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Identification
Name Ethacrynic acid
Accession Number DB00903 (APRD00251)
Type small molecule
Groups approved
Description

A compound that inhibits symport of sodium, potassium, and chloride primarily in the ascending limb of Henle, but also in the proximal and distal tubules. This pharmacological action results in excretion of these ions, increased urinary output, and reduction in extracellular fluid. This compound has been classified as a loop or high ceiling diuretic. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Etacrinic acid
Etacrynic acid
Etakrinic acid
Ethacryinic Acid
Ethacrynate
Methylenebutyrylphenoxyacetic acid
Salts Not Available
Brand names
Name Company
Crinuryl
Edecril
Edecrin
Edecrina
Endecril
Hidromedin
Hydromedin
Mingit
Otacril
Reomax
Taladren
Uregit
First Prev Next Last
Brand mixtures Not Available
Categories
  • Enzyme Inhibitors
  • Diuretics
CAS number 58-54-8
Weight Average: 303.138
Monoisotopic: 302.011264286
Chemical Formula C13H12Cl2O4
InChI Key InChIKey=AVOLMBLBETYQHX-UHFFFAOYSA-N
InChI
InChI=1S/C13H12Cl2O4/c1-3-7(2)13(18)8-4-5-9(12(15)11(8)14)19-6-10(16)17/h4-5H,2-3,6H2,1H3,(H,16,17)
Plain Text
IUPAC Name
2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid
SMILES
CCC(=C)C(=O)C1=C(Cl)C(Cl)=C(OCC(O)=O)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes
  • Phenoxyacetates
Substructures
  • Hydroxy Compounds
  • Alkanes and Alkenes
  • Acetates
  • Phenols and Derivatives
  • Phenoxyacetates
  • Short-chain Hydroxy Acids
  • Ethers
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Carboxylic Acids and Derivatives
  • Aromatic compounds
  • Anisoles
  • Benzoyl Derivatives
  • Phenyl Esters
  • Ketones
Pharmacology
Indication For the treatment of high blood pressure and edema caused by diseases like congestive heart failure, liver failure, and kidney failure.
Pharmacodynamics 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.
Mechanism of action Ethacrynic acid inhibits symport of sodium, potassium, and chloride primarily in the ascending limb of Henle, but also in the proximal and distal tubules. This pharmacological action results in excretion of these ions, increased urinary output, and reduction in extracellular fluid. Diuretics also lower blood pressure initially by reducing plasma and extracellular fluid volume; cardiac output also decreases, explaining its antihypertensive action. Eventually, cardiac output returns to normal with an accompanying decrease in peripheral resistance. Its mode of action does not involve carbonic anhydrase inhibition.
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.
Volume of distribution Not Available
Protein binding > 98%
Metabolism Hepatic.
Route of elimination Not Available
Half life Not Available
Clearance Not Available
Toxicity Overdosage may lead to excessive diuresis with electrolyte depletion.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00097 Ethacrynic Acid pathway SMP00097
Pharmacoeconomics
Manufacturers
  • Aton pharma inc
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Tablet Oral
Prices
Unit description Cost Unit
Sodium edecrin 50 mg vial 527.4 USD vial
Edecrin sodium 50 mg vial 114.0 USD vial
Ethacrynic acid 100% powder 26.4 USD g
Edecrin 25 mg tablet 3.19 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 122.5 °C PhysProp
logP 3.3 Not Available
pKa 3.5 MERCK INDEX (2001)
Predicted Properties
Property Value Source
water solubility 1.94e-02 g/l ALOGPS
logP 3.42 ALOGPS
logP 3.66 ChemAxon
logS -4.2 ALOGPS
pKa (strongest acidic) 2.8 ChemAxon
pKa (strongest basic) -5 ChemAxon
physiological charge -1 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 63.6 ChemAxon
rotatable bond count 6 ChemAxon
refractivity 72.22 ChemAxon
polarizability 28.57 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00313 Link_out
PubChem Compound 3278 Link_out
PubChem Substance 46507562 Link_out
ChemSpider 3163 Link_out
ChEBI 4876 Link_out
ChEMBL 4876 Link_out
Therapeutic Targets Database DAP000748 Link_out
PharmGKB PA449518 Link_out
HET EAA Link_out
Drug Product Database 2258528 Link_out
RxList http://www.rxlist.com/cgi/generic3/edecrin.htm Link_out
Drugs.com http://www.drugs.com/cdi/ethacrynate-sodium.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Ethacrynic_acid Link_out
ATC Codes
  • C03CC01
AHFS Codes
  • 40:28.08
PDB Entries Not Available
FDA label show (75.2 KB)
MSDS show (74 KB)
Interactions
Drug Interactions
Drug Interaction
Amikacin Increased ototoxicity
Cisplatin Increased ototoxicity
Colesevelam Bile acid sequestrants such as colesevelam may decrease the absorption of loop diuretics such as ethacrynic acid. Monitor for decreased serum concentrations/therapeutic effects of loop diuretics if coadministered with bile acid sequestrants. Separating the administration of doses by 2 or more hours may reduce (but not eliminate) the risk of interaction. The manufacturer of colesevelam recommends that drugs should be administered at least 1 hour before or 4 hours after colesevelam.
Deslanoside Possible electrolyte variations and arrhythmias
Digitoxin Possible electrolyte variations and arrhythmias
Digoxin Possible electrolyte variations and arrhythmias
Gentamicin Increased ototoxicity
Ginseng Ginseng may decrease the therapeutic effect of diuretic, ethacrynic acid.
Ibuprofen The NSAID, ibuprofen, may antagonize the diuretic and antihypertensive effects of the loop diuretic, ethacrynic acid.
Indomethacin The NSAID, indomethacin, may decrease the diuretic and antihypertensive effects of the loop diuretic, ethacrynic acid.
Kanamycin Increased ototoxicity
Netilmicin Increased ototoxicity
Streptomycin Increased ototoxicity
Sulindac The NSAID, sulindac, may decrease the diuretic and antihypertensive effects of the loop diuretic, ethacryninc acid.
Tobramycin Increased ototoxicity
Trandolapril The loop diuretic, Ethacrynic acid, may increase the hypotensive effect of Trandolapril. Ethacrynic acid may also increase the nephrotoxicity of Trandolapril.
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food Interactions
  • Take with food to reduce irritation.
Targets

