Irbesartan

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Abstract
Irbesartan interrupts the renin-angiotensin system via selective blockade of the angiotensin II subtype 1 receptor; the latter being responsible for the pressor related effects of angiotensin II. As treatment for mild to moderate hypertension, irbesartan 150 mg/day controlled diastolic BP in 56% of patients according to pooled data from several phase III studies and 77% of patients in a large phase IV study. In comparative trials, irbesartan was significantly more effective than losartan and valsartan as treatment for mild to moderate essential hypertension and as effective as enalapril or atenolol. Results from many studies show an additive antihypertensive effect when hydrochlorothiazide is added to irbesartan monotherapy. The drug also induces statistically significant regression of left ventricular mass in patients with hypertension and left ventricular hypertrophy, and preliminary evidence suggests it has beneficial haemodynamic effects in patients with heart failure. Irbesartan is very well tolerated, exhibiting an adverse event profile similar to that seen with placebo in comparative trials. In conclusion, although the role of irbesartan as a treatment for heart failure is little clearer than it was 2 years ago, the place of the drug in the management of hypertension is now better established. There is evidence to suggest the drug may have a role as initial therapy for hypertension, although formal recommendation in management guidelines will almost certainly not occur until long term morbidity and mortality benefits are established. Irbesartan is a selective angiotensin II subtype 1 (AT1) receptor antagonist, having no agonist activity and no affinity for the AT2 receptor. The drug has no affinity for α1- or α2-adrenoceptors or serotonergic receptors. In the rabbit aorta model, increasing concentrations of irbesartan caused a parallel rightward shift of the angiotensin II concentration contractile response curve and a progressive reduction in maximal response. On this basis the receptor effects of irbesartan have been described as insurmountable. In healthy volunteers, oral irbesartan (150mg), valsartan (80mg) or losartan (50mg) induced peak inhibition of the angiotensin II-induced pressor response after ∼4 hours; however, the effects of irbesartan were significantly greater, and lasted longer, than those of valsartan which were significantly greater than those of losartan. Irbesartan has been shown to inhibit angiotensin II-induced proliferation of cultured human aorta smooth muscle cells in vitro and had anti-atherosclerotic effects in genetically hypercholesterolaemic rabbits in vivo. In animals subjected to experimental heart failure, myocardial infarction or aortic stenosis, administration of irbesartan decreased the development of ventricular hypertrophy. In patients with heart failure, single doses of irbesartan produced dose-dependent acute improvement in pulmonary capillary wedge pressure. Similar effects were seen in a further study that assessed both the acute and medium term (12-week) effects of the drug. Several studies have shown that irbesartan improves glomerulosclerosis and reduces proteinuria in rats with experimentally induced renal failure. In healthy volunteers, a 50mg dose of irbesartan increased renal vasodilation zbut did not affect arterial BP or glomerular filtration rate (GFR). The drug increased sodium excretion but did not exhibit a uricosuric effect. Irbesartan prevented arterial hypertension and renal vasoconstriction in response to exogenous angiotensin II infusion in this study. Similar effects were observed in a 6-week comparison with enalapril in patients with hypertension. Both drugs caused renal vasodilation without significantly affecting GFR; however, the effects of irbesartan occurred later in the dosage interval and were more prolonged than those of enalapril. Irbesartan has a bioavailability of ∼60 to 80% and this is not affected by concomitant food intake. In healthy volunteers, peak plasma irbesartan concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increase linearly with increasing dosage although the time to peak plasma concentration (tmax) is dose-independent. The drug is 96% bound to plasma proteins and has a steady-state volume of distribution of 53 to 93L. In patients with hypertension treated with irbesartan 300 mg once daily, steady-state irbesartan Cmax (3.9 mg/L) tmax (1.5 hours) and AUCτ (22.0 mg/L · h) values were very similar to those observed in healthy volunteers. Single or multiple oral doses of irbesartan 300 mg/day produced apparent total and renal clearance values of ∼18 and 0.07 L/h. Elimination half-lives of 11 to 15 hours, independent of dosage, have been reported. In healthy volunteers, 20 and ∼30% of radioactivity from a single 150mg dose of [14C] irbesartan was recovered from urine and faeces, respectively. After oral or intravenous administration of 14C-labelled irbesartan >80% of plasma radioactivity was attributable to unmetabolised irbesartan. The primary metabolic fate of the drug appears to be oxidation via cytochrome P450 (CYP) isoform 2C9. Multiple oral doses of irbesartan ≤300 mg/day had no clinically relevant influence on the pharmacokinetic profiles of warfarin or nifedipine but a 150mg dose increased the AUCτ of fluconazole. Pooled data from 8 studies show that monotherapy with irbesartan ≥150 mg/day for 6 to 12 weeks induces a clinically significant reduction in BP. 56% of patientsresponded to an irbesartan dosage of 150 mg/day (response was defined as an endpoint DBP <90mm Hg or a reduction of ≥10mm Hg from baseline); antihy-pertensive effects increased with increasing dosage, reaching a plateau at ≥300 mg/day. Ambulatory monitoring has shown that irbesartan 150mg once daily controls...