Details of the Drug

General Information of Drug (ID: DMHAQCO)

• Drug Name: Trichlormethiazide
• Synonyms: Achletin; Anistadin; Aponorin; Aquazide; Carvacron; Chlopolidine; Cretonin; Diurazida; Diurese; Diuroral;Esmarin; Eurinol; Fluitran; Flurese; Flutra; Gangesol; Hydrotrichlorothiazide; Intromene; Isestran; Kubacron; Metahydrin; Metatensin; Nakva; Naqua; Naquasone; Schebitran; Tachionin; Tolcasone; Trichlordiuride; Trichlorex; Trichlormas; Trichlormetazid; Trichlormethiazid; Trichlormethiazidum; Trichloromethiadiazide; Trichloromethiazide; Triclordiuride; Triclormetiazida; Triclormetiazide; Triflumen;American Urologicals Brand of Trichloromethiazide; Jones Brand of Trichloromethiazide; Schering Brand of Trichlormethiazide; Triclormetiazide [DCIT]; Triclormetiazide [Italian]; Achletin (TN); Ciba 7057-Su; Diu-Hydrin; Flurese (VAN); Naqua (TN); Salurin (wadel); Trichlormethiazide W/ Reserpine; Trichlormethiazide [INN:JAN]; Trichlormethiazidum [INN-Latin]; Trichloromethiazide, 6; Triclormetiazida[INN-Spanish]; Triflumen (TN); Diu-Hydrin (TN); Trichlormethiazide (JP15/USP/INN); (+-)-6-Chloro-3-(dichloromethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide; 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3-(dichloromethyl)-3,4-dihydro-, 1,1-dioxide; 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3-(dichloromethyl)-3,4-dihydro-,1,1-dioxide; 3-(Dichloromethyl)-6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide; 3-(Dichloromethyl)-6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Dichloromethyl-6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Dichloromethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide; 3-Dichloromethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine1,1-dioxide; 3-Dichloromethylhydrochlorothiazide; 6-Chloro-3-(dichloromethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide; 6-Chloro-3-(dichloromethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide1,1-dioxide; 6-Chloro-3-(dichloromethyl)3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide; 6-Chloro-3-(dichloromethyl)3,4-dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide; 6-Chloro-3-[dichloromethyl]-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide; 6-Chloro-3-dichloromethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-Dioxide; 6-Chloro-3-dichloromethyl-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine1,1-dioxide

Indication

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[1], [2]

• Therapeutic Class: Antihypertensive Agents
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 380.7
  Topological Polar Surface Area (xlogp); 0.6
  Rotatable Bond Count (rotbonds); 2
  Hydrogen Bond Donor Count (hbonddonor); 3
  Hydrogen Bond Acceptor Count (hbondacc); 7
• ADMET Property:
  Bioavailability: 60% of drug becomes completely available to its intended biological destination(s) [3]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.1752 micromolar/kg/day [4]
• Chemical Identifiers:
  Formula: C8H8Cl3N3O4S2
  IUPAC Name: 6-chloro-3-(dichloromethyl)-1,1-dioxo-3,4-dihydro-2H-1lambda6,2,4-benzothiadiazine-7-sulfonamide
  Canonical SMILES: C1=C2C(=CC(=C1Cl)S(=O)(=O)N)S(=O)(=O)NC(N2)C(Cl)Cl
  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)
  InChIKey: LMJSLTNSBFUCMU-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 5560
  ChEBI ID: CHEBI:9683
  CAS Number: 133-67-5
  DrugBank ID: DB01021
  TTD ID: D0Y2IZ
  VARIDT ID: DR00707

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Solute carrier family 12 member 1 (SLC12A1)	TTS087L	S12A1_HUMAN	Blocker	[5]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[6]

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Same Disease as Trichlormethiazide

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Disease	REF
Acebutolol	DM0TI4U	Moderate	Increased risk of hyperglycemia by the combination of Trichlormethiazide and Acebutolol.	Hypertension [BA00-BA04]	[24]
Captopril	DM458UM	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Captopril.	Hypertension [BA00-BA04]	[25]
Nebivolol	DM7F1PA	Moderate	Increased risk of ventricular arrhythmias by the combination of Trichlormethiazide and Nebivolol.	Hypertension [BA00-BA04]	[24]

