Ethacrynic Acid (Monograph)

Brand names: Edecrin, Sodium Edecrin
Drug class: Loop Diuretics
- Diuretics, Loop
VA class: CV702

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

A loop-type diuretic¹²⁹ and antihypertensive agent.^b

Uses for Ethacrynic Acid

Edema

Management of edema associated with heart failure, hepatic cirrhosis, and renal disease (e.g., nephrotic syndrome).¹²⁹

Considered a diuretic of choice for most patients with heart failure.⁵²⁴

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.^{524 700 713}

Short-term management of ascites associated with malignancy, idiopathic edema, or lymphedema.¹²⁹

Short-term management of hospitalized pediatric patients, other than infants, with congenital heart disease or nephrotic syndrome.¹²⁹ (See Pediatric Use under Cautions.)

IV ethacrynate sodium is used when rapid onset of diuresis is needed (e.g., acute pulmonary edema).¹²⁹

Hypertension

Has been used in the management of hypertension^{† [off-label]}.^b However, not a recommended agent in current hypertension management guidelines.^{501 502 503 504 1200}

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.^{103 104 130}

IV ethacrynate sodium has been used as an adjunct to hypotensive agents in the management of hypertensive crisis^{† [off-label]}, especially when accompanied by pulmonary edema.^b

Hypercalcemia

IV ethacrynate sodium has been used in the management of hypercalcemia^{† [off-label]}, alone or with sodium chloride 0.9% injection.^b

Ethylene Glycol or Bromide Poisoning

Has been used with mannitol in the management of ethylene glycol poisoning^{† [off-label]}.^b

Management of bromide intoxication^{† [off-label]}.^b

Diabetes Insipidus

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

Ethacrynic Acid Dosage and Administration

General

Edema

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

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

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

• 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.⁵²⁴

Administration

Administer ethacrynic acid orally. ^{129 b} Administer ethacrynate sodium by IV infusion or slow IV injection.^{129 b} Do not administer ethacrynate sodium sub-Q or IM because of local pain and irritation.^{129 b}

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).^{129 b}

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.^{129 b}

Do not use if solution is hazy or opalescent, which may occur if reconstituted with 5% dextrose injection having a pH <5. ¹²⁹

Rate of Administration

Infuse slowly over 20–30 minutes through the tubing of a running IV infusion^b or by direct IV injection over several minutes.^{129 b}

Dosage

Available as ethacrynic acid and ethacrynate sodium; dosage expressed in terms of ethacrynic acid.^{129 b}

Select dosage carefully to prevent a more rapid or substantial loss of fluid or electrolyte than is indicated or necessary.¹²⁹ (See Electrolyte, Fluid, and Renal Effects under Cautions.)

Weigh patients under standard conditions before initiating and during diuretic therapy.¹²⁹

Adjust dosage according to patient’s requirements and response.^b In adults, use smallest dosage required to produce gradual weight loss of 0.45–0.9 kg (1–2 pounds) daily.¹²⁹

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

Pediatric Patients

Edema

Oral

Hospitalized pediatric patients excluding infants: Initially 25 mg.¹²⁹ Increase with caution in 25-mg increments daily until desired effect is achieved.¹²⁹ Once desired response is obtained, may reduce dosage to the minimum required for maintenance.^b (See Pediatric Use under Cautions.)

Hypertension†

IV†

Although manufacturer does not recommend IV use in pediatric patients,^{129 b} some clinicians consider 1-mg/kg doses safe and effective in such patients.^b

Adults

Edema

Oral

Day 1: 50 mg after a meal¹²⁹ (preferably in the morning).^b

Day 2: 50 mg twice daily after meals, if needed.¹²⁹

Day 3: 100 mg in the morning and 50–100 mg after the noon or evening meal, depending on response to the morning dose.^{129 b}

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

Adjust dosage gradually in increments of 25–50 mg daily to avoid alterations in electrolyte and water excretion.^{129 b} Some patients (usually those with severe, refractory edema) may require up to 200 mg twice daily.¹²⁹

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

For maintenance therapy, use smallest effective dose once or twice daily.^b May reduce frequency of administration after effective diuresis (dry weight) is achieved (usually with doses of 50–100 mg);¹²⁹ may administer drug intermittently (e.g., on alternate days or less frequently).^{129 b}

IV

Average size adults: 50 mg or 0.5–1 mg/kg; single IV doses should not exceed 100 mg. ¹²⁹ Usually only one dose is necessary; if a second dose is needed, use a new injection site to avoid possible thrombophlebitis. ¹²⁹

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;^{101 102 103 104} however, other antihypertensive agents are preferred.^{501 502 503 504 1200} (See Hypertension under Uses.)

