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Ethacrynic Acid

Class: Loop Diuretics
- Diuretics, Loop
VA Class: CV702
CAS Number: 58-54-8
Brands: Edecrin, Sodium Edecrin

Medically reviewed by Drugs.com on March 8, 2021. Written by ASHP.

Warning

  • Ethacrynic acid is a potent diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion. (See Electrolyte, Fluid, and Renal Effects under Cautions.)

  • Careful medical supervision is required; dosage selection and titration should be adjusted to the individual patient’s needs. (See Dosage and Administration.)

Introduction

A loop-type diuretic and antihypertensive agent.

Uses for Ethacrynic Acid

Edema

Management of edema associated with heart failure, hepatic cirrhosis, and renal disease (e.g., nephrotic syndrome).

Considered a diuretic of choice for most patients with heart failure.

Most experts state that all patients with symptomatic heart failure who have evidence for, or a history of, fluid retention generally should receive diuretic therapy in conjunction with moderate sodium restriction, an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., ACE inhibitor, angiotensin II receptor antagonist, angiotensin receptor-neprilysin inhibitor [ARNI]), a β-adrenergic blocking agent (β-blocker), and in selected patients, an aldosterone antagonist.

Short-term management of ascites associated with malignancy, idiopathic edema, or lymphedema.

Short-term management of hospitalized pediatric patients, other than infants, with congenital heart disease or nephrotic syndrome. (See Pediatric Use under Cautions.)

IV ethacrynate sodium is used when rapid onset of diuresis is needed (e.g., acute pulmonary edema).

Hypertension

Has been used in the management of hypertension. However, not a recommended agent in current hypertension management guidelines.

May still be considered when diuretic therapy is indicated in patients hypersensitive to sulfonamides (e.g., other loop diuretics, thiazides) because ethacrynic acid is not a sulfonamide.

IV ethacrynate sodium has been used as an adjunct to hypotensive agents in the management of hypertensive crisis, especially when accompanied by pulmonary edema.

Hypercalcemia

IV ethacrynate sodium has been used in the management of hypercalcemia, alone or with sodium chloride 0.9% injection.

Ethylene Glycol or Bromide Poisoning

Has been used with mannitol in the management of ethylene glycol poisoning.

Management of bromide intoxication.

Diabetes Insipidus

Treatment of nephrogenic diabetes insipidus that is refractory to vasopressin or chlorpropamide.

Ethacrynic Acid Dosage and Administration

General

Edema

  • Careful etiologic diagnosis should precede the use of any diuretic.

  • Hospitalization of the patient during initiation of therapy is advisable, especially for patients with hepatic cirrhosis and ascites or chronic renal failure.

  • In prolonged diuretic therapy, intermittent use of the drug (e.g., on 2-4 consecutive days each week) may be advisable.

  • For the management of fluid retention associated with heart failure (e.g., edema), experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.

Administration

Administer ethacrynic acid orally. Administer ethacrynate sodium by IV infusion or slow IV injection. Do not administer ethacrynate sodium sub-Q or IM because of local pain and irritation.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Use IV administration when a rapid onset of diuresis is desired (e.g., acute pulmonary edema, impaired GI absorption, in patients unable to take the drug orally).

Reconstitution

Reconstitute vial containing ethacrynate sodium equivalent to 50 mg of ethacrynic acid with 50 mL of 5% dextrose injection or 0.9% sodium chloride injection to provide a solution containing 1 mg of ethacrynic acid per mL.

Do not use if solution is hazy or opalescent, which may occur if reconstituted with 5% dextrose injection having a pH <5.

Rate of Administration

Infuse slowly over 20–30 minutes through the tubing of a running IV infusion or by direct IV injection over several minutes.

Dosage

Available as ethacrynic acid and ethacrynate sodium; dosage expressed in terms of ethacrynic acid.

Select dosage carefully to prevent a more rapid or substantial loss of fluid or electrolyte than is indicated or necessary. (See Electrolyte, Fluid, and Renal Effects under Cautions.)

Weigh patients under standard conditions before initiating and during diuretic therapy.

Adjust dosage according to patient’s requirements and response. In adults, use smallest dosage required to produce gradual weight loss of 0.45–0.9 kg (1–2 pounds) daily.

Some clinicians suggest not to give the drug for more than 2 consecutive days until the patient’s responsiveness is known.

Pediatric Patients

Edema
Oral

Hospitalized pediatric patients excluding infants: Initially 25 mg. Increase with caution in 25-mg increments daily until desired effect is achieved. Once desired response is obtained, may reduce dosage to the minimum required for maintenance. (See Pediatric Use under Cautions.)

