Irbesartan - An updated review of its use in cardiovascular disorders

Irbesartan interrupts the renin-angiotensin system via selective blockade o f the angiotensin II subtype 1 receptor; the latter being responsible for t he presser related effects of angiotensin II. As treatment for mild to moderate hypertension, irbesartan 150 mg/day contr olled 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 compar ative 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 addit ive 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 h ypertrophy, and preliminary evidence suggests it has beneficial haemodynami c effects in patients with heart failure. Irbesartan is very well tolerated, exhibiting an adverse event profile simi lar to that seen with placebo in comparative trials. In conclusion, although the role of irbesartan as a treatment for heart fai lure is little clearer than it was 2 years ago, the place of the drug in th e management of hypertension is now better established. There is evidence t o suggest the drug may have a role as initial therapy for hypertension, alt hough 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 (AT(1)) receptor antagon ist, having no agonist activity and no affinity for the AT(2) receptor. The drug has no affinity for alpha(1)- or alpha(2)-adrenoceptors or serotonerg ic receptors. In the rabbit aorta model, increasing concentrations of irbesartan caused a parallel rightward shift of the angiotensin II concentration contractile r esponse curve and a progressive reduction in maximal response. On this basi s the receptor effects of irbesartan have been described as insurmountable. In healthy volunteers, oral irbesartan (150mg), valsartan (80mg) or losarta n (50mg) induced peak inhibition of the angiotensin II-induced presser resp onse after approximate to 4 hours: however, the effects of irbesartan were significantly greater, and lasted longer, than those of valsartan which wer e significantly greater than those of losartan. Irbesartan has been shown to inhibit angiotensin II-induced proliferation o f cultured human aorta smooth muscle cells in vitro and had anti-atheroscle rotic effects in genetically hypercholesterolaemic rabbits in vivo. In anim als subjected to experimental heart failure, myocardial infarction or aorti c stenosis, administration of irbesartan decreased the development of ventr icular hypertrophy. In patients with heart failure, single doses of irbesartan produced dose-de pendent acute improvement in pulmonary capillary wedge pressure. Similar ef fects 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 vasodilati on but did not affect arterial BP or glomerular filtration rate (GFR). The drug increased sodium excretion but did not exhibit a uricosuric effect. Ir besartan prevented arterial hypertension and renal vasoconstriction in resp onse to exogenous angiotensin II infusion in this study. Similar effects we re observed in a 6-week comparison with enalapril in patients with hyperten sion. Both drugs caused renal vasodilation without significantly affecting GFR; however, the effects of irbesartan occurred later in the dosage interv al and were more prolonged than those of enalapril. Irbesartan has a bioavailability of approximate to 60 to 80% and this is no t affected by concomitant food intake. In healthy volunteers, peak plasma i rbesartan concentrations (C-max) and area under the plasma concentration-ti me curve (AUC) increase linearly with increasing dosage although the time t o peak plasma concentration (t(max)) is dose-independent, The drug is 96% b ound 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, st eady-state irbesartan Cmax (3.9 mg/L) tmax(1.5 hours) and AUC tau (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 to tal and renal clearance values of approximate to 18 and 0.07 L/h. Eliminati on half-lives of 11 to 15 hours, independent of dosage, have been reported. In healthy volunteers, 20 and approximate to 30% of radioactivity from a si ngle 150mg dose of [C-14] irbesartan was recovered from urine and faeces, r espectively. After oral or intravenous administration of C-14-labelled irbe sartan >80% of plasma radioactivity was attributable to unmetabolised irbes artan. The primary metabolic fate of the drug appears to be oxidation via c ytochrome P450 (CYP) isoform 2C9. Multiple oral doses of irbesartan less than or equal to 300 mg/day had no c linically relevant influence on the pharmacokinetic profiles of warfarin or nifedipine but a 150mg dose increased the AUC tau of fluconazole. Pooled data from 8 studies show that monotherapy with irbesartan greater th an or equal to 150 mg/day for 6 to 12 weeks induces a clinically significan t reduction