Вы находитесь на странице: 1из 11

Pharmacophore 2011, Vol.

2 (6), 276-286 ISSN 2229 – 5402

Pharmacophore
(An International Research Journal)

Available online at http://www.pharmacophorejournal.com/


Review Article
A REVIEW OF PHARMACOLOGICAL AND PHARMACEUTICAL
PROFILE OF IRBESARTAN
Asif Husain1*, Md Sabir Azim1 Moloy Mitra2 and Parminder S. Bhasin2
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
Jamia Hamdard (Hamdard University), Hamdard Nagar,
New Delhi-110062, India
2
Analytical Research Division, Ranbaxy Research Laboratories,
Gurgaon, India
ABSTRACT
Irbesartan is classified as an angiotensin II receptor type 1 antagonist. Angiotensin II receptor type 1
antagonists are widely used in treatment of diseases like hypertension, heart failure, myocardial infarction
and diabetic nephropathy. Irbesartan is an orally active lipophilic drug and possesses rapid oral
absorption. It causes reduction in blood pressure and is used in treatment of hypertension. Irbesartan
delays progression of diabetic nephropathy and is indicated for the reduction of renal disease progression
in patients with type 2 diabetes. It is jointly marketed by Sanofi-Aventis and Bristol-Myers Squibb under
the trade name Aptovel®, Karvea® and Avapro®. Irbesartan is also available in a combination formulation
with a low dose thiazide diuretic, invariably hydrochlorothiazide, to achieve an additive antihypertensive
effect. This paper reviews the pharmacological and pharmaceutical properties of Irbesartan. Irbesartan
could be an attractive target for the generic industries.
Keywords: Irbesartan, Hypertension, ACE inhibitors, Diabetes, Diuretic.
INTRODUCTION in water. It is a lipophilic drug and possesses
rapid oral absorption2.
Irbesartan, an angiotensin II receptor antagonist,
is used mainly for the treatment of hypertension. Hypertension is one of the most prevalent
It is an orally active nonpeptide tetrazole cardiovascular diseases in the world, affecting a
derivative and selectively inhibits angiotensin II big proportion of the adult population.
receptor type11,2. Angiotensin II receptor type1 Furthermore, hypertension is an independent risk
antagonists have been widely used in treatment factor for cardiovascular disease and is
of diseases like hypertension, heart failure, associated with an increased incidence of stroke
myocardial infarction and diabetic nephropathy. and coronary heart disease. Although there have
Irbesartan, classified as high permeability and been many advances in the treatment over the
low solubility drug, is slightly soluble in alcohol past several decades, less than 25% of all
and methylene chloride, and practically insoluble hypertensive patients have their blood pressure
adequately controlled with available therapies.
The angiotensin II angiotensin blockers (ARBs)
http://www.pharmacophorejournal.com/ 276
Asif Husain et al. / Pharmacophore 2011, Vol. 2 (6), 276-286
represent a newer class of antihypertensive preparations are marketed under similar trade
agents3. Their mechanism of action differs from names to irbesartan preparations, including
that of the angiotensin-converting enzyme Irda®, Colda®, CoAProvel®, Karvezide®,
(ACE) inhibitors, which also affect the rennin Avalide® and Avapro HCT®.
angiotensin system. The ARBs were developed The renin-angiotensin aldosterone system
to overcome several of the deficiencies of ACE (RAAS) plays an essential role in the regulation
inhibitors: competitive inhibition of ACE results of blood pressure. Renin, a proteinase enzyme, is
in a reactive increase in renin and angiotensin I secreted by the kidney in response to a reduction
levels, which may overcome the blockade effect; in renal blood flow, blood pressure or sodium
ACE is a relatively nonspecific enzyme that has concentration. Renin then converts
substrates in addition to angiotensin I, including angiotensinogen, which is secreted by the liver,
bradykinin and other tachykinins, and thus, to the decapeptide angiotensin I (AI). AI is
inhibition of ACE may result in accumulation of cleaved by angiotensin converting enzyme
these substrates; production of angiotensin II can (ACE) to the octapeptide angiotensin II (AII).
occur through non-ACE pathways as well as AII produces potent vasoconstriction via
through the primary ACE pathway, and these interaction with vascular angiotensin receptors
alternative pathways are unaffected by ACE (AT receptors). AII also promotes aldosterone
inhibition; specific adverse effects are associated secretion and therefore sodium retention by
with ACE inhibitor effects on the enzyme; and stimulation of angiotensin receptors present on
ARBs may offer more complete angiotensin II the adrenal cortex. These actions result in
inhibition by interacting selectively with the elevated blood pressure secondary to the
receptor site4. All 7 drugs (sartans) in this class vasoconstriction and enhanced cardiac output
are approved by the Food and Drug secondary to sodium retention. In addition to its
Administration for the treatment of hypertension, normal regulatory role, the RAAS also
either alone or in combination with other drugs. contributes to pathological conditions such as
Unlabeled uses include the treatment of renovascular hypertension, essential
congestive heart failure and, for losartan and hypertension and congestive heart failure. Thus
irbesartan, diabetic nephropathy5. Irbesartan is over the past several decades research efforts
indicated for the treatment of hypertension. have been directed toward developing drugs
Irbesartan also delays progression of diabetic capable of suppressing of RAAS by inhibiting
nephropathy and is also indicated for the renin release, by blocking the formation of AII
reduction of renal disease progression in patients via inhibition of ACE, or Antagonism of AII at
with type 2 diabetes, hypertension and its physiologic receptors. In the past most
microalbuminuria or proteinuria6-8.
clinically relevant success involved the
History & Development3-5, 9, 10 development of ACE inhibitors (ACEIs),
beginning with the introduction of captopril in
Irbesartan was first developed by Sanofi
1981, followed by enalapril (Vasotec®),
Research (now part of Sanofi-Aventis) and
lisinopril (Prinivil®, Zestril®), benazepril
jointly marketed by Sanofi-Aventis and Bristol-
(Lotensin®), fosinopril (Monopril®), quinapril
Myers Squibb under the trade name Aptovel®,
(Accupril®), ramipril (Altace®), moexipril
Karvea®, and Avapro®. It may be used alone or
(Univasc®) and trandolapril (Mavik®). ACEIs
in combination with other antihypertensive
have been successfully employed in the
medications. Thus, Irbesartan is available in a
combination formulation with a low dose management of various forms of hypertension as
well as congestive heart failure. However, ACE
thiazide diuretic, invariably hydrochlorothiazide,
has other physiologic actions not related to the
to achieve an additive antihypertensive effect.
regulation of RAAS, including the degradation
Irbesartan/hydrochlorothiazide combination
http://www.pharmacophorejournal.com/ 277
Asif Husain et al. / Pharmacophore 2011, Vol. 2 (6), 276-286
of bradykinin and other peptides including amide,2-Butyl-3-[[4-[2-(2-trityl-tetrazol-5-yl)
substance P. These additional actions are also phenyl] phenyl]methyl]-1,3-iazaspiro[4.4] non-
inhibited by ACEIs, and this may account for 1-en-4- one, 2-Butyl-4-spirocyclopentane-2-
some of the adverse reactions of these drugs imidazolin-5-onehydrochloride,5-(4'-
including dry cough. Thus in recent years renin (Bromomethyl) (1,1'-biphenyl)-2-yl)-1-trityl-1H-
inhibitors and AII receptor antagonists were tetrazole(Irbesartan Bromo Impurity), 4'-[(2-
targeted for development as more specific Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)
inhibitors of the RAAS and as a direct approach methyl] biphenyl-2-carbonitrile. It is also called
to block the system independent of AII as Irbesartan USP Related Compound A,
production. These efforts led to the introduction Irbesartan N1-trityl impurity, Irbesartan lactam
in recent years of several non-peptide impurity, Irbesartan bromo impurity, and
heterocyclic AII antagonists including losartan Irbesartan cyano impurity, respectively.
(Cozaar®), followed by valsartan (Diovan®) and
PHARMACOLOGY
now irbesartan. Irbesartan is well-absorbed
orally, long-acting allowing for once-daily Mechanism of Action5, 12-14
administration, and unlike losartan, does not Angiotensin II is a potent vasoconstrictor formed
exert a uricosuric effect. Irbesartan also is from angiotensin I in a reaction catalyzed by
reported to demonstrate dose-response efficacy angiotensin-converting enzyme (ACE, kinase II).
while maintaining placebo-level side effects at Angiotensin II is the principal pressor agent of
doses. the renin-angiotensin system (RAS) and also
Physicochemical Properties11 stimulates aldosterone synthesis and secretion by
adrenal cortex, cardiac contraction, renal
Irbesartan is 2-butyl-3-({4-[2-(2H-1,2,3,4- reabsorption of sodium, activity of the
tetrazol-5-yl)phenyl]phenyl}methyl)-1,3- sympathetic nervous system, and smooth muscle
diazaspiro [4.4]non-1-en-4-one (Figure1), with cell growth. Irbesartan blocks the vasoconstrictor
chemical formula C25H28N6O & molecular and aldosterone-secreting effects of angiotensin
weight of 428.53 g/mol. Irbesartan is white II by selectively binding to the AT1 angiotensin
crystalline powder with melting point 180-182 II receptor. There is also an AT2 receptor in
°C. It is soluble in alcohol and methylene many tissues, but it is not involved in
chloride, and practically insoluble in water. cardiovascular homeostasis.
Irbesartan is a tetrazole derivative (five-
membered heterocyclic ring with 4 nitrogen Irbesartan is a specific competitive antagonist of
atoms) that contains acid (pKa = 4.24) groups AT1 receptors with a much greater affinity (more
making the compound soluble in the neutral pH than 8500-fold) for the AT1 receptor than for the
range. It is a nonpolar compound with a partition AT2 receptor and no agonist activity.
coefficient (octanol/water) of 10.1 at pH of 7.4. Blockade of the AT1 receptor removes the
In vitro studies of irbesartan oxidation by negative feedback of angiotensin II on renin
cytochrome P450 isoenzymes indicated secretion, but the resulting increased plasma
irbesartan was oxidized primarily by 2C9; renin activity and circulating angiotensin II do
metabolism by 3A4 was negligible. Irbesartan not overcome the effects of irbesartan on blood
was neither metabolized by, nor did it pressure.
substantially induce or inhibit, isoenzymes
Irbesartan does not inhibit ACE or renin or affect
commonly associated with drug metabolism.
other hormone receptors or ion channels known
There was no induction or inhibition of 3A4.
to be involved in the cardiovascular regulation of
Irbesartan have different type of impurities such
blood pressure and sodium homeostasis. Because
as 1-pentanoylamino-cyclopentanecarboxylic
irbesartan does not inhibit ACE, it does not
acid [2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-
http://www.pharmacophorejournal.com/ 278
Asif Husain et al. / Pharmacophore 2011, Vol. 2 (6), 276-286
affect the response to bradykinin; whether this in the range of 157-176 ml/min and 3.0-3.5
has any clinical relevance is not known. In ml/min, respectively. With repetitive dosing,
healthy subjects irbesartan (150 or 300 mg), like irbesartan accumulates to no clinically relevant
other angiotensin antagonists, inhibits the pressor extent18.
effects of infused AII producing peak inhibition
Metabolism and Elimination19, 20
of both systolic and diastolic blood pressure rise
within 2-4 h with residual effects persisting for Irbesartan is partly metabolized and excreted
24 h. Irbesartan has been found safe in subjects mainly in bile. It is metabolized via glucuronide
with pregnancy. conjugation and oxidation. Following oral or
intravenous administration of 14C-labeled
Pharmacokinetic & Pharmcodynamic Profile irbesartan, more than 80% of the circulating
Irbesartan is an orally active agent that does not plasma radioactivity is attributable to unchanged
require biotransformation into an active form. irbesartan. The primary circulating metabolite is
The oral absorption of irbesartan is rapid and the inactive irbesartan glucuronide conjugate
complete with an average absolute (approximately 6%). The remaining oxidative
bioavailability of 60-80%. Following oral metabolites do not add appreciably to
administration of irbesartan, peak plasma pharmacologic activity irbesartan. Irbesartan and
concentrations of irbesartan are attained at 1.5-2 its metabolites are excreted by both biliary and
h after dosing. Food does not affect the renal routes. There is either oral or intravenous
bioavailability of irbesartan. The administration of 14C-labeled irbesartan; about
pharmacokinetics of irbesartan has been 20% of radioactivity is recovered in the urine
compared to the other available angiotensin and the remainder in the feces, as irbesartan or
receptor antagonists (Table1). The oral irbesartan glucuronide.
bioavailability of this AT1 antagonist is relatively In vitro studies of irbesartan oxidation by
high. cytochrome P450 isoenzymes indicated
irbesartan was oxidized primarily by 2C9;
Irbesartan is more completely absorbed from GI
metabolism by 3A4 was negligible. Irbesartan
tract than other AT antagonists and reaches peak
was neither metabolized by, nor did it
plasma concentrations within 2 h. Irbesartan is
substantially induce or inhibit, isoenzymes
not as extensively bound to plasma proteins and
commonly associated with drug metabolism
does not require metabolism to the active form.
(1A1, 1A2, 2A6, 2B6, 2D6, 2E1). There was no
It is metabolized hepatically to inactive
induction or inhibition of 3A4.
metabolites via cytochrome P450 2C9 (CYP29).
It is excreted by both biliary and renal routes and THERAPEUTIC EFFICACY5, 15, 21-25
has a longer elimination half-life (11-15 h) than In a number of multicenter, randomized,
other angiotensin antagonists. The placebo-controlled, double-blind studies in
pharmacokinetics of irbesartan are not patients with mild to moderate hypertension,
significantly altered by renal or mild-to- statistically significant reductions in trough
