Torcand-8 Mechanism of Action

Pharmacology: Pharmacodynamics: Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension, heart failure and other cardiovascular disorders.
It also has a role in the pathogenesis of end organ hypertrophy and damage. The major physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the type 1 (AT1) receptor.
Candesartan cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active substance, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an angiotensin II receptor antagonist (AIIRA), selective for AT1 receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.
Candesartan does not inhibit Angiotensin Converting Enzyme (ACE), which converts angiotensin I to angiotensin II and degrades bradykinin. There is no effect on ACE and no potentiation of bradykinin or substance P. In controlled clinical trials comparing candesartan with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. The antagonism of the angiotensin II (AT1) receptors results in dose related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.
Pharmacokinetics: Absorption and distribution: Following oral administration, candesartan cilexetil is converted to the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% after an oral solution of candesartan cilexetil. The relative bioavailability of the tablet formulation compared with the same oral solution is approximately 34% with very little variability.
The estimated absolute bioavailability of the tablet is therefore 14%. The mean peak serum concentration (Cmax) is reached 3-4 hours following tablet intake. The candesartan serum concentrations increase linearly with increasing doses in the therapeutic dose range. No gender related differences in the pharmacokinetics of candesartan have been observed. The area under the serum concentration versus time curve (AUC) of candesartan is not significantly affected by food.
Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution of candesartan is 0.1 L/kg. The bioavailability of candesartan is not affected by food.
Biotransformation and elimination: Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4. Based on in vitro data, no interaction would be expected to occur in vivo with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life of candesartan is approximately 9 hours. There is no accumulation following multiple doses.
Total plasma clearance of candesartan is about 0.37 mL/min/kg, with a renal clearance of about 0.19 mL/min/kg. The renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an oral dose of 14C-labelled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite while approximately 56% of the dose is recovered in the feces as candesartan and 10% as the inactive metabolite.
Special patient populations: In the elderly (over 65 years) Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively in comparison to young subjects. However, the blood pressure response and the incidence of adverse events are similar after a given dose of Candesartan in young and elderly patients.
In patients with mild to moderate renal impairment Cmax and AUC of candesartan increased during repeated dosing by approximately 50% and 70%, respectively, but t½ was not altered, compared to patients with normal renal function. The corresponding changes in patients with severe renal impairment were approximately 50% and 110%, respectively. The terminal t½ of candesartan was approximately doubled in patients with severe renal impairment. The AUC of candesartan in patients undergoing hemodialysis was similar to that in patients with severe renal impairment.
In two studies, both including patients with mild to moderate hepatic impairment, there was an increase in the mean AUC of candesartan of approximately 20% in one study and 80% in the other study. There is no experience in patients with severe hepatic impairment.
Toxicology: Preclinical Safety Data: There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses.
Candesartan caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). Effects on the kidneys (such as interstitial nephritis, tubular distension, basophilic tubules; increased plasma concentrations of urea and creatinine) were induced by candesartan which could be secondary to the hypotensive effect leading to alterations of renal perfusion. Furthermore, candesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells. These changes were considered to be caused by the pharmacological action of candesartan. For therapeutic doses of candesartan in humans, the hyperplasia/hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.
Foetotoxicity has been observed in late pregnancy.
Data from in vitro and in vivo mutagenicity testing indicates that candesartan will not exert mutagenic or clastogenic activities under conditions of clinical use.
There was no evidence of carcinogenicity.