Ethacrynic Acid - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

Ethacrynic acid is a diuretic medicine used to treat excessive high blood pressure and fluid retention. It promotes urine output and removes extra salt from the kidneys. It can also be used to treat fluid retention in those who have congestive heart failure (a condition where the heart fails to effectively pump blood), liver illness, or kidney problems such as nephrotic syndrome. Ethacrynic acid is a US FDA (United States Food and Drug Administration)-approved medicine used to treat edema (swelling caused by excessive fluid collection in the body's tissues), congestive heart failure, and hypertension (high blood pressure). However, excessive use might result in severe diuresis (increased urine excretion), demanding close medical observation and dose adjustment to individual patient needs. Ethacrynic acid was initially authorized for the treatment of heart failure and hypertension on January 9, 1967.

Drug Group

Ethacrynic acid is a loop diuretic that increases the flow of urine in the kidneys. It is used to treat fluid retention and edema caused by illnesses such as congestive heart failure, liver disease, and renal disease. Loop diuretics prevent salt and chloride reabsorption in the kidneys, causing higher urine output. This helps to remove extra fluid from the body, alleviating symptoms of fluid overload such as edema and hypertension.

Indications

Ethacrynic acid is recommended for treating edema that requires a more potent diuretic than widely used medications.

• Treating edema caused by congestive heart failure, liver cirrhosis (severe scarring of the liver leading to liver failure), and renal illness, including nephrotic syndrome.

• Short-term treatment for ascites caused by cancer, idiopathic edema, or lymphedema (swelling due to lymph fluid accumulation in the body).

• Provide short-term therapy for hospitalized pediatric patients with congenital heart disease or nephrotic syndrome, excluding babies.

• Intravenous Ethacrynic acid is recommended for rapid onset of diuresis in acute pulmonary edema (fluid accumulation in the lungs), impaired gastrointestinal absorption, or when oral medicine is not feasible.

Contraindications

• All diuretics, including Ethacrynic acid, should be avoided in anuria (absence of urine production). If electrolyte imbalance, azotemia (an increase in blood urea nitrogen (BUN) and serum creatinine levels), or Oliguria (low urine production) worsens with diuretic treatment for severe, progressive renal failure, discontinue the usage.

• In a few cases, this diuretic caused severe, watery diarrhea. If this occurs, it should be terminated and never used again.

• Oral and parenteral Ethacrynic acid therapy in babies is not recommended until more data is available.

• Hypersensitivity to any of Ethacrynic acid product's components.

Dosage Forms and Available Strengths

Ethacrynic acid comes in tablets and freeze-dried powders for oral and injection usage, with oral doses of 25 mg (milligrams) and injections of 50 mg.

Warnings

• Ethacrynic acid's effects on electrolytes are dose-related and linked to renal pharmacologic actions. To avoid significant electrolyte and water loss, patients ought to maintain weight throughout the treatment period, modify dosages carefully, use the medicine intermittently, and discontinue it as needed. If excessive diuresis occurs, the dosage should be lowered or the medication temporarily discontinued.

• Diuretic therapy in patients with cirrhosis and ascites (fluid accumulation in the abdomen) with Ethacrynic acid works most effectively in a hospital, although maintenance therapy can be completed as an outpatient.

• Ethacrynic acid should be administered with caution to patients with advanced liver cirrhosis, especially those who have a history of electrolyte imbalance or hepatic encephalopathy (the brain's function is compromised when a damaged liver fails to eliminate toxins from the blood). It may cause hepatic coma (liver failure leads to an altered level of consciousness) and death.

• To minimize thromboembolic events, elderly cardiac patients should refrain from sudden contractions of plasma volume and hemoconcentration. Excessive potassium loss in individuals receiving digitalis glycosides may exacerbate digitalis toxicity (a side effect of digitalis therapy, which is used to treat certain heart diseases).

• Several potentially drug-related deaths were reported in critically ill patients who have been resistant to other diuretics, such as severe myocardial disease patients who received digitalis, who suffered acute hypokalemia with fatal arrhythmia (irregular heartbeat), and severely decompensated hepatic cirrhosis with ascites who died as a result of an intensification of electrolyte defect.

• Deafness, tinnitus (ringing in ears), and vertigo (spinning sensation, usually triggered by excessive head movement) with a sense of fullness in the ears have been reported, most commonly in individuals with significant kidney function impairment. Ethacrynic acid may exacerbate the ototoxicity (ear damage due to drug side effects) of other medications.

• Lithium should not be used alongside diuretics.

