Ethacrynic acid

Ethacrynic acid is an antihypertensive agent belonging to Loop Diuretics. Ethacrynic acid is used to treat fluid retention (edema) in people with congestive heart failure, liver disease, or a kidney disorder such as nephrotic syndrome.

Onset of action is rapid, usually within 30 minutes after an oral dose Ethacrynic acid or within 5 minutes after an intravenous injection of Ethacrynic acid. After oral use, diuresis peaks in about 2 hours and lasts about 6 to 8 hour. Ethacrynic acid has bioavailability of 100% and a half-life of 2-4 hours. Ethacrynic acid is extensively bound to the plasma proteins 90%, mainly albumin. Ethacrynic acid is metabolized in the liver and both ethacrynic acid in its unchanged form as well as its metabolites are excreted in bile and urine 66%.

Ethacrynic acid shows common side effects like frequent urination (should not last longer than a few weeks), nausea, vomiting, loss of appetite, stomach pain, difficulty swallowing, loss of appetite, thirst, muscle cramps, weakness, headache, diarrhoea, etc.

Ethacrynic acid is available in the dosage form of Tablet, and Powder for Injections.

Ethacrynic acid is available in India, China, US, Europe and Canada.

Ethacrynic acid belonging to the Loop Diuretics acts as an antihypertensive agent.

Ethacrynic acid inhibits symport of sodium, potassium, and chloride primarily in ascending loop of Henle but also in the proximal and distal tubules. This pharmacological action results in the excretion of these ions increased urinary output, and reduction in extracellular fluid. Diuretics also reduce blood pressure initially by decreasing plasma and extracellular fluid volume; cardiac output also reduces, explaining its antihypertensive action. Eventually, the cardiac output returns to normal with an accompanying reduce in peripheral resistance. Its mode of action does not involve carbonic anhydrase inhibition.

The onset of action of Ethacrynic acid occurs within 30-60min (by mouth) and 5-15min (Intravenous) of administration.

The Duration of Action for Ethacrynic acid in the body is approximately 4-8 hours (by mouth) and 2-7 hours (Intravenous).

The Tmax was found within 2 hours (by mouth) and 15min (Intravenous) following the administration of Ethacrynic acid.

Ethacrynic acid is available in the form of Tablet and Powder for Injection.

Ethacrynic acid tablet is taken by mouth. Usually, once or twice a day.

Ethacrynic acid Powder for Injection by Intravenous as single dose or several dose.

Ethacrynic acid is a loop diuretic used to treat fluid retention (edema) in people with congestive heart failure, liver disease, or a kidney disorder such as nephrotic syndrome. Ethacrynic acid promotes diuresis by blocking tubular reabsorption of sodium and chloride in the proximal and distal tubules, as well as in thick ascending loop of Henle.

Ethacrynic acid is an antihypertensive agent belonging to Loop Diuretics. Ethacrynic acid acting at Na/2Cl reabsorptive pump at ascending loop of Henle and distal renal tubule. Intereference with the chloride-binding cotransport system, causes increased excretion of water, sodium, chlorine, magnesium, and calcium. Ethacrynic acid is used to treat fluid retention (edema) in people with congestive heart failure, liver disease, or a kidney disorder such as nephrotic syndrome.

Ethacrynic acid is approved for use in the following clinical indications

• Edema

Ethacrynic acid is indicated for the treatment of edema when an agent with greater diuretic potential than those commonly employed is required.

1. Treatment of the edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome.

2. Short-term management of ascites due to malignancy, idiopathic edema, and lymphedema.

3. Short-term management of hospitalized pediatric patients, other than infants, with congenital heart disease or the nephrotic syndrome.

4. Intravenous Ethacrynic acid is indicated when a rapid onset of diuresis is desired, e.g., in acute pulmonary edema, or when gastrointestinal absorption is impaired or oral medication is not practicable.