Coadministration of a Drug Treating the Disease Different from Trichlormethiazide (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Dronedarone	DMA8FS5	Major	Increased risk of ventricular arrhythmias by the combination of Trichlormethiazide and Dronedarone.	Angina pectoris [BA40]	[26]
Rabeprazole	DMMZXIW	Moderate	Increased risk of hypomagnesemia by the combination of Trichlormethiazide and Rabeprazole.	Bacterial infection [1A00-1C4Z]	[27]
Cariprazine	DMJYDVK	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Cariprazine.	Bipolar disorder [6A60]	[28]
Levomilnacipran	DMV26S8	Moderate	Increased risk of hyponatremia by the combination of Trichlormethiazide and Levomilnacipran.	Chronic pain [MG30]	[29]
Sertraline	DM0FB1J	Moderate	Increased risk of hyponatremia by the combination of Trichlormethiazide and Sertraline.	Depression [6A70-6A7Z]	[29]
Vilazodone	DM4LECQ	Moderate	Increased risk of hyponatremia by the combination of Trichlormethiazide and Vilazodone.	Depression [6A70-6A7Z]	[29]
Selegiline	DM6034S	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Selegiline.	Depression [6A70-6A7Z]	[30]
Vortioxetine	DM6F1PU	Moderate	Increased risk of hyponatremia by the combination of Trichlormethiazide and Vortioxetine.	Depression [6A70-6A7Z]	[29]
Isocarboxazid	DMAF1NB	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Isocarboxazid.	Depression [6A70-6A7Z]	[30]
Milnacipran	DMBFE74	Moderate	Increased risk of hyponatremia by the combination of Trichlormethiazide and Milnacipran.	Depression [6A70-6A7Z]	[29]
Escitalopram	DMFK9HG	Moderate	Increased risk of hyponatremia by the combination of Trichlormethiazide and Escitalopram.	Depression [6A70-6A7Z]	[29]
Desvenlafaxine	DMHD4PE	Moderate	Increased risk of hyponatremia by the combination of Trichlormethiazide and Desvenlafaxine.	Depression [6A70-6A7Z]	[29]
OPC-34712	DMHG57U	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and OPC-34712.	Depression [6A70-6A7Z]	[28]
Mepenzolate	DM8YU2F	Minor	Altered absorption of Trichlormethiazide due to GI dynamics variation caused by Mepenzolate.	Digestive system disease [DE2Z]	[31]
Oxybutynine	DMJPBAX	Minor	Altered absorption of Trichlormethiazide due to GI dynamics variation caused by Oxybutynine.	Discovery agent [N.A.]	[31]
Eslicarbazepine	DMZREFQ	Moderate	Increased risk of hyponatremia by the combination of Trichlormethiazide and Eslicarbazepine.	Epilepsy/seizure [8A61-8A6Z]	[32]
Nadolol	DMW6GVL	Moderate	Increased risk of ventricular arrhythmias by the combination of Trichlormethiazide and Nadolol.	Essential hypertension [BA00]	[24]
Solifenacin	DMG592Q	Minor	Altered absorption of Trichlormethiazide due to GI dynamics variation caused by Solifenacin.	Functional bladder disorder [GC50]	[31]
Tolterodine	DMSHPW8	Minor	Altered absorption of Trichlormethiazide due to GI dynamics variation caused by Tolterodine.	Functional bladder disorder [GC50]	[31]
Dexlansoprazole	DM1DBV5	Moderate	Increased risk of hypomagnesemia by the combination of Trichlormethiazide and Dexlansoprazole.	Gastro-oesophageal reflux disease [DA22]	[27]
Metipranolol	DMJMVKI	Moderate	Increased risk of hyperglycemia by the combination of Trichlormethiazide and Metipranolol.	Glaucoma [9C61]	[24]
