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Clinical Pharmacology: Pharmacodynamics: Mechanism of Action: Angiotensin II is formed from Angiotensin I in a reaction catalyzed by Angiotensin-Converting Enzyme (ACE, Kininase II). Angiotensin I is the principle 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. Valsartan blocks the vasoconstrictor and aldosterone secreting 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 adrenal gland. Its action is therefore independent of the pathway for Angiotensin II. 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 increase in plasma renin activity and increases in urinary potassium. The renin-aldosterone link is mediated by Angiotensin II receptor antagonist and tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazide is unknown.
Pharmacodynamics and clinical effects: Valsartan inhibits the pressor effect of Angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of a larger dose available. Removal of the negative feed back of Angiotensin II causes 2 to 3-fold rise in plasma renin and consequent rise in Angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed. In most patients, after administration of a single dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower dose (40 mg) presumably reflecting loss of inhibition of Angiotensin II. At higher dose, however (160 mg), there is little difference in peak and trough effect. During the repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long term follow up studies (without placebo control) the effect of valsartan appeared to be maintained for up to two years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in higher-renin hypertensives (frequently whites). Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.
Hydrochlorothiazide: After an oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Pharmacokinetics: Valsartan: Valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for Valsartan is about 24% (range 10%-35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C max) by about 50%. AUC and C max values of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.
Metabolism and Elimination: Valsartan, when administered as an oral dose is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, which only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. The enzyme(s) responsible for valsartan metabolism have not been identified but do not seem to be CYP 450 isozymes.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated as unchanged drug within 24 hours. The elimination half life is between 5.8 and 18.9 hours.
Distribution: Valsartan: Valsartan does not distribute into tissue extensively. Valsartan is highly bound to serum proteins (95%) mainly serum albumin.
Hydrochlorothiazide: Hydrochlorothiazide crosses the placenta but not the serum albumin blood brain barrier and is excreted in breast milk.
Special populations: Pediatric: The pharmacokinetics of valsartan have not been investigated in patients <18 years of age.
Geriatric: Exposure (measured by AUC) to valsartan is higher by 70% and half-life is longer by 35% in the elderly than in the young.
Gender: The pharmacokinetics of valsartan does not differ significantly between males and females.
Race: Pharmacokinetic differences due to race have not been studied.
Renal insufficiency: There is no apparent correlation between renal function (measured by AUC) to valsartan in patients with different degree of renal impairment. 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.
Hepatic insufficiency: On average, patients with mild to moderate chronic liver disease have twice the exposure (measured by AUC value) to valsartan of healthy volunteers (match by age, sex and weight).
