DT-Web

DB01021 - Trichlormethiazide


Identification
Name Trichlormethiazide
Accession Number DB01021 (APRD00031)
Type small molecule
Description A thiazide diuretic with properties similar to those of hydrochlorothiazide. (From Martindale, The Extra Pharmacopoeia, 30th ed, p830)
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 380.656
Groups approved
Monoisotopic Weight 378.90218026
Pharmacology
Indication Used in the treatment of oedema (including that associated with heart failure) and hypertension.
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.
Absorption Not Available
Protein binding Not Available
Biotransformation Not Available
Route of elimination Not Available
Toxicity Oral Rat LD50 = 5600 mg/kg, oral Mouse LD50 = 2600 mg/kg
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Amifostine Trichlormethiazide may increase the hypotensive effect of Amifostine. At chemotherapeutic doses of Amifostine, Trichlomethiazide should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.
Cholestyramine The bile acid sequestrant, Cholestyramine resin, may inhibit the absorption of Trichlormethiazide.
Colesevelam The bile acid sequestrant, Colesevelam, may inhibit the absorption of Trichlormethiazide.
Colestipol The bile acid sequestrant, Colestipol, may inhibit the absorption of Trichlormethiazide.
Digoxin Possible electrolyte variations and arrhythmias
Dofetilide Trichlormethiazide may increase Dofetilide serum concentrations and increase the QTc-prolonging effect of Dofetilide. Increased risk of ventricular arrhythmias.
Lithium Trichlormethiazide may increase the serum concentration of Lithium by decreasing Lithium excretion. Monitor for changes in the therapeutic/adverse effects of Lithium if Trichlorthiazide is initiated, discontinued or dose changed.
Rituximab Additive antihypertensive effects may occur. Increased risk of hypotension. Consider withholding Trichlormethiazide for 12 hours prior to administration of Rituximab.
Trandolapril The thiazide diuretic, Trichlormethiazide, may increase the hypotensive effect of Trandolapril. Trichlormethiazide may also increase the nephrotoxicity of Trandolapril. Monitor for postural hypotension at initiation of concomitant therapy and renal dysfunction during chronic therapy.
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food Interactions Not Available

Targets


Solute carrier family 12 member 1
Name Solute carrier family 12 member 1
Gene Name SLC12A1
Pharmacological action yes
Actions inhibitor
References
  • 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
  • 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
  • Smith SM: Thiazide diuretics. N Engl J Med. 2010 Feb 18;362(7):659-60; author reply 660. - Pubmed
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
DTHybrid score 0.6626
Sodium/potassium-transporting ATPase alpha-1 chain
Name Sodium/potassium-transporting ATPase alpha-1 chain
Gene Name ATP1A1
Pharmacological action yes
Actions inhibitor
References
  • 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
DTHybrid score 0.878
Carbonic anhydrase 1
Name Carbonic anhydrase 1
Gene Name CA1
Pharmacological action unknown
Actions inhibitor
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • 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
  • 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. Epub 2008 Dec 24. - Pubmed
DTHybrid score 0.7585
Carbonic anhydrase 2
Name Carbonic anhydrase 2
Gene Name CA2
Pharmacological action unknown
Actions inhibitor
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • 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
  • 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. Epub 2008 Dec 24. - Pubmed
DTHybrid score 1.8001
Carbonic anhydrase 4
Name Carbonic anhydrase 4
Gene Name CA4
Pharmacological action unknown
Actions inhibitor
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • 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
  • 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. Epub 2008 Dec 24. - Pubmed
DTHybrid score 0.5376

Enzymes


Thiopurine S-methyltransferase
Name Thiopurine S-methyltransferase
Gene Name TPMT
Actions inhibitor
References
  • 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
DTHybrid score 0.3834

