DrugBank: Ethacrynic acid (DB00903)

targets (2) enzymes (1) transporters (1) carriers (1)

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

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

Etacrinic acid
Etacrynic acid
Etakrinic acid
Ethacryinic Acid
Ethacrynate
Methylenebutyrylphenoxyacetic acid

Brand names

Crinuryl
Edecril
Edecrin
Edecrina
Endecril
Hidromedin
Hydromedin
Mingit
Otacril
Reomax
Taladren
Uregit

Brand name 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
	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

Patents

Not Available

Properties

State

solid

Melting point

122.5 oC

Experimental Properties

Property	Value	Source
logP	3.3	PhysProp
pKa	3.5	Various sources

Predicted Properties

Property	Value	Source
water solubility	1.94e-02 g/l	ALOGPS
logP	3.42	ALOGPS
logP	3.66	ChemAxon Molconvert
logS	-4.19	ALOGPS
pKa		ChemAxon Molconvert
hydrogen acceptor count	4	ChemAxon Molconvert
hydrogen donor count	1	ChemAxon Molconvert
polar surface area	63.60	ChemAxon Molconvert
rotatable bond count	6	ChemAxon Molconvert
refractivity	72.22	ChemAxon Molconvert
polarizability	28.52	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

Not Available

External Links

Resource	Link
KEGG Drug	D00313
PubChem Compound	3278
PubChem Substance	46507562
ChemSpider	3163
ChEBI	4876
ChEMBL	4876
Therapeutic Targets Database	DAP000748
PharmGKB	PA449518
HET	EAA
Drug Product Database	2258528
RxList	http://www.rxlist.com/cgi/generic3/edecrin.htm
Drugs.com	http://www.drugs.com/cdi/ethacrynate-sodium.html
Wikipedia	http://en.wikipedia.org/wiki/Ethacrynic_acid

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

Not Available

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 Gene: ATP1A1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 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 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 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 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 Gene: SLC12A1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

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:

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
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
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
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
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:

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
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 Gene: GSTA2 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 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 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 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 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

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:

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
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
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
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
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 Gene: hROAT1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 Gene: ALB Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 Bertucci C, Wainer IW: Improved chromatographic performance of a modified human albumin based stationary phase. Chirality. 1997;9(4):335-40. Pubmed 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 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

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

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

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
Bertucci C, Wainer IW: Improved chromatographic performance of a modified human albumin based stationary phase. Chirality. 1997;9(4):335-40. Pubmed
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
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 April 19, 2011 15:07

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