Trichlormethiazide

Identification

Generic Name
Trichlormethiazide
DrugBank Accession Number
DB01021
Background

A thiazide diuretic with properties similar to those of hydrochlorothiazide. (From Martindale, The Extra Pharmacopoeia, 30th ed, p830)

Type
Small Molecule
Groups
Approved, Vet approved
Structure
Weight
Average: 380.656
Monoisotopic: 378.90218026
Chemical Formula
C8H8Cl3N3O4S2
Synonyms
  • Trichlormethiazide
  • triclormetiazida

Pharmacology

Indication

Used in the treatment of oedema (including that associated with heart failure) and hypertension.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Trichloromethiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Trichloromethiazide has also been found useful in edema due to various forms of renal dysfunction such as nephrotic syndrome, acute glomer-ulonephritis, and chronic renal failure. Trichloromethiazide is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension. Like other thiazides, Trichloromethiazide promotes water loss from the body (diuretics). They 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

Trichlormethiazide seemingly appears to inhibit the active reabsorption of chloride in the ascending loop of Henle. Additionally, it may also do the same for sodium. These actions subsequently alter electrolyte transfer in the proximal tubule. This results in excretion of sodium, chloride, and water and, hence, diuresis. As a diuretic, Trichloromethiazide 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 Trichloromethiazide 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 Trichloromethiazide 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
ASodium/potassium-transporting ATPase subunit alpha-1
inhibitor
Humans
UCarbonic anhydrase 1
inhibitor
Humans
UCarbonic anhydrase 2
inhibitor
Humans
UCarbonic anhydrase 4
inhibitor
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Oral Rat LD50 = 5600 mg/kg, oral Mouse LD50 = 2600 mg/kg

Pathways
PathwayCategory
Trichlormethiazide 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
AbacavirTrichlormethiazide may increase the excretion rate of Abacavir which could result in a lower serum level and potentially a reduction in efficacy.
AbaloparatideAbaloparatide may increase the hypotensive activities of Trichlormethiazide.
AbciximabThe therapeutic efficacy of Abciximab can be decreased when used in combination with Trichlormethiazide.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Trichlormethiazide.
AcebutololThe therapeutic efficacy of Acebutolol can be increased when used in combination with Trichlormethiazide.
Food Interactions
Not Available

Products

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International/Other Brands
Anistadin / Carvacron / Diu-Hydrin / Diurese / Fluitran / Kubacron / Metahydrin / Naqua

Categories

ATC Codes
G01AE10 — Combinations of sulfonamidesC03AA06 — TrichlormethiazideC03EA02 — Trichlormethiazide and potassium-sparing agentsC03AB06 — Trichlormethiazide and potassium
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 / Benzenoids / Aryl chlorides / Aminosulfonyl compounds / Azacyclic compounds / Organopnictogen compounds / Organochlorides / Organic oxides / Hydrocarbon derivatives
show 1 more
Substituents
1,2,4-benzothiadiazine-1,1-dioxide / Alkyl chloride / Alkyl halide / Amine / Aminosulfonyl compound / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
benzothiadiazine (CHEBI:9683)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
Q58C92TUN0
CAS number
133-67-5
InChI Key
LMJSLTNSBFUCMU-UHFFFAOYSA-N
InChI
InChI=1S/C8H8Cl3N3O4S2/c9-3-1-4-6(2-5(3)19(12,15)16)20(17,18)14-8(13-4)7(10)11/h1-2,7-8,13-14H,(H2,12,15,16)
IUPAC Name
6-chloro-3-(dichloromethyl)-1,1-dioxo-3,4-dihydro-2H-1lambda6,2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=C(Cl)C=C2NC(NS(=O)(=O)C2=C1)C(Cl)Cl

