, Volume 54, Issue 2, pp 299-311
Date: 28 Nov 2012

Valsartan

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Summary

Synopsis

Valsartan competitively and selectively inhibits the actions of angiotensin II at the AT1 receptor subtype which is responsible for most of the known effects of angiotensin II.

In clinical trials in patients with mild to moderate essential hypertension valsartan was as effective as losartan, lisinopril, enalapril, amlodipine and hydrochlorothiazide. Addition of the latter reduced blood pressure in patients who did not respond sufficiently to valsartan monotherapy. Preliminary data also suggest valsartan may be effective in patients with severe essential hypertension. The drug was as effective as lisinopril as treatment for mild to moderate essential hypertension in patients with renal insufficiency and did not worsen renal function.

Headache, dizziness and fatigue were the most common adverse events in placebo-controlled studies; the incidence of these adverse events was not significantly different between placebo and valsartan recipients. Compared with ACE inhibitors, valsartan was associated with a significantly lower incidence of dry cough.

Thus, valsartan is an effective treatment for mild to moderate essential hypertension and may be particularly useful in patients who experience persistent cough during ACE inhibitor therapy.

Pharmacodynamic Properties

The nonpeptide angiotensin II receptor antagonist valsartan acts competitively at, and is selective for, the angiotensin II AT1 receptor subtype, which is responsible for most of the known effects of angiotensin II. In vivo animal studies indicate that continuous intraperitoneal administration of the drug does not affect angiotensin II receptor affinity or density. Even at high concentrations, valsartan had no affinity for many other receptor types.

In volunteers, orally administered valsartan 10 to 300mg increased plasma renin activity and angiotensin II levels in a dose-proportional manner. Multiple 200mg doses of the drug significantly increased plasma angiotensin II levels compared with placebo. The pressor effect of intravenously infused angiotensin II was inhibited by valsartan but not placebo.

Six months’ treatment with valsartan had no significant effect on indices of renal function in patients with mild hypertension and renal insufficiency. The drug did significantly increase creatinine clearance in patients with renovascular hypertension, but this was considered to have minimal clinical relevance.

Valsartan reduced hypertension-induced vascular remodelling in hypertensive rats, but no data are available regarding the effects of the drug on this parameter in humans.

Pharmaco kinetic Properties

A peak plasma concentration (Cmax) of 1.64 mg/L occurred 2 hours after oral administration of a single 80mg dose of valsartan to volunteers. A higher dose (200mg) produced a proportionately higher Cmax (3.46 mg/L) at a similar time postdose. The absolute bioavailability of the drug was 23%.

Volume of distribution and plasma clearance have been estimated at 17L and 2.2 L/h, respectively; the drug is extensively bound to plasma proteins (85 to 99%). The pharmacokinetic properties of valsartan were relatively consistent during repeated administration of 10 to 160mg daily doses to patients with hypertension indicating that accumulation does not occur.

A radiolabelled dose of valsartan was excreted mostly in the faeces (85.7%) and to a lesser extent in the urine (13.2%). It was excreted mostly unchanged with 1 metabolite (valeryl-4-hydroxy valsartan) accounting for ≈10% of recovered drug.

Mild or moderate hepatic impairment approximately doubled the area under the plasma concentration-time curve of valsartan compared with that seen in healthy volunteers; impaired renal function had no appreciable effect on the pharmacokinetic properties of the drug.

Compared with younger volunteers, elderly volunteers experienced higher systemic exposure to a given dose of valsartan; however, because of similar overall efficacy and tolerability dosage adjustments were not considered to be warranted in this patient group.

Therapeutic Useq

Dose finding studies have evaluated the therapeutic efficacy of valsartan 20 to 320 mg/day in patients with mild to moderate essential hypertension. All dosages of valsartan significantly reduced blood pressure compared with placebo. One of these trials evaluated the 24-hour blood pressure effects of valsartan; the drug significantly reduced blood pressure during day-and night-time periods without disturbing diurnal variation.

The antihypertensive efficacy of valsartan has been evaluated in a number of mostly short term comparative studies. These show the drug produces similar blood pressure reductions and response rates to losartan, lisinopril, enalapril, amlodipine and hydrochlorothiazide. In a long term (1 year) comparison in elderly patients the antihypertensive efficacy of valsartan was similar to that of lisinopril. In several trials the addition of hydrochlorothiazide provided blood pressure control in patients with insufficient response to valsartan monotherapy.

Valsartan had similar efficacy to lisinopril as treatment for mild to moderate essential hypertension in patients with renal insufficiency. Neither drug significantly affected parameters of renal function.

Tolerability

Tolerability data from placebo-controlled studies indicate headache, dizziness and fatigue were the only adverse events that occurred in more than 1% of valsartan recipients (n=2316).

In a comparison with lisinopril purpose designed to evaluate the relative incidence of dry cough, valsartan was associated with a significantly lower incidence of this adverse event than the ACE inhibitor.

During controlled trials, therapy was discontinued because of adverse events in 7.1% of 2316 valsartan recipients, 8.5% of 333 ACE inhibitor recipients and 10.5% of 888 placebo recipients.

Fewer patients in valsartan than in ACE inhibitor groups experienced laboratory abnormalities.

Dosage and Administration

The recommended starting dosage for valsartan is 80mg once daily titrated to effect. Dosages as high as 320 mg/day were well tolerated in clinical trials. A diuretic may be added in patients with incomplete response to valsartan.

Initial dosage adjustment is not required in patients with renal impairment or mild to moderate hepatic insufficiency. However, caution is advised when administering the drug to patients with hepatic impairment or severe renal impairment.

Various sections of the manuscript reviewed by:A. Breckenridge, Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, England; E.D. Freis, Department of Veterans Affairs Medical Center, Washington, District of Columbia, USA; C.I. Johnston, Department of Medicine, Austin and Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria, Australia; F.H. Messerli, Ochsner Clinic, Department of Hypertension, New Orleans, Louisiana, USA; M.G. Nicholls, Department of Medicine, Christchurch School of Medicine, Christchurch Hospital, Christchurch, New Zealand; H. Shionoiri, Yokohama City University, Yokohama, Japan; H.C.M. Yu, Department of Medicine, Austin and Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria, Australia