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Pharmacotherapeutic group: Angiotensin II antagonists, plain. ATC Code: C09CA03.
Pharmacology: Pharmacodynamics: The active hormone of the RAAS (renin-angiotensin-aldosterone system) is angiotensin II, which is formed from angiotensin I through ACE. Angiotensin II binds to specific receptors located in the cell membranes of various tissues. It has a 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 reduces the excretion of sodium and stimulates secretion of aldosterone.
Valsartan is an orally active 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. It is possible that increased plasma levels of angiotensin II following AT1 receptor blockade by valsartan induces the unblocked AT2 receptor, which seems to balance the effects of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the 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. No potentiation of bradykinin related side effects should be expected. In clinical studies where valsartan was compared with an ACE-inhibitor the incidence of dry cough was significantly lower (P<0.05) in patients treated with valsartan than in patients treated with an ACE-inhibitor (2.6% versus 7.9%, respectively). In a clinical study of patients with a history of dry cough during ACE-inhibitor treatment, 19.5% of those receiving valsartan and 19% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACE-inhibitor (P<0.05). Valsartan does neither bind to nor block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Hypertension: Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate.
In most patients antihypertensive activity is detectable within 2 hours and maximum reduction of blood pressure is reached within 4-6 hours following a single dose. The antihypertensive effects persist for over 24 hours after dosing. During repeated dosing the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term treatment. Combined with hydrochlorthiazide, a significant additional reduction in blood pressure is achieved.
Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.
Recent myocardial infarction: The VALIANT study (VALsartan In Acute myocardial iNfarcTion trial) was a randomized, controlled, multinational, double blind study in 14,703 patients with acute myocardial infarction and signs, symptoms or radiological evidence of congestive and/or evidence of left ventricular systolic dysfunction (manifested as ejection fraction ≤ 40% according to radionuclide ventriculography or ≤ 35% according to echocardiography or ventricular contrast angiography). Within 12 hours to 10 days from the onset of symptoms of myocardial infarction the patients were randomized into groups receiving valsartan, captopril or both. Duration of treatment was on average two years.
Valsartan was equally effective as captopril in reducing all-cause mortality after myocardial infarction. All-cause mortality was similar in the valsartan (19.9%), captopril (19.5%) and valsartan + captopril (19.3%) groups. Concurrent use of captopril and valsartan did not provide additional benefits compared to use of captopril alone. There was no difference between valsartan and captopril with respect to all-cause mortality, based on gender, age, race, treatments received upon onset of myocardial infarction or underlying disease. Valsartan also delayed and reduced cardiovascular mortality, hospitalization due to heart failure, recurrent myocardial infarction, resuscitation due to cardiac arrest and a non-fatal stroke.
There was no difference in all-cause mortality, cardiovascular mortality or morbidity during concurrent administration of beta-blockers and valsartan + captopril, valsartan alone or captopril alone. Irrespective of the study drug treatment, the mortality was lower in the group of patients receiving beta-blockers, which indicated that known benefits of beta-blockers in this population have remained through the study.
Pharmacokinetics: Absorption of valsartan after oral administration is rapid, although the amount absorbed varies widely. Mean absolute bioavailability for valsartan is 23%. Valsartan shows multi-exponential decay kinetics (t1/2α<1 hour and t1/2β about 9 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.
Valsartan is highly bound to serum protein (94-97%), mainly serum albumin. Steady state volume of distribution is about 17 liters. Plasma clearance is relatively slow (about 2 l/hour) compared with hepatic blood flow (about 30 l/hour). Elimination of valsartan is mainly in bile and urine, as unchanged compound. At normal glomerular filtration rate (120 ml/min) the renal clearance is about 30% of total plasma clearance. A hydroxy metabolite has been identified in plasma at low levels (less than 10% of valsartan AUC). This metabolite is pharmacologically inactive. After oral administration 83% is excreted in the faeces and 13% in the urine, mainly as unchanged compound.
When valsartan is given with food, AUC of valsartan is reduced by 48%, although from about 8 hours post dosing plasma level of valsartan are similar for the fed and fasted group. This reduction of AUC is however not associated with a clinically significant reduction in therapeutic effect.
Mean values for time to peak concentration and elimination half life of valsartan in patients with heart failure are similar to that observed in healthy volunteers. AUC and Cmax values for valsartan 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. Apparent clearance of valsartan following oral administration is about 4.5 l/hour. Age does not affect the apparent clearance in patients with heart failure.
Special populations: Elderly: A somewhat higher systemic exposure to valsartan was observed in some elderly subjects compared with young subjects; and a lower starting dose (40 mg) is recommended for the elderly.
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 mild renal impairment (creatinine clearance 20-50 ml/min). Limited data are available in patients with moderate-severe impairment of renal function and a starting dose of 40 mg is recommended for these patients. No studies have been performed in patients undergoing dialysis. However valsartan is highly bound to protein and is unlikely to be removed by dialysis.
Impaired hepatic function: 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 cholestasis. The AUC with valsartan has been observed to approximately double in patients with biliary cirrhosis or biliary obstruction (see Precautions).
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for human based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
In non-clinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) in rats caused reduction in red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of changes in renal haemodynamics (minor increase of urea in plasma, and renal tubular hyperplasia and basophilia in males). In marmosets similar doses resulted in similar alterations, though more severe, especially in the kidneys, where alterations evolved into nephropathy, which led to elevation of urea and creatinine.
Hypertrophy of renal juxtaglomerular cells was also seen in both species. All alterations were considered resulting from pharmacological action of valsartan which produces prolonged hypotension, especially in marmosets. Hypertrophy of renal juxtaglomerular cells does not seem to be of relevance in humans receiving recommended doses of valsartan.
There was no evidence of mutagenicity, clastogenicity or carcinogenicity.
