Etacrynic acid ( INN) or ethacrynic acid (

USAN 280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk（于山國）was Ulleungdo（鬱陵島） Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to th ...

), trade name Edecrin, is a

loop diuretic Loop diuretics are diuretics that act on the Na-K-Cl cotransporter along the thick ascending limb of the loop of Henle in the kidney. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure o ...

used to treat

high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

and the swelling caused by diseases like

congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

, liver failure, and

kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

. A con with etacyrnic acid compared to the other loop diuretic drugs such as furosemide is that it has a significantly steep dose-response curve, which means the drug's dosing is very important as small variance in dose can cause a significant difference in the biological response. Unlike the other loop diuretics, etacrynic acid is not a

sulfonamide In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...

and thus use is not contraindicated in those with sulfa allergies. If a patient with sulfa allergies is in need of a loop diuretic, it is more likely for the physician to prescribe etacyrnic acid for this reason.

Structural features

Ethacrynic acid is a phenoxyacetic acid derivative, which means it contains a

ketone group In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bon ...

and a

methylene group In organic chemistry, a methylene group is any part of a molecule that consists of two hydrogen atoms bound to a carbon atom, which is connected to the remainder of the molecule by two single bonds. The group may be represented as , where th ...

Medical use

Ethacrynic acid is a diuretic that is used to treat

edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...

when a stronger agent is required. It is available as a pill or injected form. The pill is used to treat edema associated with

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...

and renal disease, accumulation of liquid in the belly associated with cancer or edema, and management of hospitalized children with

congenital heart disease A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...

nephrotic syndrome Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling. Other symptoms may include weight gain, feeling tired, and foamy ...

. The injected form is used to rapidly remove water from the body when needed – for example in acute

pulmonary edema Pulmonary edema, also known as pulmonary congestion, is excessive liquid accumulation in the tissue and air spaces (usually alveoli) of the lungs. It leads to impaired gas exchange and may cause hypoxemia and respiratory failure. It is due ...

– or when a person cannot take the medicine in pill form.Merck and FD
Etacrynic acid Label
Last updated February 2005 pe
FDA site for NDA 016093 injected form
an
FDA site for NDA 016092 oral form
per inde
here
each accessed January 16, 2016

Adverse effects

As a

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics i ...

, ethacrynic acid can cause frequent urination, but this usually resolves after taking the drug for a few weeks. Ethacrynic acid can also cause low potassium levels, which may manifest as muscle cramps or weakness. It has also been known to cause reversible or permanent hearing loss (

ototoxicity Ototoxicity is the property of being toxic to the ear (''oto-''), specifically the cochlea or auditory nerve and sometimes the vestibular system, for example, as a side effect of a drug. The effects of ototoxicity can be reversible and temporary, ...

) and liver damage when administered in extremely high dosages. On oral administration, it produces diarrhea; intestinal bleeding may occur at higher doses.

Mechanism of action

Ethacrynic acid acts by inhibiting NKCC2 in the thick

ascending loop of Henle Within the nephron of the kidney, the ascending limb of the loop of Henle is a segment of the heterogenous loop of Henle downstream of the descending limb, after the sharp bend of the loop. This part of the renal tubule is divided into a thin an ...

and the

macula densa In the kidney, the macula densa is an area of closely packed specialized cells lining the wall of the distal tubule, at the point where the thick ascending limb of the Loop of Henle meets the distal convoluted tubule. The macula densa is the t ...

. Loss of potassium ions is less marked but chances of hypochloremic alkalosis are greater. The dose response curve of ethacrynic acid is steeper than that of furosemide and, in general, it is less manageable; dose range is 50–150 mg. Ethacrynic acid and its glutathione-adduct are potent inhibitors of glutathione ''S''-transferase family members, which are enzymes involved in

xenobiotic metabolism Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set ...

. This family of enzymes has recently been shown to have a high rate of genetic variability.

United States price history

The ethacrynic acid tablet market had U.S. sales of approximately $17 million for the 12 months ending April 2020 according to IQVIA. National Average Drug Acquisition Cost data from the Centers for Medicare and Medicaid Services shows that the average price paid by retail pharmacies for an Edecrin 25 MG tablet was $5.24 as 11/28/13 by Bausch Health US, LLC, formerly Valeant Pharmaceuticals. The price from Bausch Health US, LLC increased to $21.72 per tablet as of 5/18/2016. In 2015, Valeant was involved in a number of controversies surrounding drug price hikes and the use of a specialty pharmacy for the distribution of its drugs. As of September 19, 2018, the price for the generic equivalent was $10.01 per tablet from West-ward Pharmaceuticals Corp., Edenbridge Pharmaceuticals, LLC and Oceanside Pharmaceuticals. As of July 22, 2020 the price decreased to $3.45 with availability from additional generic manufacturers. As of February 17, 2021 the average price paid by pharmacies was $5.69 per 25 MG tablet with 10 generic manufacturers. Up to date price information can be found at https://data.medicaid.gov/dataset/d5eaf378-dcef-5779-83de-acdd8347d68e/data?conditions ropertyndc_description&conditions alue%25ethacrynic%20acid%25&conditions peratorlike

Price fixing investigation

It is known whether this apparent price fixing is actively being investigated, but the United States Department of Justice Antitrust Division Spring Update 2021 notes: "The Division remains committed to rooting out illegal conduct that corrupts critical healthcare markets. That work is more important now than ever before. In recent years, the Division has uncovered price-fixing, bid-rigging, and customer-allocation schemes in one of the most important markets for the health and wallets of American consumers: the

generic drug A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active c ...

industry. Indeed, nearly 90% of all prescriptions in the United States are filled with generic drugs."

References

{{Diuretics Disulfiram-like drugs Loop diuretics Piceol ethers Acetic acids Chloroarenes Carbonic anhydrase inhibitors World Anti-Doping Agency prohibited substances Vinylidene compounds