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Identification
Name Hydroflumethiazide
Accession Number DB00774 (APRD01020)
Type small molecule
Groups approved
Description

A thiazide diuretic with actions and uses similar to those of hydrochlorothiazide. (From Martindale, The Extra Pharmacopoeia, 30th ed, p822)
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Dihydroflumethazide
Hidroflumetiazid
Hydroflumethazide
Hydroflumethizide
Trifluoromethylhydrazide
Trifluoromethylhydrothiazide
Salts Not Available
Brand names
Name Company
Diuredemina
Diurometon
Enjit
Flutizide
Glomerulin
Hidroalogen
Robezon
Spandiuril
Brand mixtures Not Available
Categories
  • Antihypertensive Agents
  • Diuretics
  • Diuretics, Thiazide
  • Sodium Chloride Symporter Inhibitors
CAS number 135-09-1
Weight Average: 331.292
Monoisotopic: 330.990831754
Chemical Formula C8H8F3N3O4S2
InChI Key InChIKey=DMDGGSIALPNSEE-UHFFFAOYSA-N
InChI
InChI=1S/C8H8F3N3O4S2/c9-8(10,11)4-1-5-7(2-6(4)19(12,15)16)20(17,18)14-3-13-5/h1-2,13-14H,3H2,(H2,12,15,16)
Plain Text
IUPAC Name
1,1-dioxo-6-(trifluoromethyl)-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=CC2=C(NCNS2(=O)=O)C=C1C(F)(F)F
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzenesulfonamides
  • Sulfanilamides
Substructures
  • Sulfonyls
  • Halogen Derivatives
  • Benzene and Derivatives
  • Benzenesulfonamides
  • Aminals and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Thiadiazines
  • Sulfanilamides
  • Sulfonamides
  • Anilines
Pharmacology
Indication Used as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Also used in the management of hypertension either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in the more severe forms of hypertension.
Pharmacodynamics Hydroflumethiazide is an oral thiazide used to treat hypertension and edema. High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. Like other thiazides, Hydroflumethiazide promotes water loss from the body (diuretics). Thiazides inhibit Na+/Cl- reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue.
Mechanism of action Hydroflumethiazide is a thiazide diuretic that inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, Hydroflumethiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.
Absorption Hydroflumethiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract
Volume of distribution Not Available
Protein binding 74%
Metabolism Essentially unchanged
Route of elimination Not Available
Half life It appears to have a biphasic biological half-life with an estimated alpha-phase of about 2 hours and an estimated beta-phase of about 17 hours
Clearance Not Available
Toxicity Overdoses lead to diuresis, lethargy progressing to coma, with minimal cardiorespiratory depression and with or without significant serum electrolyte changes or dehydration.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00108 Hydroflumethiazide Pathway SMP00108
Pharmacoeconomics
Manufacturers
  • Wyeth ayerst laboratories
  • Par pharmaceutical inc
  • Watson laboratories inc
  • Shire development inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices Not Available
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 270.5 °C PhysProp
water solubility 300 mg/L (at 25 °C) MERCK INDEX (1996)
logP 0.36 HANSCH,C ET AL. (1995)
pKa 8.9 BUDAVARI,S ET AL. (1996)
Predicted Properties
Property Value Source
water solubility 8.58e-01 g/l ALOGPS
logP 0.44 ALOGPS
logP -0.3 ChemAxon
logS -2.6 ALOGPS
pKa (strongest acidic) 9.07 ChemAxon
pKa (strongest basic) -2.7 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 3 ChemAxon
polar surface area 118.36 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 64.28 ChemAxon
polarizability 25.68 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Moser M, Feig PU: Fifty years of thiazide diuretic therapy for hypertension. Arch Intern Med. 2009 Nov 9;169(20):1851-6. Pubmed 19901136
External Links
Resource Link
KEGG Drug D00654 Link_out
KEGG Compound C07763 Link_out
PubChem Compound 3647 Link_out
PubChem Substance 46505220 Link_out
ChemSpider 3521 Link_out
BindingDB 25897 Link_out
Therapeutic Targets Database DAP000747 Link_out
PharmGKB PA164752557 Link_out
RxList http://www.rxlist.com/cgi/generic2/hydroflumethiazide.htm Link_out
ATC Codes
  • C03AA02
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Digoxin Possible electrolyte variations and arrhythmias
Lithium The thiazide diuretic, hydroflumethiazide, may increase serum levels of lithium.
Trandolapril The thiazide diuretic, Hydroflumethiazide, may increase the hypotensive effect of Trandolapril. Hydroflumethiazide may also increase the nephrotoxicity of Trandolapril. Monitor for postural hypotension at initiation of concomitant therapy and renal dysfunction during chronic therapy.
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food Interactions Not Available
Targets

1. 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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Carbonic anhydrase 1

Pharmacological action: unknown
Actions: inhibitor

Reversible hydration of carbon dioxide

Organism class: human
UniProt ID: P00915 Link_out
Gene: CA1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. Epub 2008 Dec 24. Pubmed

3. Carbonic anhydrase 2

Pharmacological action: unknown
Actions: inhibitor

Reversible hydration of carbon dioxide

Organism class: human
UniProt ID: P00918 Link_out
Gene: CA2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Schaeffer P, Vigne P, Frelin C, Lazdunski M: Identification and pharmacological properties of binding sites for the atypical thiazide diuretic, indapamide. Eur J Pharmacol. 1990 Jul 17;182(3):503-8. Pubmed
  2. Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. Epub 2008 Dec 24. Pubmed

4. Carbonic anhydrase 4

Pharmacological action: unknown
Actions: inhibitor

Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4

Organism class: human
UniProt ID: P22748 Link_out
Gene: CA4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. Epub 2008 Dec 24. Pubmed

5. Carbonic anhydrase 9

Pharmacological action: unknown
Actions: inhibitor

Reversible hydration of carbon dioxide. May be involved in the control of cell proliferation and transformation. Appears to be a novel specific biomarker for a cervical neoplasia

Organism class: human
UniProt ID: Q16790 Link_out
Gene: CA9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. Epub 2008 Dec 24. Pubmed

6. Carbonic anhydrase 12

Pharmacological action: unknown
Actions: inhibitor

Reversible hydration of carbon dioxide

Organism class: human
UniProt ID: O43570 Link_out
Gene: CA12 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. Epub 2008 Dec 24. Pubmed

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

Pharmacological action: unknown
Actions: other/unknown

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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

8. Calcium-activated potassium channel subunit alpha 1

Pharmacological action: unknown
Actions: other/unknown

Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). It is also activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+) concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key role in controlling excitability in a number of systems, such as regulation of the contraction of smooth muscle, the tuning of hair cells in the cochlea, regulation of transmitter release, and innate immunity. In smooth muscles, its activation by high level of Ca(2+), caused by ryanodine receptors in the sarcoplasmic reticulum, regulates the membrane potential. In cochlea cells, its number and kinetic properties partly determine the characteristic frequency of each hair cell and thereby helps to establish a tonotopic map. Kinetics of KCNMA1 channels are determined by alternative splicing, phosphorylation status and its combination with modulating beta subunits. Highly sensitive to both iberiotoxin (IbTx) and charybdotoxin (CTX)

Organism class: human
UniProt ID: Q12791 Link_out
Gene: KCNMA1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19