AHFS Class:

• Loop Diuretics 40:28.08

Generic Name(s):

• Ethacrynic Acid

• Ethacrynate Sodium

Ethacrynic acid is a loop diuretic and antihypertensive agent.

Edema

Ethacrynic acid is used in the management of edema associated with heart failure, nephrotic syndrome, and hepatic cirrhosis. IV ethacrynate sodium may be used as an adjunct in the treatment of acute pulmonary edema.

Careful etiologic diagnosis should precede the use of any diuretic. Because the potent diuretic effect of ethacrynic acid may result in severe electrolyte imbalance and excessive fluid loss, 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 for only a few days each week may be advisable. Ethacrynic acid may be administered cautiously for additive effect with most other diuretics; however, since ethacrynic acid and other loop diuretics (e.g., furosemide) act in a similar manner, there is no rationale for using these drugs together.

Heart Failure

Ethacrynic acid is used in the management of edema associated 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., angiotensin-converting enzyme [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 Some experts state that because of limited and inconsistent data, it is difficult to make precise recommendations regarding daily sodium intake and whether it should vary with respect to the type of heart failure (e.g., reduced versus preserved ejection fraction), disease severity (e.g., New York Heart Association [NYHA] class), heart failure-related comorbidities (e.g., renal dysfunction), or other patient characteristics (e.g., age, race).524,723,724 The American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) state that limiting sodium intake to 1.5 g daily in patients with ACCF/AHA stage A or B heart failure may be reasonable.524 While data currently are lacking to support recommendation of a specific level of sodium intake in patients with ACCF/AHA stage C or D heart failure, ACCF and AHA state that limiting sodium intake to some degree (e.g., less than 3 g daily) in such patients may be considered for symptom improvement.524

Diuretics play a key role in the management of heart failure because they produce symptomatic benefits more rapidly than any other drugs, relieving pulmonary and peripheral edema within hours or days compared with weeks or months for cardiac glycosides, ACE inhibitors, or β-blockers.108 However, since there are no long-term studies of diuretic therapy in patients with heart failure, the effects of diuretics on morbidity and mortality in such patients are not known.524 Although there are patients with heart failure who do not exhibit fluid retention in the absence of diuretic therapy and even may develop severe volume depletion with low doses of diuretics, such patients are rare and the unique pathophysiologic mechanisms regulating their fluid and electrolyte balance have not been elucidated.108

Diuretics increase urinary sodium excretion and decrease physical signs of fluid retention in patients with heart failure.524 Results of short-term studies in patients with heart failure indicate that diuretic therapy is associated with a reduction in jugular venous pressures, pulmonary congestion, ascites, peripheral edema, and body weight within a few days of initiating such therapy.108,113,114 In addition, diuretics may improve cardiac function, symptoms, and exercise tolerance in these patients.112,115,116,524 However, since there are no long-term studies of diuretic therapy in patients with heart failure, the effects of diuretics on morbidity and mortality are not known.524 Nevertheless, most long-term studies of therapeutic interventions for heart failure have been in patients receiving diuretic therapy.108 Diuretics should not be used as monotherapy in patients with heart failure even if symptoms of heart failure (e.g., peripheral edema, pulmonary congestion) are well controlled, because diuretics alone do not prevent progression of heart failure.108,111,524

Depending on the dosage employed, diuretics may alter the efficacy and safety of concomitantly used drugs in heart failure, and therefore diuretic dosage should be selected carefully.108 Excessive diuretic dosages may lead to volume depletion, which can increase the risk of hypotension in patients receiving ACE inhibitors or vasodilators and renal insufficiency in patients receiving ACE inhibitors or angiotensin II receptor antagonists.108 Inadequate diuretic dosages may lead to fluid retention, which can decrease the response to ACE inhibitors and increase the risk of β-blocker therapy.108 Patients with mild heart failure may respond favorably to low doses of diuretics, since absorption of diuretics from the GI tract is rapid and the drugs are distributed rapidly to the renal tubules in such patients; however, as heart failure advances, absorption of the drugs may be delayed because of bowel edema or intestinal hypoperfusion, and distribution may be impaired because of decreases in renal perfusion and function.108 Therefore, dosage of diuretics usually needs to be increased with progression of heart failure; eventually, patients may become resistant to even high dosages of diuretics.524 If resistance to diuretics occurs, IV administration of a diuretic or concomitant use of 2 or more diuretics (e.g., a loop diuretic and metolazone, a loop diuretic and a thiazide diuretic) may be necessary; alternatively, short-term administration of a drug that increases blood flow (e.g., a positive inotropic agent such as dopamine) may be necessary.524 ACCF and AHA state that IV loop diuretics should be administered promptly to all hospitalized heart failure patients with substantial fluid overload to reduce morbidity.524 In addition, ACCF and AHA state that low-dose dopamine infusions may be considered in combination with loop diuretics to augment diuresis and preserve renal function and renal blood flow in patients with acute decompensated heart failure, although data are conflicting and additional study and experience are needed.524,714,715,716,717,718,719,720

