Bendroflumethiazide

Identification

Name
Bendroflumethiazide
Accession Number
DB00436
Description

A thiazide diuretic with actions and uses similar to those of hydrochlorothiazide. It has been used in the treatment of familial hyperkalemia, hypertension, edema, and urinary tract disorders. (From Martindale, The Extra Pharmacopoeia, 30th ed, p810)

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 421.415
Monoisotopic: 421.037781946
Chemical Formula
C15H14F3N3O4S2
Synonyms
  • ±-3-benzyl-3,4-dihydro-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide
  • 6-trifluoromethyl-3-benzyl-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide
  • Bendrofluazide
  • Bendroflumethiazid
  • Bendrofluméthiazide
  • Bendroflumethiazide
  • Bendroflumethiazidum
  • Bendroflumetiazida
  • Benzhydroflumethiazide
External IDs
  • BE 724-A
  • FT 81

Pharmacology

Indication

For the treatment of high blood pressure and management of edema related to heart failure.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
Learn More
Pharmacodynamics

Bendroflumethiazide, a thiazide diuretic, removes excess water from the body by increasing how often you urinate (pass water) and also widens the blood vessels which helps to reduce blood pressure. It inhibits 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

As a diuretic, bendroflumethiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like bendroflumethiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of bendroflumethiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle.

TargetActionsOrganism
ASolute carrier family 12 member 3
inhibitor
Humans
ACalcium-activated potassium channel subunit alpha-1
inducer
Humans
UCarbonic anhydrase 1
inhibitor
Humans
UCarbonic anhydrase 2
inhibitor
Humans
UCarbonic anhydrase 4
inhibitor
Humans
Absorption

Absorbed relatively rapidly after oral administration

Volume of distribution
Not Available
Protein binding

96%

Metabolism
Not Available
Route of elimination
Not Available
Half-life

8.5 hours

Clearance
Not Available
Adverse Effects
Learn about our commercial Adverse Effects data.
Learn More
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Bendroflumethiazide Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirBendroflumethiazide may increase the excretion rate of Abacavir which could result in a lower serum level and potentially a reduction in efficacy.
AbciximabThe therapeutic efficacy of Abciximab can be decreased when used in combination with Bendroflumethiazide.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Bendroflumethiazide.
AcebutololThe therapeutic efficacy of Acebutolol can be increased when used in combination with Bendroflumethiazide.
AceclofenacThe therapeutic efficacy of Bendroflumethiazide can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Bendroflumethiazide can be decreased when used in combination with Acemetacin.
AcenocoumarolThe therapeutic efficacy of Acenocoumarol can be decreased when used in combination with Bendroflumethiazide.
AcetaminophenBendroflumethiazide may increase the excretion rate of Acetaminophen which could result in a lower serum level and potentially a reduction in efficacy.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Bendroflumethiazide.
AcetyldigitoxinBendroflumethiazide may increase the hypokalemic activities of Acetyldigitoxin.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Take with food. Food increases bioavailability.

Products

International/Other Brands
Aprinox (Sovereign Medical) / Centyl (LEO Pharma) / Neo-Naclex (GlaxoSmithKline) / Salures (Pfizer)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NaturetinTablet5 mg/1OralE.R. Squibb & Sons, L.L.C.2005-01-012006-10-31US flag
Naturetin 5mgTabletOralSquibb Canada Inc., Division Of Bristol Myers Squibb Canada Inc.1959-12-311999-01-07Canada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
CorzideBendroflumethiazide (5 mg/1) + Nadolol (80 mg/1)TabletOralMonarch Pharmaceuticals, Inc.2006-10-102006-10-10US flag
CorzideBendroflumethiazide (5 mg/1) + Nadolol (80 mg/1)TabletOralPfizer Laboratories Div Pfizer Inc1983-05-252019-10-31US flag
CorzideBendroflumethiazide (5 mg/1) + Nadolol (40 mg/1)TabletOralMonarch Pharmaceuticals, Inc.2006-10-102006-10-10US flag
CorzideBendroflumethiazide (5 mg/1) + Nadolol (80 mg/1)TabletOralPhysicians Total Care, Inc.1983-05-252010-06-30US flag
CorzideBendroflumethiazide (5 mg/1) + Nadolol (40 mg/1)TabletOralPfizer Laboratories Div Pfizer Inc1983-05-252019-10-31US flag
Corzide Tab W Nadolol 40mgBendroflumethiazide (5 mg) + Nadolol (40 mg)TabletOralSquibb Canada Inc., Division Of Bristol Myers Squibb Canada Inc.1987-12-311997-08-14Canada flag
Corzide Tab W Nadolol 80mgBendroflumethiazide (5 mg) + Nadolol (80 mg)TabletOralSquibb Canada Inc., Division Of Bristol Myers Squibb Canada Inc.1987-12-311997-08-14Canada flag
Nadolol and BendroflumethiazideBendroflumethiazide (5 mg/1) + Nadolol (80 mg/1)TabletOralImpax Generics2007-03-30Not applicableUS flag
Nadolol and BendroflumethiazideBendroflumethiazide (5 mg/1) + Nadolol (40 mg/1)TabletOralMylan Pharmaceuticals2012-04-022012-08-31US flag
Nadolol and BendroflumethiazideBendroflumethiazide (5 mg/1) + Nadolol (40 mg/1)TabletOralImpax Generics2007-03-30Not applicableUS flag

