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Angiotensin II Antagonist.
Pharmacology: Pharmacodynamics: Irbesartan is a potent, orally active, selective angiotensin II (type AT1) receptor antagonist. It blocks 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 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 angiotensin-converting enzyme (ACE, kininase II), an enzyme that generates angiotensin II and also degrades bradykinin into inactive metabolites.
Irbesartan decreases blood pressure with minimal change in heart rate. The reduction in blood pressure is dose-related for once daily doses with a tendency towards plateau at doses above 300 mg. Doses of 150 to 300 mg once daily lower supine or seated blood pressures at trough (i.e., 24 hours after dosing) by an average of 8 to 13/5 to 8 mmHg (systolic/diastolic) greater than those associated with placebo.
Peak reduction of blood pressure is observed within 3 to 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 to 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. Irbesartan's blood pressure lowering effect is evident within 1 to 2 weeks, with maximal effect occurring by 4 to 6 weeks after start of therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertension has not been seen.
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of low dose hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7 to 10/3 to 6 mmHg (systolic/diastolic).
Irbesartan's efficacy is not influenced by age or gender. As with other medicines that affect the renin-angiotensin-aldosterone system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is coadministered with low dose hydrochlorothiazide, the antihypertensive response in black patients approaches that of white patients.
There is no effect on serum uric acid or urinary uric acid secretion.
Pharmacokinetics: Irbesartan does not require biotransformation into an active form. Its oral absorption is rapid and complete with an average absolute bioavailability of 60 to 80%. Peak plasma concentrations are attained at 1.5 to 2 hours after oral administration. Food does not affect irbesartan's bioavailability.
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 (which is twice the maximum recommended dose) was observed; the mechanism for this is unknown.
Irbesartan is 96% bound to serum proteins (primarily albumin and α1-acid glycoprotein), with negligible binding to cellular components of blood. The average volume of distribution is 53 to 93 L. Total plasma and renal clearances are 157 to 176 and 3 to 3.5 mL/min, respectively.
Irbesartan's terminal elimination half-life averaged 11 to 15 hours. Steady-state plasma concentrations are achieved within 3 days after initiation of a once a day dosing regimen. Limited accumulation of irbesartan (<20%) observed in plasma upon repeated once a day dosing is not clinically relevant.
Irbesartan is metabolized via glucuronide conjugation and oxidation. More than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan after oral or intravenous administration of 14C-labeled irbesartan. The primary circulating metabolite is the inactive irbesartan glucuronide conjugate (about 6%). The remaining oxidative metabolites do not add appreciably to irbesartan's pharmacologic activity.
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or intravenous administration of 14C-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.
In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes showed that irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was negligible. Irbesartan was neither metabolized by, nor did it substantially induce or inhibit, isoenzymes commonly associated with drug metabolism (1A1, 1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition of 3A4.
Special Populations: Geriatric: In elderly subjects 65 to 80 years old, irbesartan elimination half-life was not significantly altered, but AUC and Cmax values were about 20 to 50% greater than those of young subjects 18 to 40 years old.
Renal Insufficiency: The pharmacokinetics of irbesartan was not altered in patients with renal impairment or in patients on hemodialysis. No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also volume depleted.
Hepatic Insufficiency: The pharmacokinetics of irbesartan after repeated oral administration was not significantly affected in patients with mild to moderate liver cirrhosis. No dosage adjustment is necessary in patients with hepatic insufficiency.