moderate hepatic impairment, age or by co- systolic and diastolic blood pressures were
administration of hydrochlorothiazide5, 15-17. observed in patients receiving irbesartan in doses
Distribution of 75 mg daily or greater. Greater reductions in
blood pressure occurred when the dose was
Irbesartan is 90% bound to serum proteins
increased, but this effect leveled off at about 300
(primarily albumin and α1-acid glycoprotein)
mg. The blood pressure lowering effects of
with negligible binding to cellular components of
irbesartan were apparent after the first dose, and
blood. The average volume of distribution is 53-
reached maximal effect within 4-6 weeks.
93 liters. Total plasma and renal clearances are
Irbesartan was found to be effective in reducing
http://www.pharmacophorejournal.com/ 279
Asif Husain et al. / Pharmacophore 2011, Vol. 2 (6), 276-286
blood pressure regardless of patient age, gender continuous ambulatory blood pressure
or race. However, the effect in black patients, monitoring study, once-daily dosing with 150
typically a low renin population, is somewhat mg gave trough and mean 24 h responses similar
lower. In comparative trials irbesartan was to those observed in patients receiving twice-
shown to be at least as effective as daily dosing at the same total daily dose. In
hydrochlorothiazide, atenolol and the full dosage controlled trials, the addition of irbesartan to
of enalapril. And in combination trials, greater hydrochlorothiazide doses of 6.25, 12.5, or 25
reductions in blood pressure were observed when mg produced further dose-related reductions in
irbesartan was combined with the diuretic blood pressure similar to those achieved with the
hydrochlorothiazide. As a result of these same monotherapy dose of irbesartan. HCTZ
findings, irbesartan is indicated for the once also had an approximately additive effect.
daily treatment of hypertension and may be used Analysis of age, gender, and race subgroups of
alone or in combination with other patients showed that men and women, and
antihypertensive agents. patients over and under 65 years of age, had
The antihypertensive effects of irbesartan were generally similar responses. Irbesartan was
examined in 7 major placebo-controlled 8-12 effective in reducing blood pressure regardless of
week trials in patients with baseline diastolic race, although the effect was somewhat less in
blood pressures of 95-110 mm Hg. Doses of 1- blacks (usually a low-renin population). The
900 mg were included in these trials in order to effect of irbesartan is apparent after the first dose
fully explore the dose-range of irbesartan. These and it is close to its full observed effect at 2
studies allowed comparison of once- or twice- weeks. At the end of an 8 week exposure, about
daily regimens at 150 mg/day, comparisons of 2/3 of the antihypertensive effect was still
peak and trough effects, and comparisons of present 1 week after the last dose. Rebound
response by gender, age, and race. Two (2) of the hypertension was not observed. There was
7 placebo-controlled trials identified above essentially no change in average heart rate in
examined the antihypertensive effects of irbesartan-treated patients in controlled trials.
irbesartan and hydrochlorothiazide in
Renal Insufficiency
combination. The 7 studies of irbesartan
monotherapy included a total of 1915 patients The pharmacokinetics of irbesartan was not
randomized to irbesartan (1-900 mg) and 611 altered in patients with renal impairment or in
patients randomized to placebo. Once-daily patients on hemodialysis. Irbesartan is not
doses of 150 and 300 mg provided statistically removed by hemodialysis. No dosage adjustment
and clinically significant decreases in systolic is necessary in patients with mild to severe renal
and diastolic blood pressure with trough (24 h impairment unless a patient with renal
post-dose) effects after 6-12 weeks of treatment impairment is also volume depleted.
compared to placebo, of about 8-10/5-6 and 8- Hepatic Insufficiency
12/5-8 mm Hg, respectively. No further increase
The pharmacokinetics of irbesartan following
in effect was seen at dosages greater than 300
repeated oral administration were not
mg.
significantly affected in patients with mild to
Once-daily administration of therapeutic doses moderate cirrhosis of the liver. No dosage
of irbesartan gave peak effects at around 3-6 h adjustment is necessary in patients with hepatic
and, in one ambulatory blood pressure insufficiency.
monitoring study, again around 14 hours. This
Impaired Renal Function
was seen with both once- and twice-daily dosing.
Trough-to-peak ratios for systolic and diastolic As a consequence of inhibiting the renin-
response were generally between 60-70%. In a angiotensin-aldosterone system, changes in renal

http://www.pharmacophorejournal.com/ 280
Asif Husain et al. / Pharmacophore 2011, Vol. 2 (6), 276-286
function may be anticipated in susceptible Irbesartan was not mutagenic in a battery of in
individuals. In patients whose renal function may vitro tests (Ames microbial test, rat hepatocyte
depend on the activity of the renin-angiotensin- DNA repair test, V79 mammalian-cell forward
aldosterone system (e.g., patients with severe gene-mutation assay). Irbesartan was negative in
congestive heart failure), treatment with several tests for induction of chromosomal
angiotensin-converting-enzyme inhibitors has aberrations (in vitro -human lymphocyte
been associated with oliguria and/or progressive assay; in vivo -mouse micronucleus study).
azotemia and (rarely) with acute renal failure Irbesartan also delays progression of diabetic
and/or death. Irbesartan would be expected to nephropathy and is also indicated for the
behave similarly. In studies of ACE inhibitors in reduction of renal disease progression in patients
patients with unilateral or bilateral renal artery with type 2 diabetes, hypertension and
stenosis, increases in serum creatinine or BUN microalbuminuria or proteinuria.
have been reported. There has been no known
use of irbesartan in patients with unilateral or SAFETY AND TOLERABILITY5, 11,12,16,17
bilateral renal artery stenosis, but a similar effect The safety of antihypertensive deserves a special
should be anticipated. importance because they are likely to be used
Pregnancy long term in general practice in a number of
patients. Irbesartan has a good tolerability profile
Female patients of childbearing age should be consistent over the wide dose range. Irbesartan
told about the consequences of second- and had no adverse effects on fertility or mating of
third-trimester exposure to drugs that act on the male or female rats at oral doses ≤650
renin-angiotensin system, and they should also mg/kg/day, the highest dose providing a
be told that these consequences do not appear to systemic exposure to irbesartan (AUC0-
have resulted from intrauterine drug exposure 24h bound plus unbound) about 5 times that
that has been limited to the first trimester. These found in humans receiving the maximum
patients should be asked to report pregnancies to recommended dose of 300 mg/day.
their physicians as soon as possible.
Adverse Reactions5, 15, 26, 27
Carcinogenesis, Mutagenesis, and
Impairment of Fertility Irbesartan has been evaluated for safety in more
than 4300 patients with hypertension and about
No evidence of carcinogenicity was observed 5000 subjects overall. This experience includes
when irbesartan was administered at doses of up 1303 patients treated for over 6 months and 407
to 500/1000 mg/kg/day (males/females, patients for 1 year or more. Treatment with
respectively) in rats and 1000 mg/kg/day in mice irbesartan was well-tolerated, with an incidence
for up to 2 years. For male and female rats, 500 of adverse events similar to placebo. These
mg/kg/day provided an average systemic events generally were mild and transient with no
exposure to irbesartan [AUC (0-24h) bound plus relationship to the dose of irbesartan. In placebo-
unbound] about 3 and 11 times, respectively, the controlled clinical trials, discontinuation of
average systemic exposure in humans receiving therapy due to a clinical adverse event was
the maximum recommended dose (MRD) or 300 required in 3.3% of patients treated with
mg irbesartan/day, whereas 1000 mg/kg/day irbesartan, versus 4.5% of patients given
(administered to females only) provided an placebo. In placebo-controlled clinical trials, the
average systemic exposure about 21 times that adverse event experiences that occurred in at
reported for humans at the MRD. For male and least 1% of patients treated with irbesartan
female mice, 1000 mg/kg/day provided an
(n=1965) and at a higher incidence versus
exposure to irbesartan about 3 and 5 times, placebo (n=641) included diarrhea (3% Vs 2%),
respectively, the human exposure at 300 mg/day. dyspepsia/heartburn (2% Vs 1%),
http://www.pharmacophorejournal.com/ 281
Asif Husain et al. / Pharmacophore 2011, Vol. 2 (6), 276-286
musculoskeletal trauma (2% Vs 1%), fatigue development. Prematurity, intrauterine growth
(4% Vs 3%), and upper respiratory infection (9% retardation, and patent ductus arteriosus have
Vs 6%). also been reported, although it is not clear
whether these occurrences were due to exposure
The following adverse events occurred at an
to the drug. These adverse effects do not appear
incidence of 1% or greater in patients treated
to have resulted from intrauterine drug exposure
with irbesartan, but were at least as frequent or
that has been limited to the first trimester.
more frequent in patients receiving placebo:
abdominal pain, anxiety/nervousness, chest pain, Mothers whose embryos and fetuses are exposed
dizziness, edema, headache, influenza, to an angiotensin II receptor antagonist only
musculoskeletal pain, pharyngitis, during the first trimester should be so informed.
nausea/vomiting, rash, rhinitis, sinus Nonetheless, when patients become pregnant,
abnormality, tachycardia, and urinary tract physicians should have the patient discontinue
infection. Irbesartan use was not associated with the use of irbesartan as soon as possible.
an increased incidence of dry cough, as is Rarely (probably less often than once in every
typically associated with ACE inhibitor use. In thousand pregnancies), no alternative to a drug
placebo controlled studies, the incidence of acting on the renin-angiotensin system will be
cough in irbesartan treated patients was 2.8% Vs found. In these rare cases, the mothers should be
2.7% in patients receiving placebo. The apprised of the potential hazards to their fetuses,
incidence of hypotension or orthostatic and serial ultrasound examinations should be
hypotension was low in irbesartan treated performed to assess the intra-amniotic
patients (0.4%), unrelated to dosage, and similar environment. If oligohydramnios is observed,
to the incidence among placebo treated patients irbesartan should be discontinued unless it is
(0.2%). Dizziness, syncope, and vertigo were considered life-saving for the mother.
reported with equal or less frequency in patients Contraction stress testing (CST), a non-stress test
receiving irbesartan compared with placebo. (NST), or biophysical profiling (BPP) may be
appropriate depending upon the week of
Fetal/Neonatal Morbidity and Mortality
pregnancy. Patients and physicians should be
Drugs that act directly on the renin-angiotensin aware, however, that oligohydramnios may not
system can cause fetal and neonatal morbidity appear until after the fetus has sustained
and death when administered to pregnant irreversible injury. Infants with histories of in
women. Several dozen cases have been reported utero exposure to an angiotensin II receptor
in the world literature in patients who were antagonist should be closely observed for
taking angiotensin-converting-enzyme inhibitors. hypotension, oliguria, and hyperkalemia. If
When pregnancy is detected, irbesartan should oliguria occurs, attention should be directed
be discontinued as soon as possible. toward support of blood pressure and renal
The use of drugs that act directly on the renin- perfusion. Exchange transfusion or dialysis may
angiotensin system during the second and third be required as means of reversing hypotension
trimesters of pregnancy has been associated with and/or substituting for disordered renal function.
fetal and neonatal injury, including hypotension, Gender differences
neonatal skull hypoplasia, anuria, reversible or
No gender related differences in
irreversible renal failure, and death.
pharmacokinetics were observed in healthy
Oligohydramnios has also been reported,
elderly (age 65-80 years) or in healthy young
presumably resulting from decreased fetal renal
(age 18-40 years) subjects. In studies of
function; oligohydramnios in this setting has
hypertensive patients, there was no gender
been associated with fetal limb contractures,
difference in half-life or accumulation, but
craniofacial deformation, and hypoplastic lung

http://www.pharmacophorejournal.com/ 282
Asif Husain et al. / Pharmacophore 2011, Vol. 2 (6), 276-286
somewhat higher plasma concentrations of however, should receive an initial dose of 75 mg.
irbesartan were observed in females (11-44%). Those patients requiring further blood pressure
No gender-related dosage adjustment is reduction may be titrated to 300 mg once daily.
necessary. It is unlikely that higher doses or twice daily
dosing will produce additional antihypertensive
Geriatric
effects. No dosage adjustment is necessary in
In elderly subjects (age 65-80 years), irbesartan elderly patients or those with hepatic impairment
elimination half-life was not significantly or mild to severe renal impairment. If blood
altered, but AUC and Cmax values were about pressure is not controlled by irbesartan alone,
20-50% greater than those of young subjects another antihypertensive may be added. Also,
(age 18-40 years). No dosage adjustment is low doses of a diuretic such as
necessary in the elderly. hydrochlorothiazide may be added to improve
DRUGS INTERACTIONS15, 26-30 therapeutic effect. The recommended initial dose
of irbesartan is 150 mg once daily. Patients
No significant drug-drug pharmacokinetic (or
requiring further reduction in blood pressure
pharmacodynamic) interactions have been found
should be titrated to 300 mg once daily.
in interaction studies with hydrochlorothiazide,
digoxin, warfarin and nifedipine. A low dose of a diuretic may be added, if blood
pressure is not controlled by irbesartan alone.
In vitro studies show significant inhibition of the
Hydrochlorothiazide has been shown to have an
formation of oxidized irbesartan metabolites
additive effect. Patients not adequately treated by
with the known cytochrome CYP 2C9
the maximum dose of 300 mg once daily are
substrates/inhibitors sulphenazole, tolbutamide,
unlikely to derive additional benefit from a
and nifedipine. However, in clinical studies the
higher dose or twice-daily dosing. No dosage
consequences of concomitant irbesartan on the
adjustment is necessary in elderly patients or in
pharmacodynamics of warfarin were negligible.
patients with hepatic impairment or mild to
Based on in vitro data, no interaction would be
severe renal impairment. Irbesartan may be
expected with drugs whose metabolism is
administered with other antihypertensive agents.
dependent upon cytochrome P450 isozymes.
Irbesartan may be administered with or without
In separate studies of patients receiving food. A lower initial dose of irbesartan (75 mg)
maintenance doses of warfarin, is recommended in patients with depletion of
hydrochlorothiazide, or digoxin, irbesartan intravascular volume or salt (e.g., patients treated
administration for 7 days had no effect on the vigorously with diuretics or on hemodialysis).
pharmacodynamics of warfarin (prothrombin
time) or pharmacokinetics of digoxin. The
Irbesartan Dosing for High Blood Pressure
pharmacokinetics of irbesartan was not affected
by co- administration of nifedipine or The recommended starting dosage of irbesartan
hydrochlorothiazide. for most people with high blood
pressure (hypertension) is 150 mg once a day.
DOSAGE5, 22-29
Based on the blood pressure response
Irbesartan is available as white and off-white and/or irbesartan side effects, the dosage may be
biconvex oval tablets in 75, 150 and 300 mg increased or decreased. With each change in
strengths. The drug may be administered with or dosage, it may take several weeks to see the full
without food and the recommended initial dose effects on blood pressure.
of irbesartan is 150 mg once daily. Patients
Irbesartan Dosing for Diabetic Nephropathy
treated vigorously with diuretics or on
hemodialysis (volume-depleted patients),

