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Hydroflumethiazide

HCID 3647
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Basic information

CAS
135-09-1
Standard SMILES
NS(=O)(=O)c1cc2c(cc1C(F)(F)F)NCNS2(=O)=O
InChIKey
DMDGGSIALPNSEE-UHFFFAOYSA-N
Molecular formula
C8H8F3N3O4S2
Average molar mass
331.3 g/mol
Monoisotopic mass
330.99083258

Overview

Hydroflumethiazide is a benzothiadiazine consisting of a 3,4-dihydro-HH-1,2,4-benzothiadiazine bicyclic system dioxygenated on sulfur and carrying trifluoromethyl and aminosulfonyl groups at positions 6 and 7 respectively. A diuretic with actions and uses similar to those of hydrochlorothiazide. It has a role as a diuretic and an antihypertensive agent. It is a thiazide and a benzothiadiazine.

Names & identifiers

Preferred name
Hydroflumethiazide
IUPAC
1,1-dioxo-6-(trifluoromethyl)-3,4-dihydro-2H-1λ6,2,4-benzothiadiazine-7-sulfonamide
English name
Hydroflumethiazide
Molecular formula
C8H8F3N3O4S2
Molecular weight
331.29

Names & synonyms

hydroflumethiazide135-09-1DiuredeminaDiucardinGlomerulinSaluronHidroflumetiazidHydroflumethizideDiurometonFlutizideHidroalogenSpandiuril
Show more names
hydolRivernaclexAdemilrontylelodrinsisuril
BristabBristurinElodrineFinuretHydrenoxLeodrineOlmagranRodiuran

Database identifiers

CAS
135-09-1
PubChem CID
3647
DTXSID
DTXSID3023132
ChEMBL
CHEMBL1763
ChEBI
CHEBI:5784
UNII
501CFL162R
EC Number
205-173-8

Properties

Computed structural properties

XLogP
0.4
Topological polar surface area
135 Ų
Hydrogen bond donors
3
Hydrogen bond acceptors
10
Rotatable bonds
1
Heavy atoms
20
Formal charge
0
Complexity
578

Experimental & physicochemical properties

Drugs · 2 items

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Cardiovascular system -> Diuretics

pH1 IN 100 DISPERSION IN WATER: BETWEEN 4.5-7.5
LogP · 3 items

log Kow = 0.36

-0.2

0.36

OdorODORLESS
Color/Form · 2 items

CRYSTALS

White to cream colored, finely divided, crystalline powder

Solubility · 5 items

Solubility (mg/ml) at 25 °C: acetone >100; methanol 58; acetonitrile 43; water 0.3; ether 0.2; benzene <0.1.

INSOL IN ACID

Soluble in dilute alkali but unstable in alkaline solutions.

SOL IN ALC; FREELY SOL IN ACETONE

8.58e-01 g/L

Human Drugs · 4 items

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Thiazide Diuretics

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Safety & regulation

Safety information is for reference only and does not replace the supplier’s Safety Data Sheet (SDS), applicable regulations, or professional assessment.

GHS classification

GHS Classification · 4 items

Danger

H317 (97.6%): May cause an allergic skin reaction [Warning Sensitization, Skin]

P233, P260, P261, P271, P272, P280, P284, P302+P352, P304+P340, P321, P333+P317, P342+P316, P362+P364, P403, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 41 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Hazard information

Regulatory Information2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3,4-dihydro-6-(trifluoromethyl)-, 1,1-dioxide: Does not have an individual approval but may be used under an appropriate group standard
Other Safety InformationIMAP assessments - 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3,4-dihydro-6-(trifluoromethyl)-, 1,1-dioxide: Human health tier I assessment
FDA Requirements · 1 item

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

Hazard Classes and CategoriesSkin Sens. 1 (97.6%)

Safety & protection

Storage ConditionsCommercially available hydroflumethiazide tablets should be stored at room temperature (approximately 25 °C) ... .
Disposal Methods

Chemistry & industry

Pharmacology

ATC Code · 2 items

C - Cardiovascular system

QC - Cardiovascular system

Protein Binding74%
Pharmacodynamics · 1 item

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 · 6 items

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.

