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. Candesartan
blocks the vasoconstrictor and aldosteronesecreting effects of angiotensin II
by selectively blocking the binding of angiotensin II to the AT1 receptor in
many tissues, such as vascular smooth muscle and the adrenal gland. Its action
is, therefore, independent of the pathways for angiotensin II synthesis.
There is also an AT2 receptor found in many tissues, but
AT2 is not known to be associated with cardiovascular homeostasis. Candesartan
has much greater affinity ( > 10,000-fold) for the AT1 receptor than for the
Blockade of the renin-angiotensin system with ACE
inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin
I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit
the degradation of bradykinin, a reaction also catalyzed by ACE. Because
candesartan does not inhibit ACE (kininase II), it does not affect the response
to bradykinin. Whether this difference has clinical relevance is not yet known.
Candesartan does not bind to or block other hormone receptors or ion channels
known to be important in cardiovascular regulation.
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 angiotensin II circulating levels
do not overcome the effect of candesartan 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
Candesartan cilexetil is rapidly and completely
bioactivated by ester hydrolysis during absorption from the gastrointestinal
tract to candesartan, a selective AT1 subtype angiotensin II receptor
antagonist. Candesartan is mainly excreted unchanged in urine and feces (via
bile). It undergoes minor hepatic metabolism by O-deethylation to an inactive
metabolite. The elimination half-life of candesartan is approximately 9 hours.
After single and repeated administration, the pharmacokinetics of candesartan
are linear for oral doses up to 32 mg of candesartan cilexetil. Candesartan and
its inactive metabolite do not accumulate in serum upon repeated once-daily
Following administration of candesartan cilexetil, the
absolute bioavailability of candesartan was estimated to be 15%. After tablet
ingestion, the peak serum concentration (Cmax) is reached after 3 to 4 hours.
Food with a high fat content does not affect the bioavailability of candesartan
after candesartan cilexetil administration.
When plasma levels have been followed for at least 24
hours, the plasma half-life has been observed to vary between 5.6 and 14.8
Metabolism and Excretion
Total plasma clearance of candesartan is 0.37 mL/min/kg,
with a renal clearance of 0.19 mL/min/kg. When candesartan is administered
orally, about 26% of the dose is excreted unchanged in urine. Following an oral
dose of 14C-labeled candesartan cilexetil, approximately 33% of
radioactivity is recovered in urine and approximately 67% in feces. Following
an intravenous dose of 14C-labeled candesartan, approximately 59% of
radioactivity is recovered in urine and approximately 36% in feces. Biliary
excretion contributes to the elimination of candesartan.
Hydrochlorothiazide is not metabolized but is eliminated
rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged
within 24 hours.
The volume of distribution of candesartan is 0.13 L/kg.
Candesartan is highly bound to plasma proteins ( > 99%) and does not penetrate
red blood cells. The protein binding is constant at candesartan plasma
concentrations well above the range achieved with recommended doses. In rats,
it has been demonstrated that candesartan crosses the blood-brain barrier
poorly, if at all. It has also been demonstrated in rats that candesartan
passes across the placental barrier and is distributed in the fetus.
Hydrochlorothiazide crosses the placental but not the
blood-brain barrier and is excreted in breast milk.
The pharmacokinetics of candesartan cilexetil have not
been investigated in patients < 18 years of age.
The pharmacokinetics of candesartan have been studied in
the elderly ( ≥ 65 years). The plasma concentration of candesartan was
higher in the elderly (Cmax was approximately 50% higher, and AUC was
approximately 80% higher) compared to younger subjects administered the same
dose. The pharmacokinetics of candesartan were linear in the elderly, and
candesartan and its inactive metabolite did not accumulate in the serum of
these subjects upon repeated, once-daily administration. No initial dosage
adjustment is necessary. (See DOSAGE AND ADMINISTRATION.)
There is no difference in the pharmacokinetics of
candesartan between male and female subjects.
In hypertensive patients with renal insufficiency, serum
concentrations of candesartan were elevated. After repeated dosing, the AUC and
Cmax were approximately doubled in patients with severe renal impairment
(creatinine clearance < 30 mL/min/1.73m²) compared to patients
with normal kidney function. The pharmacokinetics of candesartan in
hypertensive patients undergoing hemodialysis are similar to those in
hypertensive patients with severe renal impairment. Candesartan cannot be
removed by hemodialysis.
