| Indication |
May be used as a first line agent to treat uncomplicated
hypertension, isolated systolic hypertension and left ventricular
hypertrophy. May be used as a first line agent to delay progression of
diabetic nephropathy. Candesartan may be also used as a second line
agent in the treatment of congestive heart failure, systolic
dysfunction, myocardial infarction and coronary artery disease in those
intolerant of ACE inhibitors. |
| Pharmacodynamics |
Candesartan cilexetil is an ARB prodrug that is rapidly
converted to candesartan, its active metabolite, during absorption from
the gastrointestinal tract. Candesartan confers blood pressure lowering
effects by antagonizing the hypertensive effects of angiotensin II via
the RAAS. RAAS is a homeostatic mechanism for regulating hemodynamics,
water and electrolyte balance. During sympathetic stimulation or when
renal blood pressure or blood flow is reduced, renin is released from
granular cells of the juxtaglomerular apparatus in the kidneys. Renin
cleaves circulating angiotensinogen to angiotensin I, which is cleaved
by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II
increases blood pressure by increasing total peripheral resistance,
increasing sodium and water reabsorption in the kidneys via aldosterone
secretion, and altering cardiovascular structure. Angiotensin II binds
to two receptors: type-1 angiotensin II receptor (AT1) and type-2
angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor
(GPCR) that mediates the vasoconstrictive and aldosterone-secreting
effects of angiotensin II. Studies performed in recent years suggest
that AT2 antagonizes AT1-mediated effects and directly affects long-term
blood pressure control by inducing vasorelaxation and increasing
urinary sodium excretion. Angiotensin receptor blockers (ARBs) are
non-peptide competitive inhibitors of AT1. ARBs block the ability of
angiotensin II to stimulate pressor and cell proliferative effects.
Unlike ACE inhibitors, ARBs do not affect bradykinin-induced
vasodilation. The overall effect of ARBs is a decrease in blood
pressure. |
| Mechanism of action |
Candesartan selectively blocks the binding of angiotensin II to
AT1 in many tissues including vascular smooth muscle and the adrenal
glands. This inhibits the AT1-mediated vasoconstrictive and
aldosterone-secreting effects of angiotensin II and results in an
overall decrease in blood pressure. Candesartan is greater than 10,000
times more selective for AT1 than AT2. Inhibition of aldosterone
secretion may increase sodium and water excretion while decreasing
potassium excretion. |
| Absorption |
Following administration of the candesartan cilexetil prodrug, the
absolute bioavailability of candesartan was estimated to be 15%. Food
with a high fat content has no affect on the bioavailability of
candesartan from candesartan cilexetil. |
| Volume of distribution |
|
| Protein binding |
Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. |
| Metabolism |
The prodrug candesartan cilexetil undergoes rapid and complete
ester hydrolysis in the intestinal wall to form the active drug,
candesartan. Elimination of candesartan is primarily as unchanged drug
in the urine and, by the biliary route, in the feces. Minor hepatic
metabolism of candesartan (<20%)occurs by O-deethylation via
cytochrome P450 2C9 to form an inactive metabolite. Candesartan
undergoes N-glucuronidation in the tetrazole ring by uridine diphosphate
glucuronosyltransferase 1A3 (UGT1A3). O-glucuronidation may also occur.
75% of candesartan is excreted as unchanged drug in urine and feces. |
| Route of elimination |
When candesartan is administered orally, about 26% of the dose is
excreted unchanged in urine. Candesartan is mainly excreted unchanged in
urine and feces (via bile). |
| Half life |
Approximately 9 hours. |
| Clearance |
|
| Toxicity |
No lethality was observed in acute toxicity studies in mice, rats
and dogs given single oral doses of up to 2000 mg/kg of candesartan
cilexetil or in rats given single oral doses of up to 2000 mg/kg of
candesartan cilexetil in combination with 1000 mg/kg of
hydrochlorothiazide. In mice given single oral doses of the primary
metabolite, candesartan, the minimum lethal dose was greater than 1000
mg/kg but less than 2000 mg/kg. |