Most experts state that loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, torsemide) are the diuretics of choice for most patients with heart failure,524 especially those with renal impairment or substantial fluid retention, since loop diuretics increase sodium excretion to 20-25% of the filtered load of sodium, enhance free water clearance, and maintain their efficacy unless renal function is severely impaired (e.g., creatinine clearance less than 5 mL/minute).108 In contrast, thiazide diuretics increase fractional sodium excretion to only 5-10% of the filtered load, tend to decrease free water clearance, and lose their efficacy in patients with moderate renal impairment (e.g., creatinine clearance less than 30 mL/minute).108 However, thiazides may be preferred in some patients with concomitant hypertension because of their sustained antihypertensive effects.524 In patients who develop azotemia or hypotension before therapeutic goals are achieved, consideration to decreasing the rate of diuresis may be made, but diuretic therapy should continue until fluid retention is eliminated, provided that decreases in blood pressure remain asymptomatic; excessive concern about hypotension and azotemia may result in suboptimal diuretic therapy leading to refractory edema.108

Once fluid retention has resolved in patients with heart failure, diuretic therapy should be maintained to prevent recurrence of fluid retention.524 Ideally, diuretic therapy should be adjusted according to changes in body weight (as an indicator of fluid retention) rather than maintained at a fixed dosage.524

Pulmonary Disease

Ethacrynate sodium may be administered IV as an adjunct in the treatment of acute pulmonary edema; however, the drug should be used cautiously when acute pulmonary edema is a complication of cardiogenic shock associated with acute myocardial infarction because diuretic-induced hypovolemia may reduce cardiac output.

Renal Disease

Ethacrynic acid also may be used cautiously in the management of edema associated with the nephrotic syndrome and in patients with hepatic cirrhosis, but such edema is frequently refractory to treatment. In patients with renal edema, hypoproteinemia may result in reduced responsiveness to ethacrynic acid and the administration of albumin human should be considered.

Other Conditions

Ethacrynic acid also is indicated for short-term management of ascites caused by malignancy, idiopathic edema, or lymphedema and for short-term management of hospitalized pediatric patients with congenital heart disease or nephrotic syndrome. When metabolic alkalosis may be anticipated, a potassium-rich diet, potassium supplements, or potassium-sparing diuretics may be necessary before and during ethacrynic acid therapy to mitigate or prevent hypokalemia in cirrhotic, nephrotic, or digitalized patients. (See Cautions: Electrolyte, Fluid, and Renal Effects.)

Hypertension

Ethacrynic acid has been used orally in the management of hypertension†. However, the drug is not recommended in current hypertension management guidelines for this use; because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics generally are considered the preferred drugs for the initial management of hypertension in adults.501,502,503,504,1200 When loop diuretics are indicated, other agents (e.g., furosemide, bumetanide, torsemide) generally are recommended.504,1200 (See Uses: Hypertension, in Furosemide 40:28.08.) However, ethacrynic acid may still be considered when diuretic therapy is indicated in patients hypersensitive to sulfonamides (e.g., other loop diuretics, thiazides) because of the drug's nonsulfonamide structure.103,130 Although some clinicians have reported good results with 200-400 mg of ethacrynic acid daily, the incidence of adverse GI effects was high and heart rate was increased substantially in some patients.

For further information on the role of diuretics in antihypertensive drug therapy and information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.

