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Pharmacology: Pharmacodynamics: Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). It is the main pressor agent of the renin-angiotensin-aldosterone system and is important in the pathophysiology of hypertension, heart failure and other cardiovascular disorders. Major physiological effects of angiotensin II include vasoconstriction, stimulation of synthesis and release of aldosterone, regulation of salt and water homeostasis, stimulation of cell growth.
Candesartan is a nonpeptide angiotensin II receptor antagonist that selectively blocks the binding of angiotensin II to the angiotensin II subtype 1 (AT1) receptor in many tissues such as vascular smooth muscles and the adrenal gland.
Candesartan's action is independent of the pathways for angiotensin II synthesis. It does not inhibit ACE (kininase II), which converts angiotensin I to angiotensin II and degrades bradykinin. Since there is no effect on the degradation of bradykinin, angiotensin II receptor antagonists are unlikely to be associated with cough. The incidence of cough was lower in patients taking candesartan in studies comparing candesartan with ACE inhibitors.
Candesartan does not bind to or block other hormone receptors or ion channels significant in cardiovascular regulation. Angiotensin II receptor antagonism results in dose-related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.
In hypertension, candesartan produces a dose-dependent, long-lasting reduction in arterial blood pressure. This is due to decreased systemic peripheral resistance, without reflex increase in heart rate. After discontinuation of treatment, there is no indication of rebound hypertension.
Candesartan once a day provides effective and smooth blood pressure reduction over 24 hours, with little difference between maximum and trough effects during the dosing interval.
The onset of antihypertensive effect of candesartan generally occurs within 2 hours after its administration given as a single dose.
In multiple-dose studies in 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, no change in the level of HbA1c was observed in patients with non-insulin-dependent (type 2) diabetes mellitus and hypertension.
Candesartan decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and decreases aldosterone levels in patients with chronic heart failure (CHF) and depressed left ventricular systolic function. In patients with CHF not receiving ACE inhibitors, orally administered candesartan cilexetil 8 mg to 16 mg once a day for up to 43 weeks significantly increased angiotensin II levels, had varying effects on the levels of atrial natriuretic factor and pro-atrial natriuretic peptide and, in combination with enalapril, transiently decreased aldosterone levels.
Pharmacokinetics: Candesartan cilexetil is the esterified prodrug of candesartan. After oral administration, candesartan cilexetil is rapidly and completely activated by enzymatic hydrolysis to candesartan during absorption from the gastrointestinal tract. Peak serum concentrations (Cmax) are observed 3 to 4 hours after oral administration. Oral bioavailability of candesartan tablet is about 15% and is not affected by food.
Plasma protein binding in humans is more than 99%, the majority of which is bound to albumin. Candesartan does not appear to penetrate red blood cells. The volume of distribution in healthy individuals is 0.13 L/kg.
Candesartan is mainly eliminated unchanged in urine and feces (via bile). It undergoes minor hepatic metabolism by O-deethylation to inactive metabolites. Approximately 26% of the dose is excreted unchanged in urine after oral administration. Candesartan's total plasma clearance is approximately 0.37 mL/min/kg and renal clearance is approximately 0.19 mL/min/kg. The terminal elimination half-life is about 9 hours.
Special Population: Elderly: In the elderly (>65 years old), both Cmax and area under the concentration-time curve (AUC) of candesartan are increased by approximately 50% and 80% respectively, compared with younger individuals. However, the blood pressure response and the incidence of adverse events are similar in younger and elderly patients.
Renal Impairment: In patients with mild to moderate renal impairment, Cmax and AUC of candesartan increased during repeated dosing by approximately 50% and 70%, respectively. The corresponding changes in patients with severe renal impairment were approximately 50% and 110% respectively. The terminal half-life 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.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, the AUC of candesartan was increased by approximately 20%. In patients with moderate to severe hepatic impairment, increase in the AUC of candesartan was approximately 80%. There is only limited experience in patients with severe hepatic impairment and/or cholestasis.
