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Pronunciation
(eth a KRIN ik AS id)
Generic Available (U.S.)
No
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of edema associated with congestive heart failure; hepatic cirrhosis or renal disease; short-term management of ascites due to malignancy, idiopathic edema, and lymphedema
Pregnancy Risk Factor
B
Pregnancy Considerations
No data available. Generally, use of diuretics during pregnancy is avoided due to risk of decreased placental perfusion.
Lactation
Contraindicated
Contraindications
Hypersensitivity to ethacrynic acid or any component of the formulation; anuria; history of severe watery diarrhea caused by this product; infants
Warnings/Precautions
Concerns related to adverse effects:
• Fluid/electrolyte loss: Loop diuretics are potent diuretics; excess amounts can lead to profound diuresis with fluid and electrolyte loss; close medical supervision and dose evaluation are required. Watch for and correct electrolyte disturbances; adjust dose to avoid dehydration.
• Hypersensitivity reactions: Can rarely occur, however, ethacrynic acid has no cross-reactivity to sulfonamides or sulfonylureas.
• Nephrotoxicity: Monitor fluid status and renal function in an attempt to prevent oliguria, azotemia, and reversible increases in BUN and creatinine; close medical supervision of aggressive diuresis required.
• Ototoxicity: Rapid I.V. administration, renal impairment, excessive doses, and concurrent use of other ototoxins is associated with ototoxicity; has been associated with a higher incidence of ototoxicity than other loop diuretics.
Disease-related concerns:
• Cirrhosis: In cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy.
Concurrent drug therapy issues:
• Antihypertensives: Coadministration of antihypertensives may increase the risk of hypotension.
Special populations:
• Elderly: May be inappropriate in this age group; other loop diuretics are preferred (Beers Criteria).
Adverse Reactions
Frequency not defined.
Central nervous system: Headache, fatigue, apprehension, confusion, fever, chills, encephalopathy (patients with pre-existing liver disease); vertigo
Dermatologic: Skin rash, Henoch-Schönlein purpura (in patient with rheumatic heart disease)
Endocrine & metabolic: Hyponatremia, hyperglycemia, variations in phosphorus, CO2 content, bicarbonate, and calcium; reversible hyperuricemia, gout, hyperglycemia, hypoglycemia (occurred in two uremic patients who received doses above those recommended)
Gastrointestinal: Anorexia, malaise, abdominal discomfort or pain, dysphagia, nausea, vomiting, and diarrhea, gastrointestinal bleeding, acute pancreatitis (rare)
Genitourinary: Hematuria
Hepatic: Jaundice, abnormal liver function tests
Hematology: Agranulocytosis, severe neutropenia, thrombocytopenia
Local: Thrombophlebitis (with intravenous use), local irritation and pain
Ocular: Blurred vision
Otic: Tinnitus, temporary or permanent deafness
Renal: Serum creatinine increased
Metabolism/Transport Effects
None known.
Drug Interactions
ACE Inhibitors: Loop Diuretics may enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Allopurinol: Loop Diuretics may enhance the adverse/toxic effect of Allopurinol. Loop Diuretics may increase the serum concentration of Allopurinol. Specifically, Loop Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Aminoglycosides: Loop Diuretics may enhance the adverse/toxic effect of Aminoglycosides. Specifically, nephrotoxicity and ototoxicity. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Beta2-Agonists: May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Loop Diuretics. Risk D: Consider therapy modification
Cardiac Glycosides: Loop Diuretics may enhance the adverse/toxic effect of Cardiac Glycosides. This by increasing the risk of hypokalemia. Risk C: Monitor therapy
CISplatin: Loop Diuretics may enhance the nephrotoxic effect of CISplatin. Loop Diuretics may enhance the ototoxic effect of CISplatin. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
CycloSPORINE (Systemic): May enhance the adverse/toxic effect of Loop Diuretics. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Dofetilide: Loop Diuretics may enhance the QTc-prolonging effect of Dofetilide. Risk C: Monitor therapy
Fosphenytoin: May diminish the diuretic effect of Loop Diuretics. Risk C: Monitor therapy
Furosemide: May enhance the ototoxic effect of Ethacrynic Acid. Risk X: Avoid combination
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Licorice: May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
Lithium: Loop Diuretics may decrease the serum concentration of Lithium. Loop Diuretics may increase the serum concentration of Lithium. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methotrexate: May diminish the therapeutic effect of Loop Diuretics. Methotrexate may increase the serum concentration of Loop Diuretics. Loop Diuretics may increase the serum concentration of Methotrexate. Management: Monitor for increased methotrexate and/or loop diuretic levels/toxicity with concomitant use of these agents and monitor for decreased therapeutic effects of loop diuretics. Methotrexate and/or loop diuretic dose reductions may be necessary. Risk D: Consider therapy modification
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Neuromuscular-Blocking Agents: Loop Diuretics may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Loop Diuretics may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May diminish the diuretic effect of Loop Diuretics. Management: Monitor for decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding concomitant use of these agents in CHF or cirrhosis with ascites. Concomitant use of bumetanide with indomethacin is not recommended. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phenytoin: May diminish the diuretic effect of Loop Diuretics. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Probenecid: May enhance the adverse/toxic effect of Loop Diuretics. Probenecid may diminish the diuretic effect of Loop Diuretics. Probenecid may increase the serum concentration of Loop Diuretics. Management: Monitor for decreased diuretic effects or increased adverse effects of loop diuretics with concomitant use of probenecid. Bumetanide prescribing information recommends against concomitant use of probenecid. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RisperiDONE: Loop Diuretics may enhance the adverse/toxic effect of RisperiDONE. Management: Consider alternative diuretic therapy (e.g., thiazides) to more potent diuretics (e.g., furosemide) in elderly patients receiving risperidone. Patients who require use of more potent diuretic therapy should be closely monitored and adequately hydrated. Risk D: Consider therapy modification
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Salicylates: May diminish the diuretic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Salicylates. Risk C: Monitor therapy
Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Ethacrynic Acid may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Compatibility
Stable in D5LR, D5NS, D5W, LR, NS.
Incompatible with whole blood or its derivatives.
Y-site administration: Compatible: Heparin, heparin with hydrocortisone sodium succinate, potassium chloride, vitamin B complex with C. Incompatible: Nesiritide.
Mechanism of Action
Inhibits reabsorption of sodium and chloride in the ascending loop of Henle and distal renal tubule, interfering with the chloride-binding cotransport system, thus causing increased excretion of water, sodium, chloride, magnesium, and calcium
Pharmacodynamics/Kinetics
Onset of action: Diuresis: Oral: ~30 minutes; I.V.: 5 minutes
Peak effect: Oral: 2 hours; I.V.: 30 minutes
Duration: Oral: 12 hours; I.V.: 2 hours
Absorption: Oral: Rapid
Protein binding: >90%
Metabolism: Hepatic (35% to 40%) to active cysteine conjugate
Half-life elimination: Normal renal function: 2-4 hours
Excretion: Feces and urine (30% to 60% as unchanged drug)
Dosage
I.V. formulation should be diluted in D5W or NS (1 mg/mL) and infused over several minutes.
Children: Oral: 1 mg/kg/dose once daily; increase at intervals of 2-3 days as needed, to a maximum of 3 mg/kg/day.
Adults:
Oral: 50-200 mg/day in 1-2 divided doses; may increase in increments of 25-50 mg at intervals of several days; doses up to 200 mg twice daily may be required with severe, refractory edema.
I.V.: 0.5-1 mg/kg/dose (maximum: 100 mg/dose); repeat doses not routinely recommended; however, if indicated, repeat doses every 8-12 hours.
Dosing adjustment/comments in renal impairment: Clcr <10 mL/minute: Avoid use.
Dialysis: Not removed by hemo- or peritoneal dialysis; supplemental dose is not necessary.
Administration: I.V.
Injection should not be given SubQ or I.M. due to local pain and irritation. Single I.V. doses should not exceed 100 mg. Administer each 10 mg over a minute.
Administration: I.V. Detail
If a second dose is needed, it is recommended to use a new injection site to avoid possible thrombophlebitis.
pH: 6.3-7.7
Monitoring Parameters
Blood pressure, renal function, serum electrolytes, and fluid status closely, including weight and I & O daily; hearing
Dietary Considerations
This product may cause a potassium loss. Your healthcare provider may prescribe a potassium supplement, another medication to help prevent the potassium loss, or recommend that you eat foods high in potassium, especially citrus fruits. Do not change your diet on your own while taking this medication, especially if you are taking potassium supplements or medications to reduce potassium loss. Too much potassium can be as harmful as too little.
Patient Education
Take prescribed dose with food early in day. Include potassium-rich foods in your diet, but do not take potassium supplements without consulting prescriber. May cause dizziness, drowsiness, or diarrhea. Report hearing changes (ringing in ears); persistent headache; unusual confusion or nervousness; abdominal pain; palpitations or chest pain; flu-like symptoms; skin rash; blurred vision; swelling of ankles or feet; weight changes; increased fatigue; or joint/muscle swelling, pain, cramping, or trembling.
Geriatric Considerations
Ethacrynic acid is rarely used because of its increased incidence of ototoxicity as compared to the other loop diuretics.
This medication is considered to be potentially inappropriate in this patient population (Beers Criteria severity: Low).
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: If given the morning of surgery, it may render the patient volume depleted and blood pressure may be labile during general anesthesia.
Cardiovascular Considerations
Note: Ethacrynic acid has limited use over other loop diuretics because of increased risk of ototoxicity.
Loop diuretic therapy has been a mainstay in the treatment of heart failure. Although loop diuretics have not demonstrated reduction in mortality associated with heart failure, they improve symptomatology associated with congestion (eg, edema, dyspnea). Due to rapid onset and predictability, intravenous loop diuretic therapy is routinely used to treat patients with acutely decompensated heart failure (ADHF). Intravenous therapy may also improve pulmonary congestion since it dilates veins and reduces preload. Until recently, prospective clinical trial data has been lacking in the treatment of ADHF. The DOSE trial prospectively evaluated the use of furosemide in a 2-by-2 factorially designed trial. Patients with ADHF (n=308) were randomized in a 1:1:1:1 fashion to either low-dose (total I.V. furosemide dose equal to total daily oral dosing) or high-dose (total I.V. furosemide dose equal to 2.5 times total daily oral dosing) and to administration of an I.V. bolus dose every 12 hours or a continuous infusion. No significant differences were seen between groups with respect to patient-assessed symptoms or change in renal function; therefore, in patients with ADHF, use of either administration method may be appropriate (Felker, 2011).
The use of loop diuretics can lead to hypokalemia and/or hypomagnesemia. Electrolyte disturbances can predispose a patient to serious cardiac arrhythmias, particularly if the patient is concurrently receiving digoxin. Fluid depletion, hypotension, and azotemia can also result from excessive use of diuretics. In contrast to thiazide diuretics, a loop diuretic can also lower serum calcium concentrations. For some patients, despite higher doses of loop diuretic treatment, an adequate diuretic response cannot be attained. Diuretic resistance can usually be overcome by intravenous administration, the use of two diuretics together (eg, furosemide and chlorothiazide), or the use of a diuretic with a positive inotropic agent. When such combinations are used, serum electrolytes need to be monitored even more closely.
Dose equivalency (approximate): Bumetanide 1 mg = furosemide 40 mg = torsemide 20 mg = ethacrynic acid 50 mg
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness; may rarely cause drowsiness, nervousness, or confusion
Mental Health: Effects on Psychiatric Treatment
Rare reports of agranulocytosis; use caution with clozapine and carbamazepine; may increase serum lithium levels, however, more likely with thiazide diuretic
Nursing: Physical Assessment/Monitoring
Monitor for dehydration and electrolyte imbalance on a regular basis.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution, as ethacrynate sodium:
Sodium Edecrin®: 50 mg
Tablet, oral:
Edecrin®: 25 mg [scored]
Pricing: U.S. (www.drugstore.com)
Tablets (Edecrin)
25 mg (100): $375.24
Extemporaneously Prepared
A 1 mg/mL oral suspension may be made with ethacrynic acid powder. Dissolve 120 mg ethacrynic acid powder in a small amount of 10% alcohol. Add a small amount of 50% sorbitol solution and stir. Adjust pH to 7 with 0.1N sodium hydroxide solution. Add sufficient quantity of 50% sorbitol solution to make a final volume of 120 mL. Add methylparaben 6 mg and propylparaben 2.4 mg as preservatives. Stable for 220 days at room temperature.
Das Gupta V, Gibbs CW Jr, and Ghanekar AG, "Stability of Pediatric Liquid Dosage Forms of Ethacrynic Acid, Indomethacin, Methyldopate Hydrochloride, Prednisone and Spironolactone," Am J Hosp Pharm, 1978, 35(11):1382-5.
Handbook on Extemporaneous Formulations, Bethesda, MD: American Society of Hospital Pharmacists, 1987.
References
Cowley AJ and Elkeles RS, “Diabetes and Therapy With Potent Diuretics,” Lancet, 1978, 1(8056):154.
Felker GM, Lee KL, Bull DA, et al, "Diuretic Strategies in Patients With Acute Decompensated Heart Failure," N Engl J Med, 2011, 364(9):797-805.
Gomolin IH and Garschick E, “Ethacrynic Acid-Induced Deafness Accompanied by Nystagmus,” N Engl J Med, 1980, 303(12):702.
Lant A, “Diuretics: Clinical Pharmacology and Therapeutic Use,” Drugs, 1985, 29(1):57-87.
Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice Guideline,” J Card Fail, 2010, 16(6):e1-194.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2012
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