Although not approved, there have been certain off-label indications. These include

• In Diuretic renal scintigraphy

Ethacrynic acid is also indicated during diuretic renal scintigraphy in patients with sulfonamide allergies. Previously, diagnosing renal obstruction in this patient group was limited to two options:

1. Using furosemide regardless of hypersensitivity because, in most cases, allergic reactions are practically mild.

2. Resorting to the less accurate non-diuretic route for patients with known severe reactions to sulfa drugs.

• In Adjuvant anticancer therapy

Ethacrynic acid may be useful as adjuvant anticancer therapy. Glutathione transferase is often overexpressed in tumor cells, conferring resistance to many antineoplastic regimens. In vitro studies have showcased ethacrynic acid's ability to inhibit glutathione transferase. Clinical trials for its efficacy as an adjuvant for multiple myeloma have also shown promise

Edema

Therapy should be individualized according to the patient response to gain maximal therapeutic response and to determine the minimal dose needed to maintain that response.

• Adults

Oral:50 to 200 mg orally per day in 1 to 2 divided doses; once effective diuresis has been achieved, adjust dose as needed in 25 mg to 50 mg increments to the minimum effective dose and give on a continuous or intermittent schedule.

Add-on dose: When adding this drug to an existing diuretic regimen, initial dose and dose changes should be in 25 mg increments.

IV: 50 mg (or 0.5 to 1 mg/kg) IV once; occasionally, a second dose at a new injection site may be required.

• Pediatric
  

1 year or older:

Initial dose: 25 mg orally

Maintenance dose: May adjust dose as needed in 25 mg increments.

Ethacrynic acid is available in various strengths as Tablets (25mg) and Powder for Injection (50mg).

Ethacrynic acid is available in the form of Tablets and Powder for Injection.

Avoid consumption of a high-salt or high-sodium diet while taking Ethacrynic acid.

Ethacrynic acid is contraindicated in following:

• Patients with anuria
• Patients with the history of hypersensitivity to Ethacrynic acid.
• Patients with progressive renal disease
• Use in infants

• Volume and Electrolyte Depletion

The effects of Ethacrynic acid on electrolytes are related to its renal pharmacologic activity and are dose dependent. The possibility of profound electrolyte and water loss may be avoided by weighing the patient throughout the treatment period, by careful adjustment of dosage, by initiating treatment with small doses, and by using the drug on an intermittent schedule when possible. When excessive diuresis occurs, the drug should be withdrawn until homeostasis is restored. When excessive electrolyte loss occurs, the dosage should be reduced, or the drug temporarily withdrawn.

• Cirrhosis

Initiation of diuretic therapy with Ethacrynic acid in the cirrhotic patient with ascites is best carried out in the hospital. When maintenance therapy has been established, the individual can be satisfactorily followed as an outpatient. Ethacrynic acid should be given with caution to patients with advanced cirrhosis of the liver, particularly those with a history of previous episodes of electrolyte imbalance or hepatic encephalopathy. Like other diuretics it may precipitate hepatic coma and death.

• Hypotensive episode

Too vigorous a diuresis, as evidenced by rapid and excessive weight loss, may induce an acute hypotensive episode. In elderly cardiac patients, rapid contraction of plasma volume and the resultant hemoconcentration should be avoided to prevent the development of thromboembolic episodes, such as cerebral vascular thromboses and pulmonary emboli which may be fatal.

• 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 patient with the 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.

• Potassium depletion

Excessive loss of potassium in patients receiving digitalis glycosides may precipitate digitalis toxicity. Care should also be exercised in patients receiving potassium-depleting steroids.

Consumption of alcohol is not recommended while you are taking this medicine due to increased risk of the severe adverse effects. These side effects may include dizziness and fainting.

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

Pregnancy category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women. Since animal reproduction studies are not always predictive of human response, Ethacrynic acid, should be used during pregnancy only if clearly needed.

Avoid consumption of high-salt or high-sodium diet while taking Ethacrynic acid.

Common Adverse effects

• Anorexia, malaise, abdominal discomfort or pain, dysphagia, nausea, vomiting, and diarrhea, vertigo, Headache, fatigue, confusion, Skin rash, fever, chills.

Rare Adverse effects

• Jaundice, Thrombocytopenia, Agranulocytosis, tinnitus, deafness, apprehension, blurred vision, hematuria.

• Lithium

Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Read circulars for lithium preparations before use of such concomitant therapy.

• Ototoxic drugs

Ethacrynic acid, may increase the ototoxic potential of other drugs such as aminoglycoside and some cephalosporin antibiotics. Their concurrent use should be avoided.