Categories

ATC Codes
C03AB01 — Bendroflumethiazide and potassiumC03EA13 — Bendroflumethiazide and potassium-sparing agentsG01AE10 — Combinations of sulfonamidesC03AA01 — Bendroflumethiazide
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 1,2,4-benzothiadiazine-1,1-dioxides. These are aromatic heterocyclic compounds containing a 1,2,4-benzothiadiazine ring system with two S=O bonds at the 1-position.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Thiadiazines
Sub Class
Benzothiadiazines
Direct Parent
1,2,4-benzothiadiazine-1,1-dioxides
Alternative Parents
Secondary alkylarylamines / Organosulfonamides / Benzene and substituted derivatives / Aminosulfonyl compounds / Azacyclic compounds / Organopnictogen compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives / Alkyl fluorides
Substituents
1,2,4-benzothiadiazine-1,1-dioxide / Alkyl fluoride / Alkyl halide / Amine / Aminosulfonyl compound / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Hydrocarbon derivative / Monocyclic benzene moiety
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
sulfonamide, benzothiadiazine (CHEBI:3013)

Chemical Identifiers

UNII
5Q52X6ICJI
CAS number
73-48-3
InChI Key
HDWIHXWEUNVBIY-UHFFFAOYSA-N
InChI
InChI=1S/C15H14F3N3O4S2/c16-15(17,18)10-7-11-13(8-12(10)26(19,22)23)27(24,25)21-14(20-11)6-9-4-2-1-3-5-9/h1-5,7-8,14,20-21H,6H2,(H2,19,22,23)
IUPAC Name
3-benzyl-1,1-dioxo-6-(trifluoromethyl)-3,4-dihydro-2H-1λ⁶,2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=CC2=C(NC(CC3=CC=CC=C3)NS2(=O)=O)C=C1C(F)(F)F

References

Synthesis Reference

Goldberg, M.; U.S. Patent 3,265,573; August 9, 1966; assigned to E.R. Squibb & Sons, Inc. Lund, F., Lyngby, K. and Godtfredsen, W.O.; U.S. Patent 3,392,168; July 9, 1968; assigned to Lovens Kemiske Fabrik ved A. Kongsted, Denmark.

General References
Not Available
Human Metabolome Database
HMDB0014580
KEGG Drug
D00650
KEGG Compound
C07758
PubChem Compound
2315
PubChem Substance
46508672
ChemSpider
2225
BindingDB
50238678
RxNav
1369
ChEBI
3013
ChEMBL
CHEMBL1684
Therapeutic Targets Database
DAP000188
PharmGKB
PA448563
Drugs.com
Drugs.com Drug Page
Wikipedia
Bendroflumethiazide
MSDS
Download (72.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentHigh Blood Pressure (Hypertension)1
4SuspendedPreventionHigh Blood Pressure (Hypertension) / Novel Coronavirus Infectious Disease (COVID-19)1
1CompletedNot AvailableHealthy Volunteers2
Not AvailableActive Not RecruitingNot AvailableCOVID / COVID - 19 / High Blood Pressure (Hypertension) / Novel Coronavirus Infectious Disease (COVID-19)1
Not AvailableCompletedTreatmentHigh Blood Pressure (Hypertension) / Left Ventricular Hypertrophy1
Not AvailableUnknown StatusTreatmentLow-Renin Hypertension1

Pharmacoeconomics

Manufacturers
  • Apothecon inc div bristol myers squibb
Packagers
  • E.R. Squibb and Sons LLC
  • King Pharmaceuticals Inc.
  • Physicians Total Care Inc.
  • Professional Co.
Dosage Forms
FormRouteStrength
TabletOral
TabletOral5 mg/1
TabletOral
Tablet2.5 mg
Prices
Unit descriptionCostUnit
Bendroflumethiazide powder45.0USD g
Corzide 80-5 tablet4.29USD tablet
Corzide 40-5 mg tablet3.46USD tablet
Corzide 40-5 tablet3.35USD tablet
Corzide 80-5 mg tablet3.23USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)222-223 °CGoldberg, M.; U.S. Patent 3,265,573; August 9, 1966; assigned to E.R. Squibb & Sons, Inc. Lund, F., Lyngby, K. and Godtfredsen, W.O.; U.S. Patent 3,392,168; July 9, 1968; assigned to Lovens Kemiske Fabrik ved A. Kongsted, Denmark.
water solubility108 mg/L (at 25 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP1.89BERTHOD,A ET AL. (1999)
logS-3.59ADME Research, USCD
pKa8.5SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.214 mg/mLALOGPS
logP1.83ALOGPS
logP1.7ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)9.04ChemAxon
pKa (Strongest Basic)-3.1ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area118.36 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity93.68 m3·mol-1ChemAxon
Polarizability36.92 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9643
Blood Brain Barrier-0.7807
Caco-2 permeable-0.7105
P-glycoprotein substrateNon-substrate0.6048
P-glycoprotein inhibitor INon-inhibitor0.7889
P-glycoprotein inhibitor IINon-inhibitor0.8383
Renal organic cation transporterNon-inhibitor0.8835
CYP450 2C9 substrateNon-substrate0.708
CYP450 2D6 substrateNon-substrate0.8398
CYP450 3A4 substrateNon-substrate0.6596
CYP450 1A2 substrateInhibitor0.8745
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.9351
CYP450 2C19 inhibitorNon-inhibitor0.9287
CYP450 3A4 inhibitorNon-inhibitor0.8607
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9081
Ames testNon AMES toxic0.8474
CarcinogenicityNon-carcinogens0.8156
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.0888 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9858
hERG inhibition (predictor II)Non-inhibitor0.8967
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00di-0353900000-1c8856fba9af1de07f87
MS/MS Spectrum - , positiveLC-MS/MSsplash10-044i-3891000000-67bb3f0457a6200bf63e

