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| __NOTOC__
| | #REDIRECT [[Valsartan#Pharmacology]] |
| {{Valsartan}}
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| {{CMG}}; {{AE}} {{SS}}
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| ==Clinical Pharmacology==
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| ===12.1 Mechanism of Action===
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| [[Angiotensin]]II is formed from [[angiotensin]]I in a reaction catalyzed by [[angiotensin-converting enzyme]] ([[ACE]], kininase II). [[angiotensin]]II is the principal 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. Diovan (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 the adrenal gland. Its action is therefore independent of the pathways for [[angiotensin]]II synthesis.
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| There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of [[angiotensin]]II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one-200th that of valsartan itself.
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| Blockade of the [[renin-angiotensin system]] with ACE inhibitors, which inhibit the biosynthesis of [[angiotensin]]II from [[angiotensin]]I, is widely used in the treatment of [[hypertension]]. ACE inhibitors also inhibit the degradation of [[bradykinin]], a reaction also catalyzed by [[ACE]]. Because valsartan does not inhibit [[ACE]] (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
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| Blockade of the [[angiotensin]]II receptor inhibits the negative regulatory feedback of [[angiotensin]]II on renin secretion, but the resulting increased plasma renin activity and [[angiotensin]]II circulating levels do not overcome the effect of valsartan on blood pressure.
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| ===12.2 Pharmacodynamics===
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| 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 larger doses is available.
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| Removal of the negative feedback of [[angiotensin]]II causes a 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.
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| In multiple-dose studies in hypertensive patients with stable [[renal insufficiency]] and patients with renovascular [[hypertension]], valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.
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| In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total [[cholesterol]], fasting [[triglycerides]], fasting serum glucose, or uric acid.
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| ===12.3 Pharmacokinetics===
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| 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 Diovan is about 25% (range 10%-35%). The bioavailability of the suspension [see Dosage and Administration; Pediatric Hypertension (2.2)] is 1.6 times greater than with the tablet. With the tablet, food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%. AUC and Cmax values of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.
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| '''Metabolism and Elimination''': Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.
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| 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).
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| '''Distribution''': The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.
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| ====Special Populations====
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| '''Pediatric''': In a study of pediatric hypertensive patients (n=26, 1-16 years of age) given single doses of a suspension of Diovan (mean: 0.9 to 2 mg/kg), the clearance (L/h/kg) of valsartan for children was similar to that of adults receiving the same formulation.
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| '''Geriatric''': Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary [see Dosage and Administration (2.1)].
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| Gender: Pharmacokinetics of valsartan does not differ significantly between males and females.
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| '''Heart Failure''': The average time to peak concentration and elimination half-life of valsartan in [[heart failure]] patients are similar to those 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.
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| '''Renal Insufficiency''': There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of [[renal impairment]]. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by [[hemodialysis]]. In the case of severe renal disease, exercise care with dosing of valsartan[see Dosage and Administration (2.1)].
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| '''Hepatic Insufficiency''': On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease [see Dosage and Administration (2.1)].<ref name="dailymed.nlm.nih.gov">{{Citace elektronické monografie | příjmení = | jméno = | titul = DIOVAN (VALSARTAN) TABLET [NOVARTIS PHARMACEUTICALS CORPORATION] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ddba454-f3e6-43c2-a7a6-58365d297213 | vydavatel = | datum vydání = | datum aktualizace = | datum přístupu = 2014-02-24 }}</ref>
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| ==References==
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| {{reflist|2}}
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| [[Category:Amides]]
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| [[Category:[[Angiotensin]]II receptor antagonists]]
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| [[Category:Biphenyls]]
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| [[Category:Carboxylic acids]]
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| [[Category:Novartis]]
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| [[Category:Tetrazoles]]
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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