• Warfarin

Ethacrynic acid have been shown to displace warfarin from plasma protein; a reduction in the usual anticoagulant dosage may be required in patients receiving both drugs.

• Non-steroidal anti-inflammatory drugs (NSAIDs)

In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Ethacrynic acid and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

The common side of Ethacrynic acid include the following

• Common

Frequent urination (should not last longer than a few weeks), nausea, vomiting, loss of appetite, stomach pain, difficulty swallowing, loss of appetite, thirst, muscle cramps, weakness, headache, diarrhoea.

•  Rare

Severe, watery diarrhoea, loss of hearing, confusion, loss of balance, ringing or fullness in the ears, yellowing of the skin or eyes, unusual bleeding or bruising, rash, hives, difficulty breathing or swallowing.

• Pregnancy

Pregnancy Category B: Reproduction studies in the mouse and rabbit at doses up to 50 times the human dose showed no evidence of external abnormalities of the fetus due to Ethacrynic acid. In a two-litter study in the dog and rat, oral doses of 5 or 20 mg/kg/day (2½ or 10 times the human dose), respectively, did not interfere with pregnancy or with growth and development of the pups. Although there was reduction in the mean body weights of the fetuses in a teratogenic study in the rat at a dose level of 100 mg/kg (50 times the human dose), there was no effect on mortality or postnatal development. Functional and morphologic abnormalities were not observed. There are, however, no adequate and well-controlled studies in pregnant women. Since animal reproduction studies are not always predictive of human response, Ethacrynic acid should be used during pregnancy only if clearly needed.

• Nursing Mothers

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

• Pediatric Use

There are no well-controlled clinical trials in pediatric patients. The information on oral dosing in pediatric patients, other than infants, is supported by evidence from empiric use in this age group.

• Geriatric Use

Of the total number of subjects in clinical studies of Ethacrynic acid, approximately 224 patients (21%) were 65 to 74 years of age, while approximately 100 patients (9%) were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patient, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patient with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Overdosage may lead to excessive diuresis with electrolyte depletion and dehydration. In the event of overdosage, symptomatic and supportive measures should be employed. Emesis should be induced, or gastric lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma, and hypotension by established procedures. If required, give oxygen or artificial respiration for respiratory impairment. In the mouse, the oral LD50 of ethacrynic acid is 627 mg/kg and the intravenous LD50 of ethacrynate sodium is 175 mg/kg.

Pharmacodynamic

Ethacrynic acid is a monosulfonamyl loop or high ceiling diuretic. Ethacrynic acid acts on the ascending limb of the loop of Henle and on the proximal and distal tubules. Urinary output is usually dose dependent and related to the magnitude of fluid accumulation. Water and electrolyte excretion may be increased several times over that observed with thiazide diuretics, since ethacrynic acid inhibits reabsorption of a much greater proportion of filtered sodium than most other diuretic agents. Therefore, ethacrynic acid is effective in many patients who have significant degrees of renal insufficiency. Ethacrynic acid has little or no effect on glomerular filtration or on renal blood flow, except following pronounced reductions in plasma volume when associated with rapid diuresis.

Pharmacokinetics

• Absorption

Onset of action is rapid, usually within 30 minutes after an oral dose of Ethacrynic acid or within 5 minutes after an intravenous injection of Ethacrynic acid. After oral use, diuresis peaks in about 2 hours and lasts about 6 to 8 hours. Ethacrynic acid having bioavailability of 100% and half-life of 2-4 hours.

• Distribution

In healthy individuals, Ethacrynic acid is extensively bound to plasma proteins 90%, mainly albumin.

• Metabolism and Excretion
  

Ethacrynic acid is metabolized in the liver and both ethacrynic acid in its unchanged form as well as its metabolites are excreted in bile and urine 66%.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/16092s042,16093s044lbl.pdf
• https://www.rxlist.com/edecrin-drug.htm#dosage
• https://go.drugbank.com/drugs/DB00903
• https://reference.medscape.com/drug/edecrin-ethacrynic-acid-342422#3
• https://www.ncbi.nlm.nih.gov/books/NBK558988/