Furosemide

Mechanism

Pharmacological Group

Loop diuretic from the sulfonamide group.

Mechanism of Action

Furosemide travels tightly bound to blood albumin and requires active secretion into the tubular lumen by the organic anion transporter-1 (OAT-1) in the TCP to reach its target. Once in the lumen, it binds reversibly to the chloride site on the NKCC2 cotransporter on the apical membrane of the Thick Ascending Branch of the Loop of Henle. It blocks the coordinated reabsorption of 1Na⁺, 1K⁺ and 2Cl^-. By abolishing the net influx of electrolytes, it extinguishes the positive transepithelial electrical gradient (+10 mV) induced by potassium efflux through ROMK. This blocks the paracellular reabsorption of calcium and magnesium, causing massive loss in urine.

Pharmacokinetics

Key Pharmacokinetics

• Routes of administration: Oral, Intravenous (IV), Intramuscular (IM).
• Bioavailability: Very erratic and variable (from 10% to 90%, with an average of 50%). Intestinal wall edema in decompensated heart failure delays and attenuates its absorption.
• Metabolism: Minimal conjugation to glucuronide in the kidney.
• Excretion: 60-85% by urine (filtration and active secretion); the rest is eliminated through the bile and fecal route.
• Half-life: 1.5 to 2 hours (very prolonged in renal and heart failure).

Asa Diuretic Resistance Phenomenon

Chronic use of high-dose furosemide induces adaptive histological remodeling in the distal nephron. The constant high delivery of sodium chloride stimulates hypertrophy and hyperplasia of the cells of the Distal Convoluted Tubulus and Collecting Tubules. These cells increase the density of the NCC and ENaC transporters, efficiently capturing the sodium that escaped from the Loop of Henle. To counteract this phenomenon, sequential nephron blockade is used clinically, combining intermittent doses of a thiazide (such as metolazone or hydrochlorothiazide) 30 minutes before the dose of the loop diuretic.

Indicators and dose

Clinical Indications

• Congestive heart failure: Reduces preload immediately by systemic venodilation mediated by prostaglandins (prior to the diuretic effect) and manages fluid overload.
• Acute lung edema: Intravenous route for rapid symptomatic relief and reduction of left ventricular filling pressures.
• Nephrotic syndrome and ascites due to cirrhosis: Control of generalized edematous states (frequently associated with spironolactone in cirrhosis).
• Acute hypercalcemia: Force urinary elimination of calcium in combination with isotonic saline.

Dosage and Settings

• Adults: Oral 20 mg to 80 mg daily as a starting dose; maximum dose of up to 600 mg per day in extreme cases of resistance. IV bolus: 20 mg to 40 mg, escalating according to response.
• Pediatrics: 1 to 2 mg/kg per dose (oral or IV); maximum 6 mg/kg.
• Renal adjustment: No reduction required for toxicity, but much higher doses are needed in patients with reduced filtration rate (e.g., 120 to 250 mg IV in advanced renal failure) to ensure that a sufficient amount of free drug reaches the tubular lumen.

Security

Contraindications

• Absolute: Anuria refractory to the drug; coma or hepatic encephalopathy induced by electrolyte imbalance; severe hypovolemia or extreme dehydration; uncorrected severe hypokalemia or hyponatremia; hypersensitivity to sulfonamides (potential cross-reaction).

Adverse Effects (ADR)

• Very common: Hypokalemia, hypochloremic metabolic alkalosis, hyponatremia, substantial hypomagnesemia, extracellular volume depletion.
• Common: Hyperuricemia (due to competition in acid secretion by OAT transporters and compensatory increase in proximal urate reabsorption mediated by URAT1), acute gout, orthostatism.
• Serious / Specific: Ototoxicity reversible or irreversible (due to blockage of NKCC1 in the stria vascularis of the cochlea, altering the endolymph; risk enhanced when combining aminoglycosides or rapid IV infusion greater than 4 mg/min).

Interactions

• NSAIDs (such as Ibuprofen, Ketorolac): They block the synthesis of intrarenal prostaglandins (PGE₂), which are necessary to sustain the vasodilation and spinal perfusion induced by loop diuretics, reducing the natriuretic response.
• Cardiac Glycosides (Digoxin): Induced hypokalemia and hypomagnesemia dramatically increase the risk of fatal arrhythmias from digoxin.
• Lithium: Volume depletion stimulates the avid reabsorption of sodium (and concomitantly lithium) in the TCP, leading to lithium intoxication.

Pregnancy and Breastfeeding

Category C. Crosses the placenta freely. It can cause reduction in uteroplacental blood flow due to maternal hypovolemia, inducing fetal growth restriction. It is secreted in breast milk and can suppress lactation due to volume depletion.