Precautions

Ethacrynic acid is a drug that is prescribed to treat hypertension, renal edema, and other disorders. It is prescribed for treating weak muscles, cramps, paraesthesia (sensation of tingling, numbness, or "pins and needles"), excessive thirst, anorexia (an eating disorder in which people worry about their weight and what they consume), hyponatremia, hypokalemia, and hypochloremic alkalosis (low chlorine levels in the body).

The drug's safety and efficacy in hypertension have not been determined; however, the dosage of co-administered antihypertensive medications may need to be adjusted.

Ethacrynic acid has minimal impact on glomerular filtration or renal blood flow, except for significant plasma volume decreases when combined with fast diuresis. A temporary increase in serum urea nitrogen may occur; however, this is normally reversed when the medicine is stopped. Hypoproteinemia (low protein levels in the blood) can impair Ethacrynic acid reactivity; hence, the use of salt-poor albumin should be investigated. Ethacrynic acid may raise the risk of stomach bleeding during corticosteroid treatment.

Laboratory testing should be conducted early in therapy and regularly during active diuresis, with any electrolyte abnormalities rectified or the medicine temporarily discontinued. Patients who get Ethacrynic acid may develop blood glucose rises and changes in glucose tolerance testing.

For Patients

What Are Hypertension and Edema?

Hypertension, often known as high blood pressure, is a significant medical disorder in which the force of blood on artery walls is constantly too high, resulting in heart disease, stroke (brain damage due to disruptions in the blood), and other health issues if not addressed.

Edema, or swelling caused by fluid retention, is frequently a symptom of several illnesses, including heart failure, kidney disease, liver problems, thyroid abnormalities, blood clots, infections, severe allergic responses, some malignancies, and certain drugs.

How Does Ethacrynic Acid Work?

Ethacrynic acid is a powerful diuretic that operates by inhibiting NKCC2 (Sodium-potassium-chloride cotransporter 2) in the loop of Henle and macula densa of the kidneys. This inhibits the body from absorbing excessive salt, allowing it to be excreted in urine. This improves urine production, allowing the body to rid itself of excess water, reduces fluid retention (edema), and lowers blood pressure, all of which are frequently caused by illnesses such as congestive heart failure, liver disease, and renal disease. However, because of its effectiveness, dosing is critical, as minor variations can significantly impact the biological response.

What Are the Clinical Uses of Ethacrynic Acid?

Ethacrynic acid is utilized in the following clinical applications:

• Treatment of Edema: It is used to treat edema in individuals suffering from congestive heart failure, liver disease, or kidney problems such as nephrotic syndrome.

• Ascites Management: Ethacrynic acid treats short-term ascites caused by cancer, idiopathic edema, or lymphedema.

• Congenital Heart Disease and Nephrotic Syndrome in Children: It is used for the short-term care of hospitalized pediatric patients, other than neonates, with congenital heart disease or nephrotic syndrome.

• High Blood Pressure: Ethacrynic acid can help treat high blood pressure.

How Is Ethacrynic Acid Administered?

Ethacrynic acid can be given either orally or intravenously. Here are the common doses:

Oral Dosage for Ascites and Edema:

• Begin with 50 to 200 mg of Ethacrynic acid daily in one to two divided doses.

• Once effective diuresis is achieved, modify the dose to the minimum effective dose in 25 to 50 mg increments.

• It can be provided on a continuous or intermittent schedule.

• When adding Ethacrynic acid to an existing diuretic program, begin with 25 mg increments.

• Initial and maintenance doses of Ethacrynic acid 200 mg twice daily may be required, particularly in patients with severe refractory edema.

• Once dry weight is obtained, the dose and frequency can typically be reduced.

Intravenous Dosage:

• 50 mg (0.5 to 1 mg/kg (milligrams per kilogram)) administered intravenously once.

• Sometimes, a second dose at an alternate injection site is needed.

• In severe cases, a single dose of Ethacrynic acid, no more than 100 mg, was delivered.

Drug Administration:

• Follow the instructions on the prescription label. The doctor might alter the dosage to ensure the best results. Do not take this drug in higher or lower doses or for longer than recommended.
• Unless otherwise directed by the doctor, take Ethacrynic acid after a meal.
• Ethacrynic acid causes individuals to urinate more frequently, and they may become dehydrated quickly. Follow the doctor's instructions for taking potassium supplements or consuming enough salt and potassium in the diet.
• Patients on Ethacrynic acid may require periodic blood tests and weight checks.
• Store at room temperature, away from moisture and heat. If not in use, keep the bottle closed tightly.

What Are the Side Effects of Ethacrynic Acid?