...BENZOTHIADIAZIDES HAVE DIRECT EFFECT ON RENAL TUBULAR TRANSPORT OF SODIUM & CHLORIDE...INDEPENDENT OF ANY EFFECT ON CARBONIC ANHYDRASE. /THIAZIDE DIURETICS/

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Compound notes

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On this pageBasic informationOverviewNames & identifiersPropertiesSafety & regulationChemistry & industryRelated reactionsCompound notes
Melting Point · 3 items

272-273

272-273 °C

272 - 273 °C

Physical DescriptionSolid
Stability/Shelf LifeUNSTABLE IN ALKALINE SOLN
Dissociation Constants · 2 items

8.9

PK1 8.9; PK2 10.7

Other Experimental PropertiesFORMS WATER-SOL SALTS WITH BASES

Physicochemical properties

Melting point
272 · 272-273
Boiling point
531.6 · 531.6±60.0 °C(Predicted)
Density
1.5955 · 1.5955 (estimate)
storage temp.
2 · Keep in dark place,Sealed in dry,2-8°C
solubility
DMSO (Slightly), Methanol (Sparingly)
form
Solid
pka
8.9 · 8.9, 8.2(at 25℃)
color
White
Water Solubility
329.9 mg/L · 329.9mg/L(room temperature)
Major Application
pharmaceuticalpharmaceutical small molecule
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)
InChIKey
DMDGGSIALPNSEE-UHFFFAOYSA-N
SMILES
O=S1(C2=CC(S(=O)(N)=O)=C(C(F)(F)F)C=C2NCN1)=O
EWG's Food Scores
1 · 1
FDA UNII
501 CFL162R · 501CFL162R
ATC code
3 AA02,C03AH02 · C03AA02,C03AH02
EPA Substance Registry System
2 H-1,2,4-Benzothiadiazine-7-sulfonamide, · 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3,4-dihydro-6-(trifluoromethyl)-, 1,1-dioxide (135-09-1)
UNSPSC Code
41116107 · 41116107
NACRES
24 · NA.24
Symbol(GHS)
8 · GHS08
Signal word
Danger
Hazard statements
317 · H317-H334
Precautionary statements
261 · P261-P280-P284-P304+P340-P342+P311
Hazard Codes
Xn,Xi
Risk Statements
42 · 42/43
Safety Statements
36 · 36
WGK Germany
2 · 2
RTECS
9625000 · DK9625000
Hazard Note
Irritant
HS Code
2935904000 · 2935904000
Storage Class
11 · 11 - Combustible Solids
Hazard Classifications
1 Skin · Resp. Sens. 1Skin Sens. 1
Hazardous Substances Data
135 · 135-09-1(Hazardous Substances Data)
Toxicity
50 in · LD50 in mice (mg/kg): >8000 orally, 750 i.v., 6280 i.p. (Piala)
· 1 item

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Toxicology

Interactions · 5 items

...DISRUPTION OF URICOSURIC THERAPY BY ADMIN OF DIURETIC WHICH INCR PLASMA URIC ACID LEVELS (THIAZIDES)... /THIAZIDE DIURETICS/

CONCURRENT ADMIN OF THIAZIDE DIURETICS & MONOAMINE OXIDASE INHIBITORS MAY INCR HYPOTENSION. /THIAZIDE DIURETICS/

ELECTROLYTE DISTURBANCES PRODUCED BY /HYDROFLUMETHIAZIDE/ PREDISPOSE PATIENT TO...TOXICITY /OF DIGITALIS GLYCOSIDES/. SEVERE POTASSIUM DEPLETION MAY OCCUR /WITH CONCOMITANT CORTICOSTEROIDS, CORTICOTROPIN & AMPHOTERICIN B/. MAY ANTAGONIZE EFFECTS OF ORAL ANTICOAGULANTS.

/HYDROFLUMETHIAZIDE MAY PROLONG/ NEUROMUSCULAR BLOCKADE /OF/ NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS...TUBOCURARINE CHLORIDE OR GALLAMINE TRIETHIODIDE...RENAL CLEARANCE OF LITHIUM...DECREASED...SERUM LITHIUM /MAY INCREASE IN PATIENTS RECEIVING LITHIUM CARBONATE & LONG-TERM DIURETIC/.

For more Interactions (Complete) data for HYDROFLUMETHIAZIDE (22 total), please visit the HSDB record page.

