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Ethacrynate Sodium

Class: Loop Diuretics
Note: This monograph also contains information on Ethacrynic Acid
VA Class: CV702
CAS Number: 58-54-8
Brands: Edecrin,, Sodium Edecrin

Warning(s)

  • Ethacrynic acid is a potent diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion.129 (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.) 129

Introduction

A loop-type diuretic129 and antihypertensive agent.b

Uses for Ethacrynate Sodium

Edema

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

Considered a diuretic of choice for most patients with CHF.108

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.)

In patients whose condition is refractory to diuretics, may use IV administration of a diuretic (e.g., ethacrynate sodium) or concomitant therapy with 2 or more diuretics (e.g., a loop diuretic and metolazone, a loop diuretic and a thiazide diuretic), or alternatively, short-term administration of a drug that increases blood flow (e.g., a positive inotropic agent such as dobutamine or dopamine) may be needed.108

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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 (alone or in combination with other classes of antihypertensive agents).b

One of several preferred initial therapies in hypertensive patients with CHF or renal disease.126

Ethacrynic acid is the only orally available nonsulfonamide diuretic; may be particularly useful in patients hypersensitive to sulfonamides (e.g., other loop diuretics, thiazides).103 104

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.126

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

Hypercalcemia

IV ethacrynate sodium has been used in the management of hypercalcemia, 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.b

Management of bromide intoxication.b

Diabetes Insipidus

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

Ethacrynate Sodium 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

  • Most experts state that all patients with symptomatic CHF who have evidence for, or a prior history of, fluid retention generally should receive diuretic therapy in conjunction with moderate sodium restriction (≤3 g of sodium daily), an ACE inhibitor, and usually a β-adrenergic blocking agent, with or without a cardiac glycoside.108

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

Hypertension

  • If added to regimen of a patient stabilized on a potent hypotensive agent, consider dosage reduction of preexisting therapy to avoid severe hypotension.b

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 infusionb 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 25mg.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

Initially: 25 mg daily;101 102 103 104 if necessary, increase dosage gradually until desired response is achieved or a usual maximum dosage of 100 mg daily, in 2 or 3 divided doses is attained.102 104

In patients with renal insufficiency or CHF, may increase dosage until desired therapeutic response is achieved, adverse effects become intolerable, or suggested maximum dosage of 200 mg daily, in divided doses, is attained.101

Usually administered in 2 or 3 divided doses daily for the management of hypertension.103 104

Prescribing Limits

Adults

Edema
Oral

Maximum 200 mg twice daily.129

IV

Maximum 100 mg per dose. b

Hypertension
Oral

Maximum 100mg daily, in divided doses; b in patients with renal insufficiency or CHF, 200 mg daily, in divided doses.101

Special Populations

Hepatic Impairment

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

Renal Impairment

Higher dosages (>100 mg) may be necessary for management of hypertension in adults with renal insufficiency.101 102 May increase dosage until desired therapeutic response is achieved, adverse effects become intolerable, or suggested maximum dosage of 200 mg daily, in divided doses, is attained.101

CHF

Higher dosages (>100 mg) may be necessary for management of hypertension in adults with CHF. 101 102 May increase dosage until desired therapeutic response is achieved, adverse effects become intolerable, or suggested maximum dosage of 200 mg daily, in divided doses, is attained.101

Geriatric Patients

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

Cautions for Ethacrynate Sodium

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

Interactions for Ethacrynate Sodium

Specific Drugs

Drug

Interaction

Comments

Alcohol

May augment effects of alcoholb

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

Possible antagonism of hypoglycemic effect as result of hypokalemiab

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

Antihypertensive agents

Additive antihypertensive effect; orthostatic hypotension may occurb

Reduce dosage of both drugsb

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

May potentiate action of carbonic anhydrase inhibitors; augmentation of natriuresis and kaliuresis129

Cautiously dose ethacrynic acid 129

Cardiac glycosides (e.g., digoxin)

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

Periodically monitor electrolytes; correct hypokalemiab

Corticosteroids

Possible increased risk of gastric hemorrhage associated with corticosteroids129

(See also Drugs that Cause Potassium Loss)

Diuretics

Enhanced therapeutic effect129 b

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

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

Share similar mechanisms of actionb

No therapeutic rationale for concomitant useb

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

Possible reduction in potassium loss129

May be used for therapeutic advantage129

Diuretics, thiazides

Additive diuretic effectb

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

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

Additive hypokalemic effectsb

Monitor electrolytes; correct hypokalemiab

Lithium

Reduced renal clearance of lithium and increased risk of lithium toxicity129 b

Avoid concomitant use; if concomitant therapy is necessary, hospitalize patient and monitor for lithium toxicity129 b

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

Potential for prolonged neuromuscular blockade, associated with potassium depletionb

NSAIAs

Possible decreased diuretic, natriuretic effect, and antihypertensive effects.108 119 129 b Increased risk of developing renal failure associated with decreased renal blood flow, resulting from prostaglandin inhibition by NSAIAs117 118

Monitor closely for desired diuretic effect129

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

Possible additive ototoxic effect (transient or permanent deafness), especially with IV ethacrynate sodium 129 b

Avoid concomitant use129 b

Uricosuric drugs (probenecid, sulfinpyrazone)

Urinary excretion and efficacy of ethacrynic acid may decrease.b Possible antagonism of uricosuric effectsb

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

Warfarin

Possible potentiation of anticoagulant effect (because of displacement of warfarin from protein-binding sites)129 b

Monitor INR closely; consider reducing warfarin dose129 b

Ethacrynate Sodium 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 placentab 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

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.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.)