Hypertensive Crisis

IV ethacrynate sodium has been used as an adjunct to hypotensive agents in the management of hypertensive crises†, especially when accompanied by pulmonary edema. In addition to producing rapid diuresis, ethacrynic acid enhances the hypotensive effects of other drugs and counteracts the sodium retention caused by some of these agents.

Other Uses

Ethacrynic acid has been used IV alone or with 0.9% sodium chloride injection to increase renal excretion of calcium in patients with hypercalcemia†. The drug has also been used concomitantly with mannitol in the management of ethylene glycol poisoning† and to increase bromide excretion in the management of bromide intoxication†.

Ethacrynic acid has been used with success in the treatment of nephrogenic diabetes insipidus† that is not responsive to vasopressin or chlorpropamide.

Reconstitution and Administration

Ethacrynic acid is administered orally.129 Ethacrynate sodium is administered IV 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 Ethacrynate sodium should not be given subcutaneously or IM because of local pain and irritation .129

Ethacrynate sodium for IV injection is reconstituted by adding 50 mL of 5% dextrose injection or 0.9% sodium chloride injection to a vial labeled as containing ethacrynate sodium equivalent to 50 mg of ethacrynic acid.129 The resulting solution contains the equivalent of 1 mg of ethacrynic acid per mL.129 If the commercially available powder is reconstituted with 5% dextrose injection having a pH below 5, the resulting solution may be hazy or opalescent and should not be used.129 For IV administration, ethacrynate sodium solutions may be infused slowly through the tubing of a running IV infusion or by direct IV injection over a period of several minutes.129

Ethacrynate sodium injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.129

Dosage

Dosage of ethacrynate sodium is expressed in terms of ethacrynic acid.129 Dosage must be adjusted according to the patient's requirements and response.129 The smallest dose required to produce a gradual weight loss of 0.45-0.9 kg (1-2 pounds) daily should be used.129 Some clinicians have suggested that the drug not be given for more than 2 days consecutively until the patient's responsiveness is known. If ethacrynic acid is added to the regimen of a patient stabilized on a potent hypotensive agent, the dosage of the hypotensive agent may require reduction to avoid severe hypotension.

For the management of fluid retention (e.g., edema) associated with heart failure, 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

Edema

Oral Dosage

The usual initial adult oral dose of ethacrynic acid is 50 mg given as a single dose after a meal on the first day,129 preferably in the morning. On the second day, 50 mg may be administered twice daily after meals, if needed.129 On the third day, 100 mg may be administered in the morning and 50-100 mg may be administered after the noon or evening meal, depending on the response to the morning dose.129 Alternatively, some clinicians believe it is safer to administer 50 mg daily for several days, and then to increase the dosage only if necessary. Dosage adjustments usually are made gradually in increments of 25-50 mg daily to avoid alterations in electrolyte and water excretion.129 Some patients (usually those with severe, refractory edema) may require up to 200 mg twice daily.129 When ethacrynic acid is added to an existing diuretic regimen, the initial dose should be 25 mg and dosage should be increased in increments of 25 mg. For maintenance therapy, the smallest effective dose should be administered once or twice daily. The dosage and frequency of administration may be reduced after effective diuresis (dry weight) is achieved (usually with doses of 50-100 mg);129 the drug may then be administered intermittently (e.g., on alternate days, less frequently).129

For the management of congenital heart disease or nephrotic syndrome in hospitalized pediatric patients (excluding infants), the usual initial oral dose of ethacrynic acid is 25 mg.129 This dose may be increased cautiously in 25-mg increments daily until the desired effect is achieved.129 Once the desired response is obtained, dosage may be reduced to the minimum required for maintenance. Oral administration of the drug is not recommended by the manufacturer in infants†.129 (See Cautions: Precautions and Contraindications.)

IV Dosage

The usual adult IV dose of ethacrynic acid is 0.5-1 mg/kg or 50 mg for an adult of average size; single IV doses should not exceed 100 mg.129 Usually only one dose is necessary; if a second dose is needed, a new injection site should be selected in order to avoid possible thrombophlebitis.129

Hypertension

Oral Dosage

For the management of hypertension† in adults, an initial ethacrynic acid dosage of 25 mg daily and a usual maximum dosage of 100 mg daily (in 2 or 3 divided doses) have been used;101,102,103,104 however, other antihypertensive agents are preferred.501,502,503,504 (See Uses: Hypertension.)