If patients exhibit symptoms of an allergic response, like hives, difficulty breathing, or swelling of the face, lips, tongue, or throat, seek emergency medical care.

Ethacrynic acid may have substantial adverse effects. Call the doctor immediately if patients have:

• Weight loss.

• Severe diarrhea.

• Hearing issues and ear fullness.

• Muscle weakness, muscle cramps, numbness, or tingling sensation.

• Light-headedness.

• Sudden numbness, speech and balance issues, chest pain, and bloody cough.

• Symptoms of low potassium include leg cramps, constipation, irregular heartbeats, fluttering in the chest region, increased thirst or urination, numbness or tingling, muscle weakness, or limp feeling.

• Symptoms of low sodium include headache, confusion, slurred speech, severe weakness, vomiting, lack of coordination, and feeling shaky.

Common side effects of Ethacrynic acid can include:

• Nausea, vomiting, diarrhea, or other stomach pain.

• Trouble swallowing.

• Loss of appetite.

• Blurred vision.

• Fever, chills.

• Headache and feeling fatigued.

What Are the Things to Inform the Doctor Before Taking Ethacrynic Acid?

• Ethacrynic acid should not be taken by individuals with allergies, urinary inability, or recent acute watery diarrhea.

• In order to ensure that Ethacrynic acid is suitable for individuals, consult a medical professional if people are suffering from:

  • Cirrhosis or another type of liver disease.

  • Heart illness.

  • Electrolyte imbalance (for example, low potassium or magnesium levels in the blood).

  • Kidney disease.

  • Gout (arthritis due to uric acid crystallization and deposition in the joints).

• If people are following a low-salt diet.

• Ethacrynic acid is not thought to harm an unborn fetus. Inform the doctor if patients are pregnant or plan to become pregnant when using Ethacrynic acid.

• Whether Ethacrynic acid penetrates breast milk or affects a nursing baby is uncertain. One should not breastfeed when taking Ethacrynic acid.

• Ethacrynic acid is not approved for use by any individual under 18.

Dietary Considerations

Follow the doctor's diabetes treatment plan, which may include daily exercise, a low-salt diet, potassium supplements, and increased potassium-rich foods.

Missed Dose

Take the missed dose of Ethacrynic acid immediately as one remembers it; skip it if the medication's nearing the time for the next regular dose; and avoid taking any extra Ethacrynic acid dose to compensate.

Overdose

Xerostomia (dry mouth), excessive thirst, mood changes, disorientation, ringing in the ears, loss of appetite, vomiting, muscle discomfort or weakness, fatigue, rapid heartbeat, and little or no urination are some of the signs of an Ethacrynic acid overdose. If someone suspects one has overdosed on Ethacrynic acid, then one should seek medical assistance immediately or call the Poison Help line.

Storage and Handling

• Keep Ethacrynic acid securely sealed, out of the reach of children, and at room temperature.

• Lock safety caps and store Ethacrynic acid in a secure area.

• Unneeded Ethacrynic acid medication should be disposed of properly, especially through a medicine take-back program.

For Doctors:

What Are the Pharmacological Actions of Ethacrynic Acid?

Pharmacodynamics

Ethacrynic acid is a monosulfonamyl loop, sometimes known as a high-ceiling diuretic. Ethacrynic acid operates on the ascending limb of the Henle's loop, as well as the proximal and distal tubules. Urinary output is usually dose-dependent and proportional to the amount of fluid accumulated because Ethacrynic acid inhibits the reabsorption of a substantially more significant proportion of filtered sodium than most other diuretics. Water and electrolyte excretion can be raised severalfold over that of thiazide diuretics. As a result, many patients with severe renal insufficiency benefit from Ethacrynic acid. Ethacrynic acid has little to no effect on glomerular filtration or renal blood flow, especially when plasma volume is significantly reduced due to fast diuresis.

Chemical Taxonomy

Ethacrynic acid is a phenoxyacetic acid derivative with a ketone and methylene group that is substituted with chlorines and a 2-methylidenebutanoyl group. The IUPAC nomenclature represents ethacrynic acid's molecular structure - ([2,3-dichloro-4-(2-methylenebutanoyl)phenoxy]acetic acid).

Mechanism of Action

Ethacrynic acid blocks sodium, potassium, and chloride symport in the ascending limb of Henle and the proximal and distal tubules. This pharmacological effect causes ion excretion, increased urine output, and decreased extracellular fluid. Diuretics first lower blood pressure by lowering plasma and extracellular fluid volume; cardiac output also falls, which explains their antihypertensive effects. Eventually, cardiac output recovers to normal, with a decrease in peripheral resistance. Its mechanism of action does not require carbonic anhydrase inhibition.

Pharmacokinetics

Ethacrynic acid has distinct pharmacokinetic properties:

Absorption: Ethacrynic acid is quickly absorbed after oral dosing. Oral administration results in diuresis after 30 minutes, while intravenous administration takes 5 minutes. The peak effect is achieved in approximately two hours for oral administration and 30 minutes for intravenous administration.

Metabolism: In the liver, it is converted (thirty-five to forty percent) into an active cysteine conjugate.

Excretion: It is eliminated in stools and urine (30 to 60 percent unaltered medication). Half-life elimination is approximately two to four hours in people with normal renal function. Ethacrynic acid is mainly attached to proteins, accounting for about 90 percent. Ethacrynic acid operates on the ascending limb of the Henle's loop and the proximal and distal tubules. Urinary output is often dose-dependent and proportional to the amount of fluid accumulation.

It should be noted that the systemic availability of Ethacrynic acid following oral treatment is limited and variable. This supports the intravenous method of administration's potential value in the treatment of drug resistance.

Toxicity

Ethacrynic acid, like other drugs, can have harmful adverse effects under some circumstances. These include ototoxicity (hearing loss), liver damage, low potassium levels, diarrhea, allergic responses, severe watery diarrhea, and electrolyte imbalance. High doses of Ethacrynic acid can harm the liver, whereas low potassium levels might cause muscle cramps or paralysis. Oral ingestion can cause diarrhea, with intestinal bleeding at higher doses. If people have recently experienced severe watery diarrhea, then one should avoid using Ethacrynic acid. Patients with advanced liver cirrhosis, especially those who have a history of electrolyte imbalance or hepatic encephalopathy, should be treated with caution.

What Are the Drug Interactions of Ethacrynic Acid?

• Lithium should not be taken with diuretics since they impede renal clearance and increase the risk of lithium toxicity.

• Before using such concurrent therapy, read the lithium preparation circulars.

• Ethacrynic acid may exacerbate the ototoxicity of other medications, including aminoglycosides and certain cephalosporin antibiotics. Concurrent use should be avoided.

• Several medications, including Ethacrynic acid, have been demonstrated to displace Warfarin from plasma protein; in patients receiving both treatments, the standard anticoagulant dosage may need to be reduced.

• In some people, nonsteroidal anti-inflammatory medication can diminish the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and Thiazide diuretics. As a result, when Ethacrynic acid and nonsteroidal anti-inflammatory medications are administered concurrently, the patient should be constantly monitored to establish whether the desired effect of the diuretic is achieved.

Clinical Studies

Several clinical trials have been undertaken to understand better how Ethacrynic acid affects disorders like hypertension and edema.

In a trial of 31 edematous patients, a single intravenous dose of Ethacrynic acid induced a diuretic response on 61 occasions. Maximum water, sodium, chloride, and potassium diuresis happened within the first hour, extending to the following day.

Ethacrynic acid was most beneficial when administered to eight patients with pulmonary edema twelve times.

Another study examined the impact of intravenous Ethacrynic acid on renal function, water, and electrolyte excretion in eight hospitalized, non-edematous patients. None of these patients had clinical renal or cardiac problems.

The hemodynamic effects of intravenous Ethacrynic acid were evaluated in five normal people and five patients with advanced congestive heart failure. Normal participants experienced an average diuresis of 1.2 liters in 90 minutes, resulting in a 14 percent drop in plasma volume.

These trials suggest that Ethacrynic acid may be useful in treating hypertension and edema.

Use in Specific Populations

Pregnancy: Some drugs are not recommended during pregnancy because they can harm the fetus or newborn without creating abnormalities. Although animal research has demonstrated lower fetal body weights, there is no controlled data on human pregnancy. The US FDA pregnancy category B (animal studies have not shown any significant risk to the fetus, despite the lack of adequate human studies) depends on animal reproduction studies that did not show a risk to the fetus, as well as a lack of adequate and well-controlled research in pregnant women.

Breastfeeding: The decision to quit nursing or the medicine should take into account the mother's importance. The effects on nursing infants are unknown; no information on the drug's excretion into human and animal milk is available.

Pediatric Use: There are no well-controlled clinical trials involving pediatric patients. The evidence for oral doses in pediatric patients other than infants is backed by empiric use in this age range.

Geriatric Use: Ethacrynic acid is appropriate for elderly individuals, although it should be carefully watched for potential side effects and interactions with other drugs. There have been no reports of geriatric-specific issues that would limit its efficacy. Elderly people are more likely to experience age-related kidney issues, which may necessitate dosage modifications.