Mechanism Of Action
Angiotensin II is formed from angiotensin I in a reaction
catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II
is the principal pressor agent of the renin-angiotensin system, with effects
that include vasoconstriction, stimulation of synthesis and release of
aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan
blocks the vasoconstrictor effects of angiotensin II by selectively blocking
the binding of angiotensin II to the AT1 receptor in vascular smooth
muscle. Its action is, therefore, independent of the pathways for angiotensin
An AT2 receptor is found also in many tissues,
but this receptor is not known to be associated with cardiovascular
homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT2
receptor than for the AT2 receptor.
Blockade of the angiotensin II receptor inhibits the
negative regulatory feedback of angiotensin II on renin secretion, but the
resulting increased plasma renin activity and circulating angiotensin II levels
do not overcome the effect of olmesartan on blood pressure.
Hydrochlorothiazide is a thiazide diuretic. Thiazides
affect the renal tubular mechanisms of electrolyte reabsorption, directly
increasing excretion of sodium and chloride in approximately equivalent
amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma
volume, with consequent increases in plasma renin activity, increases in
aldosterone secretion, increases in urinary potassium loss, and decreases in
serum potassium. The renin-aldosterone link is mediated by angiotensin II, so
coadministration of an angiotensin II receptor antagonist tends to reverse the
potassium loss associated with these diuretics. The mechanism of the
antihypertensive effect of thiazides is not fully understood.
Olmesartan medoxomil doses of 2.5 to 40 mg inhibit the
pressor effects of angiotensin I infusion. The duration of the inhibitory
effect was related to dose, with doses of olmesartan medoxomil > 40 mg giving
> 90% inhibition at 24 hours.
Plasma concentrations of angiotensin I and angiotensin II
and plasma renin activity (PRA) increase after single and repeated
administration of olmesartan medoxomil to healthy subjects and hypertensive patients.
Repeated administration of up to 80 mg olmesartan medoxomil had minimal
influence on aldosterone levels and no effect on serum potassium.
After oral administration of hydrochlorothiazide,
diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12
Alcohol, barbiturates, or narcotics: Potentiation
of orthostatic hypotension may occur.
Skeletal muscle relaxants, non-depolarizing (e.g.,
tubocurarine): Increased responsiveness to the muscle relaxant may occur.
Digitalis glycosides: Thiazide-induced hypokalemia
or hypomagnesemia may predispose to digoxin toxicity.
Olmesartan: Olmesartan medoxomil is completely
bioactivated by ester hydrolysis to olmesartan during absorption from the
gastrointestinal tract. The absolute bioavailability of olmesartan is
approximately 26%. After oral administration, the peak plasma concentration (Cmax)
of olmesartan is reached after 1 to 2 hours. Food does not affect the
bioavailability of olmesartan.
Olmesartan shows linear pharmacokinetics following single
oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state
levels of olmesartan are achieved within 3 to 5 days and no accumulation in
plasma occurs with once-daily dosing.
Hydrochlorothiazide: The estimated absolute
bioavailability of hydrochlorothiazide after oral administration is about 70%.
Peak plasma hydrochlorothiazide concentrations (Cmax) are reached within 2 to 5
hours after oral administration. There is no clinically significant effect of
food on the bioavailability of hydrochlorothiazide.
The pharmacokinetics of hydrochlorothiazide is dose
proportional in the range of 12.5 to 75 mg.
Olmesartan: The volume of distribution of
olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins
(99%) and does not penetrate red blood cells. The protein binding is constant at
plasma olmesartan concentrations well above the range achieved with recommended
In rats, olmesartan crossed the blood-brain barrier
poorly, if at all. Olmesartan passed across the placental barrier in rats and
was distributed to the fetus. Olmesartan was distributed to milk at low levels in
Hydrochlorothiazide: Hydrochlorothiazide binds to
albumin (40 to 70%) and distributes into erythrocytes. Following oral
administration, plasma hydrochlorothiazide concentrations decline
biexponentially, with a mean distribution half-life of about 2 hours and an
elimination half-life of about 10 hours.
