Pharmacology: Pharmacodynamics: Mechanism of Action: Irbesartan: Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system (RAS) and also stimulates aldosterone synthesis and secretion by adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth. Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT1 angiotensin II receptor. There is also an AT2 receptor in many tissues, but it is not involved in cardiovascular homeostasis.
Irbesartan is a specific competitive antagonist of AT1 receptors with a much greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2 receptor, and no agonist activity.
Blockade of the AT1 receptor removes the negative feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II do not overcome the effects of irbesartan on blood pressure.
Irbesartan does not inhibit ACE or renin or affect other hormone receptors or ion channels known to be involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Because irbesartan does not inhibit ACE, it does not affect the response to bradykinin; whether this has clinical relevance is not known.
Hydrochlorothiazide: Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is not fully understood.
Pharmacokinetics: Irbesartan: Irbesartan is an orally active agent that does not require biotransformation into an active form. The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60–80%. Following oral administration of irbesartan, peak plasma concentrations of irbesartan are attained at 1.5-2 hours after dosing. Food does not affect the bioavailability of irbesartan.
Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range.
The terminal elimination half-life of irbesartan averaged 11-15 hours. Steady-state concentrations are achieved within 3 days. Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing.
Hydrochlorothiazide: When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.
Metabolism and Elimination: Irbesartan: Irbesartan is metabolized via glucuronide conjugation and oxidation. Following oral or intravenous administration of 14C-labeled irbesartan, more than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan. The primary circulating metabolite is the inactive irbesartan glucuronide conjugate (approximately 6%). The remaining oxidative metabolites do not add appreciably to irbesartan's pharmacologic activity.
Irbesartan and its metabolites are excreted by both biliary and renal routes. Following 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.
In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes indicated 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.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.
Distribution: Irbesartan: Irbesartan is 90% bound to serum proteins (primarily albumin and α1-acid glycoprotein) with negligible binding to cellular components of blood. The average volume of distribution is 53-93 liters. Total plasma and renal clearances are in the range of 157-176 and 3.0-3.5 mL/min, respectively. With repetitive dosing, irbesartan accumulates to no clinically relevant extent.
Studies in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain barrier and placenta.
Irbesartan is excreted in the milk of lactating rats.
Hydrochlorothiazide: Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Special Populations: Pediatric: Irbesartan-hydrochlorothiazide pharmacokinetics have not been investigated in patients <18 years of age.
Gender: No gender related differences in pharmacokinetics were observed in healthy elderly (age 65-80 years) or in healthy young (age 18-40 years) subjects. In studies of hypertensive patients, there was no gender difference in half-life or accumulation, but somewhat higher plasma concentrations of irbesartan were observed in females (11-44%). No gender-related dosage adjustment is necessary.
Geriatric: In elderly subjects (age 65-80 years), irbesartan elimination half-life was not significantly altered, but AUC and Cmax values were about 20-50% greater than those of young subjects (age 18-40 years). No dosage adjustment is necessary in the elderly.
Race: In healthy black subjects, Irbesartan AUC values were approximately 25% greater than whites; there were no differences in Cmax values.
Renal Insufficiency: The pharmacokinetics of irbesartan were not altered in patients with renal impairment or in patients on hemodialysis. Irbesartan is not removed by 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 following repeated oral administration were not significantly affected in patients with mild to moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.