For additional information on the management of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.

Pediatric Dosage

Although IV administration of ethacrynic acid in infants or children† is not recommended by the manufacturer (see Cautions: Precautions and Contraindications and see Cautions: Pediatric Precautions), some clinicians have reported doses of 1 mg/kg to be safe and effective. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Electrolyte, Fluid, and Renal Effects

Ethacrynic acid may produce profound diuresis resulting in fluid and electrolyte (chloride, calcium, magnesium, sodium) depletion.129 Fluid and electrolyte depletion are especially likely to occur when large doses are given and/or in patients on restricted salt intake.

Too vigorous diuresis, as evidenced by rapid and excessive weight loss, may induce orthostatic hypotension or acute hypotensive episodes, and the patient's blood pressure should be closely monitored. Excessive dehydration is most likely to occur in geriatric patients and/or patients with chronic cardiac disease treated with prolonged sodium restriction or those receiving sympatholytic agents. The resultant hypovolemia may result in hemoconcentration which could lead to circulatory collapse or thromboembolic episodes such as possibly fatal vascular thromboses and/or pulmonary emboli. Pronounced reductions in plasma volume associated with rapid or excessive diuresis may also result in an abrupt fall in glomerular filtration rate and renal blood flow, which may be restored by replacement of fluid loss. If excessive diuresis occurs, the drug should be discontinued until homeostasis is restored.129 If excessive electrolyte depletion occurs, dosage should be reduced or the drug should be temporarily withdrawn.129

Potassium depletion occurs frequently in patients with secondary hyperaldosteronism which may be associated with cirrhosis or nephrosis and is particularly important in cirrhotic, nephrotic, or digitalized patients. 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. In patients with cor pulmonale, alkalosis may cause compensatory respiratory depression. Intermittent administration of ethacrynic acid and/or ingestion of potassium-rich foods or administration of a potassium-sparing diuretic may reduce or prevent potassium depletion. However, potassium supplements may be necessary in patients whose serum potassium concentration is less than approximately 3 mEq/L or those receiving digitalis glycosides. To prevent hypokalemic and hypochloremic alkalosis, potassium chloride or potassium-sparing agents should be used.129 Ethacrynic acid increases calcium excretion and rarely tetany has been reported following vigorous diuresis. Magnesium depletion may also occur.

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.

Ethacrynic acid may cause a transient rise in BUN which is usually readily reversible upon withdrawal of the drug. Elevated BUN is especially likely to occur in patients with chronic renal disease. Reversible hyperuricemia has resulted from ethacrynic acid administration and gout has been precipitated; patients with a history of gout or elevated serum uric acid concentrations should be observed closely during therapy. However, IV administration of ethacrynate sodium or high doses of ethacrynic acid may cause temporary uricosuria.

GI Effects

Ethacrynic acid may cause adverse GI effects, including anorexia, abdominal discomfort or pain, nausea, vomiting, malaise, diarrhea, and dysphagia. Adverse GI effects occur most frequently when large doses are employed or after 1-3 months of continuous therapy and may necessitate discontinuing the drug.129 Severe, profuse, watery diarrhea may occur; the drug should be permanently discontinued if this occurs.129 GI bleeding has been reported, most frequently in patients receiving IV ethacrynate sodium therapy and especially in patients receiving heparin sodium concomitantly. Acute necrotizing pancreatitis, with an increase in serum amylase, has been reported.

Hematologic Effects

Thrombocytopenia, severe neutropenia, and agranulocytosis, sometimes resulting in fatalities, have been reported rarely in critically ill patients receiving ethacrynic acid with other drugs. Henoch-Schönlein purpura has occurred rarely in patients with rheumatic heart disease receiving ethacrynic acid and other drugs.

Nervous System Effects

Vertigo, tinnitus with a sense of fullness in the ears, and temporary (lasting 1-24 hours) or permanent deafness have occurred following use of ethacrynic acid. These effects are most likely to occur after IV administration of ethacrynate sodium in patients with severe impairment of renal function, in patients receiving other ototoxic drugs (See Drug Interactions: Other Drugs), or in those who received ethacrynic acid or ethacrynate sodium doses larger than those recommended.129 Headache, fatigue, apprehension, and mental confusion have also occurred in patients receiving ethacrynic acid.

