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

Inotropic agents, digoxin
Heart failure
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791
Renin
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Angiotensin I
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Angiotensin II
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Aldosterone
Renin
inhibitors
ACE
inhibitors
AT 1 receptor
antagonists
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Spironolactone
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distal nephron segments (see Chapter 25). These drugs
also enhance K + secretion, particularly in the presence
of elevated aldosterone levels, as is typical in CHF.
The bioavailability of orally administered furosemide ranges
from 40-70%. High drug concentrations often are required to initiate
diuresis in patients with worsening symptoms or in those with
impaired gastrointestinal absorption, as may occur in severely hypervolemic
patients with CHF- induced gut edema (Gottlieb, 2004). In
contrast, the oral bioavailabilities of bumetanide and torsemide are
>80%, and as a result, these agents are more consistently absorbed
but are financially more costly.
Furosemide and bumetanide are short- acting drugs, and
rebound Na + retention that occurs with sub- steady state drug levels
make ≥2/day dosing an acceptable treatment strategy when using
these agents, provided adequate monitoring of daily body weight
and blood electrolyte level monitoring is possible.
Thiazide Diuretics. Monotherapy with thiazide diuretics
(DIURIL, HYDRODIURIL, others) has a limited role in CHF.
However, combination therapy with loop diuretics is
often effective in those refractory to loop diuretics
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Digoxin
β antagonists
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Vasodilators
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cardiac output
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Sympathetic nervous
system activation
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Vasoconstriction
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Cardiac
remodeling
Elevated cardiac filling pressures
Na + and water retention
Diuretics
Figure 28–1. Pathophysiologic mechanisms of heart failure and major sites of drug action. Congestive heart failure is accompanied
by compensatory neurohormonal responses, including activation of the sympathetic nervous and renin–angiotensin–aldosterone axis.
Increased ventricular afterload, due to systemic vasoconstriction and chamber dilation, causes depression in systolic function. In addition,
increased afterload and the direct effects of angiotensin and norepinephrine on the ventricular myocardium cause pathologic
remodeling characterized by progressive chamber dilation and loss of contractile function. Key congestive heart failure medications
and their targets of action are presented. ACE, angiotensin- converting enzyme; AT 1
receptor, type 1 angiotensin receptor.
alone. Thiazide diuretics act on the Na + Cl − cotransporter
in the distal convoluted tubule (see Chapter 25)
and are associated with a greater degree K + wasting per
fluid volume reduction when compared to loop diuretics
(Gottlieb, 2004).
K + -Sparing Diuretics. K + -sparing diuretics (see
Chapter 25) inhibit apical membrane Na + -conductance
channels in renal epithelial cells (e.g., amiloride, triamterene)
or are mineralocorticoid (e.g., aldosterone)
receptor antagonists (e.g., canrenone [not commercially
available in the U.S.], spironolactone, and eplerenone).
Collectively, these agents are weak diuretics, but have
historically been used to achieve volume reduction with
limited K + and Mg 2+ wasting. The beneficial role of
aldosterone receptor blockers on survival in CHF is discussed
later.
Diuretics in Clinical Practice. The majority of CHF
patients will require chronic administration of a loop
diuretic to maintain euvolemia. In patients with clinically
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CHAPTER 28
PHARMACOTHERAPY OF CONGESTIVE HEART FAILURE