References

General References
Not Available
Human Metabolome Database
HMDB0015156
KEGG Drug
D00658
KEGG Compound
C07767
PubChem Compound
5560
PubChem Substance
46508880
ChemSpider
5359
BindingDB
26998
RxNav
10772
ChEBI
9683
ChEMBL
CHEMBL1054
Therapeutic Targets Database
DAP000035
PharmGKB
PA164752426
Wikipedia
Trichlormethiazide
MSDS
Download (73.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
  • Sanofi aventis us llc
  • Schering corp sub schering plough corp
  • Lannett co inc
  • Mm mast and co
  • Impax laboratories inc
  • Par pharmaceutical inc
  • Sandoz inc
  • Tg united labs llc
  • Watson laboratories inc
Packagers
  • C.O. Truxton Inc.
  • Carlisle Laboratories Inc.
  • PD-Rx Pharmaceuticals Inc.
  • Professional Co.
Dosage Forms
FormRouteStrength
Pill
Tablet
Prices
Unit descriptionCostUnit
Trichlormethiazide powder15.0USD g
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)270 dec °CPhysProp
water solubility800 mg/L (at 25 °C)MERCK (1989)
logP0.62SANGSTER (1994)
logS-2.68ADME Research, USCD
pKa8.6Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.415 mg/mLALOGPS
logP0.86ALOGPS
logP0.97Chemaxon
logS-3ALOGPS
pKa (Strongest Acidic)8.32Chemaxon
pKa (Strongest Basic)-4.1Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area118.36 Å2Chemaxon
Rotatable Bond Count2Chemaxon
Refractivity77.44 m3·mol-1Chemaxon
Polarizability31.97 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9356
Blood Brain Barrier-0.9431
Caco-2 permeable-0.7869
P-glycoprotein substrateNon-substrate0.6958
P-glycoprotein inhibitor INon-inhibitor0.8804
P-glycoprotein inhibitor IINon-inhibitor0.9432
Renal organic cation transporterNon-inhibitor0.8959
CYP450 2C9 substrateNon-substrate0.7173
CYP450 2D6 substrateNon-substrate0.8454
CYP450 3A4 substrateNon-substrate0.6828
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.9454
CYP450 2D6 inhibitorNon-inhibitor0.9582
CYP450 2C19 inhibitorNon-inhibitor0.9611
CYP450 3A4 inhibitorNon-inhibitor0.9325
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9502
Ames testNon AMES toxic0.9209
CarcinogenicityNon-carcinogens0.844
BiodegradationNot ready biodegradable1.0
Rat acute toxicity1.8282 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9721
hERG inhibition (predictor II)Non-inhibitor0.9276
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (8.06 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-016r-5190000000-adca0c41d4316946e8e7
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-01p2-2950000000-2584307bcbe6b5fd0ba0
MS/MS Spectrum - , positiveLC-MS/MSsplash10-01p2-2950000000-2584307bcbe6b5fd0ba0
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-0009000000-ce64ec4fa0af63909dd3
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-0009000000-1eda943031af387a29a6
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-0009000000-96340548c18ddd9bbf08
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-1009000000-84407b5f4b064bc468e4
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0w29-1291000000-858bd6d30e7b3f78a970
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-9110000000-af0429bfb7c21f2013d3
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-166.0991319
predicted
DarkChem Lite v0.1.0
[M-H]-164.14183
predicted
DeepCCS 1.0 (2019)
[M+H]+166.6183319
predicted
DarkChem Lite v0.1.0
[M+H]+166.49982
predicted
DeepCCS 1.0 (2019)
[M+Na]+166.0446319
predicted
DarkChem Lite v0.1.0
[M+Na]+173.5555
predicted
DeepCCS 1.0 (2019)

Targets

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Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
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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. Li J, Wang DH: Function and regulation of epithelial sodium transporters in the kidney of a salt-sensitive hypertensive rat model. J Hypertens. 2007 May;25(5):1065-72. [Article]
  2. Hasannejad H, Takeda M, Taki K, Shin HJ, Babu E, Jutabha P, Khamdang S, Aleboyeh M, Onozato ML, Tojo A, Enomoto A, Anzai N, Narikawa S, Huang XL, Niwa T, Endou H: Interactions of human organic anion transporters with diuretics. J Pharmacol Exp Ther. 2004 Mar;308(3):1021-9. Epub 2003 Nov 10. [Article]
  3. Smith SM: Thiazide diuretics. N Engl J Med. 2010 Feb 18;362(7):659-60; author reply 660. [Article]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
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 th...
Gene Name
ATP1A1
Uniprot ID
P05023
Uniprot Name
Sodium/potassium-transporting ATPase subunit alpha-1
Molecular Weight
112895.01 Da
References
  1. Takahashi N, Kondo Y, Fujiwara I, Ito O, Igarashi Y, Abe K: Characterization of Na+ transport across the cell membranes of the ascending thin limb of Henle's loop. Kidney Int. 1995 Mar;47(3):789-94. [Article]
Details
3. Carbonic anhydrase 1
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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  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. [Article]
  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. [Article]
Details
4. Carbonic anhydrase 2
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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  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. [Article]
  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. [Article]
Details
5. Carbonic anhydrase 4
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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  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. [Article]
  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. [Article]

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. [Article]

Drug created at June 13, 2005 13:24 / Updated at February 02, 2024 22:47