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

738 • ACE inhibitors may increase Ang(1–7) levels more than do ARBs.
ACE is involved in the clearance of Ang(1–7), so inhibition of
ACE may increase Ang(1–7) levels more so than do ARBs.
• ACE inhibitors increase the levels of a number of ACE substrates,
including bradykinin and Ac- SDKP.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Whether the pharmacological differences between ARBs and
ACE inhibitors result in significant differences in therapeutic outcomes
is an open question.
Clinical Pharmacology. Oral bioavailability of ARBs generally is
low (<50%, except for irbesartan, with 70% available), and protein
binding is high (>90%).
Candesartan Cilexetil (ATACAND). Candesartan cilexetil is an inactive
ester prodrug that is completely hydrolyzed to the active form, candesartan,
during absorption from the gastrointestinal tract. Peak plasma
levels are obtained 3-4 hours after oral administration, and the plasma
t 1/2
is ~9 hours. Plasma clearance of candesartan is due to renal elimination
(33%) and biliary excretion (67%). The plasma clearance of candesartan
is affected by renal insufficiency but not by mild- to- moderate
hepatic insufficiency. Candesartan cilexetil should be administered
orally once or twice daily for a total daily dose of 4-32 mg.
Eprosartan (TEVETEN). Peak plasma levels are obtained 1-2 hours
after oral administration, and the plasma t 1/2
is 5-9 hours. Eprosartan
is metabolized in part to the glucuronide conjugate. Clearance is by
renal elimination and biliary excretion. The plasma clearance of
eprosartan is affected by both renal insufficiency and hepatic insufficiency.
The recommended dosage of eprosartan is 400-800 mg/day
in one or two doses.
Irbesartan (AVAPRO). Peak plasma levels are obtained ~1.5-2 hours
after oral administration, and the plasma t 1/2
is 11-15 hours.
Irbesartan is metabolized in part to the glucuronide conjugate, and
the parent compound and its glucuronide conjugate are cleared by
renal elimination (20%) and biliary excretion (80%). The plasma
clearance of irbesartan is unaffected by either renal or mild- tomoderate
hepatic insufficiency. The oral dosage of irbesartan is
150-300 mg once daily.
Losartan (COZAAR). Approximately 14% of an oral dose of losartan
is converted to the 5-carboxylic acid metabolite EXP 3174, which is
more potent than losartan as an AT 1
receptor antagonist. The metabolism
of losartan to EXP 3174 and to inactive metabolites is mediated
by CYP2C9 and CYP3A4. Peak plasma levels of losartan and
EXP 3174 occur ~1-3 hours after oral administration, respectively,
and the plasma half- lives are 2.5 and 6-9 hours, respectively. The
plasma clearances of losartan and EXP 3174 are due to renal
clearance and hepatic clearance (metabolism and biliary excretion).
The plasma clearance of losartan and EXP 3174 is affected by
hepatic but not renal insufficiency. Losartan should be administered
orally once or twice daily for a total daily dose of 25-100 mg. In
addition to being an ARB, losartan is a competitive antagonist of
the thromboxane A 2
receptor and attenuates platelet aggregation
(Levy et al., 2000). Also, EXP 3179, a metabolite of losartan without
angiotensin receptor effects, reduces COX-2 mRNA upregulation
and COX- dependent prostaglandin generation (Krämer et al., 2002).
Olmesartan Medoxomil (BENICAR). Olmesartan medoxomil is an inactive
ester prodrug that is completely hydrolyzed to the active form,
olmesartan, during absorption from the gastrointestinal tract. Peak
plasma levels are obtained 1.4-2.8 hours after oral administration,
and the plasma t 1/2
is between 10 and 15 hours. Plasma clearance of
olmesartan is due to both renal elimination and biliary excretion.
Although renal impairment and hepatic disease decrease the plasma
clearance of olmesartan, no dose adjustment is required in patients
with mild- to- moderate renal or hepatic impairment. The oral dosage
of olmesartan medoxomil is 20-40 mg once daily.
Telmisartan (MICARDIS). Peak plasma levels are obtained 0.5-1 hour
after oral administration, and the plasma t 1/2
is ~24 hours.
Telmisartan is cleared from the circulation mainly by biliary secretion
of intact drug. The plasma clearance of telmisartan is affected
by hepatic but not renal insufficiency. The recommended oral dosage
of telmisartan is 40-80 mg once daily.
Valsartan (DIOVAN). Peak plasma levels occur 2-4 hours after oral
administration, and the plasma t 1/2
is ~9 hours. Food markedly
decreases absorption. Valsartan is cleared from the circulation by the
liver (~70% of total clearance). The plasma clearance of valsartan is
affected by hepatic but not renal insufficiency. The oral dosage of
valsartan is 80-320 mg once daily.
Therapeutic Uses of AngII Receptor Antagonists. All
ARBs are approved for the treatment of hypertension.
In addition, irbesartan and losartan are approved for
diabetic nephropathy, losartan is approved for stroke
prophylaxis, and valsartan is approved for heart failure
and to reduce cardiovascular mortality in clinically
stable patients with left ventricular failure or left ventricular
dysfunction following myocardial infarction.
The efficacy of ARBs in lowering blood pressure is
comparable with that of ACE inhibitors and other
established antihypertensive drugs, with a favorable
adverse- effect profile. ARBs also are available as
fixed- dose combinations with hydrochlorothiazide or
amlodipine (Chapters 27 and 28).
Losartan is well tolerated in patients with heart failure and is
comparable to enalapril with regard to improving exercise tolerance
(Lang et al., 1997). The Evaluation of Losartan in the Elderly
(ELITE) study reported that in elderly patients with heart failure,
losartan was as effective as captopril in improving symptoms and
better in reducing mortality (Pitt et al., 1997). However, the greater
reduction in mortality by losartan was not confirmed in the larger
Losartan Heart Failure Survival Study (ELITE II) trial (Pitt et al.,
2000). The Valsartan in Acute Myocardial Infarction (VALIANT)
trial demonstrated that valsartan is as effective as captopril in patients
with myocardial infarction complicated by left ventricular systolic
dysfunction with regard to all- cause- mortality (Pfeffer et al., 2003).
Both valsartan and candesartan reduce mortality and morbidity in
heart failure patients (Maggioni et al., 2002; Granger et al., 2003).
Current recommendations are to use ACE inhibitors as first- line
agents for the treatment of heart failure and to reserve ARBs for
treatment of heart failure in patients who cannot tolerate or have an
unsatisfactory response to ACE inhibitors.
At present, there is conflicting evidence regarding the advisability
of combining an ARB and an ACE inhibitor in heart failure
patients. The Candesartan in Heart Failure Assessment of Reduction
in Mortality (CHARM- additive) and the Valsartan in Heart Failure
(ValHeFt) studies indicate that a combination of ARB and ACE
inhibitors decrease morbidity and mortality in patients with heart