Human Toxicity Excerpts · 2 items

In addition to diuresis and resultant dehydration, overdosage of thiazides may produce lethargy, nausea, weakness, and electrolyte imbalance; lethargy may progress to coma within a few hours with minimal depression of respiratory and cardiovascular function and without evidence of dehydration or serum electryolye change. The mechanism of thiazide-induced CNS depression is unknown. GI irritation and hypermotility may occur, and temporary elevation of the BUN has been reported. Serum electrolyte changes (e.g., hypokalemia, hypochloremia, hyponatremia) may occur, especially in patients with impaired renal function. /Thiazides/

May suppress lactation, but compatible /SRP: with breast feeding/. /Thiazide diuretics, from table/

Drug Induced Liver Injury · 6 items

Drug Induced Liver Injury Rank (DILIrank 2.0)

Hydroflumethiazide

Ambiguous-DILI-concern

2

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

Antidote and Emergency TreatmentThiazide diuretic overdose should be treated by immediate evacuation of the stomach followed by supportive symptomatic treatment and monitoring of serum electrolyte concentrations and renal function. /Thiazide diuretic/
Effects During Pregnancy and Lactation◉ Summary of Use during Lactation

Regulatory information

FDA Requirements · 1 item

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

Safety data

wgk
2
rtecs
DK9625000
hs_code
2935904000
Toxicity
LD50 in mice (mg/kg): >8000 orally, 750 i.v., 6280 i.p. (Piala)
risk_code
42/43
Signal word
Danger
Symbol(GHS)
GHS08
hazard_code
Xn,Xi
hazard_note
Irritant
safety_code
36
Storage Class
11 - Combustible Solids
Hazard statements
H317-H334
Hazard Classifications
Resp. Sens. 1Skin Sens. 1
Precautionary statements
P261-P280-P284-P304+P340-P342+P311
Hazardous Substances Data
135-09-1(Hazardous Substances Data)

NATURE OF CHEM INTERACTION BETWEEN THIAZIDES & SPECIFIC RENAL RECEPTORS RESPONSIBLE FOR CHLORURETIC EFFECT IS NOT KNOWN; NO CRITICAL ENZYMATIC REACTIONS HAVE BEEN IDENTIFIED. /THIAZIDES/

THIAZIDES INHIBIT REABSORPTION OF SODIUM &...CHLORIDE IN DISTAL SEGMENT. ... AS CLASS...HAVE IMPORTANT ACTION ON EXCRETION OF POTASSIUM THAT RESULTS FROM INCR SECRETION OF CATION BY DISTAL TUBULE. ... GLOMERULAR FILTRATION RATE MAY BE REDUCED BY THIAZIDES, PARTICULARLY WITH IV ADMIN FOR EXPTL PURPOSES. /THIAZIDES/

THIAZIDES MAY DECR EXCRETION OF URIC ACID IN MAN, THUS INCR ITS CONCN IN PLASMA. HYPERURICEMIC EFFECT RESULTS PRIMARILY FROM INHIBITION OF TUBULAR SECRETION OF URATE. ... UNLIKE MOST OTHER NATRIURETIC AGENTS...DECR RENAL EXCRETION OF CALCIUM RELATIVE TO THAT OF SODIUM... /ENHANCE/ EXCRETION OF MAGNESIUM... /THIAZIDES/

For more Mechanism of Action (Complete) data for HYDROFLUMETHIAZIDE (11 total), please visit the HSDB record page.

Biological Half-Life · 3 items

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

Half-life is 12-27 hr. /From table/

/Hydroflumethiazide has a/ estimated distribution half-life of approximately 2 hours and an estimated terminal elimination half-life of approximately 17 hours ... .

Metabolism/Metabolites · 2 items

Essentially unchanged

AFTER REPEATED ORAL ADMIN OF 100 MG EVERY 24 HR FOR 7 DAYS TO HEALTHY MALES, METABOLITE 2,4-DISULFAMYL-5-TRIFLUOROMETHYLANILINE DETERMINED.

FDA Pharmacological Classification · 6 items

501CFL162R

HYDROFLUMETHIAZIDE

Physiologic Effects [PE] - Increased Diuresis

Established Pharmacologic Class [EPC] - Thiazide Diuretic

Chemical Structure [CS] - Thiazides

Hydroflumethiazide is a Thiazide Diuretic. The physiologic effect of hydroflumethiazide is by means of Increased Diuresis.