Hypertension†
IV†

Although manufacturer does not recommend IV use in pediatric patients, some clinicians consider 1-mg/kg doses safe and effective in such patients.

Adults

Edema
Oral

Day 1: 50 mg after a meal (preferably in the morning).

Day 2: 50 mg twice daily after meals, if needed.

Day 3: 100 mg in the morning and 50–100 mg after the noon or evening meal, depending on response to the morning dose.

Some clinicians recommend a dosage of 50 mg daily for several days and then increasing dosage only if necessary.

Adjust dosage gradually in increments of 25–50 mg daily to avoid alterations in electrolyte and water excretion. Some patients (usually those with severe, refractory edema) may require up to 200 mg twice daily.

When added to existing diuretic regimen, initial dose should be 25 mg; increase in increments of 25 mg.

For maintenance therapy, use smallest effective dose once or twice daily. May reduce frequency of administration after effective diuresis (dry weight) is achieved (usually with doses of 50–100 mg); may administer drug intermittently (e.g., on alternate days or less frequently).

IV

Average size adults: 50 mg or 0.5–1 mg/kg; single IV doses should not exceed 100 mg. Usually only one dose is necessary; if a second dose is needed, use a new injection site to avoid possible thrombophlebitis.

Hypertension†
Oral

Initial dosage of 25 mg daily and usual maximum dosage of 100 mg daily (in 2 or 3 divided doses) have been recommended; however, other antihypertensive agents are preferred. (See Hypertension under Uses.)

Prescribing Limits

Adults

Edema
Oral

Maximum 200 mg twice daily.

IV

Maximum 100 mg per dose.

Special Populations

Hepatic Impairment

Initiate therapy in a hospital in cirrhotic patients with ascites.

Geriatric Patients

Select dosage with caution because of age-related decreases in renal function.

Cautions for Ethacrynic Acid

Contraindications

  • Anuria, hypotension, dehydration with low serum sodium concentrations, or metabolic alkalosis with hypokalemia.

  • Increasing azotemia and/or oliguria, electrolyte imbalance, or severe, watery diarrhea that occurs during use.

  • Known hypersensitivity to ethacrynic acid or any ingredient in the formulation.

  • Use in infants.

Warnings/Precautions

Warnings

Electrolyte, Fluid, and Renal Effects

Excessive diuresis may cause fluid and electrolyte (chloride, calcium, magnesium, sodium) depletion; these effects likely to occur with large doses of the drug, in patients on restricted salt intake, those with secondary hyperaldosteronism (associated with cirrhosis and nephrosis), or use of digoxin. Resultant hypovolemia may result in dehydration, blood volume reduction leading to circulatory collapse and thromboembolic episodes (e.g., cerebral vascular thrombosis, pulmonary emboli [may be fatal]), particularly in geriatric patients.

Fatal arrhythmias associated with hypokalemia reported in patients with severe myocardial disease receiving digitalis. Hypokalemia and hypochloremia may result in metabolic alkalosis, especially in patients with other losses of potassium and chloride resulting from vomiting, diarrhea, GI drainage, excessive sweating, paracentesis, or potassium-losing renal diseases. To reduce or prevent potassium depletion, administer drug intermittently and/or give potassium-rich foods or a potassium-sparing diuretic. Potassium supplements may be necessary in patients whose serum potassium concentration is less than approximately 3 mEq/L or those receiving digitalis glycosides.

Risk of orthostatic hypotension or acute hypotensive episodes, especially with brisk diuresis (evidenced by rapid and excessive weight loss) or in patients receiving other antihypertensive agents; monitor BP closely.

Rapid or excessive diuresis may cause an abrupt fall in GFR and renal blood flow.

Transient rise in BUN may occur, especially in patients with chronic renal disease; usually reversible upon discontinuance.

If excessive diuresis occurs, discontinue the drug until homeostasis is restored.

If excessive electrolyte depletion occurs, reduce dosage or withdraw drug temporarily.

Adequate Patient Evaluation and Monitoring

Monitor serum electrolytes, BUN, and CO2 early in therapy and periodically thereafter; discontinue or reduce dosage if excessive diuresis and/or electrolyte abnormalities occur. Correct electrolyte abnormalities as appropriate.

Observe carefully for manifestations of fluid and electrolyte depletion (e.g., thirst, weakness, lethargy, dizziness, faintness, mental confusion, lassitude, restlessness, muscle pains or cramps, muscular fatigue, headache, paresthesia, anorexia, hypotension, oliguria, arrhythmia, nausea, vomiting).

Ototoxicity

Tinnitus, vertigo with a sense of fullness in the ears, and temporary (lasting 1–24 hours) or permanent deafness have occurred, usually after IV administration in patients with severe renal impairment or in those concomitantly receiving ototoxic drugs or in those who received ethacrynic acid or ethacrynate sodium doses larger than those recommended. (See Specific Drugs under Interactions.)