in BP. 56% of patients responded to an irbesartan dosage of 150 mg/day (response was defined as an endpoint DBP <90mm Hg or a reduction of greater than or equal to 10mm Hg from baseline); antihypertensive effects increased with increasing dosage, reaching a plateau at greater than or equ al to 300 mg/day. Ambulatory monitoring has shown that irbesartan 150mg onc e daily controls 24-hour BP as effectively as 75mg twice daily. A phase IV study involving 7314 evaluable patients reported a 77% response rate to irb esartan 150 mg/day as monotherapy. In randomised double-blind studies, irbesartan was significantly more effec tive than losartan or valsartan in patients with mild to moderate essential hypertension. Irbesartan was as effective as enalapril or atenolol in othe r well-designed studies. Pooled results from 1- to 2-year extensions of studies evaluating the effic acy of irbesartan less than or equal to 300 mg/day +/- hydrochlorothiazide initially in a total of 1006 patients with hypertension revealed a clinical ly relevant reduction from baseline in BP after 2 to 4 months treatment tha t plateaued after 6 to 8 months. BP normalised in 83% of patients and the o verall response rate was 90% in this analysis. A matrix study evaluating several combinations of irbesartan and hydrochlor othiazide showed that regimens containing higher dosages of irbesartan appe ared to have greater antihypertensive efficacy than those containing higher dosages of hydrochlorothiazide. In a further study, addition of hydrochlorothiazide to irbesartan monothera py in patients not responsive to the latter resulted in additive antihypert ensive effects within 2 weeks. In the reverse situation, addition of irbesartan to hydrochlorothiazide was found to be significantly more effective than hydrochlorothiazide plus pla cebo. Results from several preliminary studies show that irbesartan induces stati stically significant regression of left ventricular mass (LVM) in patients with hypertension. Two randomised double-blind studies have compared the ef fects of irbesartan and atenolol on left ventricular hypertrophy in patient s with hypertension. In both studies LVM-index decreased to a greater exten t with irbesartan than with atenolol. The antihypertensive efficacy of irbesartan less than or equal to 300 mg/da y was not influenced by mild to severe renal impairment in a noncomparative study in patients with hypertension and renal impairment; however, the eff ects of the drug were enhanced in patients undergoing haemodialysis compare d with those with mild to severe renal impairment. A 12-week randomised double-blind study evaluating the effects of irbesarta n 12.5 to 150 mg/day in patients with heart failure reported that significa ntly fewer patients receiving higher dosages (greater than or equal to 75 m g/day) of irbesartan discontinued treatment or were hospitalised because of worsening heart failure. Analysis of pooled tolerability data from 9 studies (mean treatment duratio n 9 weeks) involving 2606 patients with mild to moderate hypertension revea led no clinically relevant difference between irbesartan and placebo in the incidence of any adverse event. The most common adverse event in these tri als, headache, occurred significantly more frequently in placebo (17%) than in irbesartan-treated patients (12%). All other adverse events occurring a t a rate greater than or equal to 2% had a similar incidence in each group. 21% of irbesartan versus 20% of placebo recipients experienced greater tha n or equal to 1 adverse event. In a post-marketing surveillance study 1232 of 9009 patients ( 13.7%) repor ted a total of 1766 events of which 1257 were considered related to irbesar tan. Most adverse events were mild to moderate in severity; the incidence o f headache and dizziness, the most common adverse events, were 1.8 and 1.9% , respectively. 119 adverse events considered serious occurred in 85 patien ts; of these 20 were thought to be treatment related. Irbesartan is indicated for the treatment of hypertension in adults, either alone or in combination with other antihypertensive agents. The recommende d starting dosage of irbesartan is 150mg administered once daily. In patien ts who are volume or salt depleted as a result of vigorous treatment with d iuretics or haemodialysis, a lower starting dosage (75 mg/day) is recommend ed. The maximum recommended dosage of irbesartan is 300mg once daily. In pa tients who do not achieve an adequate BP response to monotherapy, the combi nation of irbesartan plus hydrochlorothiazide 12.5 mg/day may be used. Dosa ge adjustments an not required in elderly patients or in patients with rena l or hepatic impairment.