Metabolic Effects

Rarely, ethacrynic acid has produced acute hypoglycemia with seizures in uremic patients who received doses larger than those recommended. The drug has also reduced fasting insulin concentrations, lessened the increase in insulin concentrations after glucose ingestion, and caused hyperglycemia and glycosuria, especially when daily doses of greater than 200 mg were administered to both diabetic and nondiabetic patients. Carbohydrate intolerance is especially likely to occur in patients with decompensated liver disease or potassium depletion.

Other Adverse Effects

Rarely, jaundice and hepatocellular damage, with elevated serum bilirubin, AST (SGOT), and ALT (SGPT) concentrations, have occurred in seriously ill patients receiving ethacrynic acid with other drugs. Other adverse effects associated with ethacrynic acid include rash, chills, fever, and hematuria. Reduced excretion of cortisol may also occur. Local irritation, pain, and thrombophlebitis may occur following IV injection of ethacrynate sodium.

Precautions and Contraindications

Patients receiving ethacrynic acid must be carefully observed for signs of hypovolemia, hyponatremia, hypokalemia, hypochloremia, hypocalcemia, and hypomagnesemia. Patients should be informed of the signs and symptoms of electrolyte imbalance and instructed to report to their physicians if weakness, dizziness, fatigue, faintness, mental confusion, lassitude, muscle cramps, headache, paresthesia, thirst, anorexia, nausea, and/or vomiting occur. Excessive fluid and electrolyte loss may be minimized by initiating therapy with small doses, careful dosage adjustment, using an intermittent dosage schedule if possible, and monitoring the patient's weight. To prevent hyponatremia and hypochloremia, intake of sodium may be liberalized in most patients; however, patients with cirrhosis usually require at least moderate sodium restriction while on diuretic therapy. Determinations of serum electrolytes, BUN, and carbon dioxide should be performed early in therapy with ethacrynic acid and periodically thereafter. If excessive diuresis and/or electrolyte abnormalities occur, the drug should be withdrawn or dosage reduced until homeostasis is restored. Electrolyte abnormalities should be corrected by appropriate measures.

Ethacrynic acid should be used with caution in patients with advanced hepatic cirrhosis, especially those with a history of electrolyte imbalance or hepatic encephalopathy. Since ethacrynic acid has caused serious adverse hematologic and hepatic effects, frequent leukocyte counts and liver function tests should be performed during prolonged therapy with the drug. Since ethacrynic acid may alter carbohydrate metabolism, the drug should be administered with caution in diabetic patients.

Ethacrynic acid is contraindicated in patients with anuria, hypotension, dehydration with low serum sodium concentrations, or metabolic alkalosis with hypokalemia. The drug is contraindicated for further use if increasing azotemia and/or oliguria, electrolyte imbalance, or severe, watery diarrhea occurs. Ethacrynic acid is also contraindicated in patients with known hypersensitivity to the drug or any of the ingredients in the formulations. The drug is contraindicated in infants.129

Pediatric Precautions

Pending further accumulation of data, ethacrynic acid and ethacrynate sodium should not be administered to infants since safety and efficacy of these preparations in infants have not been established.129 In addition, safety and efficacy of ethacrynate sodium in children have not been established. The manufacturer states that dosage recommendations for the 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.129 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Geriatric Precautions

No overall differences in efficacy or safety were observed between geriatric and younger adults, and other clinical experience has not revealed evidence of age-related differences in response; however, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out.129 The drug is substantially excreted by the kidney, and the risk of severe adverse reactions may be increased in patients with impaired renal function.129 Because geriatric patients may have decreased renal function, careful dosage selection and monitoring of renal function are advised.129