Predictions


Id Partner name Gene Name Score
466 Solute carrier family 12 member 3 SLC12A3 0.2058
610 Calcium-activated potassium channel subunit alpha 1 KCNMA1 0.1385
1729 Solute carrier family 22 member 6 SLC22A6 0.1295
6126 Carbonic anhydrase 7 CA7 0.1194
3007 Carbonic anhydrase 12 CA12 0.1188
4205 Carbonic anhydrase 9 CA9 0.1187
1253 Interferon gamma IFNG 0.1133
310 Solute carrier family 12 member 2 SLC12A2 0.0808
3932 Glutathione S-transferase A2 GSTA2 0.0662
6123 Carbonic anhydrase 5A, mitochondrial CA5A 0.0655
4512 Cytochrome P450 3A4 CYP3A4 0.0568
170 Succinate semialdehyde dehydrogenase, mitochondrial ALDH5A1 0.0539
566 Serotransferrin TF 0.0538
253 Sodium/potassium-transporting ATPase gamma chain FXYD2 0.052
4757 Cytochrome P450 2C9 CYP2C9 0.0489
87 Hypoxanthine-guanine phosphoribosyltransferase HPRT1 0.0485
6142 Solute carrier family 22 member 8 SLC22A8 0.0438
587 Serum albumin ALB 0.0427
6131 Carbonic anhydrase 14 CA14 0.0392
3947 Xanthine dehydrogenase/oxidase XDH 0.0386
6122 Carbonic anhydrase 3 CA3 0.0374
53 Solute carrier family 12 member 5 SLC12A5 0.0343
663 Solute carrier family 12 member 4 SLC12A4 0.0343
1024 Solute carrier family 22 member 11 SLC22A11 0.0307
6150 Solute carrier organic anion transporter family member 4C1 SLCO4C1 0.028
6016 Cytochrome P450 2C19 CYP2C19 0.0276
4031 Glutathione S-transferase A1 GSTA1 0.027
1025 Aquaporin-1 AQP1 0.0263
896 Glutathione S-transferase Mu 1 GSTM1 0.026
304 Solute carrier family 12 member 7 SLC12A7 0.0243
157 Solute carrier family 12 member 6 SLC12A6 0.0242
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0241
2164 Multidrug resistance-associated protein 4 ABCC4 0.0239
781 ATP-sensitive inward rectifier potassium channel 11 KCNJ11 0.0234
3426 Glutamine synthetase glnA 0.0232
3987 Glutamine synthetase GLUL 0.0232
6223 Penicillin-binding protein 1C pbpC 0.0227
1198 Serum paraoxonase/arylesterase 1 PON1 0.0227
6020 Aldehyde oxidase AOX1 0.0212
3623 Divalent-cation tolerance protein cutA cutA 0.0206
6171 Solute carrier family 28 member 3 SLC28A3 0.0195
158 Sodium channel protein type 1 subunit alpha SCN1A 0.0184
2222 Equilibrative nucleoside transporter 1 SLC29A1 0.0177
6124 Carbonic anhydrase 5B, mitochondrial CA5B 0.0171
382 Glutamate receptor, ionotropic kainate 1 GRIK1 0.0168
6136 Multidrug resistance-associated protein 5 ABCC5 0.0164
6017 Cholesterol side-chain cleavage enzyme, mitochondrial CYP11A1 0.0156
6158 Solute carrier organic anion transporter family member 1C1 SLCO1C1 0.0143
115 Penicillin-binding protein 2 mrdA 0.0138
6069 Penicillin-binding protein 2 mrdA 0.0138
6118 Penicillin-binding protein 2 penA 0.0138
6187 Penicillin-binding protein 2 pbpA 0.0138
6686 Penicillin-binding protein 2 pbp2 0.0138
6939 Penicillin-binding protein 2 mrdA 0.0138
7163 Penicillin-binding protein 2 pbpA 0.0138
1588 Multidrug resistance protein 1 ABCB1 0.0136
3226 UPF0234 protein HI1034 HI_1034 0.0135
3384 Macrophage migration inhibitory factor MIF 0.0132
6013 Cytochrome P450 2E1 CYP2E1 0.0132
6024 Cytochrome P450 1A1 CYP1A1 0.0129
543 Penicillin-binding protein 1B mrcB 0.0129
6186 Penicillin-binding protein 1B ponB 0.0129
6822 Penicillin-binding protein 1b pbp1b 0.0129
6844 Penicillin-binding protein 1b pbp1b 0.0129
1 Peptidoglycan synthetase ftsI ftsI 0.0129
4155 Peptidoglycan synthetase ftsI ftsI 0.0129
645 Penicillin-binding protein 1A mrcA 0.0127
5805 Penicillin-binding protein 1A ponA 0.0127
6185 Penicillin-binding protein 1A mrcA 0.0127
6799 Penicillin-binding protein 1A pbpA 0.0127
4119 Cytochrome P450 2D6 CYP2D6 0.0124
6157 Solute carrier organic anion transporter family member 1B3 SLCO1B3 0.0124
20 Prostaglandin G/H synthase 1 PTGS1 0.0122
4924 Cytochrome P450 2C8 CYP2C8 0.0121
964 Voltage-dependent T-type calcium channel subunit alpha-1H CACNA1H 0.0117
6040 6-phosphogluconate dehydrogenase, decarboxylating PGD 0.0114
