Irbisat Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity.
Clinical Efficacy: Hypertension: Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by an average of 8-13/5-8 mmHg (systolic/diastolic) greater than those associated with placebo.
Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended doses. Once-daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice daily dosing on the same total dose.
The blood pressure lowering effect of Irbesartan is evident within 1-2 weeks, with the maximal effect occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long-term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertension has not been observed.
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mmHg (systolic/diastolic).
Hypertension and type-2 diabetes with renal disease: Irbesartan decreases the progression of renal disease in patients with chronic renal insufficiency and overt proteinuria. Irbesartan 300 mg delays progression to overt proteinuria in patients with albuminuria.
Pharmacokinetics: Absorption: After oral administration, irbesartan is well absorbed. Concomitant food intake does not significantly influence the bioavailability of irbesartan.
Distribution: Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. The volume of distribution is 53-93 litres.
Metabolism: Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). Irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect.
Linearity/non-linearity: Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5 to 2.0 hours after oral administration. The total body and renal clearance are 157-176 and 3-3.5 ml/min respectively. The terminal elimination half-life of irbesartan is 11-15 hours. Steady state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing.
Elimination: Irbesartan and its metabolites are eliminated by both biliary and renal pathways. Less than 2% of dose is excreted in the urine as unchanged irbesartan.
Renal impairment: In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis.
Hepatic impairment: In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment.