Furosemide

1. Drug Name

• Generic Name: Furosemide

• Brand Names: Lasix, Furocot, Diuril, Frusemide (various brand names across different countries)

2. Drug Classification

• Class: Loop Diuretic

• Subclass: Sulfonamide-based Diuretic

3. Mechanism of Action

Furosemide is a potent loop diuretic that acts primarily on the thick ascending limb of the loop of Henle in the kidney. It exerts its effects by:

• Inhibition of Sodium, Potassium, and Chloride Cotransporter (NKCC2): Furosemide inhibits the Na+/K+/2Cl− symporter in the thick ascending limb of the loop of Henle, leading to a significant reduction in sodium, chloride, and potassium reabsorption. This results in increased urinary excretion of sodium, chloride, and water (diuresis), and also potassium and calcium.

• Increased Urinary Excretion of Electrolytes: The inhibition of Na+/K+/2Cl− transporter disrupts the electrochemical gradient needed for reabsorption of various electrolytes, leading to loss of sodium, potassium, calcium, and magnesium in the urine.

• Reduction of Blood Volume: By promoting significant diuresis, furosemide reduces the volume of blood (plasma volume), which leads to decreased cardiac output and blood pressure.

• Potent Effect on Edema: Its effects on water and electrolyte balance make it useful in treating conditions with significant edema, including heart failure, cirrhosis, and kidney disease.

4. Pharmacokinetics

• Absorption: Furosemide is rapidly absorbed from the gastrointestinal tract, with oral bioavailability ranging from 50-70%. Its onset of action is typically 30-60 minutes when taken orally, with peak effects occurring within 1-2 hours. Intravenous administration results in a much faster onset, usually within 5 minutes.

• Distribution: It has a volume of distribution (Vd) of approximately 0.14-0.2 L/kg, indicating moderate tissue penetration. Furosemide is about 91-99% bound to plasma proteins, primarily albumin.

• Metabolism: Furosemide is minimally metabolized in the liver. About 25% of the dose is metabolized, while the remaining 75% is excreted unchanged by the kidneys. It undergoes partial conjugation with glucuronic acid in the liver.

• Excretion: Furosemide is primarily eliminated by the kidneys (about 80%) as unchanged drug, with a smaller fraction excreted in bile. Its half-life (t½) is typically 1-2 hours, but this can be prolonged in patients with renal impairment.

• Special Considerations: In patients with renal impairment, the clearance of furosemide is reduced, and its half-life may be prolonged. Dose adjustments may be required in these patients.

5. Indications

• Primary Indications:

  • Edema: Used to treat edema associated with conditions such as congestive heart failure, liver cirrhosis, renal disease (including nephrotic syndrome), and acute pulmonary edema.

  • Hypertension: Furosemide can be used to manage hypertension, particularly in patients with heart failure or chronic kidney disease.

• Off-Label Uses:

  • Hypercalcemia: Furosemide may be used in the treatment of hypercalcemia to promote the excretion of calcium.

  • Acute Renal Failure: In specific cases, furosemide may be used to induce diuresis in acute renal failure (though its efficacy in improving renal function in this setting is debated).

• Special Populations:

  • Pediatrics: Furosemide is often used in pediatric patients for the treatment of heart failure and edema, but dosing must be done carefully to avoid dehydration and electrolyte imbalances.

  • Geriatrics: Elderly patients are more prone to electrolyte disturbances, particularly hypokalemia and dehydration, and require close monitoring.

6. Dosage and Administration

• Adult Dosing:

  • Edema: Initial dose is typically 20-80 mg, taken orally once daily. The dose may be increased by 20-40 mg increments every 6-8 hours, depending on response. The usual effective dose is 40-120 mg daily.

  • Hypertension: 40 mg once or twice daily, alone or in combination with other antihypertensive agents.

• Pediatric Dosing:

  • Edema (Children): Usual dosing is 1-2 mg/kg/day, given as a single dose or in divided doses. In severe cases, doses may be higher, but should be carefully monitored.

• Renal Impairment: For patients with renal insufficiency (CrCl <30 mL/min), the dose should be reduced. In such cases, intravenous administration may be more appropriate.

• Maximum Safe Dose: Typically, 600 mg/day for adults, though higher doses may be used in specialized settings (e.g., in cases of severe edema or acute pulmonary edema).

7. Contraindications

• Absolute Contraindications:

  • Anuria: Furosemide is contraindicated in patients who are unable to produce urine (anuric patients) due to the drug's diuretic effects.

  • Hypersensitivity: Known hypersensitivity to furosemide or sulfonamide-related drugs.

• Relative Contraindications:

  • Severe Electrolyte Imbalances: Use with caution in patients with hypokalemia, hyponatremia, or hypocalcemia.

