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Identification
NameHydroflumethiazide
Accession NumberDB00774  (APRD01020)
TypeSmall Molecule
GroupsApproved
Description

A thiazide diuretic with actions and uses similar to those of hydrochlorothiazide. (From Martindale, The Extra Pharmacopoeia, 30th ed, p822)

Structure
Thumb
Synonyms
SynonymLanguageCode
DihydroflumethazideNot AvailableNot Available
HidroflumetiazidGermanINN
HidroflumetiazidaSpanishINN
HydrofluméthiazideFrenchINN
HydroflumethiazideNot AvailableNot Available
HydroflumethiazidumLatinINN
IdroflumetiazideNot AvailableDCIT
MetforylthiadiazinNot AvailableIS
SaluronNot AvailableNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
LeodrineLeo
SaluronShire
Brand mixtures
Brand NameIngredients
AldactideHydroflumethiazide and Spironolactone
SaltsNot Available
Categories
CAS number135-09-1
WeightAverage: 331.292
Monoisotopic: 330.990831754
Chemical FormulaC8H8F3N3O4S2
InChI KeyDMDGGSIALPNSEE-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)
IUPAC Name
1,1-dioxo-6-(trifluoromethyl)-3,4-dihydro-2H-1λ⁶,2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=CC2=C(NCNS2(=O)=O)C=C1C(F)(F)F
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as benzothiadiazines. These are organic compounds containing a benzene fused to a thiadiazine ring (a six-member ring with two nitrogen atoms and a sulfur atom).
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassThiadiazines
Sub ClassBenzothiadiazines
Direct ParentBenzothiadiazines
Alternative Parents
Substituents
  • Benzothiadiazine
  • Secondary aliphatic/aromatic amine
  • Benzenoid
  • Aminosulfonyl compound
  • Sulfonyl
  • Sulfonic acid derivative
  • Sulfonamide
  • Azacycle
  • Secondary amine
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Amine
  • Alkyl halide
  • Alkyl fluoride
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationUsed 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.
PharmacodynamicsHydroflumethiazide 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 actionHydroflumethiazide 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.
AbsorptionHydroflumethiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract
Volume of distributionNot Available
Protein binding74%
Metabolism

Essentially unchanged

Route of eliminationNot Available
Half lifeIt 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
ClearanceNot Available
ToxicityOverdoses 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9636
Blood Brain Barrier-0.902
Caco-2 permeable-0.8221
P-glycoprotein substrateNon-substrate0.6668
P-glycoprotein inhibitor INon-inhibitor0.8016
P-glycoprotein inhibitor IINon-inhibitor0.787
Renal organic cation transporterNon-inhibitor0.8592
CYP450 2C9 substrateNon-substrate0.7732
CYP450 2D6 substrateNon-substrate0.8302
CYP450 3A4 substrateNon-substrate0.6442
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 substrateNon-inhibitor0.9071
CYP450 2D6 substrateNon-inhibitor0.9232
CYP450 2C19 substrateNon-inhibitor0.9025
CYP450 3A4 substrateNon-inhibitor0.9544
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9324
Ames testNon AMES toxic0.8463
CarcinogenicityNon-carcinogens0.8011
BiodegradationNot ready biodegradable1.0
Rat acute toxicity3.1299 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9868
hERG inhibition (predictor II)Non-inhibitor0.8734
Pharmacoeconomics
Manufacturers
  • Wyeth ayerst laboratories
  • Par pharmaceutical inc
  • Watson laboratories inc
  • Shire development inc
Packagers
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point272-273U.S. Patent 3,254,076.
water solubility300 mg/L (at 25 °C)MERCK INDEX (1996)
logP0.36HANSCH,C ET AL. (1995)
pKa8.9BUDAVARI,S ET AL. (1996)
Predicted Properties
PropertyValueSource
Water Solubility0.858 mg/mLALOGPS
logP0.44ALOGPS
logP-0.3ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)9.07ChemAxon
pKa (Strongest Basic)-2.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area118.36 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity64.28 m3·mol-1ChemAxon
Polarizability25.68 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

U.S. Patent 3,254,076.

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
ATC CodesC03AA02
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AlfentanilAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
BuprenorphineAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
ButorphanolAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
CodeineAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
DihydrocodeineAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
FentanylAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
HydrocodoneAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
HydromorphoneAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
LevorphanolAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
MethadoneAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
MorphineAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
NalbuphineAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
OxycodoneAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
OxymorphoneAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
PethidineAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
RemifentanilAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
SufentanilAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
TapentadolAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
TramadolAnalgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
Food InteractionsNot Available

Targets

1. 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. 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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 1 P00915 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 2 P00918 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 4 P22748 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 9 Q16790 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 12 O43570 Details

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 subunit alpha-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other/unknown

Components

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

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other/unknown

Components

Name UniProt ID Details
Calcium-activated potassium channel subunit alpha-1 Q12791 Details

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

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Drug created on June 13, 2005 07:24 / Updated on April 29, 2014 10:49