Valsartan

1. Drug Name

• Generic Name: Valsartan

• Brand Names: Diovan, Prexxartan, Co-Diovan (combination with hydrochlorothiazide), and others.

2. Drug Classification

• Class: Angiotensin II Receptor Blocker (ARB)

• Subclass: Non-peptide Angiotensin II Antagonist

3. Mechanism of Action

Valsartan 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 increases blood pressure by causing vasoconstriction and stimulating aldosterone release. Valsartan blocks the AT1 receptor, preventing these effects, resulting in vasodilation, reduced secretion of aldosterone, and a decrease in blood volume.

• Reduction of Blood Pressure: Valsartan reduces systemic vascular resistance by blocking the vasoconstrictor effects of angiotensin II. It also helps reduce blood volume and fluid retention, leading to a decrease in blood pressure.

• Renal Protection: In patients with conditions like diabetic nephropathy, valsartan provides renal protection by reducing glomerular pressure, improving renal blood flow, and decreasing proteinuria.

• Heart Failure Management: Valsartan is beneficial in heart failure by reducing afterload, preload, and myocardial oxygen demand, which can improve symptoms and slow disease progression.

4. Pharmacokinetics

• Absorption: Valsartan is well absorbed after oral administration, with a bioavailability of about 25%. Peak plasma concentrations occur within 2-4 hours after oral administration. Food reduces its absorption slightly but does not significantly affect its overall bioavailability.

• Distribution: The volume of distribution (Vd) of valsartan is approximately 17 L. It is highly protein-bound (94-97%), primarily to albumin.

• Metabolism: Valsartan is not extensively metabolized by the liver. It does not undergo significant first-pass metabolism, which contributes to its predictable pharmacokinetics. It is primarily excreted unchanged in the urine.

• Excretion: Valsartan has a terminal half-life (t½) of 9-18 hours, allowing for once-daily dosing. It is excreted primarily through the feces (about 83%) and to a lesser extent through the urine (about 13%).

• Special Considerations:

  • Renal Impairment: In patients with renal impairment (CrCl <30 mL/min), the elimination of valsartan is slowed, and dosing may need to be adjusted.

  • Hepatic Impairment: Valsartan is minimally metabolized by the liver and does not require dose adjustments in mild to moderate hepatic impairment.

5. Indications

• Primary Indications:

  • Hypertension: Valsartan is commonly used as a first-line treatment for hypertension either alone or in combination with other antihypertensive agents.

  • Heart Failure: Used to reduce mortality and hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF).

  • Post-Myocardial Infarction: Valsartan is used to improve survival and reduce the risk of heart failure development in post-myocardial infarction patients with left ventricular systolic dysfunction.

• Off-Label Uses:

  • Diabetic Nephropathy: Valsartan may be used to reduce proteinuria and slow the progression of renal impairment in patients with diabetic nephropathy, particularly in type 2 diabetes.

  • Chronic Kidney Disease (CKD): Used to prevent the progression of CKD, particularly in patients with hypertension and proteinuria.

• Special Populations:

  • Elderly: Valsartan can be used in elderly patients with hypertension and heart failure. Care should be taken to monitor renal function and blood pressure closely.

  • Pediatrics: Approved for use in children ≥6 years for the treatment of hypertension.

6. Dosage and Administration

• Adult Dosing:

  • Hypertension: The typical starting dose is 80 mg once daily, with a target dose of 160 mg to 320 mg daily, depending on blood pressure control.

  • Heart Failure: Initial dose is usually 40 mg once daily, with gradual titration to 160 mg once daily, based on clinical response and tolerance.

  • Post-Myocardial Infarction: The recommended starting dose is 20 mg once daily, with titration to higher doses as tolerated.

• Pediatric Dosing:

  • Hypertension (6-16 years): Starting dose is 0.3 mg/kg once daily, with a maximum dose of 160 mg daily for children weighing over 35 kg.

• Renal Impairment: In patients with severe renal impairment (CrCl <30 mL/min), valsartan should be used with caution, and the dose may need to be adjusted.

• Hepatic Impairment: Valsartan can be used at standard doses in patients with mild-to-moderate hepatic impairment. In severe hepatic impairment, the use of valsartan should be avoided.

7. Contraindications

• Absolute Contraindications:

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

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

  • Bilateral Renal Artery Stenosis: Contraindicated in patients with bilateral renal artery stenosis or stenosis of a solitary kidney, as it may precipitate renal failure.

• Relative Contraindications:

  • Hyperkalemia: Valsartan may worsen hyperkalemia, particularly in patients with renal dysfunction or those using potassium-sparing diuretics or supplements.