3105 M-phase inducer phosphatase 2 CDC25B 0.0108
6152 Solute carrier organic anion transporter family member 2A1 SLCO2A1 0.0108
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0108
741 Potassium voltage-gated channel subfamily KQT member 1 KCNQ1 0.0103
2184 Cystic fibrosis transmembrane conductance regulator CFTR 0.0095
997 Protein kinase C beta type PRKCB 0.0095
6047 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A PDE1A 0.0093
634 Squalene monooxygenase SQLE 0.0088
7196 Squalene monooxygenase ERG1 0.0088
1970 Protein kinase C alpha type PRKCA 0.0087
5692 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B PDE1B 0.0087
392 Voltage-dependent P/Q-type calcium channel subunit alpha-1A CACNA1A 0.0087
2408 Tyrosine-protein kinase SYK SYK 0.0086
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.0086
1561 Troponin C, slow skeletal and cardiac muscles TNNC1 0.0081
4160 Voltage-dependent calcium channel subunit alpha-2/delta-2 CACNA2D2 0.008
118 Organic cation/carnitine transporter 2 SLC22A5 0.008
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0075
6127 Carbonic anhydrase-related protein CA8 0.0072
6129 Carbonic anhydrase-related protein 11 CA11 0.0072
6133 Sodium channel subunit beta-2 SCN2B 0.0072
6128 Carbonic anhydrase-related protein 10 CA10 0.0072
6132 Sodium channel subunit beta-1 SCN1B 0.0072
6134 Sodium channel subunit beta-3 SCN3B 0.0072
6135 Sodium channel subunit beta-4 SCN4B 0.0072
6141 Sodium/bile acid cotransporter SLC10A1 0.0071
3627 UPF0190 protein yedY yedY 0.0067
1392 Catenin beta-1 CTNNB1 0.0067
3352 Structural polyprotein Not Available 0.0067
3628 Structural polyprotein Not Available 0.0067
4892 Structural polyprotein Not Available 0.0067
2236 Casein kinase II subunit alpha CSNK2A1 0.0067
6130 Carbonic anhydrase 13 CA13 0.0067
6167 Organic solute transporter subunit beta OSTB 0.0066
6166 Organic solute transporter subunit alpha OSTA 0.0066
3803 Sodium channel protein type 3 subunit alpha SCN3A 0.0065
465 Calmodulin CALM1 0.0062
215 Sodium channel protein type 11 subunit alpha SCN11A 0.0061
6143 Solute carrier family 22 member 7 SLC22A7 0.0059
6263 cAMP-dependent protein kinase catalytic subunit alpha PRKACA 0.0059
3802 Sodium channel protein type 2 subunit alpha SCN2A 0.0057
290 Prostaglandin G/H synthase 2 PTGS2 0.0055
6153 Solute carrier organic anion transporter family member 4A1 SLCO4A1 0.0054
3804 Sodium channel protein type 4 subunit alpha SCN4A 0.0053
1995 Sodium channel protein type 9 subunit alpha SCN9A 0.0053
15 Voltage-dependent T-type calcium channel subunit alpha-1I CACNA1I 0.0048
365 Dihydrofolate reductase DHFR 0.0046
2381 Dihydrofolate reductase DFR1 0.0046
2833 Dihydrofolate reductase Not Available 0.0046
2931 Dihydrofolate reductase folA 0.0046
3544 Dihydrofolate reductase folA 0.0046
3682 Dihydrofolate reductase folA 0.0046
6642 Dihydrofolate reductase folA 0.0046
6756 Dihydrofolate reductase dfrA 0.0046
535 Voltage-dependent T-type calcium channel subunit alpha-1G CACNA1G 0.0046
6046 Voltage-gated calcium channel beta 1 subunit splice variant CavB1d CACNB1 0.0044
1632 Solute carrier organic anion transporter family member 2B1 SLCO2B1 0.0042
776 Bile salt export pump ABCB11 0.0041
315 Arginase-1 ARG1 0.004
6045 Voltage-dependent calcium channel subunit alpha-2/delta-3 CACNA2D3 0.004
220 Sodium channel protein type 5 subunit alpha SCN5A 0.0035
3939 Amine oxidase [flavin-containing] B MAOB 0.0035
3941 Amine oxidase [flavin-containing] A MAOA 0.0035
3970 Voltage-dependent N-type calcium channel subunit alpha-1B CACNA1B 0.0031
762 Voltage-dependent calcium channel subunit alpha-2/delta-1 CACNA2D1 0.0026
4110 Voltage-dependent L-type calcium channel subunit beta-2 CACNB2 0.0026
4115 Voltage-dependent L-type calcium channel subunit alpha-1D CACNA1D 0.0026
4111 Voltage-dependent L-type calcium channel subunit alpha-1S CACNA1S 0.0026