Hydrochlorothiazide crosses the placental but not the
blood-brain barrier and is excreted in breast milk.
Olmesartan: Olmesartan does not undergo further
Hydrochlorothiazide: Hydrochlorothiazide is not
Olmesartan: Olmesartan appears to be eliminated in
a biphasic manner with a terminal elimination halflife of approximately 13
hours. Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of
0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine
while the remainder is eliminated in feces via the bile.
Hydrochlorothiazide: About 70% of an orally
administered dose of hydrochlorothiazide is eliminated in the urine as
Pediatric: The pharmacokinetics of olmesartan were
studied in pediatric hypertensive patients aged 1 to16 years. The clearance of
olmesartan in pediatric patients was similar to that in adult patients when adjusted
by the body weight. Olmesartan pharmacokinetics have not been investigated in
pediatric patients less than 1 year of age.
Geriatric: The pharmacokinetics of olmesartan were
studied in the elderly ( ≥ 65 years). Overall, maximum plasma
concentrations of olmesartan were similar in young adults and the elderly.
Modest accumulation of olmesartan was observed in the elderly with repeated
dosing; AUCss,τ was 33% higher in
elderly patients, corresponding to an approximate 30% reduction in CLR.
Gender: Minor differences were observed in the
pharmacokinetics of olmesartan in women compared to men. AUC and Cmax were
10-15% higher in women than in men.
Renal insufficiency: In patients with renal
insufficiency, serum concentrations of olmesartan were elevated compared to
subjects with normal renal function. After repeated dosing, the AUC was approximately
tripled in patients with severe renal impairment (creatinine clearance < 20
mL/min). The pharmacokinetics of olmesartan in patients undergoing hemodialysis
has not been studied.
Hepatic insufficiency: Increases in AUC and C for
olmesartan were observed in patients with moderate hepatic impairment compared
to those in matched controls, with an increase in AUC of about 60%.
Renal insufficiency: In a study in individuals
with impaired renal function, the mean elimination half-life of
hydrochlorothiazide doubled in individuals with mild/moderate renal impairment
(30 < CrCl < 90 mL/min) and tripled in severe renal impairment ( ≤
30 mL/min), when compared to individuals with normal renal function (CrCl >
No significant drug interactions were reported in studies
in which olmesartan medoxomil was coadministered with digoxin or warfarin in
The bioavailability of olmesartan medoxomil was not significantly
altered by the co-administration of antacids [Al(OH)3/Mg(OH)2].
Olmesartan medoxomil is not metabolized by the cytochrome
P450 system and has no effects on P450 enzymes; thus, interactions with drugs
that inhibit, induce, or are metabolized by those enzymes are not expected.
Bile Acid Sequestering Agent Colesevelam
Concomitant administration of 40 mg olmesartan medoxomil
and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28%
reduction in Cmax and 39% reduction in AUC of olmesartan. Lesser effects, 4%
and 15% reduction in Cmax and AUC respectively, were observed when olmesartan medoxomil
was administered 4 hours prior to colesevelam hydrochloride [see DRUG
Drugs that alter gastrointestinal motility: The
bioavailability of thiazide-type diuretics may be increased by anticholinergic
agents (e.g. atropine, biperiden), apparently due to a decrease in
gastrointestinal motility and the stomach emptying rate. Conversely,
pro-kinetic drugs may decrease the bioavailability of thiazide diuretics.
Cholestyramine: In a dedicated drug interaction
study, administration of cholestyramine 2 h before hydrochlorothiazide resulted
in a 70% reduction in exposure to hydrochlorothiazide. Further, administration
of hydrochlorothiazide 2 h before cholestyramine, resulted in 35% reduction in
exposure to hydrochlorothiazide.
Lithium: Diuretic agents reduce the renal
clearance of lithium and increase the risk of lithium toxicity [see DRUG
Antineoplastic agents (e.g. cyclophosphamide,
methotrexate): Concomitant use of thiazide diuretics may reduce renal
excretion of cytotoxic agents and enhance their myelosuppressive effects.
