DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Stroke volume
Normal
Severe
myocardial
dysfunction
Outflow resistance
Hypertension
Moderate
myocardial
dysfunction
Figure 28–4. Relationship between ventricular outflow resistance
and stroke volume in patients with systolic ventricular dysfunction.
An increase in ventricular outflow resistance, a principal
determinant of afterload, has little effect on stroke volume in normal
hearts, as illustrated by the relatively flat curve. In contrast,
in patients with systolic ventricular dysfunction, an increase in
outflow resistance often is accompanied by a sharp decline in
stroke volume. With more severe ventricular dysfunction, this
curve becomes steeper. Because of this relationship, a reduction
in systemic vascular resistance (one component of outflow resistance)
in response to an arterial vasodilator may markedly
increase stroke volume in patients with severe myocardial dysfunction.
The resultant increase in stroke volume may be sufficient
to offset the decrease in systemic vascular resistance,
thereby preventing a fall in systemic arterial pressure. (Adapted
with permission from Cohn and Franciosa, 1977. Copyright ©
Massachusetts Medical Society. All rights reserved.)
activation of sodium nitroprusside is rapid (2-5 minutes),
and the drug is quickly metabolized to NO, properties
that afford easy titration to achieve the desired
hemodynamic effect.
Nitroprusside is particularly effective in treating
critically ill patients with CHF who have elevated systemic
vascular resistance or mechanical complications
that follow acute MI (e.g., mitral regurgitation or ventricular
septal defect- induced left- to- right shunts). As
with other vasodilators, the most common adverse side
effect of nitroprusside is hypotension. In general, nitroprusside
initiation in patients with severe CHF 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 LV contractile dysfunction.
Cyanide produced during the biotransformation of nitroprusside
is rapidly metabolized by the liver to thiocyanate, which
is then renally excreted. Thiocyanate and/or cyanide toxicity is
uncommon but may occur in the setting of hepatic or renal failure,
or following prolonged periods of high- dose drug infusion (see
Chapter 27 for details). Typical symptoms include unexplained
abdominal pain, mental status changes, convulsions, and lactic acidosis.
Methemoglobinemia is another unusual complication and is
due to the oxidation of hemoglobin by NO • .
Intravenous Nitroglycerin. Intravenous nitroglycerin, like
nitroprusside, is a vasoactive NO donor that is commonly
used in the intensive care unit setting. Unlike
nitroprusside, nitroglycerin is relatively selective for
venous capacitance vessels, particularly at low infusion
rates. In CHF, intravenous nitroglycerin is most commonly
used in the treatment of LV dysfunction due to
an acute myocardial ischemia. Parenteral nitroglycerin
also is used in the treatment of nonischemic cardiomyopathy
when expeditious LV filling pressure reduction
is desired. At higher infusion rates, this drug also may
decrease systemic arterial resistance, although this
effect is less predictable. Nitroglycerin therapy may be
limited by headache and nitrate tolerance; tolerance
may be partially offset by increasing the dosage.
Administration requires the use of an infusion pump
capable of controlling the rate of administration.
Hydralazine. Hydralazine is a direct vasodilator that has
long been in clinical use, yet its precise mechanism of
action is poorly understood. The effects of this agent
are not mediated through recognized neurohumoral systems,
and its mechanism of action at the cellular level
in vascular smooth muscle is uncertain. Lack of mechanistic
understanding not with standing, hydralazine is
an effective antihypertensive drug (see Chapter 27),
particularly when combined with agents that blunt compensatory
increases in sympathetic tone and salt and
water retention. In CHF, hydralazine reduces right and
left ventricular afterload by reducing pulmonary and
systemic vascular resistance. This results in an augmentation
of forward stroke volume and a reduction in ventricular
wall stress in systole. Hydralazine also appears
to have moderate “direct” positive inotropic activity in
cardiac muscle independent of its afterload- reducing
effects. Hydralazine is effective in reducing renal vascular
resistance and in increasing renal blood flow to a
greater degree than are most other vasodilators, with
the exception of ACE inhibitors. For this reason,
hydralazine often is used in CHF patients with renal
dysfunction intolerant of ACE- inhibitor therapy.
The landmark Veterans Administration Cooperative
Vasodilator- Heart Failure Trial I (V- HeFT I) demonstrated that
combination therapy with isosorbide dinitrate and hydralazine (a pill