Sensitivity Reactions

Rash has been reported.

General Precautions

Metabolic Effects

Hyperglycemia and alterations in glucose tolerance reported.

Specific Populations

Pregnancy

Category B.

Lactation

Not known whether ethacrynic acid is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in infants; do not administer to infants until further accumulation of data. (See Contraindications under Cautions.)

The manufacturer states that dosage recommendations for short-term management of hospitalized pediatric patients (excluding infants) with edema associated with congenital heart disease or nephrotic syndrome are empiric, since no well-controlled studies have been published.

Safety and efficacy of ethacrynate sodium in pediatric patients not established.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out. Other reported clinical experience has not identified differences in responses between geriatric and younger patients.

Assess renal function periodically, since ethacrynic acid is substantially eliminated by kidneys and geriatric patients are more likely to have decreased renal function. Select dosage with caution.

Hepatic Impairment

Manufacturer recommends initiating therapy in a hospital in cirrhotic patients with ascites.

Administer with caution in patients with advanced cirrhosis, especially those with a history of previous episodes of electrolyte imbalance or hepatic encephalopathy.

In patients with hepatic cirrhosis, rapid alterations in fluid and electrolyte balance may precipitate hepatic pre-coma or coma. Deaths have occurred in patients with severely decompensated hepatic cirrhosis with ascites, with or without encephalopathy as a result of intensification of preexisting electrolyte imbalance.

Potassium depletion possible; consider supplemental potassium and/or potassium-sparing agents in cirrhotic patients.

Renal Impairment

When used in the treatment of renal edema, hypoproteinemia may reduce responsiveness to ethacrynic acid and the use of albumin human should be considered.

Potassium depletion possible; consider supplemental potassium and/or potassium-sparing agents in nephrotic patients.

Common Adverse Effects

Anorexia, malaise, abdominal pain/discomfort, dysphagia, nausea, vomiting, diarrhea, reversible hyperuricemia, hyperglycemia, acute gout, deafness, tinnitus, vertigo, headache, fatigue, apprehension, confusion, rash, fever, chills, hematuria; local irritation and pain has been occasionally reported after IV use.

Interactions for Ethacrynic Acid

Specific Drugs

Drug

Interaction

Comments

Alcohol

May augment effects of alcohol

Antidiabetic agents (e.g., insulin, oral agents)

Possible antagonism of hypoglycemic effect as result of hypokalemia

Observe for possible decreased diabetic control; correct potassium deficit and/or adjust dosage of antidiabetic agent

Antihypertensive agents

Additive antihypertensive effect; orthostatic hypotension may occur

Reduce dosage of both drugs

Carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, methazolamide)

May potentiate action of carbonic anhydrase inhibitors; augmentation of natriuresis and kaliuresis

Cautiously dose ethacrynic acid

Cardiac glycosides (e.g., digoxin)

Possible electrolyte disturbances (e.g., hypokalemia, hypomagnesemia), increased risk of cardiac glycoside toxicity and/or fatal cardiac arrhythmias

Periodically monitor electrolytes; correct hypokalemia

Corticosteroids

Possible increased risk of gastric hemorrhage associated with corticosteroids

(See also Drugs that Cause Potassium Loss)

Diuretics

Enhanced therapeutic effect

Reduce ethacrynic acid dosage when it is added to an existing diuretic regimen

Diuretics, loop (e.g., bumetanide, furosemide, torsemide)

Share similar mechanisms of action

No therapeutic rationale for concomitant use

Diuretics, potassium-sparing (e.g., amiloride, spironolactone, triamterene)

Possible reduction in potassium loss

May be used for therapeutic advantage

Diuretics, thiazides

Additive diuretic effect

Use reduced dosage of ethacrynic acid when added to existing diuretic regimen

Drugs that cause potassium loss (e.g., corticosteroids, corticotropin, amphotericin B)

Additive hypokalemic effects

Monitor electrolytes; correct hypokalemia

Lithium

Reduced renal clearance of lithium and increased risk of lithium toxicity

Avoid concomitant use; if concomitant therapy is necessary, hospitalize patient and monitor for lithium toxicity

Neuromuscular blocking agents, nondepolarizing (e.g., tubocurarine chloride)

Potential for prolonged neuromuscular blockade, associated with potassium depletion

NSAIAs

Possible decreased diuretic, natriuretic, and antihypertensive effects

Increased risk of developing renal failure associated with decreased renal blood flow, resulting from prostaglandin inhibition by NSAIAs

Monitor closely for desired diuretic effect

Ototoxic drugs (e.g., aminoglycosides, some cephalosporins)

Possible additive ototoxic effect (transient or permanent deafness), especially with IV ethacrynate sodium

Avoid concomitant use

Uricosuric drugs (probenecid, sulfinpyrazone)

Urinary excretion and efficacy of ethacrynic acid may decrease.