478 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C 0.0025
5718 Cytochrome P450 2A6 CYP2A6 0.0018
6030 Cytochrome P450 2B6 CYP2B6 0.0017
6107 Cytochrome P450 3A7 CYP3A7 0.0016
4118 Cytochrome P450 3A5 CYP3A5 0.0016
4200 Cytochrome P450 1A2 CYP1A2 0.0015
4037 Hypothetical protein GPX1 0.0008
4297 Hypothetical protein SP_1951 0.0008
4521 Hypothetical protein BC_2969 0.0008
4540 Hypothetical protein TM_1070 0.0008
4555 Hypothetical protein MT1739 0.0008
4569 Hypothetical protein mshD 0.0008
4578 Hypothetical protein PA3270 0.0008
4747 Hypothetical protein PA3967 0.0008
5177 Hypothetical protein TM_0096 0.0008
5194 Hypothetical protein PA1204 0.0008
5240 Hypothetical protein Rv2991 0.0008
5370 Hypothetical protein TM_1158 0.0008
5710 Hypothetical protein Tb927.5.1360 0.0008
4527 Putative hydrolase ycdX ycdX 0.0008
4536 Transcriptional regulator, IclR family TM_0065 0.0008
2501 Protein ygbM ygbM 0.0008
4545 Molybdopterin-converting factor subunit 2 moaE 0.0008
4522 Arginine N-succinyltransferase subunit alpha astA 0.0008
4106 Guanylate kinase GUK1 0.0008
4516 Guanylate kinase gmk 0.0008
4538 Hypothetical protein VC1899 VC_1899 0.0008
4529 Oxalate decarboxylase oxdC oxdC 0.0008
4514 Citrate lyase beta subunit-like protein citE 0.0008
4781 Citrate lyase beta subunit-like protein DR_1240 0.0008
4526 Oligopeptide ABC transporter, periplasmic oligopeptide-binding protein TM_1223 0.0008
4524 Mannose-6-phosphate isomerase yvyI 0.0008
4535 Glutaconyl-CoA decarboxylase subunit alpha gcdA 0.0008
4547 Iron binding protein FbpA fbpA 0.0008
4548 Gyrase B gyrB 0.0008
4546 Aminotransferase, putative TM_1131 0.0008
658 Para-aminobenzoate synthase component 1 pabB 0.0008
4515 Peripheral plasma membrane protein CASK CASK 0.0008
4496 C-terminal-binding protein 1 CTBP1 0.0008
4517 Probable butyrate kinase 2 buk2 0.0007
3261 Signal recognition particle protein ffh 0.0007
4528 Phenazine biosynthesis protein PhzD phzD1 0.0007
4533 Glyoxalase family protein BC_1747 0.0007
56 Delta-aminolevulinic acid dehydratase ALAD 0.0007
2356 Delta-aminolevulinic acid dehydratase hemB 0.0007
3613 Delta-aminolevulinic acid dehydratase hemB 0.0007
3674 Delta-aminolevulinic acid dehydratase hemB 0.0007
3759 Glutathione S-transferase gst 0.0007
4541 Glutathione S-transferase GST 0.0007
4542 Glutaminase 1 glsA1 0.0007
4544 Glutaminase 1 glsA1 0.0007
2929 (S)-2-haloacid dehalogenase dhlB 0.0007
2995 (S)-2-haloacid dehalogenase Not Available 0.0007
3237 Beta-lactamase OXA-2 bla 0.0007
4532 Gephyrin GPHN 0.0007
2230 Catalase CAT 0.0007
3249 Catalase katA 0.0007
3625 Catalase katA 0.0007
4539 Catalase katA 0.0007
4941 Catalase katB 0.0007
4531 Putative ketoacyl reductase actIII 0.0007
2775 Dihydroorotate dehydrogenase pyrD 0.0007
3467 Methylglyoxal synthase mgsA 0.0007
3583 6-phosphogluconolactonase pgl 0.0007
2525 3-phosphoshikimate 1-carboxyvinyltransferase aroA 0.0006
3201 3-phosphoshikimate 1-carboxyvinyltransferase aroA 0.0006
2688 Peptide deformylase def 0.0006
2708 Peptide deformylase def 0.0006
3004 Peptide deformylase def 0.0006
4337 Peptide deformylase def 0.0006
4338 Peptide deformylase def 0.0006
5368 Peptide deformylase def 0.0006
5371 Peptide deformylase def 0.0006
6375 Peptide deformylase def 0.0006
6378 Peptide deformylase def 0.0006
6379 Peptide deformylase def 0.0006
6776 Peptide deformylase def 0.0006
6900 Peptide deformylase def 0.0006
4534 Cytohesin-2 CYTH2 0.0006
2548 Subtilisin Carlsberg apr 0.0006
4269 Hypoxanthine-guanine phosphoribosyltransferase, putative HGPRTase 0.0006
760 Fibroblast growth factor 1 FGF1 0.0005
810 Heme oxygenase 1 HMOX1 0.0005
3391 Heme oxygenase 1 pbsA1 0.0005
3027 Streptavidin Not Available 0.0005
500 Monocarboxylate transporter 4 SLC16A3 0.0005
76 Nitric-oxide synthase, brain NOS1 0.0004
5682 Ribonuclease pancreatic RNASE1 0.0004
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