| Indication |
For the treatment of hypertension, as well as diabetic nephropathy
with an elevated serum creatinine and proteinuria (>300 mg/day) in
patients with type 2 diabetes and hypertension. Irbesartan is also used
as a second line agent in the treatment of congestive heart failure. |
| Pharmacodynamics |
Angiotensin II, the principal pressor agent of the
renin-angiotensin system, is responsible for effects such as
vasoconstriction, stimulation of synthesis and release of aldosterone,
cardiac stimulation, and renal reabsorption of sodium. 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. Irbesartan's inhibition of
angiotensin II binding to the AT1 receptor leads to multiple effects
including vasodilation, a reduction in the secretion of vasopressin, and
reduction in the production and secretion of aldosterone. The resulting
effect is a decrease in blood pressure. |
| Mechanism of action |
Irbesartan is a nonpeptide tetrazole derivative and an angiotensin
II antagonist that selectively blocks the binding of angiotensin II to
the AT1 receptor. In the renin-angiotensin system,
angiotensin I is converted by angiotensin-converting enzyme (ACE) to
form angiotensin II. Angiotensin II stimulates the adrenal cortex to
synthesize and secrete aldosterone, which decreases the excretion of
sodium and increases the excretion of potassium. Angiotensin II also
acts as a vasoconstrictor in vascular smooth muscle. Irbesartan, by
blocking the binding of angiotensin II to the AT1 receptor,
promotes vasodilation and decreases the effects of aldosterone. The
negative feedback regulation of angiotensin II on renin secretion is
also inhibited, but the resulting rise in plasma renin concentrations
and consequent rise in angiotensin II plasma concentrations do not
counteract the blood pressure–lowering effect that occurs. The action of
ARBs is different from ACE inhibitors, which block the conversion of
angiotensin I to angiotensin II, meaning that the production of
angiotensin II is not completely inhibited, as the hormone can be formed
via other enzymes. Also, unlike ACE inhibitors, irbesartan and other
ARBs do not interfere with response to bradykinins and substance P,
which allows for the absence of adverse effects that are present in ACE
inhibitors (eg. dry cough). |
| Absorption |
Rapid and complete with an average absolute bioavailability of 60-80%. Food has no affect on bioavailability. |
| Volume of distribution |
|
| Protein binding |
90% bound to serum proteins (primarily albumin and a1-acid
glycoprotein) with negligible binding to cellular components of blood. |
| Metabolism |
Hepatic. Irbesartan is metabolized via glucuronide conjugation
and oxidation. In vitro studies of irbesartan oxidation by cytochrome
P450 isoenzymes indicated irbesartan was oxidized primarily by 2C9;
metabolism by 3A4 was negligible. |
| Route of elimination |
Irbesartan is metabolized via glucuronide conjugation and
oxidation. Irbesartan and its metabolites are excreted by both biliary
and renal routes. Irbesartan is excreted in the milk of lactating rats. |
| Half life |
11-15 hours |
| Clearance |
|
| Toxicity |
Hypotension and tachycardia; bradycardia might also occur from overdose, LD50=mg/kg(orally in rat) |