Olmesartan Medoxomil And Hydrochlorothiazide
No teratogenic effects were observed when 1.6:1
combinations of olmesartan medoxomil and hydrochlorothiazide were administered
to pregnant mice at oral doses up to 1625 mg/kg/day (122 times the maximum
recommended human dose [MRHD] on a mg/m² basis) or pregnant rats at oral doses
up to 1625 mg/kg/day (280 times the MRHD on a mg/m² basis). In rats, however,
fetal body weights at 1625 mg/kg/day (a toxic, sometimes lethal dose in the dams)
were significantly lower than control. The no observed effect dose for
developmental toxicity in rats, 162.5 mg/kg/day, is about 28 times, on a mg/m² basis,
the MRHD of BENICAR HCT (40 mg olmesartan medoxomil /25 mg
Olmesartan Medoxomil And Hydrochlorothiazide
In clinical trials 1230 patients were exposed to the
combination of olmesartan medoxomil (2.5 mg to 40 mg) and hydrochlorothiazide
(12.5 mg to 25 mg). These trials included one placebo-controlled factorial trial
in mild-moderate hypertensive patients (n=502) with combinations of olmesartan
medoxomil (10 mg, 20 mg, 40 mg, or placebo) and hydrochlorothiazide (12.5 mg,
25 mg, or placebo). The antihypertensive effect of the combination on trough
blood pressure was related to the dose of each component (see Table 2).
Once-daily dosing with 20 mg olmesartan medoxomil and
12.5 mg hydrochlorothiazide, 40 mg olmesartan medoxomil and 12.5 mg
hydrochlorothiazide or 40 mg olmesartan medoxomil and 25 mg hydrochlorothiazide
produced mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing)
ranging from 17/8 to 24/14 mm Hg.
Table 2: Placebo-Adjusted Reductions in Sitting
Systolic/Diastolic Blood Pressure (mmHg)
The antihypertensive effect had onset within 1 week and
was near maximal at 4 weeks. The antihypertensive effect was independent of
gender, but there were too few subjects to identify response differences based
on race or age greater than or less than 65 years. No appreciable changes in
trough heart rate were observed with combination therapy.
There are no trials of BENICAR HCT demonstrating
reductions in cardiovascular risk in patients with hypertension, but at least
one drug pharmacologically similar to olmesartan medoxomil has demonstrated such
benefits, and hydrochlorothiazide demonstrated reduction of cardiovascular risk
in patients with hypertension.
The antihypertensive effects of olmesartan medoxomil have
been demonstrated in seven placebocontrolled studies at doses ranging from 2.5
to 80 mg for 6 to 12 weeks, each showing statistically significant reductions
in peak and trough blood pressure. A total of 2693 patients (2145 olmesartan medoxomil;
548 placebo) with essential hypertension were studied. Olmesartan medoxomil
once daily (QD) lowered diastolic and systolic blood pressure. The response was
dose-related. An olmesartan medoxomil dose of 20 mg daily produced a trough
sitting BP reduction over placebo of about 10/6 mm Hg and a dose of 40 mg daily
produced a trough sitting BP reduction over placebo of about 12/7 mm Hg.
Olmesartan medoxomil doses greater than 40 mg had little additional effect. The
onset of the antihypertensive effect occurred within 1 week and was largely
manifest after 2 weeks.
The blood pressure lowering effect was maintained
throughout the 24-hour period with olmesartan medoxomil once daily, with
trough-to-peak ratios for systolic and diastolic response between 60 and 80%.
The blood pressure lowering effect of olmesartan
medoxomil, with and without hydrochlorothiazide, was maintained in patients
treated for up to 1 year. There was no evidence of tachyphylaxis during
longterm treatment with olmesartan medoxomil or rebound effect following abrupt
withdrawal of olmesartan medoxomil after 1 year of treatment.
The antihypertensive effect of olmesartan medoxomil was
similar in men and women and in patients older and younger than 65 years. The
effect was smaller in black patients (usually a low-renin population), as has
been seen with other ACE inhibitors, angiotensin receptor blockers, and
betablockers. Olmesartan medoxomil had an additional blood pressure lowering
effect when added to hydrochlorothiazide.