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

790 Congestive heart failure is the pathophysiologic
state in which the heart is unable to pump blood at a
rate commensurate with the requirements of metabolizing
tissues, or can do so only from an elevated filling
pressure (Braunwald and Bristow, 2000).
Heart failure is a complex of symptoms— fatigue,
shortness of breath, and congestion— that are related to
the inadequate perfusion of tissue during exertion and
often to the retention of fluid. Its primary cause is an
impairment of the heart’s ability to fill or empty the left
ventricle properly (Cohn, 1996).
From these definitions, one may consider CHF as
a condition in which failure of the heart to provide adequate
forward output at normal end- diastolic filling
pressures results in a clinical syndrome of decreased
exercise tolerance with pulmonary and systemic venous
congestion. Numerous cardiovascular co morbidities are
associated with CHF, including coronary artery disease,
MI, and sudden cardiac death.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
PHARMACOLOGIC TREATMENT
OF HEART FAILURE
The abnormalities of myocardial structure and function
that characterize CHF are often irreversible. These
changes narrow the end- diastolic volume range that is
compatible with normal cardiac function. Although CHF
is predominately a chronic disease, subtle changes to an
individual’s hemodynamic status (e.g., increased circulating
volume from high dietary sodium intake, increased
systemic blood pressure from medication nonadherence)
often provoke an acute clinical decompensation.
Not surprisingly, therefore, CHF therapy has for
many years utilized diuretics to control volume overload
and subsequent worsening in LV function. Other
proven pharmacotherapies target ventricular wall stress,
the renin–angiotensin–aldosterone axis, and the sympathetic
nervous system to decrease pathologic ventricular
remodeling, attenuate disease progression, and
improve survival in selected patients with severe CHF
and low LV ejection fraction. Figure 28–1 provides an
overview of the sites of action for major drug classes
commonly used in clinical practice. Note that these
therapies largely improve cardiac hemodynamics and
function through preload reduction, afterload reduction,
and enhancement of inotropy (i.e., myocardial contractility).
In addition, pharmacotherapeutics that target
peripheral and coronary vascular function are receiving
increased attention as potential participants in the comprehensive
management of CHF patients.
Diuretics
Diuretics remain central in the pharmacologic management
of congestive symptoms in patients with CHF.
The pharmacologic properties of these agents are presented
in detail in Chapter 25. Their importance (and
frequency of use) in CHF management reflects the
deleterious downstream effects of volume expansion on
increased LV end- diastolic volume, an intermediate
step in the development of elevated right- heart pressure,
pulmonary venous congestion, and peripheral edema
(Hillege et al., 2000).
Diuretics reduce extracellular fluid volume and
ventricular filling pressure (or “preload”). Because
CHF patients often operate on a “plateau” phase of the
Frank- Starling curve (Figure 28–2), incremental preload
reduction occurs under these conditions without a
reduction in cardiac output. Sustained natriuresis and/or
a rapid decline in intravascular volume, however, may
“push” one’s profile leftward on the Frank- Starling
curve, resulting in an unwanted decrease in cardiac
output. In this way, excessive diuresis is counterproductive
secondary to reciprocal neurohormonal overactivation
from volume depletion (McCurley et al., 2004).
For this reason, it is preferable to avoid diuretics in
patients with asymptomatic LV dysfunction and to only
administer the minimal dose required to maintain euvolemia
in those patients symptomatic from hypervolemia.
Despite the efficacy of loop or thiazide diuretics
in controlling congestive symptoms and improving
exercise capacity, their use is not associated with a
reduction in CHF mortality.
Dietary Sodium Restriction. All patients with clinically
significant LV dysfunction, regardless of symptom status,
should be advised to limit dietary sodium intake to
2-3 g/day. More stringent salt restriction is seldom necessary
and may be counterproductive, as it can lead to
hyponatremia, hypokalemia, and hypochloremic metabolic
alkalosis when combined with loop diuretic
administration.
Loop Diuretics. Of the loop diuretics currently available,
furosemide (LASIX, others), bumetanide (BUMEX, others),
and torsemide (DEMADEX, others) are widely used
in the treatment of CHF. Due to the increased risk of
ototoxicity, ethacrynic acid (EDECRIN) is recommended
only for patients with sulfonamides allergies or who are
intolerant to alternative options.
Loop diuretics inhibit a specific ion transport protein,
the Na + -K + -2Cl – symporter on the apical membrane
of renal epithelial cells in the ascending limb of
the loop of Henle to increase Na + and fluid delivery to