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

weighed against the increased likelihood for inducing hyperkalemia,
hypotension, and elevated elective treatment withdrawal rates
reported in some trials. Data regarding mortality benefit attendant
to combination therapy are not available at present.
In CHF from impaired diastolic relaxation (i.e., preserved LV
ejection fraction), the role of AT 1
receptor antagonists is unresolved.
These drugs do not appear to improve mortality or echocardiographic
indices of diastolic relaxation but are associated with fewer
CHF hospitalizations (Yusuf et al., 2003; Solomon et al., 2007;
Massie et al., 2008). Some have suggested that ARB- induced
improvement in arteriolar flow reserve may be protective in patients
with diastolic CHF, although this hypothesis remains speculative at
present (Kamezaki et al., 2007).
Direct Renin Inhibitors. There is accumulating scientific
and clinical evidence to suggest that maximal pharmacologic
ACE inhibition alone is insufficient for optimal
attenuation of AngII- induced cardiovascular dysfunction
in patients with CHF. Several molecular mechanisms
have been ascribed to explain this hypothesis
(Abassi et al., 2009), including:
• the presence of ACE- independent pathways that
facilitate AngI conversion to AngII
• the activation of ACE homologues (e.g., ACE2) that
are insensitive to conventional ACE- I therapy
• the suppression of the negative feedback effect
exerted by AngI on renin secretion in the kidney
For these reasons, inhibition of renin has pharmacotherapeutic
objectives for enhanced suppression of
AngII synthesis in CHF.
Renin- mediated conversion of angiotensinogen to
AngI is the first and rate- limiting step in the biochemical
cascade that generates AngII and aldosterone (see
Figures 26–1 and 28–3). The first generation of orally
administered direct renin inhibitors was studied in the
1980s and was designed for the treatment of hypertension,
but the broader use of these agents was hampered
by the drugs’ suboptimal efficacy, reflecting, at least in
part, their limited bioavailability (Staessen et al.,
2006). Aliskiren (TEKTURNA, RASILEZ) is the first orally
administered direct renin inhibitor to obtain FDA
approval for use in clinical practice. The pharmocokinetic
advantages of aliskiren over earlier direct renin
inhibitor prototypes include an increased bioavailability
(2.7%) and a long plasma t 1/2
(~23 hour). Pilot clinical
trials in humans established that aliskiren induces a
concentration- dependent decrease in plasma renin
activity and AngI and AngII levels that was associated
with a decrease in systemic blood pressure without significant
reflex tachycardia. The pharmacology of
aliskiren is presented in more detail in Chapter 26.
The effect of aliskiren on blood pressure is the most thoroughly
evaluated cardiovascular treatment endpoint. Several small
studies have concluded that aliskiren is superior to placebo or to an
ARB for monotherapy of mild- to- moderate hypertension (Sanoski,
2009). Aliskiren also appears to exert beneficial effects on myocardial
remodeling by decreasing LV mass in hypertensive patients, suggesting
that, similar to observations in ACE inhibitor or ARB
therapy, direct renin inhibition may attenuate hypertension- induced
end- organ damage (Solomon et al., 2009). Collectively, these observations
provide evidence that aliskiren- mediated reductions in
plasma renin activity and circulating levels of AngII may have salutary
effects on the cardiovascular system in hypertension, thus opening
the door for investigation of this therapy in patients with CHF.
The safety profile of aliskiren in CHF was established
recently by the Aliskiren Observation of Heart Failure Treatment
(ALOFT) trial (McMurray et al., 2008). Aliskiren (150 mg/day) addon
therapy to a β receptor antagonist and an ACE inhibitor or ARB
was not associated with a significant increase in hypotension or
hyperkalemia in a study cohort that mainly included symptomatic
CHF patients with a low LV ejection fraction (~30%). Results from
this trial also demonstrated that compared with placebo, aliskiren
significantly decreased plasma N- terminal- proBNP levels, a clinically
useful neurohumoral biomarker of active CHF. These findings
affirm that inhibition of renin activity is an important potential target
for improving symptoms and functional capacity in CHF.
However, aliskiren has not yet been studied in sufficiently powered
randomized- controlled clinical trials designed to analyze the efficacy
of this drug in treatment of CHF.
Vasopressin Receptor Antagonists. Neurohumoral dysregulation
in CHF extends beyond the renin–
angiotensin–aldosterone axis to include abnormal arginine
vasopressin (AVP) secretion, resulting in the perturbation
of fluid balance, among various additional
pathophysiogic effects. In response to 1) serum
hypertonicity- induced activation of anterior pituitary
osmoreceptors and 2) a perceived drop in blood pressure
detected by baroreceptors in the carotid artery, aortic
arch, and left atrium, AVP is secreted into the systemic
circulation (Arai et al., 2007). The physiology and pharmacology
of vasopressin are presented in Chapter 25.
The active form of AVP is a 9–amino acid peptide
that interacts with three receptor subtypes: V 1a
, V 1b
,
and V 2
(see Chapter 25). The AVP- V 2
receptor interaction
on the basolateral membrane of the renal collecting
ducts stimulates de novo synthesis of aquaporin-2 water
channels that mediate free water reabsorption, thereby
impairing diuresis and, ultimately, correcting plasma
hypertonicity. Additional cell signaling pathways
important in the pathophysiology of CHF include vasoconstriction,
cell hypertrophy, and increased platelet
aggregation mediated by activation of V 1a
receptors in
vascular smooth muscle cells and cardiac myocytes. In
addition, AngII- mediated activation of centrally located
AT 1
receptors is associated with increased AVP levels in
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CHAPTER 28
PHARMACOTHERAPY OF CONGESTIVE HEART FAILURE