Irbesartan

Irbesartan is an antihypertensive agent belonging to Angiotensin II Receptor Blocker.

Irbesartan is approved for treatment of hypertension and also used to treat kidney disease in patient with type 2 diabetes.

The oral absolute bioavailability is about 60% to 80%. Following oral administration of Irbesartan, the peak plasma concentrations of Irbesartan are attained at 1.5 to 2 hours after dosing. The terminal elimination half-life of Irbesartan averaged 11 to 15 hours. Irbesartan is 90% bound to serum proteins. The average volume of distribution is 53 L to 93 L. Irbesartan is metabolized via glucuronide conjugation and oxidation. Irbesartan and its metabolites are excreted by both biliary and renal routes.

Irbesartan shows common side effects like dizziness, tachycardia, hyperkalemia, dyspnea, swelling of face, lips, eyelids, tongue, hands and feet, etc

Irbesartan is available in the form of Tablet.

Irbesartan is available in India, US, Europe and Canada.

Irbesartan, belonging to the Angiotensin II Receptor Blocker, acts as an antihypertensive agent.

Irbesartan works by relaxing blood vessels by blocking the action of a chemical that usually makes blood vessels tighter. This lowers blood pressure, allowing the blood to flow more easily.

Irbesartan block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT1 angiotensin II receptor. There is also AT2 receptor in many tissues, but it is not involved in cardiovascular homeostasis. Irbesartan is a specific competitive antagonist of AT1 receptor having greater affinity for AT1 receptor than for AT2 receptor and no agonist activity. Blockade of the AT1 receptor remove the negative feedback of angiotensin II on renin secretion but resulting increased plasma renin activity and circulating angiotensin II do not overcome the effect of Irbesartan on the blood pressure.

The time taken for Irbesartan to show its effect is about 1-2 hours.

Irbesartan may remain in your body for approximately 24 hours.

The Tmax was found within 1.5-2 hours following the administration of Irbesartan, and the Cmax was about 3617.19 and 3295.77 ng/mL.

Irbesartan is available in the form of Tablet.

Irbesartan tablet is taken as directed by physician, and the regular tablet is often taken once a day, swallowed with plenty of water, with or without Food.

Irbesartan approved for treatment of hypertension and also used to treat kidney disease in patient with type 2 diabetes. Lowering of high blood pressure helps prevent strokes, heart attacks, and kidney problem. It work by relaxing blood vessels so that blood can flow more easily. It is used alone or in combination with other medications, such as hydrochlorothiazide, to treat high blood pressure.

Irbesartan is an antihypertensive agent belonging to Angiotensin II Receptor Blocker which blocks vasoconstrictor and aldosterone secreting effect of angiotensin II by selectively blocking the binding of angiotensin II to AT1 receptor. Hence relaxation of blood vessels, so blood flows more efficiently to treat Hypertension.

• Hypertension

Adult

Irbesartan is indicated for the treatment of hypertension, to lower blood pressure. Dose 150 mg/day orally initially; may be increased to 300 mg/day orally. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular (CV) events, primarily strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. Irbesartan may be used alone or in combination with other antihypertensive agents.

Pediatric

In children, hypertension occurs less frequently, and the causes is more likely to be secondary to other causes, including renal parenchymal and renovascular disease. There is evidence to support the concept that essential hypertension may begin during childhood or adolescence. Thus, treatment of hypertension earlier in life may provide considerable cardiovascular and renal protection.

• Proteinuria reduction in chronic kidney diseases

Hypertension is a major contributor to the progression of chronic renal diseases 1,2 and is present in most patients with progressive renal disease and in all individuals with hypertensive nephrosclerosis. Irbesartan therapy was safely initiated and well tolerated by patients with renal disease.

• Nephropathy In Type 2 Diabetic Patients

Irbesartan is indicated for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension, an elevated serum creatinine, and proteinuria (>300 mg/day). In this population, Irbesartan reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation).

• Hypertension

Adult

The recommended initial dose of Irbesartan is 150 mg once daily. Patients requiring further reduction in blood pressure should be titrated to 300 mg once daily. A low dose of a diuretic may be added, if blood pressure is not controlled by Irbesartan alone. Hydrochlorothiazide has been shown to have an additive effect. No dosage adjustment is necessary in elderly patients.

Pediatric

<6 years: Safety and efficacy have not been established.

6-12 years: Initial dose of 75 mg as a single daily oral dose; maximum dose of 150 mg once daily.

13-16 years: Initial dose of 150 mg as a single daily oral dose; maximum dose of 300 mg once daily.

• Proteinuria reduction in chronic kidney diseases

Once daily Irbesartan given as monotherapy at dose of 150-300 mg or in combination with other antihypertensive drugs is effective in reducing blood pressure in hypertensive patients with chronic renal disease.

• Nephropathy In Type 2 Diabetic Patients

The recommended dose is 300 mg once daily.

• Volume and Salt-Depleted Patients

The recommended initial dose is 75 mg once daily in patients with depletion of intravascular volume or salt (e.g., patients treated vigorously with diuretics or on hemodialysis)

Irbesartan is available in dosage strengths of 75mg, 150mg, and 300mg.

Irbesartan is available in the dosage form of Tablets.

• Hypertension:

Salt substitutes containing potassium are avoided, and low salt or low sodium diet is maintained systematically.

The dietary restriction should be individualized as per patient requirements.

Irbesartan is contraindicated in patients with

• Hypersensitivity
• Do not coadminister with aliskiren in patients has diabetes
• Pregnancy

• Fetal Toxicity

Irbesartan can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with the fetal lung hypoplasia and skeletal deformities. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Irbesartan as soon as possible.

• Hypotension In Volume or Salt-Depleted Patients

In patients with an activated renin-angiotensin system, such as volume or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initialization of treatment with Irbesartan. Correct volume or salt depletion prior to administration of Irbesartan or use a lower starting dose.

• Impaired Renal Function

Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion) may be at particular risk of developing acute renal failure or death on Irbesartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Irbesartan.

During the treatment with Irbesartan, the consumption of alcohol is not recommended as it may lower blood pressure and can cause headache, dizziness, lightheadedness, and/or changes in the heart rate.

There are no available data on the presence of Irbesartan in human milk, effects on milk production, or the breastfed infant. Irbesartan or some metabolite of Irbesartan is secreted in milk of lactating rats. Because of the potential for adverse effects on the nursing infant, the use of Irbesartan in breastfeeding women is not recommended.

Pregnancy Category: C (1st trimester); D (2nd and 3rd trimesters)

Female of childbearing age should be told about the consequences of second and third-trimester exposure to drug that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from the intrauterine drug exposure that have been limited to first trimester. These patient should be asked to report pregnancies to their physician as soon as possible.

The food warning while consuming Irbesartan is that it should be taken in concentrations during its consumption

• Potassium Rich Foods: Irbesartan may cause high blood potassium levels. Hence, avoid potassium-rich food while taking this medicine.

The adverse reactions related to Irbesartan can be categorized as follows:

Common Adverse effects

• Diarrhea
• Fatigue
• Dizziness

Less Common Adverse effects

• Nausea
• Coughing
• Asthma
• Postural hypotension
• Muscle spasm

Rare adverse effect

• Skin rash
• Pruritus
• Angio edema

The clinically relevant drug interactions of the molecule Irbesartan is briefly summarized here.

• Agents Increasing Serum Potassium

Coadministration of Irbesartan with other drug that raise serum potassium level may result in hyperkalemia, sometimes severe. Monitor serum potassium in such patients.

• Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of Irbesartan and lithium. Monitor lithium levels in patients receiving Irbesartan and lithium.

• Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including Irbesartan) may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Irbesartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including Irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.

• Dual Blockade of The Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Irbesartan and other agent that affect the RAS.