http://www.pharmacophorejournal.com/ 283
Asif Husain et al. / Pharmacophore 2011, Vol. 2 (6), 276-286
The recommended starting dosage of irbesartan serum potassium levels are not significantly
for people with diabetic nephropathy is 300 mg affected at recommended doses. In hypertensive
once a day. patients, chronic oral doses of irbesartan (up to
300 mg) had no effect on glomerular filtration
Overdosage26, 30
rate, renal plasma flow or filtration fraction. In
No data are available in regard to overdosage in multiple dose studies in hypertensive patients,
humans. However, daily doses of 900 mg for 8 there were no clinically important effects on
weeks were well-tolerated. The most likely fasting triglycerides, total cholesterol, HDL-
manifestations of overdosage are expected to be cholesterol, or fasting glucose concentrations.
hypotension and tachycardia; bradycardia might There was no effect on serum uric acid during
also occur from overdose. Irbesartan is not chronic oral administration, and no uricosuric
removed by hemodialysis. To obtain up-to-date effect.
information about the treatment of overdosage, a
good resource is a certified Regional Poison CONCLUSION
Control Center. In managing overdose, consider Irbesartan is a potent, long-acting, nonpeptide
the possibilities of multiple-drug interactions, angiotensin II receptor antagonist having high
drug-drug interactions, and unusual drug kinetics selectivity for the AT1 subtype (angiotensin I). It
in the patient. Laboratory determinations of is potentially safe and more tolerable than other
serum levels of irbesartan are not widely classes of antihypertensive drugs. Irbesartan
available, and such determinations have, in any reduces the chances of cardiac failure,
event, no known established role in the myocardial infarction, sudden death, and death
management of irbesartan overdose. Acute oral from progressive systolic failure. Irbesartan is an
toxicity studies with irbesartan in mice and rats effective antihypertensive agent in patients with
indicated acute lethal doses were in excess of mild to moderate hypertension. The drug also
2000 mg/kg, about 25- and 50-fold the maximum reduces blood pressure when used as
recommended human dose (300 mg). monotherapy in patients with severe
In healthy subjects, single oral irbesartan doses hypertension or when used adjunctively in
of up to 300 mg produced dose-dependent patients with resistant hypertension. Importantly,
inhibition of the press or effect of angiotensin II Irbesartan appears to be as effective and well
infusions. Inhibition was complete (100%) 4 h tolerated as other commonly used
following oral doses of 150 or 300 mg and antihypertensive agents. The drug therefore
partial inhibition was sustained for 24 h (60% represents a useful therapeutic option in the
and 40% at 300 mg and 150 mg, respectively). In management of patients with hypertension and
hypertensive patients, angiotensin II receptor diabetic nephropathy will be particularly useful
inhibition following chronic administration of in patients not responding to, or intolerant of,
irbesartan causes a 1.5- to 2-fold rise in anti-hypertensive agents from other drug classes.
angiotensin II plasma concentration and a 2- to Irbesartan may be an appropriate choice for first-
3-fold increase in plasma renin levels. line treatment of patients with mild-to-moderate
Aldosterone plasma concentrations generally hypertension, heart failure, myocardial infarction
decline following irbesartan administration, but and diabetic nephropathy.

