Candez Plus Mechanism of Action

Pharmacology: Pharmacodynamics: Candesartan: 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.
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 HbA_1c 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 to 16 mg once daily 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.
Hydrochlorothiazide: Hydrochlorothiazide (HCTZ), a thiazide diuretic, increases the excretion of water by inhibiting the reabsorption of sodium and chloride ions at the distal renal tubule. The natriuretic effects are accompanied by a secondary loss of potassium and bicarbonate which can cause a mild hypokalemic, hypochloremic, metabolic alkalosis. Thiazides also decrease the elimination of calcium and uric acid. Thiazide diuretics usually do not affect normal blood pressure. When chronically administered, thiazide diuretics decrease peripheral vascular resistance. The exact mechanism responsible for lowered peripheral resistance is not known, however, excretion of urinary sodium by the kidneys is required to achieve blood pressure reduction.
Indirectly, the diuretic action of HCTZ reduces plasma volume, with consequent increases in plasma renin activity, aldosterone secretion, urinary potassium loss, and decrease in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of angiotensin II receptor antagonist tends to reverse the potassium loss associated with HCTZ.
Diuresis begins with 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours after oral administration of HCTZ.
Pharmacokinetics: Candesartan: 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 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.
Hydrochlorothiazide: HCTZ is well absorbed from the gastrointestinal tract. Oral bioavailability is approximately 65 to 75%. The drug crosses the placenta, but not the blood-brain barrier and is distributed in breast milk. It appears to be preferentially bound to red blood cells. HCTZ is not metabolized but is eliminated rapidly as unchanged drug in the urine. HCTZ's elimination half-life ranged from 5.6 to 14.8 hours when plasma levels were followed for at least 24 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours.