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

(75-300 mg) reductions in blood pressure. Aliskiren is
as effective as ACE inhibitors (ramipril), ARBs (losartan,
irbesartan, valsartan), and hydrochlorothiazide
(HCTZ) in lowering blood pressure in patients with mild- tomoderate
hypertension (Oparil et al., 2007; Sanoski,
2009). Aliskiren also is as effective as lisinopril in lowering
blood pressure in patients with severe hypertension
(Strasser et al., 2007). The long t 1/2
of aliskiren allows its
antihypertensive effects to be sustained for several days
following termination of therapy (Oh et al., 2007).
Many short- term studies indicate that the effect of aliskiren in
combination with ACE inhibitors, ARBs, and HCTZ is additive in
lowering blood pressure. The antihypertensive effects of aliskiren in
monotherapy and in combination therapy were evaluated in patients
with mild- to- moderate hypertension. In these studies, supplementing
aliskiren to ramipril, irbesartan, valsartan, or HCTZ induced additional
decreases in systolic and diastolic blood pressure that were
larger than that induced by any of the drugs alone. PRA is inhibited
by aliskiren but significantly elevated with ramipril, irbesartan, and
HCTZ (Table 26-1). Co- administration of aliskiren with ramipril,
irbesartan, or HCTZ neutralized the increase in plasma renin activity
to baseline levels (Staessen, 2006; Sanoski, 2009). Because
plasma renin levels correlate with the capacity to generate AngII,
the ability of aliskiren to neutralize plasma renin in combination
therapy may contribute to better control of blood pressure than
monotherapy.
The antihypertensive effect of aliskiren is significantly
augmented in combination with HCTZ (Oparil et al., 2007). Fixeddose
combinations of aliskiren/HCTZ are marketed for antihypertensive
therapy (Baldwin and Plosker, 2009).
Therapeutic Uses of Aliskiren in End-Organ Damage. The
ability of aliskiren to inhibit the increased PRA caused
by ACE inhibitors and ARBs theoretically provides a
more comprehensive blockade of the RAS and may
limit activation of the local (tissue) RAS (Table 26-1).
Studies are ongoing to address whether aliskiren provides
better protection against end- organ damage in
cardiovascular and renal diseases.
The ALLAY trial (Aliskiren in Left Ventricular Hypertrophy
trial) compared the effect of aliskiren with losartan on left ventricular
hypertrophy as a marker of end- organ damage. Both aliskiren
and losartan were equivalent in reducing blood pressure and
decreasing left ventricular mass, but there was no additional reduction
in left ventricular mass with combination therapy (Solomon
et al., 2009).
The ALOFT trial (Aliskiren Observation of Heart Failure
Treatment) indicated that aliskiren was beneficial when added to
ACE inhibitors in heart failure treatment (McMurray et al., 2008).
Patients received aliskiren or placebo in addition to standard heart
failure treatment (ACE inhibitors, ARBs, β blockers), and the primary
outcome measured was changes in N- terminal proB type natriuretic
peptide (BNP). Aliskiren caused a significant decrease in
plasma BNP levels, urinary BNP, and aldosterone levels, indicating
favorable neurohormonal effects of aliskiren in heart failure when
added to standard therapy. A follow- up SPHERE trial (Aliskiren
Trial to Mediate Outcome Prevention in Heart Failure) will address
long- term outcome in heart failure patients.
The AVOID trial (Aliskiren in Evaluation of Proteinuria I
Diabetes Trial) reported aliskiren to be renoprotective in patients
with hypertension and type 2 diabetes. Patients were on the maximal
dose of losartan for 3 months before adding aliskiren or placebo for
6 months. At the end of the study period, patients taking aliskiren
had their mean urinary albumin- to- creatinine ratio significantly
decreased by 20%, and the decrease was 50% or more in 24.7% of
patients compared with placebo. The renoprotective effects of
aliskiren were independent of blood pressure–lowering effects
Table 26–1
Effects of Anti-hypertensive Agents on Components of the RAS
DIRECT Ca 2+
RENIN
CHANNEL
INHIBITORS ACE-INHIBITORS ARBs DIURETICS BLOCKERS β BLOCKERS
PRC a a a a i b
PRA b a a a i b
Ang I b a a a i b
Ang II b b a a i b
ACE i b i
Bradykinin i a i
AT 1
i i inhibition
receptors
AT 2
i i stimulation
receptors
PRC, plasma renin concentration; PRA, plasma renin activity; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker.