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Sunday, July 27, 2025

Irbesartan


Generic Name: Irbesartan
Drug Class: Angiotensin II Receptor Blocker (ARB)
ATC Code: C09CA04
Regulatory Status: Prescription-only medicine (Rx)
Common Brand Names: Avapro, Aprovel, Karvea (region dependent)

Mechanism of Action

Irbesartan is a selective antagonist of the angiotensin II type 1 (AT1) receptor. Angiotensin II, a potent vasoconstrictor, is a key part of the renin-angiotensin-aldosterone system (RAAS) and contributes to blood pressure elevation and sodium retention. By blocking the binding of angiotensin II to the AT1 receptor, irbesartan causes vasodilation, decreases aldosterone secretion, and reduces both peripheral resistance and blood pressure.

Irbesartan does not inhibit angiotensin-converting enzyme (ACE), hence it does not affect bradykinin metabolism, which accounts for its lower incidence of cough compared to ACE inhibitors.

Therapeutic Indications

  1. Essential Hypertension
    Indicated for the treatment of adult patients with high blood pressure, either alone or in combination with other antihypertensive agents.

  2. Diabetic Nephropathy in Type 2 Diabetes
    Irbesartan slows the progression of renal disease in patients with type 2 diabetes mellitus and hypertension with evidence of renal impairment (microalbuminuria or overt proteinuria).

  3. Heart Failure (off-label use)
    Sometimes used off-label as an alternative to ACE inhibitors in patients intolerant to them, although ARBs like candesartan or valsartan are more commonly preferred for this indication.

Pharmacokinetics

  • Absorption: Oral bioavailability approximately 60–80%. Food has no clinically relevant effect.

  • Time to Peak Plasma Level: 1.5–2 hours post-dose

  • Protein Binding: ~90% to albumin

  • Metabolism: Primarily hepatic via glucuronidation; minimal CYP450 involvement (CYP2C9)

  • Elimination Half-life: ~11–15 hours; allows once-daily dosing

  • Excretion: Approximately 80% via feces (biliary route), 20% in urine (mostly as unchanged drug)

Dosage and Administration

Adults:

  • Hypertension: Initial dose typically 150 mg once daily. Dose may be increased to 300 mg once daily if additional blood pressure control is needed.

  • Diabetic Nephropathy: Target dose is 300 mg once daily.

  • Elderly or renal impairment (mild to moderate): No dose adjustment generally required.

Pediatric use: Not routinely recommended; safety and efficacy not fully established in children under 18 years of age.

Contraindications

  • Hypersensitivity to irbesartan or any component of the formulation

  • Pregnancy (especially second and third trimesters)

  • Severe hepatic impairment

  • Concomitant use with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²)

  • Bilateral renal artery stenosis

Warnings and Precautions

  • Hypotension: Risk is increased in volume- or salt-depleted patients (e.g., diuretic use, vomiting, diarrhea)

  • Renal Function Impairment: Monitor serum creatinine and potassium periodically; may cause acute renal failure in susceptible individuals

  • Hyperkalemia: Use caution with potassium-sparing diuretics, potassium supplements, or salt substitutes

  • Angioedema: Rare but serious; discontinue if occurs

  • Pregnancy: Category D – teratogenic; discontinue immediately if pregnancy is detected

  • Breastfeeding: Not recommended due to unknown excretion in human milk

Adverse Reactions

Common (>1%)

  • Dizziness

  • Fatigue

  • Nausea

  • Hyperkalemia

  • Orthostatic hypotension

  • Headache

  • Diarrhea

Uncommon to Rare

  • Angioedema

  • Hepatic dysfunction, including hepatitis

  • Impaired renal function

  • Rash, pruritus

  • Muscle cramps

  • Cough (less frequent than with ACE inhibitors)

  • Anemia

Laboratory Abnormalities

  • Elevated serum creatinine

  • Elevated BUN

  • Hyperkalemia

  • Mild transaminase elevation

Drug Interactions

1. Potassium-elevating agents

  • Potassium supplements, potassium-sparing diuretics (e.g., spironolactone, amiloride), and salt substitutes may increase the risk of hyperkalemia.

