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

failure (McMurray et al., 2003; Cohn and Tognoni, 2001). In contrast,
the VALIANT and ONTARGET (Ongoing Telmisartan Alone
and in Combination with Ramipril Global Endpoint) findings show
no added benefits with combination therapy, which was associated
with more adverse effects (Pfeffer et al., 2003; ONTARGET
Investigators, 2008).
ARBs are renoprotective in type 2 diabetes mellitus, in part
via blood pressure–independent mechanisms (Viberti et al., 2002).
Based on these results, many experts now consider them the drugs
of choice for renoprotection in diabetic patients. The Losartan
Intervention For Endpoint (LIFE) Reduction in Hypertension
Study demonstrated the superiority of an ARB compared with a
β 1
adrenergic receptor antagonist with regard to reducing stroke in
hypertensive patients with left ventricular hypertrophy (Dahlöf et
al., 2002). Also, irebesartan appears to maintain sinus rhythm in
patients with persistent, long- standing atrial fibrillation (Madrid
et al., 2002). Losartan is reported to be safe and highly effective in
the treatment of portal hypertension in patients with cirrhosis and
portal hypertension (Schneider et al., 1999) without compromising
renal function.
Adverse Effects. ARBs are generally well tolerated. The incidence of
angioedema and cough with ARBs is less than that with ACE
inhibitors. As with ACE inhibitors, ARBs have teratogenic potential
and should be discontinued in pregnancy. In patients whose arterial
blood pressure or renal function is highly dependent on the RAS (e.g.,
renal artery stenosis), ARBs can cause hypotension, oliguria, progressive
azotemia, or acute renal failure. ARBs may cause hyperkalemia
in patients with renal disease or in patients taking K + supplements or
K + -sparing diuretics. ARBs enhance the blood pressure–lowering
effect of other antihypertensive drugs, a desirable effect but one that
may necessitate dosage adjustment. There are rare postmarketing
reports of anaphylaxis, abnormal hepatic function, hepatitis, neutropenia,
leukopenia, agranulocytosis, pruritus, urticaria, hyponatremia,
alopecia, and vasculitis, including Henoch- Schönlein purpura.
DIRECT RENIN INHIBITORS
DRIs are a novel class of antihypertensive drugs that
inhibit the RAS at its origin. Angiotensinogen is the
only specific substrate for renin, and its conversion to
AngI presents a rate- limiting step for the generation of
downstream components of the RAS.
Aliskiren (TEKTURNA) is the only DRI approved
for clinical use.
O
O
O
NH 2
O
O
N
NH 2
OH
H
ALISKIREN
History. The earlier renin inhibitors were orally inactive peptide
analogs of the prorenin propeptide or analogs of renin- substrate
cleavage site. Orally active, first- generation renin inhibitors
(enalkiren, zankiren, CGP38560A, and remikiren) were effective in
reducing AngII levels, but none of them made it past clinical trials
due to their low potency, poor bioavailability, and short t 1/2
. Lowmolecular-
weight renin inhibitors were designed based on molecular
modeling and crystallographic structural information of
renin- substrate interaction (Wood et al., 2003; Staessen et al., 2006).
This led to the development of aliskiren, a second- generation renin
inhibitor that was approved by the U.S. FDA in 2007 for the treatment
of hypertension. Aliskiren has blood pressure–lowering effects
similar to those of ACE inhibitors and ARBs.
Pharmacological Effects. Aliskiren is a low- molecularweight
non- peptide that is a potent competitive
inhibitor of renin. It binds the active site of renin to
block conversion of angiotensinogen to AngI, thus
reducing the consequent production of AngII. Aliskiren
has a 10,000-fold higher affinity to renin (IC 50
~0.6 nM)
than to any other aspartic peptidases.
In healthy volunteers, aliskiren (40-640 mg/day)
induces a dose- dependent decrease in blood pressure,
reduces PRA and AngI and AngII levels, but increases
plasma renin concentration by 16-34-fold due to the
loss of the short- loop negative feedback by AngII.
Aliskiren also decreases plasma and urinary aldosterone
levels and enhances natriuresis (Nussberger
et al., 2002).
Aliskiren binds with great specificity to human and primate
renin, but is less specific for non- primate renins (e.g., dog, cat, rat,
pig) and induces a dose- dependent reduction in blood pressure in
Na + -depleted marmosets, equivalent to valsartan or benazepril
(Wood et al., 2003; Wood et al., 2005). In double transgenic rats
expressing human renin and human angiotensinogen genes, aliskiren
is similar to the high dose of valsartan in lowering blood pressure,
reducing albuminuria, normalizing serum creatinine, and protecting
against end- organ damage (Pilz et al., 2005).
Clinical Pharmacology. Aliskiren is recommended as a single oral
dose of 150 or 300 mg/day. Bioavailability of aliskiren is low
(~2.5%), but its high affinity and potency compensate for the low
bioavailability. Peak plasma concentrations are reached within
3-6 hours. The t 1/2
is 20-45 hours. Steady state in plasma is achieved
in 5-8 days. Plasma protein binding is 50% and is independent of
concentration. Aliskiren is a substrate for P- glycoprotein (Pgp),
which accounts for low absorption. Fatty meals significantly
decrease the absorption of aliskiren. Hepatic metabolism by
CYP3A4 is minimal. Elimination is mostly as unchanged drug in
feces. About 25% of the absorbed dose appears in the urine as parent
drug. Aliskiren is well tolerated in the elderly population, in
patients with hepatic disease and renal insufficiency, and in patients
with type 2 diabetes (Vaidyanathan et al., 2008).
Therapeutic Uses of Aliskiren in Hypertension. Clinical
studies confirm aliskiren as an effective antihypertensive
agent that induces significant dose- dependent
739
CHAPTER 26
RENIN AND ANGIOTENSIN