The common side of Irbesartan includes the following

Major side effects

• Hyperkalemia
• Dizziness
• Tachycardia
• Dyspnea
• Orthostatic hypotension
• Swelling of face, lips, eyelids, tongue, hands and feet

Minor side effects

• Rash
• Headache
• Diarrhoea
• Stomach pain
• Heartburn
• Dark coloured urine

• Pregnancy

Pregnancy Categories C (first trimester) and D (second and third trimesters)

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Irbesartan as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to the drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazard to their fetuses, and serial ultrasound examination should be performed to assess the intraamniotic environment. If oligohydramnios is observed, Irbesartan should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

• Nursing Mothers

It is not known whether Irbesartan is excreted in human milk, but Irbesartan or some metabolite of Irbesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use

Irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower blood pressure effectively in pediatric patients ages 6 to 16 years. Irbesartan has not been studied in pediatric patients less than 6 years old.

• Geriatric Use

In elderly subjects (age 65-80 years), Irbesartan elimination half-life was not significantly altered, but AUC and Cmax values were about 20% to 50% greater than those of young subjects (age 18-40 years). No dosage adjustment is necessary in the elderly.

• Renal Impairment

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 Impairment

The pharmacokinetics of irbesartan following repeated oral administration were not significantly affected in patient with mild to moderate cirrhosis of the liver. No dosage adjustment is necessary in patient with hepatic insufficiency.

No data are available in regard to overdosage in human. However, daily doses of 900 mg for 8 week were well-tolerated. The most likely manifestation of overdosage are expected to be hypotension and tachycardia; bradycardia may also occur from overdose. Irbesartan is not removed by hemodialysis.

Acute oral toxicity studies with Irbesartan in mice and rats indicated acute lethal doses were in excess of 2000 mg/kg, about 25-fold and 50-fold the MRHD based on body surface area, respectively.

Pharmacodynamics

In healthy subjects, single oral Irbesartan doses of up to 300 mg produced dose-dependent inhibition of the pressor effect of angiotensin II infusions. Inhibition was complete (100%) 4 hours following oral doses of 150 mg or 300 mg and partial inhibition was sustained for 24 hours (60% and 40% at 300 mg and 150 mg, respectively). In hypertensive patients, angiotensin II receptor inhibition following chronic administration of Irbesartan causes a 1.5- to 2-fold rise in angiotensin II plasma concentration and a 2- to 3-fold increase in plasma renin levels. Aldosterone plasma concentrations generally decline following Irbesartan administration, but serum potassium levels are not significantly affected at recommended doses. In hypertensive patients, chronic oral doses of Irbesartan (up to 300 mg) had no effect on glomerular filtration rate, renal plasma flow, or filtration fraction. In multiple dose studies in hypertensive patients, there were no clinically important effects on fasting triglycerides, total cholesterol, HDL-cholesterol, or fasting glucose concentrations. There was no effect on serum uric acid during chronic oral administration, and no uricosuric effect.

Pharmacokinetics

• Absorption

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% to 80%. Following oral administration of Irbesartan, peak plasma concentration of Irbesartan are attained at 1.5 to 2 hours after dosing. Food does not affect the bioavailability of Irbesartan. Irbesartan exhibits linear pharmacokinetic over the therapeutic dose range. The terminal elimination half-life of Irbesartan averaged 11 to 15 hours. Steady-state concentrations are achieved within 3 days. Limited accumulation of Irbesartan (<20%) is observed in plasma upon repeated once-daily dosing.

• Distribution

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 liters to 93 liters. Total plasma and renal clearances are in the range of 157 mL/min to 176 mL/min and 3.0 mL/min to 3.5 mL/min, respectively. With repetitive dosing, Irbesartan accumulates to no clinically relevant extent.

• Metabolism and Elimination

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.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020757s055lbl.pdf
• https://go.drugbank.com/drugs/DB01029
• https://www.rxlist.com/avapro-drug.htm#overdosage
• https://reference.medscape.com/drug/avapro-irbesartan-342319
• https://www.practo.com/medicine-info/irbesartan-658-api