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transporter activity
Specific Function
Key mediator of sodium and chloride reabsorption in this nephron segment, accounting for a significant fraction of renal sodium reabsorption.
Gene Name
SLC12A3
Uniprot ID
P55017
Uniprot Name
Solute carrier family 12 member 3
Molecular Weight
113138.04 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Monroy A, Plata C, Hebert SC, Gamba G: Characterization of the thiazide-sensitive Na(+)-Cl(-) cotransporter: a new model for ions and diuretics interaction. Am J Physiol Renal Physiol. 2000 Jul;279(1):F161-9. [PubMed:10894798]
  3. Vallon V, Rieg T, Ahn SY, Wu W, Eraly SA, Nigam SK: Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am J Physiol Renal Physiol. 2008 Apr;294(4):F867-73. doi: 10.1152/ajprenal.00528.2007. Epub 2008 Jan 23. [PubMed:18216144]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inducer
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 activati...
Gene Name
KCNMA1
Uniprot ID
Q12791
Uniprot Name
Calcium-activated potassium channel subunit alpha-1
Molecular Weight
137558.115 Da
References
  1. Tricarico D, Barbieri M, Mele A, Carbonara G, Camerino DC: Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats. FASEB J. 2004 Apr;18(6):760-1. Epub 2004 Feb 6. [PubMed:14766795]
Kind
Protein
Organism
Humans
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
Uniprot Name
Carbonic anhydrase 1
Molecular Weight
28870.0 Da
References
  1. Tricarico D, Mele A, Conte Camerino D: Carbonic anhydrase inhibitors ameliorate the symptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels. Neuromuscul Disord. 2006 Jan;16(1):39-45. doi: 10.1016/j.nmd.2005.10.005. Epub 2005 Dec 20. [PubMed:16368240]
  2. Berg JT, Ramanathan S, Gabrielli MG, Swenson ER: Carbonic anhydrase in mammalian vascular smooth muscle. J Histochem Cytochem. 2004 Aug;52(8):1101-6. [PubMed:15258186]
Kind
Protein
Organism
Humans
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 in...
Gene Name
CA2
Uniprot ID
P00918
Uniprot Name
Carbonic anhydrase 2
Molecular Weight
29245.895 Da
References
  1. Tricarico D, Mele A, Conte Camerino D: Carbonic anhydrase inhibitors ameliorate the symptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels. Neuromuscul Disord. 2006 Jan;16(1):39-45. doi: 10.1016/j.nmd.2005.10.005. Epub 2005 Dec 20. [PubMed:16368240]
  2. Berg JT, Ramanathan S, Gabrielli MG, Swenson ER: Carbonic anhydrase in mammalian vascular smooth muscle. J Histochem Cytochem. 2004 Aug;52(8):1101-6. [PubMed:15258186]
Kind
Protein
Organism
Humans
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 an...
Gene Name
CA4
Uniprot ID
P22748
Uniprot Name
Carbonic anhydrase 4
Molecular Weight
35032.075 Da
References
  1. Tricarico D, Mele A, Conte Camerino D: Carbonic anhydrase inhibitors ameliorate the symptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels. Neuromuscul Disord. 2006 Jan;16(1):39-45. doi: 10.1016/j.nmd.2005.10.005. Epub 2005 Dec 20. [PubMed:16368240]
  2. Wistrand PJ, Carter ND, Conroy CW, Mahieu I: Carbonic anhydrase IV activity is localized on the exterior surface of human erythrocytes. Acta Physiol Scand. 1999 Feb;165(2):211-8. doi: 10.1046/j.1365-201x.1999.00478.x. [PubMed:10090333]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Thiopurine s-methyltransferase activity
Specific Function
Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine.
Gene Name
TPMT
Uniprot ID
P51580
Uniprot Name
Thiopurine S-methyltransferase
Molecular Weight
28180.09 Da
References
  1. Lysaa RA, Giverhaug T, Wold HL, Aarbakke J: Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide. Eur J Clin Pharmacol. 1996;49(5):393-6. [PubMed:8866635]

Drug created on June 13, 2005 07:24 / Updated on October 02, 2020 03:01

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