Levobunolol	DMTNFCQ	Moderate	Increased risk of hypertriglyceridemia by the combination of Trichlormethiazide and Levobunolol.	Glaucoma [9C61]	[24]
Carvedilol	DMHTEAO	Moderate	Increased risk of hypertriglyceridemia by the combination of Trichlormethiazide and Carvedilol.	Heart failure [BD10-BD1Z]	[24]
Procarbazine	DMIK367	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Procarbazine.	Hodgkin lymphoma [2B30]	[30]
Belladonna	DM2RBWK	Minor	Altered absorption of Trichlormethiazide due to GI dynamics variation caused by Belladonna.	Infectious gastroenteritis/colitis [1A40]	[31]
ITI-007	DMUQ1DO	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and ITI-007.	Insomnia [7A00-7A0Z]	[28]
Arsenic trioxide	DM61TA4	Major	Increased risk of ventricular arrhythmias by the combination of Trichlormethiazide and Arsenic trioxide.	Mature B-cell lymphoma [2A85]	[33]
Ozanimod	DMT6AM2	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Ozanimod.	Multiple sclerosis [8A40]	[30]
Promethazine	DM6I5GR	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Promethazine.	Nausea/vomiting [MD90]	[28]
Sibutramine	DMFJTDI	Moderate	Increased risk of hyponatremia by the combination of Trichlormethiazide and Sibutramine.	Obesity [5B80-5B81]	[29]
Ibuprofen	DM8VCBE	Moderate	Antagonize the effect of Trichlormethiazide when combined with Ibuprofen.	Pain [MG30-MG3Z]	[34]
Flavoxate	DMKV4NL	Minor	Altered absorption of Trichlormethiazide due to GI dynamics variation caused by Flavoxate.	Pain [MG30-MG3Z]	[31]
Safinamide	DM0YWJC	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Safinamide.	Parkinsonism [8A00]	[30]
Rasagiline	DM3WKQ4	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Rasagiline.	Parkinsonism [8A00]	[30]
Methylscopolamine	DM5VWOB	Minor	Altered absorption of Trichlormethiazide due to GI dynamics variation caused by Methylscopolamine.	Peptic ulcer [DA61]	[31]
Quetiapine	DM1N62C	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Quetiapine.	Schizophrenia [6A20]	[28]
Iloperidone	DM6AUFY	Moderate	Increased risk of ventricular arrhythmias by the combination of Trichlormethiazide and Iloperidone.	Schizophrenia [6A20]	[35]
Paliperidone	DM7NPJS	Moderate	Increased risk of ventricular arrhythmias by the combination of Trichlormethiazide and Paliperidone.	Schizophrenia [6A20]	[35]
Molindone	DMAH70G	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Molindone.	Schizophrenia [6A20]	[28]
Thiothixene	DMDINC4	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Thiothixene.	Schizophrenia [6A20]	[28]
Amisulpride	DMSJVAM	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Amisulpride.	Schizophrenia [6A20]	[28]
Asenapine	DMSQZE2	Moderate	Additive hypotensive effects by the combination of Trichlormethiazide and Asenapine.	Schizophrenia [6A20]	[28]
Pimozide	DMW83TP	Major	Increased risk of ventricular arrhythmias by the combination of Trichlormethiazide and Pimozide.	Schizophrenia [6A20]	[36]
Amiodarone	DMUTEX3	Major	Increased risk of ventricular arrhythmias by the combination of Trichlormethiazide and Amiodarone.	Ventricular tachyarrhythmia [BC71]	[37]