1. Sodium/potassium-transporting ATPase alpha-1 chain

Pharmacological action: yes
Actions: inhibitor

This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients

Organism class: human
UniProt ID: P05023 Link_out
Gene: ATP1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ronquist G, Agren GK: A Mg2+- and Ca2+-stimulated adenosine triphosphatase at the outer surface of Ehrlich ascites tumor cells. Cancer Res. 1975 Jun;35(6):1402-6. Pubmed
  2. Proverbio F, Condrescu-Guidi M, Whittembury G: Ouabain-insensitive Na+ stimulation of an Mg-2+ -dependent ATPase in kidney tissue. Biochim Biophys Acta. 1975 Jun 25;394(2):281-92. Pubmed
  3. Valdes RM, Huff MO, El-Masri MA, El-Mallakh RS: Effect of ethacrynic acid on sodium pump alpha isoforms in SH-SY5Y cells. Bipolar Disord. 2003 Apr;5(2):123-8. Pubmed
  4. Kiil F, Sejersted OM: Analysis of energy metabolism and mechanism of loop diuretics in the thick ascending limb of Henle’s loop in dog kidneys. Acta Physiol Scand. 2003 May;178(1):73-82. Pubmed
  5. Schurek HJ, Aulbert E, Ebel H, Muller-Suur C: Influence of ouabain and ethacrynic acid on sodium transport and NaK-ATPase activity in the isolated perfused rat kidney. Curr Probl Clin Biochem. 1975;4:162-8. Pubmed

2. Solute carrier family 12 member 1

Pharmacological action: yes
Actions: inhibitor

Electrically silent transporter system. Mediates sodium and chloride reabsorption. Plays a vital role in the regulation of ionic balance and cell volume

Organism class: human
UniProt ID: Q13621 Link_out
Gene: SLC12A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Bowes TJ, Gupta RS: Induction of mitochondrial fusion by cysteine-alkylators ethacrynic acid and N-ethylmaleimide. J Cell Physiol. 2005 Mar;202(3):796-804. Pubmed
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Enzymes

1. Glutathione S-transferase A2

Actions: inhibitor

Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles

UniProt ID: P09210 Link_out
Gene: GSTA2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Depeille P, Cuq P, Passagne I, Evrard A, Vian L: Combined effects of GSTP1 and MRP1 in melanoma drug resistance. Br J Cancer. 2005 Jul 25;93(2):216-23. Pubmed
  2. Awasthi S, Srivastava SK, Ahmad F, Ahmad H, Ansari GA: Interactions of glutathione S-transferase-pi with ethacrynic acid and its glutathione conjugate. Biochim Biophys Acta. 1993 Jul 10;1164(2):173-8. Pubmed
  3. Iersel ML, Ploemen JP, Struik I, van Amersfoort C, Keyzer AE, Schefferlie JG, van Bladeren PJ: Inhibition of glutathione S-transferase activity in human melanoma cells by alpha,beta-unsaturated carbonyl derivatives. Effects of acrolein, cinnamaldehyde, citral, crotonaldehyde, curcumin, ethacrynic acid, and trans-2-hexenal. Chem Biol Interact. 1996 Oct 21;102(2):117-32. Pubmed
  4. van Iersel ML, Ploemen JP, Lo Bello M, Federici G, van Bladeren PJ: Interactions of alpha, beta-unsaturated aldehydes and ketones with human glutathione S-transferase P1-1. Chem Biol Interact. 1997 Dec 12;108(1-2):67-78. Pubmed
  5. Morrow CS, Smitherman PK, Townsend AJ: Combined expression of multidrug resistance protein (MRP) and glutathione S-transferase P1-1 (GSTP1-1) in MCF7 cells and high level resistance to the cytotoxicities of ethacrynic acid but not oxazaphosphorines or cisplatin. Biochem Pharmacol. 1998 Oct 15;56(8):1013-21. Pubmed
Transporters

1. Solute carrier family 22 member 6

Actions: inhibitor
UniProt ID: Q4U2R8 Link_out
Gene: hROAT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Sekine T, Watanabe N, Hosoyamada M, Kanai Y, Endou H: Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem. 1997 Jul 25;272(30):18526-9. Pubmed
Carriers

1. Serum albumin

Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood

UniProt ID: P02768 Link_out
Gene: ALB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Bertucci C, Nanni B, Raffaelli A, Salvadori P: Chemical modification of human albumin at cys34 by ethacrynic acid: structural characterisation and binding properties. J Pharm Biomed Anal. 1998 Oct;18(1-2):127-36. Pubmed
  2. Bertucci C, Wainer IW: Improved chromatographic performance of a modified human albumin based stationary phase. Chirality. 1997;9(4):335-40. Pubmed
  3. Fehske KJ, Muller WE: High-affinity binding of ethacrynic acid is mediated by the two most important drug binding sites of human serum albumin. Pharmacology. 1986;32(4):208-13. Pubmed
  4. Lebedev AA, Samokrutova OV: [Study of the binding of diuretics by serum proteins according to changes in tryptophan fluorescence] Farmakol Toksikol. 1989 May-Jun;52(3):40-3. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19