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

808 acid level reduction (over 24 weeks) is associated with functional
class improvement, but only in those with baseline serum uric acid
levels >9.5 mg/dL. Overall, randomized, placebo- controlled clinical
trials examining the long- term efficacy of allopurinol therapy in CHF
are sparse, and active investigation in this area continues.
Statins and Vascular Dysfunction.HMG-CoA (3-hydroxy-
3- methyl- glutaryl–coenzyme A) reductase catalyzes the
formation of L- mevalonic acid, a key biochemical precursor
in the cholesterol synthesis pathway (Goldstein
and Brown, 1990). Current evidence suggests a role of
crosstalk between mevalonate metabolism and cell signaling
pathways involved in inflammation and oxidant
stress. In this way, HMG- CoA reductase inhibitors, or
“statins”, may exert beneficial cardiovascular effects
beyond their original intent of low- density lipoprotein
reduction; specifically, statins are associated with positive
LV remodeling, increased arteriolar blood flow, and
decreased circulating platelet aggregation (Liao et al.,
2005).
Intermediate byproducts of mevalonate metabolism
(i.e., isopenylated proteins that upregulate activation of
Rho, RAS, and other G proteins) are linked to impaired
vascular function by increasing levels of oxidant stress
and decreasing bioavailable NO levels (Hernandez- Perera
et al., 1998). Statins inhibit these intermediary pathways
and appear to restore endothelium- dependent (Feron et
al., 2001) and endothelium-independent vascular function
(Drexler et al., 1993). The pharmacology of the
statins and other cholesterol- lowering agents is presented
in Chapter 31.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
A large number of population studies have demonstrated a
favorable effect of statin therapy on outcome in CHF. For example,
one retrospective analysis of ischemic- and non- ischemic cardiomyopathy
patients with CHF reported a significant reduction in mortality
in those treated with a statin for 1 year compared to case- matched
patients treated only with standard medical therapy (Horwich et al.,
2004). Others have suggested that statins delay CHF in at- risk
patients with ischemic heart disease (Kjekshus et al., 1997).
Unfortunately, there is a paucity of sufficiently powered prospective,
randomized, placebo- controlled clinical trials demonstrating a
favorable effect of statin therapy on outcome in patients with CHF.
Overall, the evidence in support of statin use in CHF (of either
ischemic or non- ischemic etiologies) is primarily based on observational
clinical data. The clinical indications for statin therapy in CHF,
preferred drug isoform, and optimal drug concentration, for example,
remain undefined.
Direct Activators of Soluble Guanylyl Cyclase. Soluble
guanylyl cyclase (sGC) is an enzyme that catalyzes the
conversion of guanosine triphosphate to cyclic GMP, a
second messenger necessary for normal vascular
smooth muscle cell relaxation (Koesling, 1999). Under
physiologic conditions, NO is the primary biologically
active stimulator of sGC. Elevated levels of oxidant
stress deactivate sGC through various molecular mechanisms.
For example, aldosterone levels comparable to
those observed in patients with decompensated CHF
are associated with increased oxidant stress that converts
sGC to an NO-insensitive state (Maron et al.,
2009), thereby disrupting vasodilatory signaling necessary
for normal vascular function.
Organic nitrates, which promote sGC activation by
increasing bioavailable NO levels, are subject to pharmacologic
tolerance that complicates long- term drug use,
dosing, and administration frequency (see the organic
nitrates section in Chapter 27). Although the precise
mechanism to explain this phenomenon is unknown, it is
likely mediated in part by elevated levels of oxidant stress
that convert sGC to an NO-insensitive state. BAY compounds
(e.g., BAY 58-2667 [cinaciguat]) activate sGC by
an NO-independent mechanism, thereby promoting normal
sGC function despite conditions of oxidant stress
(Stasch et al., 2006). Data from preclinical CHF studies
in animals have validated these beneficial molecular
effects. In healthy humans, BAY compound administration
has not been associated with severe side effects, but
hypotension and headache have been reported. Likewise
in humans, circulating plasma drug concentrations are
decreased to clinically insignificant levels ≤30 minutes
after infusion termination (Frey et al., 2008).
The utility of BAY 58-2667 in the clinical management of
patients with CHF is a topic of ongoing investigation, although early
published reports suggest potential for the use of this novel drug
class. In a group of patients with acutely decompensated CHF, BAY
58-2667 responders demonstrated a significant decrease in pulmonary
capillary wedge pressure, mean right atrial pressure, mean
pulmonary artery pressure, pulmonary vascular resistance, and systemic
vascular resistance. Cardiac output was significantly increased
as well (Lapp et al., 2009). The potential mainstream application of
BAY 58-2667 (and other similar compounds) is currently under evaluation
in larger clinical trials. Nevertheless, these preliminary observations
are encouraging and may expose sustained sGC activity
despite enzyme insensitivity to NO • as a promising therapeutic target
for CHF patients.
CLINICAL SUMMARY
Congestive heart failure is a chronic and usually progressive
illness instigated by a primary myocardial
insult that impairs myocardial structure and function.
Treatment (Figure 28–8) ideally begins with prevention
of cardiac dysfunction via the identification and remediation
of risk factors that predispose individuals to the
development of structural heart disease. For example,
because coronary artery disease is the most common