References

• [1] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7314).
• [2] Current usage of diuretics among hypertensive patients in Japan: the Japan Home versus Office Blood Pressure Measurement Evaluation (J-HOME) study. Hypertens Res. 2006 Nov;29(11):857-63.
• [3] Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches
• [4] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [5] 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.
• [6] Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug-drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments. Drug Metab Dispos. 2011 Jun;39(6):1031-8.
• [7] Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3. Drug Metab Pharmacokinet. 2004 Oct;19(5):369-74.
• [8] Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J Pharmacol Exp Ther. 2002 Apr;301(1):293-8.
• [9] Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002 Mar;300(3):918-24.
• [10] Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001 May;59(5):1277-86.
• [11] Murine renal organic anion transporters mOAT1 and mOAT3 facilitate the transport of neuroactive tryptophan metabolites. Am J Physiol Cell Physiol. 2005 Nov;289(5):C1075-84.
• [12] Organic anion transporter 3 is involved in the brain-to-blood efflux transport of thiopurine nucleobase analogs. J Neurochem. 2004 Aug;90(4):931-41.
• [13] Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase. J Pharm Pharmacol. 2005 Oct;57(10):1305-11.
• [14] The contribution of organic anion transporters OAT1 and OAT3 to the renal uptake of rosuvastatin. J Pharmacol Exp Ther. 2007 Sep;322(3):1221-7.
• [15] Aspirin and probenecid inhibit organic anion transporter 3-mediated renal uptake of cilostazol and probenecid induces metabolism of cilostazol in the rat. Drug Metab Dispos. 2014 Jun;42(6):996-1007.
• [16] Nongenomic effect of aldosterone on ion transport pathways of red blood cells. Cell Physiol Biochem. 2008;22(1-4):269-78.
• [17] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [18] Update of diuretics in the treatment of hypertension. Am J Ther. 2007 Mar-Apr;14(2):154-60.
• [19] Nerve Terminal GABAA Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release. J Biol Chem. 2009 Mar 27;284(13):8726-37.
• [20] Na-K-Cl cotransport regulates intracellular volume and monolayer permeability of trabecular meshwork cells. Am J Physiol. 1995 Apr;268(4 Pt 1):C1067-74.
• [21] Genetic variation in the renal sodium transporters NKCC2, NCC, and ENaC in relation to the effects of loop diuretic drugs. Clin Pharmacol Ther. 2007 Sep;82(3):300-9.
• [22] DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.
• [23] The 45-year story of the development of an anti-aldosterone more specific than spironolactone. Mol Cell Endocrinol. 2004 Mar 31;217(1-2):45-52.
• [24] Dean S, Kendall MJ, Potter S, Thompson MH, Jackson DA "Nadolol in combination with indapamide and xipamide in resistant hypertensives." Eur J Clin Pharmacol 28 (1985): 29-33. [PMID: 3987783]
• [25] Burnakis TG, Mioduch HJ "Combined therapy with captopril and potassium supplementation: a potential for hyperkalemia." Arch Intern Med 144 (1984): 2371-2. [PMID: 6391404]
• [26] Product Information. Multaq (dronedarone). sanofi-aventis , Bridgewater, NJ.
• [27] FDA. U.S. Food and Drug Administration "FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of proton pump inhibitor drugs (PPIs).".
• [28] Aronowitz JS, Chakos MH, Safferman AZ, Lieberman JA "Syncope associated with the combination of clozapine and enalapril." J Clin Psychopharmacol 14 (1994): 429-30. [PMID: 7884028]
• [29] Product Information. Savella (milnacipran). Forest Pharmaceuticals, St. Louis, MO.
• [30] Ban TA "Drug interactions with psychoactive drugs." Dis Nerv Syst 36 (1975): 164-6. [PMID: 1116424]
• [31] Beermann B, Groschinsky-Grind M "Enhancement of the gastrointestinal absorption of hydrochlorothiazide by propantheline." Eur J Clin Pharmacol 13 (1978): 385-7. [PMID: 668798]
• [32] Product Information. Aptiom (eslicarbazepine). Sunovion Pharmaceuticals Inc, Marlborough, MA.
• [33] Ohnishi K, Yoshida H, Shigeno K, et al. "Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia." Ann Intern Med 133 (2000): 881-5. [PMID: 11103058]
• [34] Muller FO, Schall R, Devaal AC, Groenewoud G, Hundt HKL, Middle MV "Influence of meloxicam on furosemide pharmacokinetics and pharmacodynamics in healthy volunteers." Eur J Clin Pharmacol 48 (1995): 247-51. [PMID: 7589049]
• [35] Cerner Multum, Inc. "Australian Product Information.".
• [36] Product Information. Orap Tablets (pimozide). Gate Pharmaceuticals, Sellersville, PA.
• [37] Antonelli D, Atar S, Freedberg NA, Rosenfeld T "Torsade de pointes in patients on chronic amiodarone treatment: contributing factors and drug interactions." Isr Med Assoc J 7 (2005): 163-5. [PMID: 15792261]