Losartan

1. Drug Name

• Generic Name: Losartan

• Brand Names: Cozaar, Lozap, Hyzaar (when combined with hydrochlorothiazide), and others.

2. Drug Classification

• Class: Angiotensin II Receptor Blocker (ARB)

• Subclass: Non-peptide Angiotensin II Antagonist

3. Mechanism of Action

Losartan is an angiotensin II receptor antagonist (ARB) that works by selectively blocking the type 1 angiotensin II receptor (AT1) in various tissues, including the heart, blood vessels, kidneys, and adrenal glands.

• Inhibition of Angiotensin II Effects: Angiotensin II is a potent vasoconstrictor that also stimulates aldosterone secretion, which leads to increased sodium and water retention, raising blood pressure. By blocking the AT1 receptor, losartan prevents these effects, resulting in vasodilation, reduced aldosterone secretion, and decreased fluid retention.

• Reduction of Blood Pressure: The primary clinical effect of losartan is the lowering of blood pressure. This is achieved through decreased systemic vascular resistance due to vasodilation, as well as reduced secretion of aldosterone and antidiuretic hormone (ADH), which further reduces blood volume.

• Renal Benefits: Losartan has a beneficial effect on the kidneys, particularly in patients with diabetic nephropathy or chronic kidney disease, by reducing glomerular pressure and improving renal function.

• Anti-inflammatory Effects: ARBs like losartan also have mild anti-inflammatory properties, contributing to their beneficial effects in reducing organ damage caused by chronic hypertension and diabetes.

4. Pharmacokinetics

• Absorption: Losartan is well absorbed after oral administration, with a bioavailability of approximately 33%. Peak plasma concentrations occur within 1-2 hours after oral administration.

• Distribution: The volume of distribution (Vd) of losartan is approximately 34 L. It is highly protein-bound, about 99%, primarily to albumin.

• Metabolism: Losartan is extensively metabolized in the liver by cytochrome P450 enzymes, mainly CYP2C9, into its active metabolite, EXP3174, which is approximately 10-40 times more potent than losartan in blocking the AT1 receptor. The elimination half-life (t½) of losartan is about 2 hours, while that of EXP3174 is about 9-13 hours.

• Excretion: Both losartan and its active metabolite are primarily excreted in the urine (about 35%) and feces (about 60%) as unchanged drug and metabolites. Losartan has a terminal half-life of about 2 hours, whereas its active metabolite has a half-life of 6-9 hours, contributing to prolonged effects.

• Special Considerations:

  • Renal Impairment: In patients with renal impairment, losartan’s clearance is reduced, and dosing adjustments may be necessary.

  • Hepatic Impairment: Losartan is primarily metabolized by the liver, so it should be used with caution in patients with hepatic dysfunction.

5. Indications

• Primary Indications:

  • Hypertension: Losartan is used to treat hypertension either alone or in combination with other antihypertensive medications.

  • Diabetic Nephropathy: It is indicated to reduce the progression of diabetic nephropathy in type 2 diabetes patients with hypertension and proteinuria.

  • Chronic Heart Failure: Used as part of a comprehensive treatment plan for heart failure, particularly in patients who cannot tolerate ACE inhibitors.

• Off-Label Uses:

  • Stroke Prevention: In patients with hypertension and left ventricular hypertrophy (LVH), losartan can be used to reduce the risk of stroke.

  • Chronic Kidney Disease (CKD): Used off-label for patients with CKD to delay the progression of renal dysfunction, particularly when proteinuria is present.

• Special Populations:

  • Pediatrics: Losartan is approved for use in children 6 years and older for the treatment of hypertension.

  • Elderly: In elderly patients, careful monitoring is required due to the increased risk of hypotension, especially with the initiation of therapy.

6. Dosage and Administration

• Adult Dosing:

  • Hypertension: The typical starting dose is 50 mg once daily, with a maintenance dose of 25-100 mg once daily. The dose may be titrated based on blood pressure response.

  • Diabetic Nephropathy: The usual dose is 50 mg once daily. This can be adjusted to 100 mg daily if necessary for optimal blood pressure control and renal protection.

  • Heart Failure: Initial dose is typically 5-10 mg once daily, with titration based on clinical response.

• Pediatric Dosing:

  • Hypertension (6-16 years): The usual starting dose is 0.7 mg/kg once daily, with a maximum dose of 50 mg per day.

• Renal Impairment: In patients with renal impairment (e.g., CrCl <30 mL/min), dosing may need to be adjusted. Close monitoring is recommended.

• Hepatic Impairment: Losartan should be used with caution, and a lower dose may be required in patients with mild to moderate liver impairment.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity: Known hypersensitivity to losartan or any component of the formulation.

  • Pregnancy: Losartan is contraindicated during pregnancy, particularly in the second and third trimesters, due to the risk of fetal harm.