2. NSAIDs (e.g., ibuprofen, naproxen)

  • May reduce the antihypertensive effect and increase the risk of renal dysfunction, especially in dehydrated or elderly patients.

3. Lithium

  • Risk of lithium toxicity may be increased; serum lithium levels should be monitored if used concurrently.

4. Diuretics (e.g., thiazides, loop diuretics)

  • May enhance the blood pressure-lowering effect, but also increase the risk of hypotension, especially at therapy initiation.

5. Dual RAAS blockade (e.g., ACE inhibitors, aliskiren)

  • Increases risk of hypotension, hyperkalemia, and renal impairment. Combination should generally be avoided.

6. CYP2C9 inhibitors (e.g., fluconazole)

  • May slightly increase plasma levels of irbesartan, though typically not clinically significant.

Clinical Trials and Efficacy

1. IRMA-2 (Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria)

  • Demonstrated irbesartan (particularly 300 mg) significantly reduced the progression from microalbuminuria to overt nephropathy compared to placebo and amlodipine.

2. IDNT (Irbesartan Diabetic Nephropathy Trial)

  • Irbesartan was shown to significantly reduce the risk of doubling serum creatinine and progression to end-stage renal disease compared with amlodipine or placebo in hypertensive type 2 diabetics.

3. Hypertension trials

  • Multiple studies confirm that irbesartan monotherapy reduces blood pressure effectively and is generally well tolerated. Its efficacy is comparable to ACE inhibitors and other ARBs.

Special Populations

  • Renal Impairment: Dose adjustment not needed unless severe

  • Hepatic Impairment: Caution advised in moderate impairment; not recommended in severe impairment

  • Elderly: No specific dose adjustment required; monitor renal function

  • Black Patients: ARBs, including irbesartan, may be less effective as monotherapy in black patients due to lower renin levels

Storage and Stability

  • Store at controlled room temperature, 20–25°C (68–77°F)

  • Protect from moisture and heat

  • Dispense in tight containers

Overdose Management

Symptoms:

  • Hypotension

  • Dizziness

  • Tachycardia or bradycardia (less common)

Treatment:

  • Supportive care including IV fluids and vasopressors if necessary

  • Activated charcoal may be useful if ingestion is recent

  • Irbesartan is not significantly removed by hemodialysis

Comparison with Similar Agents

Vs. Losartan:

  • Irbesartan has a longer half-life, allowing for more consistent once-daily dosing

  • Higher affinity for AT1 receptors than losartan

  • Losartan undergoes more extensive hepatic metabolism (CYP2C9/3A4), unlike irbesartan

Vs. Valsartan or Candesartan:

  • All have similar blood pressure-lowering efficacy

  • Irbesartan has more established evidence for diabetic nephropathy compared to valsartan

  • Candesartan more frequently used in heart failure

Available Formulations

  • Oral tablets: 75 mg, 150 mg, and 300 mg

  • Also available in fixed-dose combinations with hydrochlorothiazide (e.g., irbesartan 150 mg + HCTZ 12.5 mg)

Regulatory and Safety Alerts

  • Periodic reviews have reaffirmed its renal and cardiovascular safety when used within recommended indications

  • No significant black box warnings reported by major regulatory authorities such as the FDA or EMA, aside from standard ARB warnings regarding fetal toxicity

Monitoring Parameters

  • Blood pressure (baseline and regularly)

  • Renal function (serum creatinine, BUN)

  • Electrolytes (especially potassium)

  • Signs of angioedema or allergic reactions

  • Albuminuria in diabetic nephropathy patients

Patient Counseling Points

  • Take once daily at the same time for best effect

  • May be taken with or without food

  • Continue taking even if you feel well; hypertension often has no symptoms

  • Avoid potassium supplements or salt substitutes without medical advice

  • Inform your healthcare provider if you become pregnant or plan pregnancy




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