  • Renal Impairment: Caution should be exercised in patients with pre-existing renal insufficiency, as high doses may worsen renal function or lead to acute renal failure.

8. Warnings and Precautions

• Electrolyte Imbalances: Furosemide can cause significant electrolyte disturbances, including:

  • Hypokalemia: Risk of low potassium levels, leading to muscle weakness, cramping, and arrhythmias.

  • Hyponatremia: Low sodium levels, resulting in symptoms like confusion, seizures, and dizziness.

  • Hypocalcemia: Low calcium levels, which may present as tetany or muscle spasms.

• Dehydration and Hypotension: Due to its potent diuretic effects, furosemide can lead to dehydration and hypotension, particularly in patients with impaired renal function.

• Ototoxicity: Furosemide has been associated with ototoxicity, especially when given in high intravenous doses or rapidly infused.

• Gout: Furosemide may exacerbate gout by increasing serum uric acid levels.

• Pregnancy and Lactation: Classified as Category C for pregnancy, furosemide should only be used during pregnancy if the benefits outweigh the risks. It is excreted in breast milk, so its use should be avoided in breastfeeding mothers unless necessary.

9. Adverse Effects

• Common Adverse Effects:

  • Dizziness or light-headedness

  • Hypokalemia

  • Hypotension

  • Nausea and vomiting

• Less Common but Clinically Significant Side Effects:

  • Ototoxicity (hearing impairment, especially with rapid IV infusion)

  • Hyperglycemia

  • Photosensitivity

  • Hyperuricemia (may trigger gout attacks)

• Rare/Serious Adverse Reactions:

  • Severe electrolyte imbalances (e.g., hypokalemia, hyponatremia)

  • Severe dehydration

  • Anaphylaxis

  • Stevens-Johnson Syndrome

10. Drug Interactions

• Major Drug Interactions:

  • Aminoglycosides (e.g., gentamicin): Increased risk of ototoxicity when combined with furosemide, especially when given intravenously.

  • Lithium: Furosemide can increase the levels of lithium, leading to a higher risk of lithium toxicity.

  • Digoxin: Furosemide can increase the risk of digoxin toxicity, particularly due to hypokalemia.

  • NSAIDs: Nonsteroidal anti-inflammatory drugs may reduce the efficacy of furosemide by decreasing renal blood flow and glomerular filtration rate.

• Food-Drug Interactions: No major food interactions, though it is often recommended to take furosemide with food to reduce gastrointestinal irritation.

11. Clinical Pharmacology

• Pharmacodynamics: Furosemide is a potent loop diuretic that increases urine output by inhibiting sodium and chloride reabsorption in the loop of Henle. This leads to a reduction in extracellular fluid volume, blood pressure, and edema.

• Additional Effects: Furosemide has significant effects on electrolytes, including sodium, potassium, calcium, and magnesium, and may also influence uric acid levels, contributing to gout attacks in susceptible individuals.

12. Special Populations

• Pregnancy: Category C. Furosemide should be used in pregnancy only when necessary, and the potential benefits should outweigh the risks to the fetus.

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

• Geriatrics: Elderly patients are at higher risk for electrolyte disturbances and hypotension. Close monitoring is essential.

13. Therapeutic Uses

• Hypertension: Furosemide can be used to treat hypertension, though it is typically not a first-line treatment. It is often used in conjunction with other antihypertensive agents.

• Edema: First-line treatment for edema associated with heart failure, cirrhosis, and nephrotic syndrome. It is particularly useful in patients with severe fluid overload.

14. Monitoring and Follow-Up

• Electrolyte Monitoring: Regular monitoring of electrolytes, especially potassium, sodium, and calcium, is critical during furosemide therapy.

• Kidney Function: Monitor renal function through serum creatinine and eGFR, especially in patients with pre-existing renal impairment.

15. Overdose Management

• Symptoms of Overdose: Overdose symptoms may include extreme diuresis, electrolyte imbalances (especially hypokalemia and hyponatremia), hypotension, dehydration, and tinnitus or hearing loss.

• Treatment: Supportive care with fluid and electrolyte replenishment. Hypotension may be managed with intravenous fluids or vasopressors. In severe cases, dialysis may be required to remove the drug from the system.

16. Patient Counseling Information

• Key Points:

  • Take the medication exactly as prescribed.

  • Monitor for signs of electrolyte imbalances, such as muscle weakness or cramps, dizziness, or confusion.

  • Drink plenty of fluids to avoid dehydration, but avoid excessive fluid intake.

• Seek Immediate Medical Attention: If you experience dizziness, fainting, unusual tiredness, muscle cramps, or confusion, seek medical help immediately.