Possible antagonism of uricosuric effects

Monitor serum uric acid concentrations; dosage of uricosuric agents may need to be increased

Warfarin

Possible potentiation of anticoagulant effect (because of displacement of warfarin from protein-binding sites)

Monitor INR closely; consider reducing warfarin dose

Ethacrynic Acid Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from the GI tract.

Onset

Following oral administration, diuretic effect occurs within 30 minutes and peaks in about 2 hours.

Following IV administration of ethacrynate sodium, diuresis usually occurs within 5 minutes and reaches a maximum within 15–30 minutes.

Duration

Diuretic effect persists 6–8 hours (up to 12 hours) following oral administration, and about 2 hours following IV administration of ethacrynate sodium.

Distribution

Extent

In animals, substantial amounts accumulate only in the liver.

Does not enter the CSF.

Not known whether ethacrynic acid crosses the placenta or is distributed into human milk.

Elimination

Metabolism

Metabolized to a cysteine conjugate (which may contribute to the pharmacologic effects of the drug) and to an unstable, unidentified compound.

Elimination Route

IV Ethacrynate sodium: Excreted in urine (about 30–65%) and in bile (about 35–40%); partially as the cysteine conjugate.

Rate of urinary excretion increases as urinary pH increases.

Stability

Storage

Oral

Tablets

Tight containers at 25°C (may be exposed to 15–30°C).

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).

Use reconstituted solutions within 24 hours of preparation.

Reconstituted solutions stable for short periods of time at pH 7 at room temperature; less stable as pH and/or temperature increase. Some 5% dextrose solutions have pH <5, which may result in a hazy or opalescent solution that should not be used.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibilityb

Compatible

Dextrose 5% in water

Dextrose 5% in sodium chloride 0.9%

Ringer’s injection

Ringer’s injection, lactated

Sodium chloride 0.9%

Incompatible

Normosol-M

Drug CompatibilityHID
Admixture Compatibility

Compatible

Chlorpromazine HCl

Prochlorperazine edisylate

Incompatible

Hydralazine HCl

Procainamide HCl

Ranitidine HCl

Y-Site Compatibility

Compatible

Heparin sodium with hydrocortisone sodium succinate

Potassium chloride

Incompatible

Nesiritide

Actions

  • Loop diuretic with rapid onset of action.

  • In vitro, inhibits active transport of chloride in the lumen of the ascending limb of the loop of Henle and thereby, diminishes reabsorption of sodium and chloride at that site.

  • Increases potassium excretion in the distal renal tubule, and exerts a direct effect on electrolyte transport at the proximal tubule.

  • Does not inhibit carbonic anhydrase and is not an aldosterone antagonist. Aldosterone secretion may increase during therapy and may contribute to hypokalemia.

  • Enhances excretion of sodium, chloride, potassium, hydrogen, calcium, and magnesium.

  • Initially, sodium and chloride excretion is substantial, and chloride loss exceeds that of sodium.

  • With prolonged administration, sodium and chloride excretion declines, and excretion of potassium and hydrogen may increase. Excessive losses of potassium, hydrogen, and chloride may result in metabolic alkalosis.

  • Maximum diuresis and electrolyte loss are greater with ethacrynic acid than with the thiazides or most other diuretics except furosemide.

  • Has little or no direct effect on GFR or renal blood flow; however, a fall in GFR may accompany pronounced reductions in plasma volume associated with rapid or excessive diuresis.

  • A hypotensive effect may result from decreased plasma volume.

Advice to Patients

  • Importance of reporting manifestations of fluid and electrolyte depletion (e.g., dryness of mouth, thirst, weakness, dizziness, faintness, mental confusion, lassitude, lethargy, drowsiness, restlessness, muscle pains or cramps, paresthesia, muscular fatigue, hypotension, headache, oliguria, tachycardia, arrhythmia, anorexia, nausea, vomiting).

  • Importance of discussing dietary measures and supplementation to prevent or correct hypokalemia.

  • Importance of informing patients with diabetes mellitus that blood glucose and urine glucose concentrations may increase.

  • Importance of immediately reporting severe diarrhea.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ethacrynic Acid

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

25 mg

Edecrin (scored)

Aton Pharma

Ethacrynate Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use only

equivalent to ethacrynic acid 50 mg

Sodium Edecrin

Aton Pharma

AHFS DI Essentials™. © Copyright 2021, Selected Revisions March 18, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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