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

798 counterproductive in symptomatic CHF patients. Therefore, it is reasonable
to consider initiation of these drugs while congestive symptoms
are present. ACE- inhibitor doses customarily are increased
over several days in hospitalized patients or over weeks in ambulatory
patients, with careful observation of blood pressure, serum electrolytes,
and serum creatinine levels.
If possible, drug doses are targeted in practice to match those
affording maximum clinical benefit in controlled trials: captopril, 50 mg
three times daily (Pfeffer et al., 1992); enalapril, 10 mg twice daily
(SOLVD Investigators, 1992; Cohn et al., 1991); lisinopril, 10 mg
once daily (GISSI-3, 1994); and ramipril, 5 mg twice daily (AIRE
Study Investigators, 1993). If an adequate clinical response is not
achieved at these doses, further increases, as tolerated, may be effective
(Packer et al., 1999).
In CHF patients with decreased renal blood flow, ACE
inhibitors, unlike nitrosovasodilators, impair autoregulation of
glomerular perfusion pressure, reflecting their selective effect on
efferent (over afferent) arteriolar tone (Kittleson et al., 2003). In the
event of acute renal failure or a decrease in the glomerular filtration
rate by >20%, ACE- inhibitor dosing should be reduced or the drug
discontinued. Rarely, renal function impairment following drug initiation
is indicative of bilateral renal artery stenosis.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
ACE- Inhibitor Side Effects. Elevated bradykinin levels
from ACE inhibition are associated with angioedema, a
potentially life- threatening drug side effect. If this
occurs, immediate and permanent cessation of all ACE
inhibitors is indicated. Angioedema may occur at any
time over the course of ACE inhibitor therapy. A characteristic,
dry cough from the same mechanism is common;
in this case, substitution of an AT 1
receptor
antagonist for the ACE inhibitor often is curative. A
small rise in serum K + levels is common with ACEinhibitor
use. This increase may be substantial, however,
in patients with renal impairment or in diabetic
patients with type IV renal tubular acidosis. Mild
hyperkalemia is best managed by institution of a lowpotassium
diet but may require drug dose adjustment.
The inability to implement ACE inhibitors as a consequence
of cardiorenal side effects (e.g., excessive
hypotension, progressive renal insufficiency, hyperkalemia)
is itself a poor prognostic indicator in the CHF
patient (Kittleson et al., 2003).
ACE Inhibitors and Survival in CHF. A number of randomized,
placebo- controlled clinical trials have demonstrated
that ACE inhibitors improve survival in patients
with CHF due to systolic dysfunction, independent of
etiology. For example, ACE inhibitors prevent mortality
and the development of clinically significant LV
dysfunction after acute MI (Pfeffer et al., 1992;
Konstam et al., 1992; St. John Sutton et al., 1994). This
occurs through attenuation or prevention of increased
LV end- diastolic and end- systolic volumes, and the
decline in LV ejection fraction that is central to the natural
history of AMI. ACE inhibitors appear to confer
these benefits by preventing postinfarction- associated
adverse ventricular remodeling.
The Cooperative North Scandinavian Enalapril Survival
Study (CONSENSUS Trial Study Group 1987) demonstrated a 40%
mortality reduction after 6 months of enalapril therapy in severe
CHF, while others have shown that enalapril also improves survival
in patients with mild- to- moderate CHF (SOLVD Investigators,
1992). Furthermore, across the spectrum of CHF severity, when
compared with other vasodilators, ACE inhibitors appear superior
in reducing mortality (Fonarow et al., 1992). In asymptomatic
patients with LV dysfunction, ACE inhibitors slow the development
of symptomatic CHF.
AT 1
Receptor Antagonists. Activation of the AT 1
receptor
mediates most of the deleterious effects of AngII that
are described earlier. AT 1
-receptor antagonism, in turn,
largely obviates AngII “escape” and substantially
decreases the probability of developing bradykininmediated
side effects associated with ACE inhibition.
Importantly, however, although rare, angioedema has
been reported with AT 1
-receptor antagonist use.
Therefore, caution is still warranted when prescribing
these agents to patients with a history of ACEinhibitor–associated
angioedema.
AT 1
receptor blockers (ARBs) are effective antihypertensives,
and their influence on mortality in acute or chronic CHF from systolic
dysfunction after acute MI is akin to that of ACE- inhibitor therapy
(Konstam et al., 2005; Dickstein et al., 2002; White et al., 2005).
Owing to their favorable side- effect profile, ARBs are an excellent
alternative in CHF patients intolerant of ACE inhibitors (Pitt et al.,
1997; Doggrell, 2005). Interestingly, age >75 years may increase the
probability of developing clinically significant hypotension, renal
dysfunction, and hyperkalemia (White et al., 2005).
The role of combination ACE- inhibitor and ARB therapy in
the treatment of CHF remains unresolved. Although preliminary
studies suggested that combined therapy with candesartan and
enalapril, e.g., favorably affected cardiovascular hemodynamics, LV
remodeling, and neurohormonal profile compared to therapy with
either agent alone (McKelvie et al., 1999), subsequent trials have
been unable to demonstrate an incremental mortality benefit from
combination therapy despite a significant reduction in CHFassociated
hospitalizations (McMurray et al., 2003).
Based on the hypothesis that ARB efficacy is at least in part
a consequence of reduced circulating aldosterone levels, combined
treatment with aldosterone receptor inhibition has been explored.
Combination therapy is associated with a significant increase in LV
ejection fraction and quality of life scores in patients with CHF from
systolic dysfunction treated for 1 year with candesartan (8 mg daily)
and spironolactone (25 mg daily) compared to those treated with
candesartan alone (Chan et al., 2007). Others have corroborated the
beneficial effects of combined therapy on LV remodeling, 6-minute
walk distance, and functional capacity (Kum et al., 2008). The
beneficial effects of dual therapy are provocative but must be