MeSH Pharmacological Classification · 3 items

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Agents that promote the excretion of urine through their effects on kidney function.

Agents that inhibit SODIUM CHLORIDE SYMPORTERS. They act as DIURETICS. Excess use is associated with HYPOKALEMIA.

Absorption, Distribution and Excretion · 6 items

Hydroflumethiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract

THIAZIDES ARE ABSORBED FROM GI TRACT & OWE THEIR USEFULNESS LARGELY TO THEIR EFFECTIVENESS BY ORAL ROUTE. ABSORPTION IS RELATIVELY RAPID. MOST AGENTS SHOW DEMONSTRABLE DIURETIC EFFECT WITHIN HR AFTER ORAL ADMIN. /THIAZIDE DIURETICS/

IN GENERAL, THIAZIDES WITH RELATIVELY LONG DURATIONS OF ACTION SHOW PROPORTIONATELY HIGH DEGREE OF BINDING TO PLASMA PROTEINS & ARE REABSORBED BY RENAL TUBULES. ... DRUG PASSES READILY THROUGH PLACENTAL BARRIER TO FETUS. ALL THIAZIDES PROBABLY UNDERGO ACTIVE SECRETION IN PROXIMAL TUBULE. /THIAZIDE DIURETICS/

AFTER IV INFUSION OF HYDROFLUMETHIAZIDE, 2 DISTRIBUTION PHASES, T/2 OF 0.26 & 0.85 HR. AFTER SINGLE ORAL DOSE OF 2 UMOL/KG, T/2 BETA SHORTER THAN AFTER DOSE OF 6 UMOL/KG, WITH MEAN T/2 BETA OF 8.7 & 17.9 HR.

AFTER ORAL ADMIN OF HYDROFLUMETHIAZIDE EVERY 24 HR FOR 7 DAYS, MEAN BIOL T/2 OF 6.85 HR; MEAN T/2 OF METABOLITE WAS 17.7 HR. 0.652 OF DOSE EXCRETED UNCHANGED IN URINE, 0.049 AS METABOLITE. MEAN RENAL PLASMA CLEARANCE OF DRUG WAS 0.356 L/HR/KG.

For more Absorption, Distribution and Excretion (Complete) data for HYDROFLUMETHIAZIDE (8 total), please visit the HSDB record page.

Cellular LocationsCytoplasm
Metabolite PathwaysHydroflumethiazide Action Pathway

Uses & manufacturing

UsesTHERAP CAT: Antihypertensive; diuretic.
Methods of Manufacturing · 2 items

HOLDREDGE ET AL, J AM CHEM SOC 81, 4807 (1959); CLOSE ET AL, J AM CHEM SOC 82, 1132 (1960); YALE ET AL J AM CHEM SOC 2042; NOVELLO ET AL, J ORG CHEM 25, 970 (1960). NUMEROUS PATENTS, EG, LUND ET AL, US PATENT 3,254,076 (1966 TO LOVENS).

m-Aminobenzotrifluoride + chlorosulfonic acid + ammonia + formaldehyde (chlorosulfonation/sulfonamide formation/carbonyl condensation).

Formulations/Preparations · 2 items

MARKET PREPN (TABLETS) 50 MG.

Grade: National Formulary grade of chemical.

Use ClassificationPharmaceuticals
General Manufacturing InformationSOLUBILITY VALUES OF HYDROFLUMETHIAZIDE INCR BY RAISING TEMP IN PRESENCE OF VARIOUS TWEENS.

Applications

UsesLabelled Hydroflumethiazide. Antihypertensive; diuretic.

Upstream & downstream products

Upstream raw materials

AmmoniaChlorosulfonic acidParaformaldehyde
Additional notes · 1 item

DefinitionChEBI: Hydroflumethiazide is a benzothiadiazine consisting of a 3,4-dihydro-HH-1,2,4-benzothiadiazine bicyclic system dioxygenated on sulfur and carrying trifluoromethyl and aminosulfonyl groups at positions 6 and 7 respectively. A diuretic with actions and uses similar to those of hydrochlorothiazide. It has a role as a diuretic and an antihypertensive agent. It is a benzothiadiazine and a thiazide.