Identification

Name
Trichlormethiazide
Accession Number
DB01021  (APRD00031)
Type
Small Molecule
Groups
Approved, Vet approved
Description

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

Structure
Thumb
Synonyms
Not Available
International/Other Brands
Anistadin / Carvacron / Diu-Hydrin / Diurese / Fluitran / Kubacron / Metahydrin / Naqua
Categories
UNII
Q58C92TUN0
CAS number
133-67-5
Weight
Average: 380.656
Monoisotopic: 378.90218026
Chemical Formula
C8H8Cl3N3O4S2
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-1λ⁶,2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=C(Cl)C=C2NC(NS(=O)(=O)C2=C1)C(Cl)Cl

Pharmacology

Indication

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

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 appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering 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
Human
ASodium/potassium-transporting ATPase subunit alpha-1
inhibitor
Human
UCarbonic anhydrase 1
inhibitor
Human
UCarbonic anhydrase 2
inhibitor
Human
UCarbonic anhydrase 4
inhibitor
Human
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
Toxicity

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

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Trichlormethiazide Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1S,6R)-3-{[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL]CARBONYL}-6-(2,4,5-TRIFLUOROPHENYL)CYCLOHEX-3-EN-1-AMINEThe therapeutic efficacy of (1S,6R)-3-{[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL]CARBONYL}-6-(2,4,5-TRIFLUOROPHENYL)CYCLOHEX-3-EN-1-AMINE can be decreased when used in combination with Trichlormethiazide.
(4R)-limoneneThe therapeutic efficacy of Trichlormethiazide can be decreased when used in combination with (4R)-limonene.
16-Bromoepiandrosterone16-Bromoepiandrosterone may increase the hypokalemic activities of Trichlormethiazide.
19-norandrostenedione19-norandrostenedione may increase the hypokalemic activities of Trichlormethiazide.
1alpha-Hydroxyvitamin D5The risk or severity of hyperkalemia can be increased when 1alpha-Hydroxyvitamin D5 is combined with Trichlormethiazide.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Trichlormethiazide.
5-androstenedione5-androstenedione may increase the hypokalemic activities of Trichlormethiazide.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Trichlormethiazide.
AbediterolAbediterol may increase the hypokalemic activities of Trichlormethiazide.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Trichlormethiazide.
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0015156
KEGG Drug
D00658
KEGG Compound
C07767
PubChem Compound
5560
PubChem Substance
46508880
ChemSpider
5359
BindingDB
26998
ChEBI
9683
ChEMBL
CHEMBL1054
Therapeutic Targets Database
DAP000035
PharmGKB
PA164752426
Wikipedia
Trichlormethiazide
ATC Codes
C03AA06 — TrichlormethiazideC03AB06 — Trichlormethiazide and potassiumC03EA02 — Trichlormethiazide and potassium-sparing agentsG01AE10 — Combinations of sulfonamides
MSDS
Download (73.2 KB)

Clinical Trials

Clinical Trials
Not Available

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
Not Available
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-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/MSsplash10-01p2-2950000000-2584307bcbe6b5fd0ba0

Taxonomy

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 / Secondary aliphatic/aromatic amine / Aryl chloride / Aryl halide / Organosulfonic acid amide / Benzenoid / Organic sulfonic acid or derivatives / Organosulfonic acid or derivatives / Aminosulfonyl compound / Sulfonyl
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
benzothiadiazine (CHEBI:9683)

Targets

Kind
Protein
Organism
Human
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. [PubMed:17414671]
  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. [PubMed:14610216]
  3. Smith SM: Thiazide diuretics. N Engl J Med. 2010 Feb 18;362(7):659-60; author reply 660. [PubMed:20187262]
  4. 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
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. [PubMed:7752578]
Details
3. Carbonic anhydrase 1
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
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. [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]
Details
4. Carbonic anhydrase 2
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 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. [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]
Details
5. Carbonic anhydrase 4
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 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. [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]

Enzymes

Kind
Protein
Organism
Human
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 01, 2018 12:58