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Pharmacology: Pharmacodynamics: The active hormone of the RAAS angiotensin II, which is formed from angiotensin I through ACE. Angiotensin II binds to a specific receptors located in the cell membranes of various tissues. It has wide variety of physiological effects, including in particular both direct and indirect involvement in the regulation of blood pressure. As a potent vasoconstrictor, angiotensin II exerts a direct pressor response. In addition, it promotes sodium retention and stimulation of aldosterone secretion.
Valsartan is an orally active, potent and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of Ang II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at AT1 receptor and has much (about 20,000 fold) greater affinity for the AT1 receptor than for the AT2 receptor.
Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with cough. Valsartan does not bind or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Pharmacokinetics: Absorption: Following oral administration of valsartan alone, peak plasma concentrations are reached in 2-4 hours. Mean absolute bioavailability is 23%. When valsartan is given with food, the area under the plasma concentration curve (AUC) of valsartan is reduced by 48%, although from about 8 hours post dosing, plasma valsartan concentrations are similar to fed and fasted group. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without foods.
Distribution: Steady-state volume of distribution of valsartan after intravenous administration is about 17 liters, indicating that valsartan is not distributed into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly as serum albumin.
Biotransformation: Valsartan is not biotransformed to a high extent as only 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite pharmacologically inactive.
Elimination: Valsartan shows multiexponential decay kinetics (t1/2 α <1 h and t1/2 β about 9 h). Valsartan is primarily eliminated in feces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal clearance is 0.62 L/h (about 30% of total clearance). The half-life of valsartan is 6 hours.
The pharmacokinetics of valsartan are linear in the dose range tested. There is no change in the kinetics of valsartan on repeated administration, and little accumulation when dosed once daily. Plasma concentrations were observed to be similar in males and females.
The average time to peak concentration and elimination half-life of valsartan in heart failure patients are similar to that observed in healthy volunteers. AUC and Cmax values of valsartan increase linearly and are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a day). The average accumulation factor is about 1.7. The apparent clearance of valsartan following oral administration is approximately 4.5 L/h. Age does not affect the apparent clearance in heart failure patients.
Special Populations: Elderly: A somewhat higher systemic exposure to valsartan was observed in some elderly subjects compared to the subjects; however, this has not been shown to have any clinical significance.
Impaired renal function: As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation was seen between renal function and systemic exposure to valsartan. Dose adjustment is therefore not required in patients with renal impairment. No studies have been performed in patients undergoing dialysis. However, valsartan is highly bound to plasma protein and is unlikely to be removed by dialysis.
Hepatic impairment: About 70% of the absorbed dose is excreted in the bile mainly as unchanged compound. Valsartan does not undergo extensive biotransformation, and as expected, systemic exposure to valsartan is not correlated with the degree of liver dysfunction. No dose adjustment for valsartan is therefore necessary in patients with hepatic insufficiency of non-biliary origin and without cholestatis. The AUC with valsartan has been observed to approximately double in patients with biliary cirrhosis or biliary obstruction.
Pediatric population: In a study of 26 pediatric hypertensive patients (aged 1 to 16 years) given a single dose of suspension of valsartan (mean: 0.9 to 2 mg/kg, with a maximum dose of 80 mg), the clearance (liters/h/kg) of valsartan was comparable across the age range 1 to 16 years and similar to that of adults receiving the same formulation.
