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Identification
NameEthacrynic acid
Accession NumberDB00903  (APRD00251)
Typesmall molecule
Groupsapproved
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
Synonyms
SynonymLanguageCode
(2,3-Dichloro-4-(2-methylene-1-oxobutyl)phenoxy)acetic acidNot AvailableNot Available
Acide etacryniqueNot AvailableNot Available
Acido etacrinicoNot AvailableNot Available
Acidum etacrynicumNot AvailableNot Available
CrinurylNot AvailableNot Available
EdecrilNot AvailableNot Available
EdecrinaNot AvailableNot Available
EndecrilNot AvailableNot Available
Etacrinic acidNot AvailableNot Available
Etacrynic acidNot AvailableINN
Etakrinic acidNot AvailableNot Available
Ethacryinic AcidNot AvailableNot Available
EthacrynateNot AvailableNot Available
Ethacrynic acidNot AvailableNot Available
HidromedinNot AvailableNot Available
HydromedinNot AvailableNot Available
Methylenebutyrylphenoxyacetic acidNot AvailableNot Available
MingitNot AvailableNot Available
OtacrilNot AvailableNot Available
ReomaxNot AvailableNot Available
TaladrenNot AvailableNot Available
UregitNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
CrinurylAssia
EdecrilMerck
EdecrinAton
HydromedinMerck
ReomaxBioindustria
TaladrenMalesci
Brand mixturesNot Available
Categories
CAS number58-54-8
WeightAverage: 303.138
Monoisotopic: 302.011264286
Chemical FormulaC13H12Cl2O4
InChI KeyAVOLMBLBETYQHX-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)
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenoxyacetic Acid Derivatives
Direct parentPhenoxyacetic Acid Derivatives
Alternative parentsButyrophenones; Phenylpropenes; Acetophenones; Dichlorobenzenes; Phenol Ethers; Benzoyl Derivatives; Alkyl Aryl Ethers; Aryl Chlorides; Enones; Acryloyl Compounds; Enolates; Polyamines; Carboxylic Acids; Organochlorides
Substituentsacetophenone; phenylpropene; 1,2-dichlorobenzene; benzoyl; phenol ether; alkyl aryl ether; chlorobenzene; aryl chloride; aryl halide; enone; acryloyl-group; ketone; carboxylic acid; polyamine; carboxylic acid derivative; ether; enolate; organohalogen; organochloride; carbonyl group
Classification descriptionThis compound belongs to the phenoxyacetic acid derivatives. These are compounds containing an anisole where the methane group is linked to an acetic acid or a derivative.
Pharmacology
IndicationFor the treatment of high blood pressure and edema caused by diseases like congestive heart failure, liver failure, and kidney failure.
PharmacodynamicsEthacrynic 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 actionEthacrynic 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.
AbsorptionOnset 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 distributionNot Available
Protein binding> 98%
Metabolism

Hepatic.

Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityOverdosage may lead to excessive diuresis with electrolyte depletion.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Ethacrynic Acid Action PathwayDrug actionSMP00097
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9591
Blood Brain Barrier - 0.6921
Caco-2 permeable + 0.5597
P-glycoprotein substrate Substrate 0.54
P-glycoprotein inhibitor I Non-inhibitor 0.5574
P-glycoprotein inhibitor II Non-inhibitor 0.9828
Renal organic cation transporter Non-inhibitor 0.9052
CYP450 2C9 substrate Non-substrate 0.8508
CYP450 2D6 substrate Non-substrate 0.8947
CYP450 3A4 substrate Non-substrate 0.5262
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Inhibitor 0.8949
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.831
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8384
Ames test Non AMES toxic 0.9133
Carcinogenicity Non-carcinogens 0.8344
Biodegradation Ready biodegradable 0.6545
Rat acute toxicity 2.4505 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9228
hERG inhibition (predictor II) Non-inhibitor 0.9044
Pharmacoeconomics
Manufacturers
  • Aton pharma inc
Packagers
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous
TabletOral
Prices
Unit descriptionCostUnit
Sodium edecrin 50 mg vial527.4USDvial
Edecrin sodium 50 mg vial114.0USDvial
Ethacrynic acid 100% powder26.4USDg
Edecrin 25 mg tablet3.19USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point118.5-120.5Schultz, E.M. and Sprague, J.M.; U.S. Patent 3,255,241; June 7, 1966; assigned to Merck & co., Inc.
logP3.3Not Available
pKa3.5MERCK INDEX (2001)
Predicted Properties
PropertyValueSource
water solubility1.94e-02 g/lALOGPS
logP3.42ALOGPS
logP3.66ChemAxon
logS-4.2ALOGPS
pKa (strongest acidic)2.8ChemAxon
pKa (strongest basic)-5ChemAxon
physiological charge-1ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count1ChemAxon
polar surface area63.6ChemAxon
rotatable bond count6ChemAxon
refractivity72.22ChemAxon
polarizability28.57ChemAxon
number of rings1ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Schultz, E.M. and Sprague, J.M.; U.S. Patent 3,255,241; June 7, 1966; assigned to Merck
& co., Inc.

General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00313
PubChem Compound3278
PubChem Substance46507562
ChemSpider3163
ChEBI4876
ChEMBLCHEMBL456
Therapeutic Targets DatabaseDAP000748
PharmGKBPA449518
HETEAA
Drug Product Database2258528
RxListhttp://www.rxlist.com/cgi/generic3/edecrin.htm
Drugs.comhttp://www.drugs.com/cdi/ethacrynate-sodium.html
WikipediaEthacrynic_acid
ATC CodesC03CC01
AHFS Codes
  • 40:28.08
PDB EntriesNot Available
FDA labelshow(75.2 KB)
MSDSshow(74 KB)
Interactions
Drug Interactions
Drug
AmikacinIncreased ototoxicity
CisplatinIncreased ototoxicity
ColesevelamBile 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.
DeslanosidePossible electrolyte variations and arrhythmias
DigitoxinPossible electrolyte variations and arrhythmias
DigoxinPossible electrolyte variations and arrhythmias
GentamicinIncreased ototoxicity
GinsengGinseng may decrease the therapeutic effect of diuretic, ethacrynic acid.
IbuprofenThe NSAID, ibuprofen, may antagonize the diuretic and antihypertensive effects of the loop diuretic, ethacrynic acid.
IndacaterolConcomitant therapy may increase the risk of hypokalemia via intracellular shunting. Monitor for adverse effects and especially for cardiovascular effects associated with hypokalemia.
IndomethacinThe NSAID, indomethacin, may decrease the diuretic and antihypertensive effects of the loop diuretic, ethacrynic acid.
KanamycinIncreased ototoxicity
NetilmicinIncreased ototoxicity
StreptomycinIncreased ototoxicity
SulindacThe NSAID, sulindac, may decrease the diuretic and antihypertensive effects of the loop diuretic, ethacryninc acid.
TobramycinIncreased ototoxicity
TrandolaprilThe loop diuretic, Ethacrynic acid, may increase the hypotensive effect of Trandolapril. Ethacrynic acid may also increase the nephrotoxicity of Trandolapril.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food Interactions
  • Take with food to reduce irritation.

Targets

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium/potassium-transporting ATPase subunit alpha-1 P05023 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier family 12 member 1 Q13621 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Glutathione S-transferase A2 P09210 Details

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

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Serum albumin P02768 Details

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

Transporters

1. Solute carrier family 22 member 6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier family 22 member 6 Q4U2R8 Details

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

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Drug created on June 13, 2005 07:24 / Updated on April 17, 2014 13:38