Prescribing Limits

Adults

Edema

Oral

Maximum 200 mg twice daily.¹²⁹

IV

Maximum 100 mg per dose. ^b

Special Populations

Hepatic Impairment

Initiate therapy in a hospital in cirrhotic patients with ascites. ¹²⁹

Geriatric Patients

Select dosage with caution because of age-related decreases in renal function.¹²⁹

Cautions for Ethacrynic Acid

Contraindications

• Anuria, hypotension, dehydration with low serum sodium concentrations, or metabolic alkalosis with hypokalemia.^{129 b}

• Increasing azotemia and/or oliguria, electrolyte imbalance, or severe, watery diarrhea that occurs during use.^{129 b}

• Known hypersensitivity to ethacrynic acid or any ingredient in the formulation.^{129 b}

• Use in infants.¹²⁹

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,^b those with secondary hyperaldosteronism (associated with cirrhosis and nephrosis),^b or use of digoxin.^b 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.^{129 b}

Fatal arrhythmias associated with hypokalemia reported in patients with severe myocardial disease receiving digitalis.¹²⁹ 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.^b To reduce or prevent potassium depletion, administer drug intermittently and/or give potassium-rich foods or a potassium-sparing diuretic.^b Potassium supplements may be necessary in patients whose serum potassium concentration is less than approximately 3 mEq/L or those receiving digitalis glycosides.^b

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.^{129 b}

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

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

If excessive diuresis occurs, discontinue the drug until homeostasis is restored.¹²⁹

If excessive electrolyte depletion occurs, reduce dosage or withdraw drug temporarily.¹²⁹

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.^{129 b} Correct electrolyte abnormalities as appropriate.^{129 b}

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).^b

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.¹²⁹ (See Specific Drugs under Interactions.)

Sensitivity Reactions

Rash has been reported. ¹²⁹

General Precautions

Metabolic Effects

Hyperglycemia and alterations in glucose tolerance reported.¹²⁹

Specific Populations

Pregnancy

Category B.¹²⁹

Lactation

Not known whether ethacrynic acid is distributed into milk.^{129 b} Discontinue nursing or the drug.^{129 b}

Pediatric Use

Safety and efficacy not established in infants; do not administer to infants until further accumulation of data.^{129 109} (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.^{109 129}

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

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out. ¹²⁹ Other reported clinical experience has not identified differences in responses between geriatric and younger patients.¹²⁹

Assess renal function periodically, since ethacrynic acid is substantially eliminated by kidneys and geriatric patients are more likely to have decreased renal function.¹²⁹ Select dosage with caution.¹²⁹

Hepatic Impairment

Manufacturer recommends initiating therapy in a hospital in cirrhotic patients with ascites.¹²⁹

Administer with caution in patients with advanced cirrhosis, especially those with a history of previous episodes of electrolyte imbalance or hepatic encephalopathy.¹²⁹

In patients with hepatic cirrhosis, rapid alterations in fluid and electrolyte balance may precipitate hepatic pre-coma or coma.¹²⁹ 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.¹²⁹

Potassium depletion possible; consider supplemental potassium and/or potassium-sparing agents in cirrhotic patients.¹²⁹

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.^{129 b}

Potassium depletion possible; consider supplemental potassium and/or potassium-sparing agents in nephrotic patients. ¹²⁹

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. ¹²⁹

Drug Interactions

Specific Drugs

Ethacrynic Acid Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from the GI tract.^b

Onset

Following oral administration, diuretic effect occurs within 30 minutes and peaks in about 2 hours.^{129 b}

Following IV administration of ethacrynate sodium, diuresis usually occurs within 5 minutes and reaches a maximum within 15–30 minutes.^{129 b}

Duration

Diuretic effect persists 6–8 hours (up to 12 hours) following oral administration, and about 2 hours following IV administration of ethacrynate sodium.^{129 b}

Distribution

Extent

In animals, substantial amounts accumulate only in the liver.^b

Does not enter the CSF.^{129 b}

Not known whether ethacrynic acid crosses the placenta^b or is distributed into human milk.^{129 b}

Elimination

Metabolism

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

Elimination Route

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

Rate of urinary excretion increases as urinary pH increases. ^b

Stability

Storage

Oral

Tablets

Tight containers at 25°C (may be exposed to 15–30°C).^{120 129}

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).^{120 129}

Use reconstituted solutions within 24 hours of preparation.^{129 b}

Reconstituted solutions stable for short periods of time at pH 7 at room temperature; less stable as pH and/or temperature increase.^b Some 5% dextrose solutions have pH <5, which may result in a hazy or opalescent solution that should not be used.¹²⁹

Compatibility

Parenteral

Solution Compatibilityb

Drug CompatibilityHID

Actions

• Loop diuretic with rapid onset of action.^{129 b}

• 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.^b

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

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

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

• Initially, sodium and chloride excretion is substantial, and chloride loss exceeds that of sodium.¹²⁹

• With prolonged administration, sodium and chloride excretion declines, and excretion of potassium and hydrogen may increase.^{129 b} 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.^b

• 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.¹²⁹

• A hypotensive effect may result from decreased plasma volume.^b

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).^{129 b}

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

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

• Importance of immediately reporting severe diarrhea.^b

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.¹²⁹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹²⁹

• Importance of informing patients of other important precautionary information.¹²⁹ (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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