Ibetan 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.
Pharmacokinetics: After oral administration, irbesartan is well absorbed. Studies of absolute bioavailability gave values of approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of irbesartan. Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. The volume of distribution is 53-93 liters. Following oral or intravenous administration of ₁₄C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan.
Irbesartan is metabolized by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidized by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. 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 greater than 600 mg (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5-2 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 t½ 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.
In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and C_max values were also somewhat greater in older subjects (≥65 years) than those of young subjects (18-40 years). However, the terminal half-life was not significantly altered. No dosage adjustment is necessary in older people.
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV administration of ₁₄C irbesartan, about 20% of the radioactivity is recovered in the urine and the remainder in the feces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.
Pharmacokinetics in Special Populations: Renal Impairment: In patients with renal impairment or those undergoing hemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by hemodialysis.
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.
Pediatric Population: The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that C_max, AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing.