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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
Dihydroflumethazide
Hidroflumetiazid
Hidroflumetiazida
Hydrofluméthiazide
Hydroflumethiazide
Hydroflumethiazidum
Idroflumetiazide
Metforylthiadiazin
Saluron
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
LeodrineLeo
SaluronShire
Brand mixturesNot Available
SaltsNot Available
Categories
UNII501CFL162R
CAS number135-09-1
WeightAverage: 331.292
Monoisotopic: 330.990831754
Chemical FormulaC8H8F3N3O4S2
InChI KeyInChIKey=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)
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.
Related Articles
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
Pathways
PathwayCategorySMPDB ID
Hydroflumethiazide Action PathwayDrug actionSMP00108
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 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9232
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
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
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis Reference

U.S. Patent 3,254,076.

General References
  1. Moser M, Feig PU: Fifty years of thiazide diuretic therapy for hypertension. Arch Intern Med. 2009 Nov 9;169(20):1851-6. doi: 10.1001/archinternmed.2009.342. [PubMed:19901136 ]
External Links
ATC CodesC03AB02C03AH02C03AA02
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Acetylsalicylic acid is combined with Hydroflumethiazide.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Hydroflumethiazide.
BuprenorphineThe risk or severity of adverse effects can be increased when Buprenorphine is combined with Hydroflumethiazide.
ButorphanolThe risk or severity of adverse effects can be increased when Butorphanol is combined with Hydroflumethiazide.
CaffeineThe risk or severity of adverse effects can be increased when Caffeine is combined with Hydroflumethiazide.
ChlorphenamineThe risk or severity of adverse effects can be increased when Chlorphenamine is combined with Hydroflumethiazide.
CodeineThe risk or severity of adverse effects can be increased when Codeine is combined with Hydroflumethiazide.
DihydrocodeineThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Hydroflumethiazide.
FentanylThe risk or severity of adverse effects can be increased when Fentanyl is combined with Hydroflumethiazide.
HydrocodoneThe risk or severity of adverse effects can be increased when Hydrocodone is combined with Hydroflumethiazide.
HydromorphoneThe risk or severity of adverse effects can be increased when Hydromorphone is combined with Hydroflumethiazide.
LevorphanolThe risk or severity of adverse effects can be increased when Levorphanol is combined with Hydroflumethiazide.
MethadoneThe risk or severity of adverse effects can be increased when Methadone is combined with Hydroflumethiazide.
MorphineThe risk or severity of adverse effects can be increased when Morphine is combined with Hydroflumethiazide.
NalbuphineThe risk or severity of adverse effects can be increased when Nalbuphine is combined with Hydroflumethiazide.
OxycodoneThe risk or severity of adverse effects can be increased when Oxycodone is combined with Hydroflumethiazide.
OxymorphoneThe risk or severity of adverse effects can be increased when Oxymorphone is combined with Hydroflumethiazide.
PentazocineThe risk or severity of adverse effects can be increased when Pentazocine is combined with Hydroflumethiazide.
PethidineThe risk or severity of adverse effects can be increased when Pethidine is combined with Hydroflumethiazide.
RemifentanilThe risk or severity of adverse effects can be increased when Remifentanil is combined with Hydroflumethiazide.
SufentanilThe risk or severity of adverse effects can be increased when Sufentanil is combined with Hydroflumethiazide.
TapentadolThe risk or severity of adverse effects can be increased when Tapentadol is combined with Hydroflumethiazide.
TramadolThe risk or severity of adverse effects can be increased when Tramadol is combined with Hydroflumethiazide.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Sodium:potassium:chloride symporter activity
Specific Function:
Electrically silent transporter system. Mediates sodium and chloride reabsorption. Plays a vital role in the regulation of ionic balance and cell volume.
Gene Name:
SLC12A1
Uniprot ID:
Q13621
Molecular Weight:
121449.13 Da
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:17139284 ]
  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:17016423 ]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea.
Gene Name:
CA1
Uniprot ID:
P00915
Molecular Weight:
28870.0 Da
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:17139284 ]
  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:17016423 ]
  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. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye. Contributes to intracellular pH regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption. Stimulates the chloride-bicarbonate ex...
Gene Name:
CA2
Uniprot ID:
P00918
Molecular Weight:
29245.895 Da
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:2226620 ]
  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. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid.
Gene Name:
CA4
Uniprot ID:
P22748
Molecular Weight:
35032.075 Da
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:17139284 ]
  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:17016423 ]
  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. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Reversible hydration of carbon dioxide. Participates in pH regulation. May be involved in the control of cell proliferation and transformation. Appears to be a novel specific biomarker for a cervical neoplasia.
Gene Name:
CA9
Uniprot ID:
Q16790
Molecular Weight:
49697.36 Da
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. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Reversible hydration of carbon dioxide.
Gene Name:
CA12
Uniprot ID:
O43570
Molecular Weight:
39450.615 Da
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. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
other/unknown
General Function:
Steroid hormone binding
Specific Function:
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.
Gene Name:
ATP1A1
Uniprot ID:
P05023
Molecular Weight:
112895.01 Da
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:17139284 ]
  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:17016423 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
other/unknown
General Function:
Voltage-gated potassium channel activity
Specific Function:
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 ...
Gene Name:
KCNMA1
Uniprot ID:
Q12791
Molecular Weight:
137558.115 Da
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:17139284 ]
  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:17016423 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23