Carcinogenicity

No evidence of a carcinogenic effect was observed in rats receiving oral ethacrynic acid dosages up to 45 times the human dosage for 79 weeks.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in dogs and rats receiving oral ethacrynic acid dosages of 5 and 20 mg/kg daily (approximately 2.5 or 10 times the daily human dosage), respectively, did not reveal evidence of interference with pregnancy or with growth and development of the offspring. In rats receiving 100 mg/kg (50 times the human dose), mean fetal body weight was reduced, but no effects on mortality or postnatal development or functional or morphologic abnormalities were observed. Reproduction studies in mice and rabbits receiving ethacrynic acid at dosages up to 50 times the recommended human dosage have not revealed evidence of external abnormalities of the fetus.129 Safety and efficacy of ethacrynic acid in toxemia of pregnancy have not been established. Because there are no adequate and well-controlled studies to date using ethacrynic acid in pregnant women and animal studies are not always predictive of human response, the drug should be used during pregnancy only when clearly needed.129 Polyhydramnios (suggesting increased fetal urine production) and neonatal diuresis and nephrolithiasis occurred following chronic maternal ethacrynic acid therapy (50 mg twice daily orally) during pregnancy.100

Fertility

There was no effect on fertility in a 2-litter study in rats or a 2-generation study in mice receiving 10 times the human dose.129

Lactation

It is not known whether ethacrynic acid is distributed into milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions to ethacrynic acid in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.129

Diuretics

Concomitant administration of ethacrynic acid and most other diuretics results in enhanced effects, and ethacrynic acid should be administered in reduced dosage when the drug is added to an existing diuretic regimen. Spironolactone or triamterene may reduce the potassium loss caused by ethacrynic acid therapy; this effect has been used to therapeutic advantage.

Drugs Affected by or Causing Potassium Depletion

In patients receiving cardiac glycosides, electrolyte disturbances produced by ethacrynic acid (principally hypokalemia but also hypomagnesemia) predispose the patient to glycoside toxicity. Possibly fatal cardiac arrhythmias may result. Periodic electrolyte determinations should be performed in patients receiving a cardiac glycoside and ethacrynic acid, and correction of hypokalemia should be undertaken if warranted. (See Cautions: Electrolyte, Fluid, and Renal Effects.)

Ethacrynic acid reportedly causes prolonged neuromuscular blockade in patients receiving nondepolarizing neuromuscular blocking agents (e.g., tubocurarine chloride, gallamine triethiodide [no longer commercially available in the US]), presumably because of potassium depletion.

Some drugs such as corticosteroids, corticotropin, and amphotericin B also cause potassium loss, and severe potassium depletion may occur when one of these drugs is administered during ethacrynic acid therapy. Ethacrynic acid may increase the risk of gastric hemorrhage associated with corticosteroid treatment.129

Lithium

Renal clearance of lithium is apparently decreased in patients receiving diuretics, and lithium toxicity may result. Ethacrynic acid and lithium should generally not be given together. If concomitant therapy is necessary, the patient should be hospitalized. Serum lithium concentrations should be monitored carefully and dosage adjusted accordingly.

Antidiabetic Agents

Administration of ethacrynic acid to diabetic patients may interfere with the hypoglycemic effect of insulin or oral antidiabetic agents, possibly as a result of hypokalemia. Patients should be observed for possible decrease of diabetic control. If correction of the potassium deficit does not restore control, dosage adjustments of the antidiabetic agent may be needed.

Hypotensive Agents

The hypotensive effects of hypotensive agents may be enhanced when given concomitantly with ethacrynic acid and orthostatic hypotension may result. Dosage of the antihypertensive agent, and possibly of both drugs, should be reduced when ethacrynic acid is added to an existing regimen.

Probenecid

Animal studies indicate that probenecid may decrease the urinary excretion and possibly the effectiveness of ethacrynic acid. In addition, it has been suggested that ethacrynic acid, by increasing serum uric acid concentrations, may interfere with the uricosuric effects of probenecid or sulfinpyrazone. Serum uric acid concentrations should be monitored in patients receiving both drugs, and dosage of the uricosuric drug should be increased if necessary.

