Ethacrynic Acid

Mechanism

Pharmacological Group

Loop diuretic derived from phenoxyacetic acid.

Mechanism of Action

It reversibly and potently blocks the apical transporter NKCC2 in the Thick Ascending Branch of Henle. Unlike the other loop options (furosemide, torasemide, bumetanide), it does not contain a sulfur atom in its structure (it is not a sulfonamide). It reacts with intracellular and membrane sulfhydryl groups of RAG, modulating ion transport enzymes.

Pharmacokinetics

Key Pharmacokinetics

• Administration: Oral, Intravenous (IV).
• Bioavailability: 100% orally. Its absorption is rapid.
• Metabolism: Partially metabolized through conjugation with glutathione (active ethacrynic acid-cysteine adduct, which is a highly effective NKCC2 inhibitor).
• Excretion: 60% by active renal secretion; 40% excreted via bile.
• Half-life: 2 to 4 hours.

Indicators and dose

Clinical Indications

• Patients with documented severe allergy to sulfonamides: It is the only alternative high-potency loop diuretic for patients who develop anaphylaxis, interstitial nephritis, or severe sulfa-induced rashes.
• Management of severe refractory edema of cardiac or renal origin.

Dosage and Settings

• Oral: Start with 50 mg once daily, with a usual therapeutic range of 50 mg to 200 mg daily.
• IV: 0.5 mg to 1 mg/kg per dose (slow bolus administered over not less than 5 to 10 minutes).
• Renal adjustment: Avoid use at CrCl < 30 mL/min unless the benefits far outweigh the potential risk of irreversible ototoxicity due to accumulation of free drug in plasma.

Security

Severe Ototoxicity Alert

Ethacrynic acid has the highest potential for ototoxicity (both reversible and permanent) of all commercially available loop diuretics. Its affinity for inner ear cellular transporters and its interference with electrolyte homeostasis in the stria vascularis of the cochlea is markedly high. It should be strictly reserved for patients with proven allergy to sulfonamides and its coadministration with other ototoxic agents should be avoided (such as aminoglycosides, vancomycin or cisplatin).

Contraindications

• Anuria; uncompensated hypovolemia; history of diuretic-induced ototoxicity; concomitant use with aminoglycosides; breastfeeding.

Adverse Effects (ADR)

• Very common: Severe hypokalemia, marked metabolic alkalosis, dehydration, orthostatic hypotension.
• Common: Severe watery diarrhea (specific effect induced in the intestinal mucosa by the phenoxyacetic group; requires permanent suspension if it occurs continuously).
• Serious: Sudden sensorineural deafness, tinnitus, transient neutropenia.

Interactions

Extreme potentiation of aminoglycoside toxicity. Pharmacodynamic antagonism with NSAIDs.

Pregnancy and Breastfeeding

Category C. There are no adequate clinical studies in pregnant women. Contraindicated in breastfeeding due to the risk of milk excretion and affectation of the infant.