Thiazide diuretics are eliminated by the kidney, with a
terminal half-life of 5-15 hours. In a study of patients with impaired renal
function (mean creatinine clearance of 19 mL/min), the half-life of
hydrochlorothiazide elimination was lengthened to 21 hours. (See DOSAGE AND
Safety and effectiveness of ATACAND HCT in patients with
severe renal impairment (CrCL ≤ 30 ml/min) have not been established. No
dose adjustment is required in patients with mild (CrCL 60-90 ml/min) or
moderate (CrCL 30-60 ml/min) renal impairment.
The pharmacokinetics of candesartan were compared in
patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment
to matched healthy volunteers following a single dose of 16 mg candesartan
cilexetil. The AUC for candesartan in patients with mild and moderate hepatic
impairment was increased 30% and 145% respectively. The Cmax for candesartan
was increased 56% and 73% respectively. The pharmacokinetics of candesartan in
severe hepatic impairment have not been studied. No dose adjustment is
recommended for patients with mild hepatic impairment. In patients with
moderate hepatic impairment, ATACAND HCT is not recommended for initiation
because the appropriate starting dose, 8 mg, cannot be given. (See DOSAGE
Monitor patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte
balance may precipitate hepatic coma.
Candesartan inhibits the pressor effects of angiotensin
II infusion in a dose-dependent manner. After 1 week of once-daily dosing with
8 mg of candesartan cilexetil, the pressor effect was inhibited by
approximately 90% at peak with approximately 50% inhibition persisting for 24
Plasma concentrations of angiotensin I and angiotensin
II, and plasma renin activity (PRA), increased in a dose-dependent manner after
single and repeated administration of candesartan cilexetil to healthy subjects
and hypertensive patients. ACE activity was not altered in healthy subjects
after repeated candesartan cilexetil administration. The once-daily administration
of up to 16 mg of candesartan cilexetil to healthy subjects did not influence
plasma aldosterone concentrations, but a decrease in the plasma concentration
of aldosterone was observed when 32 mg of candesartan cilexetil was
administered to hypertensive patients. In spite of the effect of candesartan
cilexetil on aldosterone secretion, very little effect on serum potassium was
In multiple-dose studies with hypertensive patients,
there were no clinically significant changes in metabolic function including
serum levels of total cholesterol, triglycerides, glucose, or uric acid. In a
12-week study of 161 patients with non-insulin-dependent (type 2) diabetes
mellitus and hypertension, there was no change in the level of HbA1c.
After oral administration of hydrochlorothiazide,
diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12
Of 12 controlled clinical trials involving 4588 patients,
5 were double-blind, placebo controlled and evaluated the antihypertensive
effects of single entities vs the combination. These 5 trials, of 8 to 12 weeks
duration, randomized 3037 hypertensive patients. Doses ranged from 2 to 32 mg
candesartan cilexetil and from 6.25 to 25 mg hydrochlorothiazide administered
once daily in various combinations.
The combination of candesartan
cilexetil-hydrochlorothiazide resulted in placebo-adjusted decreases in sitting
systolic and diastolic blood pressures of 14-18/8-11 mm Hg at doses of 16-12.5
mg and 32-12.5 mg. The combination of candesartan cilexetil and
hydrochlorothiazide 32-25 mg resulted in placebo-adjusted decreases in sitting
systolic and diastolic blood pressures of 16-19/9-11 mm Hg. The placebo
corrected trough to peak ratio was evaluated in a study of candesartan
cilexetil-hydrochlorothiazide 32-12.5 mg and was 88%.
Most of the antihypertensive effect of the combination of
candesartan cilexetil and hydrochlorothiazide was seen in 1 to 2 weeks with the
full effect observed within 4 weeks. In long-term studies of up to 1 year, the
blood pressure lowering effect of the combination was maintained. The
antihypertensive effect was similar regardless of age or gender, and overall
response to the combination was similar in black and non-black patients. No
appreciable changes in heart rate were observed with combination therapy in