Nonsteroidal Anti-inflammatory Agents

Patients receiving diuretics may have an increased risk of developing renal failure secondary to decreased renal blood flow resulting from prostaglandin inhibition by NSAIAs.117,118 In addition, NSAIAs may interfere with the diuretic, natriuretic, and antihypertensive response to diuretics108,119,129 whose activity depends in part on prostaglandin-mediated alterations in renal blood flow (e.g., loop diuretics).119 Diuretic effect of ethacrynic acid should be closely monitored.129

Carbonic Anhydrase Inhibitors

Ethacrynic acid may potentiate action (augmentation of natriuresis and kaliuresis) of carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, methazolamide).129 Therefore, when adding ethacrynic acid to a carbonic anhydrase inhibitor regimen, the initial dose and change in a dose should be given in 25-mg increments, to avoid electrolyte depletion.129

Other Drugs

Concomitant administration of ethacrynic acid and aminoglycosides, some cephalosporins, or other ototoxic drugs, particularly when the diuretic is administered IV, may result in an increased incidence of transient or permanent deafness, and concomitant use of these drugs should be avoided. In addition, the possibility that IV ethacrynate sodium may increase aminoglycoside toxicity by altering serum and tissue concentrations of the antibiotic should be considered. It has been proposed, but not proven, that ethacrynic acid may enhance the nephrotoxicity of neomycin.

Ethacrynic acid displaces warfarin from protein-binding sites and potentiation of the anticoagulant effect of coumarin and indandione derivatives may occur, necessitating a reduction in the dosage of the anticoagulant.

In dogs, ethacrynic acid has caused a transient increase in blood ethanol concentrations; the possibility that the drug may augment the effects of alcohol or produce alcohol intolerance in humans should be kept in mind.

Acute Toxicity

In mice, the oral LD₅₀ of ethacrynic acid is 627 mg/kg and the IV LD₅₀ of ethacrynate sodium is 175 mg/kg.129

If acute overdosage of the drugs occur, supportive and symptomatic treatment should be initiated.129 In acute overdosage, the stomach should be emptied immediately by inducing emesis or gastric lavage.129 If dehydration, electrolyte imbalance, hepatic coma, or hypotension occurs, appropriate therapy should be instituted.129 Patients with respiratory depression may require administration of oxygen or artificial respiration.129

Pharmacology

The pharmacologic effects of ethacrynic acid are similar to those of furosemide. The exact mode of action of ethacrynic acid has not been clearly defined but may involve inhibition of sulfhydryl-catalyzed enzyme systems. The drug binds with sulfhydryl groups of renal cellular proteins, but by a different mechanism than do the mercurial diuretics. In vitro, ethacrynic acid inhibits the active transport of chloride in the lumen of the ascending limb of the loop of Henle, thereby diminishing reabsorption of sodium and chloride at that site. Because this inhibition occurred with lower concentrations of ethacrynic acid in the presence of cysteine, it has been proposed that the ethacrynate-cysteine metabolite is the most active form of the drug. The drug increases potassium excretion in the distal renal tubule and exerts a direct effect on electrolyte transport at the proximal tubule. Ethacrynic acid does not inhibit carbonic anhydrase, and it is not an aldosterone antagonist. Aldosterone secretion may increase during therapy with the drug and may contribute to the hypokalemia caused by ethacrynic acid.

Ethacrynic acid diuresis results in enhanced excretion of sodium, chloride, potassium, hydrogen, calcium, and magnesium. Initially, the amount of chloride excreted approaches or approximately equals the combined quantities of sodium and potassium excreted. With prolonged administration, sodium and chloride excretion declines, and potassium and hydrogen excretion may increase. Bicarbonate excretion remains essentially unchanged. Excessive losses of potassium, hydrogen, and chloride may result in metabolic alkalosis. Urinary ammonium concentration and pH fall after administration of ethacrynic acid. Low doses of the drug promote uric acid retention; however, IV administration of ethacrynate sodium or high oral doses of ethacrynic acid may cause temporary uricosuria. Maximum diuresis and electrolyte loss are greater with ethacrynic acid than with the thiazides or most other diuretics except furosemide. Like the thiazide diuretics and furosemide, and unlike mercurial diuretics, the effectiveness of ethacrynic acid is independent of the acid-base balance of the patient.

Ethacrynic acid has little or no direct effect on glomerular filtration rate or renal blood flow; however, a fall in glomerular filtration rate may accompany pronounced reductions in plasma volume associated with rapid or excessive diuresis. As with other diuretics, a hypotensive effect may result from decreased plasma volume in patients receiving ethacrynic acid.