• Relative Contraindications:

  • Bilateral Renal Artery Stenosis: Use with caution in patients with bilateral renal artery stenosis due to the potential for acute renal failure.

  • Hyperkalemia: Losartan should be avoided in patients with hyperkalemia (serum potassium >5.5 mEq/L) due to the risk of worsening potassium levels.

8. Warnings and Precautions

• Pregnancy Category: Category D (second and third trimesters). Losartan is contraindicated in pregnancy due to the risk of fetal injury or death, including renal failure, hypotension, and skull hypoplasia.

• Hypotension: Excessive lowering of blood pressure, particularly in volume-depleted or salt-depleted patients, can occur, leading to dizziness, fainting, or syncope.

• Hyperkalemia: Monitor potassium levels regularly, especially in patients with renal dysfunction or those on potassium-sparing diuretics or potassium supplements.

• Renal Function: Losartan can affect renal function, and renal function should be monitored, especially in patients with pre-existing kidney disease or when used in combination with other drugs that affect the kidneys.

• Cough: Unlike ACE inhibitors, losartan does not typically cause a persistent dry cough, which can be an advantage for patients intolerant to ACE inhibitors.

9. Adverse Effects

• Common Adverse Effects:

  • Dizziness or lightheadedness

  • Hyperkalemia

  • Fatigue

  • Hypotension

• Less Common but Clinically Significant Side Effects:

  • Angioedema (swelling of the deeper layers of skin, often around the eyes and lips)

  • Acute renal failure

  • Rash

• Rare/Serious Adverse Reactions:

  • Fetal Toxicity: Contraindicated in pregnancy, as it can cause birth defects or fetal death.

  • Elevated Liver Enzymes: Hepatic dysfunction, though rare, can occur and may require discontinuation of therapy.

10. Drug Interactions

• Major Drug Interactions:

  • Potassium-Sparing Diuretics (e.g., spironolactone): Increased risk of hyperkalemia. Monitor potassium levels carefully.

  • NSAIDs (e.g., ibuprofen, naproxen): NSAIDs can reduce the antihypertensive effects of losartan by decreasing renal blood flow.

  • Lithium: Losartan can increase serum lithium levels, potentially leading to lithium toxicity.

• Food-Drug Interactions: Losartan can be taken with or without food. However, grapefruit juice may increase the plasma concentrations of losartan and its active metabolite, so caution is advised.

11. Clinical Pharmacology

• Pharmacodynamics: Losartan effectively lowers blood pressure by blocking the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Its primary mechanism is through antagonism of the AT1 receptor, leading to vasodilation and decreased fluid retention.

• Additional Effects: In addition to lowering blood pressure, losartan provides renal protective effects in patients with diabetes and proteinuria, making it particularly useful in patients with diabetic nephropathy.

12. Special Populations

• Pregnancy: Category D. Losartan should not be used during pregnancy, especially in the second and third trimesters, due to the risk of fetal injury.

• Lactation: Losartan is excreted in breast milk in low amounts, and its use in breastfeeding mothers should be avoided unless absolutely necessary.

• Pediatrics: Losartan is approved for children aged 6 years and older for the treatment of hypertension.

• Geriatrics: The elderly population is more sensitive to blood pressure changes and may be at a higher risk of adverse effects, including hypotension and hyperkalemia.

13. Therapeutic Uses

• Hypertension: First-line treatment for managing primary hypertension, either alone or in combination with other antihypertensive agents.

• Diabetic Nephropathy: Used to reduce the progression of kidney damage in patients with diabetic nephropathy.

• Heart Failure: May be used as part of a comprehensive treatment plan for heart failure, particularly when ACE inhibitors are contraindicated.

14. Monitoring and Follow-Up

• Electrolytes: Monitor serum potassium levels periodically, particularly in patients with renal impairment or those on concomitant medications that increase potassium levels.

• Renal Function: Regular assessment of serum creatinine and eGFR is essential, especially for patients with pre-existing renal dysfunction.

15. Overdose Management

• Symptoms of Overdose: Symptoms of overdose may include hypotension, dizziness, or fainting. Severe overdose could result in marked hypotension, renal failure, or electrolyte imbalances.

• Treatment: Overdose management is primarily symptomatic. Hypotension can be treated with intravenous fluids, and in cases of severe overdose, dialysis may be required to remove the drug and restore electrolyte balance.

16. Patient Counseling Information

• Key Points:

  • Take losartan exactly as prescribed, usually once daily.

  • Monitor for signs of low blood pressure, such as dizziness or lightheadedness, especially after the first dose.

  • Avoid potassium supplements or salt substitutes without consulting your healthcare provider.

• Seek Immediate Medical Attention: If you experience symptoms of severe hypotension, such as fainting, dizziness, or confusion, or if you develop swelling of the face, lips, or throat (signs of angioedema), seek emergency medical help immediately.