Preparations

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

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Edecrin 25MG Tablets (VALEANT): 100/$375.24 or 300/$1,056.81

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 9, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

Only references cited for selected revisions after 1984 are available electronically.

100. Fischer AF, Parker BR, Stevenson DK. Nephrolithiasis following in utero diuretic exposure: an unusual case. Pediatrics. 1988; 81:712-4. [IDIS 241064] [PubMed 3282218]

101. The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The 1984 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1984; 144:1045-57. [IDIS 184763] [PubMed 6143542]

102. 1988 Joint National Committee. The 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1988; 148:1023-38. [IDIS 242588] [PubMed 3365073]

103. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med. 1993; 153:154-83. [IDIS 309043] [PubMed 8422206]

104. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health. (NIH publication No. 98-4080.)

105. Kaplan NM. Choice of initial therapy for hypertension. JAMA. 1996; 275:1577-80. [IDIS 365188] [PubMed 8622249]

106. Psaty BM, Smith NL, Siscovich DS et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA. 1997; 277:739-45. [IDIS 380501] [PubMed 9042847]

107. Whelton PK, Appel LJ, Espeland MA et al. for the TONE Collaborative Research Group. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). JAMA. 1998; 279:839-46. [PubMed 9515998]

108. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Part II. Management of heart failure: approaches to the prevention of heart failure. Am J Cardiol. 1999; 83:9A-38A.

109. Merck. Edecrin (ethacrynic acid) tablets and Intravenous Sodium Edecrin (ethacrynate sodium) prescribing information (dated 1997 Jun). In: Physicians’ desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:1790-1.

110. Leary WP, Reyes AJ. Drug interactions with diuretics. S Afr Med J. 1984; 65:455-61. [IDIS 186610] [PubMed 6701709]

111. The Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA. 1988; 259:539-44. [IDIS 237362] [PubMed 2447297]

112. Richardson A, Bayliss J, Scriven AJ et al. Double-blind comparison of captopril alone against frusemide plus amiloride in mild heart failure. Lancet. 1987; 2:709-11. [IDIS 234108] [PubMed 2888942]

113. Sherman LG, Liang CS, Baumgardner S et al. Piretanide, a potent diuretic with potassium-sparing properties, for the treatment of congestive heart failure. Clin Pharmacol Ther. 1986; 40:587-94. [IDIS 224725] [PubMed 3533372]

114. Patterson JH, Adams KF Jr, Applefeld MM et al. Oral torsemide in patients with chronic congestive heart failure: effects on body weight, edema, and electrolyte excretion. Pharmacotherapy. 1994; 14:514-21. [IDIS 336083] [PubMed 7997385]

115. Wilson JR, Reichek N, Dunkman WB et al. Effect of diuresis on the performance of the failing left ventricle in man. Am J Med. 1981;70:234-9.

116. Parker JO. The effects of oral ibopamine in patients with mild heart failure—a double blind placebo controlled comparison to furosemide. Int J Cardiol. 1993; 40:221-7. [PubMed 8225657]

117. Hansten PD, Horn JR. Diuretics and non-steroidal anti-inflammatory drugs. Drug Interact Newsl. 1986; 6:27-9.

118. O’Brien WM. Pharmacology of nonsteroidal anti-inflammatory drugs: practical review for clinicians. Am. J Med. 1983; 10:32-9.

119. Brater DC. Drug-drug and drug-disease interactions with nonsteroidal anti-inflammatory drugs. Am J Med. 1986; 80(Suppl 1A):62-77. [IDIS 212035] [PubMed 3511686]

120. Edecrin (ethacrynic acid and ethacrynate sodium) tablets and injection. In: MedWatch: summary of safety-related drug labeling changes approved by FDA. Rockville, MD: US Food and Drug Administration; 1999 Oct.

121. The United States pharmacopeia, 24th rev, and The national formulary, 19th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 2000:689.

122. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension. 2000; 35:1021-4. [PubMed 10818056]

123. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension. 2000; 35:1019-20. [PubMed 10818055]

124. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000; 36:646-61. [IDIS 452007] [PubMed 10977801]

125. Associated Press (American Diabetes Association). Diabetics urged: drop blood pressure. Chicago, IL; 2000 Aug 29. Press Release from web site.

126. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) Express. Bethesda, MD: May 14 2003. From NIH website. (Also published in JAMA. 2003; 289.

127. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. J Am Coll Cardiol. 2001;38:2101-2113.

128. The Guidelines Subcommittee of the WHO/ISH Mild Hypertension Liaison Committee. 1999 guidelines for the management of hypertension. J Hypertension. 1999; 17:392-403.

129. Aton Pharma, Inc. Edecrin and Sodium Edecrin (ethacrynic acid and ethacrynate sodium) tablets and injection prescribing information. Lawrenceville, NJ; 2007 Oct. Accessed 2/27/08.

b. AHFS Drug Information. McEvoy GK, ed. Ethacrynic Acid, Ethacrynate Sodium. Bethesda, MD: American Society of Health-System Pharmacists; 2008:2753-2756.

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2013:463-4.

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