Ethacrynic acid appears to have less effect on carbohydrate metabolism and blood glucose concentrations than do the thiazides; however, the drug has reduced fasting insulin concentrations, lessened the increase in insulin concentrations after glucose ingestion, and caused hyperglycemia and glycosuria especially when daily doses of greater than 200 mg were administered. These effects may have resulted from hypokalemia. When administered to uremic patients in doses larger than those recommended, ethacrynic acid has produced acute hypoglycemia with seizures.

Paradoxically, ethacrynic acid may decrease urine volume in patients with nephrogenic diabetes insipidus. The mechanism of this effect is not completely understood, but it has been postulated that urinary volume is indirectly reduced as a result of sodium depletion.

Pharmacokinetics

Absorption

Ethacrynic acid is rapidly absorbed from the GI tract. Following oral administration, the diuretic effect occurs within 30 minutes and reaches a peak in approximately 2 hours. The duration of action following oral administration is usually 6-8 hours but may continue up to 12 hours. Following IV administration of ethacrynate sodium, diuresis usually occurs within 5 minutes, reaches a maximum within 15-30 minutes, and persists for approximately 2 hours.

Distribution

In animals, substantial quantities of ethacrynic acid accumulate only in the liver. The drug does not enter the CSF. It is not known whether ethacrynic acid crosses the placenta or is distributed into milk in humans.

Elimination

Animal studies indicate that ethacrynic acid is metabolized to a cysteine conjugate (which may contribute to the pharmacologic effects of the drug) and to an unstable, unidentified compound. Approximately 30-65% of an IV dose of ethacrynate sodium is secreted by the proximal renal tubules and is excreted in urine; approximately 35-40% is excreted in bile, partially as the cysteine conjugate. In dogs, approximately 30-40% of the drug excreted in urine is unchanged, 20-30% is the cysteine conjugate, and 33-40% is an unstable, unidentified compound. The rate of urinary excretion of ethacrynic acid increases as urinary pH increases and is decreased by probenecid.

Chemistry and Stability

Chemistry

Ethacrynic acid, an alpha-beta unsaturated ketone derivative of an aryloxyacetic acid, is a loop diuretic. The drug occurs as a white or practically white, odorless or practically odorless, crystalline powder with a pK_a of 3.5 and is very slightly soluble in water and freely soluble in alcohol.

Ethacrynate sodium powder for injection is prepared by the neutralization of ethacrynic acid with the aid of sodium hydroxide. Commercially available ethacrynate sodium for injection occurs as a white, crystalline powder or plug, has a solubility of about 70 mg/mL in water at 25°C, and contains 0.17 mEq of sodium, and 62.5 mg of mannitol in each vial labeled as containing the equivalent of 50 mg of ethacrynic acid. Following reconstitution with 5% dextrose injection or 0.9% sodium chloride injection, ethacrynate sodium solutions have a pH of 6.3-7.7. Ethacrynate sodium for injection is labeled in terms of the equivalent amount of ethacrynic acid.

Stability

Ethacrynic acid tablets and ethacrynate sodium powder for injection should be stored at a controlled room temperature of 25°C, but may be exposed to temperatures ranging from 15-30°C;120 the tablets should be stored in tight containers. However, USP recommends that the tablets be stored in well-closed containers.121 Commercially available ethacrynic acid tablets have an expiration date of 5 years and ethacrynate sodium powder for injection has an expiration date of 2 years following the date of manufacture.

Solutions of ethacrynate sodium are stable for short periods of time at pH 7 at room temperature and should be used within 24 hours of their preparation. The solutions are less stable as pH and/or temperature increase. If the commercially available powder for injection is reconstituted with 5% dextrose injection having a pH of 5 or less, the resulting solution may be hazy or opalescent and should not be used. In a study using solutions manufactured by Abbott Laboratories, ethacrynate sodium injection was physically and chemically compatible with 0.9% sodium chloride, 5% dextrose, 5% dextrose in 0.9% sodium chloride, Ringer's, lactated Ringer's, 6% dextran 75 in 0.9% sodium chloride, Normosol-R^® (pH 7.4), and water for injection. Ethacrynate sodium solutions are incompatible with Normosol-M^® and with solutions of hydralazine hydrochloride, procainamide hydrochloride, reserpine, or tolazoline hydrochloride in sodium chloride injection. Specialized references should be consulted for specific compatibility information. Solutions of ethacrynate sodium should not be mixed or infused simultaneously with whole blood or its derivatives.

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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