduction of systemic arterial pressure may limit or prevent an increase in renal blood flow in patients with more severe contractile dysfunction. Cyanide produced during the biotransformation of nitroprusside is rapidly metabolized by the liver to thiocyanate, which is cleared by the kidney. Thiocyanate and/or cyanide toxicity is uncommon but may occur in the setting of hepatic or renal failure, or following prolonged, high-dose infusion of the drug. Typical symptoms include unexplained abdominal pain, mental status changes, convulsions, or lactic acidosis. Methemoglobinemia, another unusual complication of prolonged, high-dose nitroprusside infusion, is due to the oxidation of hemoglobin by NO.
INTRAVENOUS NITROGLYCERIN intravenous nitroglycerin, like nitroprusside, is a vasoactive NO source that is commonly used in intensive care units. Its structure and basic pharmacology are described in Chapter 31. Unlike nitroprusside, nitroglycerin is relatively selective for venous capacitance vessels, particularly at low infusion rates. In patients with CHF, intravenous nitroglycerin is most clearly indicated in the treatment of left heart failure due to acute myocardial ischemia. Parenteral nitroglycerin also is used in the treatment of nonischemic left heart failure when expeditious reduction of ventricular filling pressures is desired; nitroglycerin can be particularly useful in patients with symptomatic volume overload in whom effective diuresis has not been established. At higher infusion rates, this drug can also reduce systemic arterial resistance, although this effect is less predictable. Nitroglycerin therapy may be limited by headache and the development of nitrate tolerance, although the latter is generally overcome by uptitration of the infusion rate to maintain the desired response. Since nitroglycerin is administered in ethanol, high infusion rates can be associated with significant elevation of blood alcohol levels.
NESIRITIDE Nesiritide (natrecor), a recombinant form of human brain natriuretic peptide (BNP), is FDA-approved for treatment of dyspnea due to congestive heart failure. The natriuretic peptides—atrial natriuretic peptide (ANP), BNP, and C-type natriuretic peptide—are a family of endogenous hormones that possess potent natriuretic, diuretic, and vasodilator properties. BNP is secreted by ventricular cardiac myocytes in response to stretch; circulating levels of BNP correlate with the severity of heart failure. In the setting of heart failure, the effects of BNP counteract the effects of AnglI and NE by producing vasodilation, natriuresis, and diuresis.
The BNP receptor is the extracellular domain of type A guanylyl cyclase, GC-A. The active receptor— cyclase complex is a homodimer. Activation of GC-A by nesiritide (BNP) increases cyclic GMP content in target tissues, including vascular, endothelial, and smooth muscle cells. As with nitrova-sodilators, elevated cyclic GMP leads to relaxation of vascular smooth muscle and vasodilation in both the venous and arterial systems. BNP is metabolized by specific clearance receptors, which facilitate its internalization and enzymatic degradation. It is also inactivated by neutral endopeptidases (NEP). Dose adjustment is not required in patients with renal dysfunction.
Nesiritide lowers right and left side cardiac filling pressures without a direct chronotropic or inotropic action. The hemodynamic response to nesiritide is characterized by decreased right atrial, pulmonary arterial, and pulmonary capillary wedge pressures; systemic vascular resistance is reduced and cardiac index is increased. Improvement in global clinical status, attenuation of dyspnea and fatigue, and enhanced diuretic responsiveness have been reported. When compared to intravenous nitroglycerin and placebo in the treatment of decompensated heart failure, nesiritide was associated with greater reductions in pulmonary capillary wedge pressure and improvements in dyspnea were comparable to nitroglycerin and better than placebo. In contrast to the effects of parenteral inotropic agents, nesiritide is not associated with increased ventricular or atrial arrhythmias. Thus, nesiritide may be preferable to inotropic drugs when treating refractory heart failure in patients at risk for arrhythmia
Nesiritide therapy is initiated with a loading dose of 2 ^ g/kg followed by an infusion rate of 0.01 ng/kg/min that can be increased in increments of 0.005 ^g/kg/min to a maximum of 0.03 ng/kg/min. The primary side effect is hypotension that is reversible upon discontinuation of the drug. The t122 of the drug is 18 minutes; however, hypotensive effects may persist for a longer period than would be predicted on the basis of the elimination t1/2. Although there is no specific systolic blood pressure below which nesiritide therapy is contraindicated, studies have typically excluded patients with systolic blood pressure <90 mm Hg; inotropic support may be preferred in such patients. Also of concern, recent meta-analyses have suggested that nesiritide therapy of CHF is associated with an increased risk of renal dysfunction and death.
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