8. Warnings and Precautions

• Pregnancy Category: Category D (second and third trimesters). Valsartan should not be used during pregnancy due to the risk of fetal injury, including renal failure, hypotension, and skull hypoplasia.

• Hypotension: Valsartan may cause symptomatic hypotension, especially in volume-depleted or salt-depleted patients. Care should be taken when initiating treatment.

• Hyperkalemia: Hyperkalemia is a significant concern, particularly in patients with renal dysfunction or those on potassium-sparing diuretics. Serum potassium should be monitored regularly.

• Renal Function: Valsartan can cause a decline in renal function, particularly in patients with pre-existing renal impairment or in those who are dehydrated.

• Angioedema: Though rare, valsartan may cause angioedema, a serious allergic reaction characterized by swelling of the face, lips, or throat.

9. Adverse Effects

• Common Adverse Effects:

  • Dizziness or lightheadedness

  • Fatigue

  • Hyperkalemia

  • Hypotension

• Less Common but Clinically Significant Side Effects:

  • Angioedema (swelling of the face, lips, or throat)

  • Elevated liver enzymes

  • Acute renal failure

• Rare/Serious Adverse Reactions:

  • Fetal Toxicity: Valsartan can cause birth defects or fetal death, particularly in the second and third trimesters of pregnancy.

  • Severe Hyperkalemia: Dangerous increases in potassium levels, which can lead to life-threatening arrhythmias.

10. Drug Interactions

• Major Drug Interactions:

  • Potassium-Sparing Diuretics (e.g., spironolactone): Increased risk of hyperkalemia. Serum potassium should be closely monitored.

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

  • Lithium: Valsartan can increase the serum concentration of lithium, increasing the risk of lithium toxicity.

  • ACE Inhibitors or Other ARBs: The combination of valsartan with an ACE inhibitor or another ARB may increase the risk of renal dysfunction, hyperkalemia, and hypotension.

• Food-Drug Interactions: Valsartan can be taken with or without food. However, high-fat meals may slightly reduce its absorption.

11. Clinical Pharmacology

• Pharmacodynamics: Valsartan works by blocking the AT1 receptor, leading to vasodilation, decreased secretion of aldosterone, and reduced blood pressure. It does not inhibit ACE and does not lead to the accumulation of bradykinin, which is often responsible for the cough seen with ACE inhibitors.

• Additional Effects: Valsartan provides renal protection, particularly in patients with hypertension and diabetes, by reducing proteinuria and glomerular pressure.

12. Special Populations

• Pregnancy: Contraindicated in pregnancy (Category D), especially in the second and third trimesters due to fetal harm.

• Lactation: Valsartan is excreted in breast milk in low amounts. Use with caution or avoid during breastfeeding.

• Pediatrics: Approved for children aged 6 years and older for the treatment of hypertension. Dosing should be weight-based for optimal results.

• Geriatrics: Older adults may be more susceptible to the hypotensive effects of valsartan, requiring careful titration and monitoring.

• Renal Impairment: Dose adjustments are necessary for patients with renal dysfunction. Serum creatinine and potassium should be regularly monitored.

• Hepatic Impairment: Valsartan can be used in patients with mild-to-moderate hepatic impairment but should be avoided in severe hepatic dysfunction.

13. Therapeutic Uses

• Hypertension: First-line treatment for essential hypertension, used alone or in combination with other antihypertensive agents (such as diuretics).

• Heart Failure: Improves outcomes in patients with HFrEF when used alongside other heart failure treatments, such as beta-blockers and diuretics.

• Post-Myocardial Infarction: Reduces the risk of post-MI mortality and prevents heart failure development.

14. Monitoring and Follow-Up

• Blood Pressure: Monitor regularly to ensure the antihypertensive effect is achieved.

• Serum Creatinine and eGFR: Monitor renal function, especially in patients with renal impairment or those taking other medications that affect the kidneys.

• Potassium Levels: Check potassium levels regularly to prevent hyperkalemia.

15. Overdose Management

• Symptoms of Overdose: Overdose symptoms may include severe hypotension, dizziness, tachycardia, and renal impairment.

• Treatment: Overdose management includes symptomatic treatment, such as intravenous fluids to counter hypotension. In severe overdose cases, hemodialysis may be required to remove the drug from circulation and restore electrolyte balance.

16. Patient Counseling Information

• Key Points:

  • Take valsartan as prescribed, with or without food, usually once daily.

  • Monitor for signs of low blood pressure, such as dizziness or lightheadedness.

  • Avoid potassium supplements or salt substitutes unless instructed by a healthcare provider.

• Seek Immediate Medical Attention: If you experience swelling of the face, lips, or throat (signs of angioedema), dizziness, fainting, or confusion, seek medical help immediately.