http://www.pharmacophorejournal.com/ 284
Asif Husain et al. / Pharmacophore 2011, Vol. 2 (6), 276-286
Table 1: Pharmacokinetic profile of Irbesartan with other sartans

Parameter Losartan Valsartan Irbesartan


Oral bioavailability, % 33 25 60-80
Food effect, (AUC/Cmax) 10% redn. 40% redn. None
Protein binding, % 99 95 90
Distribution, L 34 17 50-90
Elimination half-life, hrs) 2 6 11-15
Metabolism, % 14 20 <20
Metabolic enzymes CYP2C9 CYP2C9 CYP2C9
Urinary recovery, % 35 13 20
Fecal recovery, % 60 80 80

HN N
O
N N
N

Figure 1: Chemical structure of Irbesartan

REFERENCES 5. Anon (1997), “Angiotensin II receptor


1. Aronson, JK (2009), “Irbesartan; antagonists”, Facts and Comparisons,
Angiotensin II receptor antagonists”, May, (1997).
General Information, 121-829. 6. Olin, BR (2002), “Drug Facts and
2. Powell, JR; Reeves, RA; Marino, MR; Comparisons”, St. Louis, JB Lippincott
Cazaubon, C and Nisato, D (1998), “A Co, 514-518.
review of the new angiotensin II-receptor 7. Rossi, S (2006), “Australian Medicines
antagonist irbesartan”, Cardiovasc. Drug Handbook”, Adelaide, Australian.
Rev., 16, 169-194. 8. http://www.clevelandclinicmeded.com/m
3. Ellis, ML and Patterson, JH (1996), “A edicalpubs/diseasemanagement/nephrolo
new class of antihypertensive therapy: gy/diabetic-nephropathy/#cesec10.
angiotensin II receptor antagonists”, 9. www.wikipedia.org/wiki/Irbesartan.
Pharmacotherapy, 16, 849-860. 10. www.wikipedia.org/wiki/Irbesartan/comb
4. Burnier, M and Brunner, HR (2000), ination with diuretics.
“Angiotensin II receptor antagonists”, 11. http://www.rxlist.com/avapro-drug.htm,
Lancet, 355, 637-645. http://www.molcan.com/irbesartan.htm.
12. http://www.orgyn.com/resources/genrx/D
003356.asp/ mechanism of action.

http://www.pharmacophorejournal.com/ 285
Asif Husain et al. / Pharmacophore 2011, Vol. 2 (6), 276-286
13. http://en.wikipedia.org/wiki/Hypertensio antagonist” Am. J. Hyperten., 10(2),
n. 172A.
14. Gibson, Paul, “Hypertension and 24. Larochelle P et al. (1997), “Irbesartan
Pregnancy”, eMedicine Obstetrics and versus enalapril in severe hypertension”,
Gynecology, Medscape. Am. J. Hyperten., 10(2), 131A.
http://emedicine.medscape.com/article/26 25. Kochar M et al. (1997), “Irbesartan in
1435-overview. combination with hydrochlorothiazide in
15. http://en.wikipedia.org/wiki/Discovery_a mild-to-moderate hypertension”, Am. J.
nd_development_of_angiotensin_recepto Hyperten., 10(2), 106A.
r_blocker. 26. Massie, BM; Carson, PE; McMurray, JJ
16. Stumpe, KO et al. (1997), “Comparison and Komajda, M (2008), “Irbesartan in
of angiotensin II receptor antagonist patients with heart failure and preserved
irbesartan and atenolol for the treatment ejection fraction”, N. Engl. J. Med., 23,
of hypertension”, J. Hypertens., 15(4), 359.
S115. 27. Morales-Olivas, FJ et al. (2004), “The
17. Marino, MR et al. (1967), KARTAN study: a post marketing
“Pharmacokinetics (PK) and assessment of irbesartan in patients with
antihypertensive effects of irebesartan (an hypertension”, Clin. Ther., 26, 232-244.
AII receptor antagonist) in subjects with 28. Raju, RR and Babu, NB (2011),
hypertension” J. Hypertens., 14(1), “Development and validation of HPLC
S348. method for the estimation of irbesartan in
18. http://www.orgyn.com/resources/genrx/D pharmaceutical dosage form”,
003356.asp/distribution. Pharmacophore, 2(2), 145-149.
19. Tripathi, KD, “Essentials of Medical 29. Lewis, EJ et al (2001), “Collaborative
Pharmacology”, 6th Ed., Chater-36, Study Group: Renoprotective effect of
Drugs affecting Renin –Angitension the angiotensin-receptor antagonist
system and Plasma Kinin. irbesartan in patients with nephropathy
20. http://www.orgyn.com/resources/genrx/D due to type 2 diabetes”, N. Engl. J. Med.,
003356.asp/metabolism and elimination. 345(12), 851-860.
21. Goodfriend, TL; Elliott, ME and Catt, KJ 30. Siddiqui, N.; Husain, A.; Chaudhry, L
(1996), “Angiotensin receptors and (2011), “Pharmacological and
antagonists”, N. Engl. J. Med., 25, 1649- Pharmaceutical Profile of Valsartan: A
1654. Review”, J. Applied Pharm. Sci. 01(04),
22. Lasseter, KC et al., (1997) 12-16.
“Pharmacodynamics of irbesartan in
*Corresponding author’s E-mail: drasifhusain@yahoo.com
subjects with mild-to-moderate
hypertension”, Am. J. Hyperten., 10(2),
D64.
23. Guthrie, RM et al. (1997), “Dose-related
reductions in blood pressure with
irbesartan, the angiotensin II receptor

http://www.pharmacophorejournal.com/ 286