Identification

Name
Chlorothiazide
Accession Number
DB00880  (APRD00721)
Type
Small Molecule
Groups
Approved, Vet approved
Description

A thiazide diuretic with actions and uses similar to those of hydrochlorothiazide. (From Martindale, The Extra Pharmacopoeia, 30th ed, p812)

Structure
Thumb
Synonyms
  • 6-Chloro-1,1-dioxo-1,2-dihydro-1lambda*6*-benzo[1,2,4]thiadiazine-7-sulfonic acid amide
  • 6-chloro-7-Sulfamoyl-2H-1,2,4-benzothiadiazine 1,1-dioxide
  • Chlorothiazid
  • Chlorothiazide
  • Chlorothiazidum
  • Chlorthiazide
  • Clorotiazida
  • Mechlozid
  • Uroflux
Product Ingredients
IngredientUNIICASInChI Key
Chlorothiazide SodiumSN86FG7N2K7085-44-1CPIWHAFLBZQYLQ-UHFFFAOYSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DiurilSuspension250 mg/5mLOralSalix Pharmaceuticals1962-02-15Not applicableUs
DiurilSuspension250 mg/5mLOralMerck Sharp & Dohme Limited1961-10-062008-10-31Us
DIURIL SodiumInjection, powder, lyophilized, for solution0.5 g/18mLIntravenousMERCK and CO., INC.2006-04-07Not applicableUs
Sodium DiurilInjection, powder, lyophilized, for solution0.5 g/18mLIntravenousLundbeck Inc.1958-10-032011-12-22Us
Sodium DiurilInjection0.5 mg/18mLIntravenousOak Pharmaceuticals, Inc. (Subsidiary of Akorn, Inc.)1958-10-03Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ChlorothiazideTablet250 mg/1OralWest Ward Pharmaceutical2005-08-30Not applicableUs
ChlorothiazideTablet250 mg/1OralMylan Pharmaceuticals Inc.1975-06-26Not applicableUs
ChlorothiazideTablet500 mg/1OralGolden State Medical Supply2005-08-302017-01-02Us00143 1210 01 nlmimage10 b304d9c6
ChlorothiazideTablet500 mg/1OralPhysicians Total Care, Inc.2005-08-302012-06-30Us
ChlorothiazideInjection, powder, lyophilized, for solution500 mg/18mLIntravenousFresenius Kabi2009-10-21Not applicableUs
ChlorothiazideTablet250 mg/1OralGolden State Medical Supply2005-08-302017-01-02Us
ChlorothiazideTablet250 mg/1OralAvera McKennan Hospital2015-03-01Not applicableUs
ChlorothiazideTablet500 mg/1OralWest Ward Pharmaceutical2005-08-30Not applicableUs0143 121020180819 11162 1fx9mgn
ChlorothiazideTablet500 mg/1OralMylan Pharmaceuticals Inc.1975-07-17Not applicableUs00378 0162 01 nlmimage10 b83ddc0e
Chlorothiazide SodiumInjection, powder, lyophilized, for solution500 mg/18mLIntravenousSagent Pharmaceuticals2015-10-12Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
DiupresChlorothiazide (500 mg/1) + Reserpine (0.125 mg/1)TabletOralMerck & Co., Inc.2006-03-02Not applicableUs
DiupresChlorothiazide (250 mg/1) + Reserpine (0.125 mg/1)TabletOralMerck & Co., Inc.2006-03-02Not applicableUs
Supres 150 TabChlorothiazide (150 mg) + Methyldopa (250 mg)TabletOralMerck Frosst Canada & Cie, Merck Frosst Canada & Co.1972-12-312000-06-14Canada
Supres 250 TabChlorothiazide (250 mg) + Methyldopa (250 mg)TabletOralMerck Frosst Canada & Cie, Merck Frosst Canada & Co.1972-12-312000-06-14Canada
Categories
UNII
77W477J15H
CAS number
58-94-6
Weight
Average: 295.723
Monoisotopic: 294.948824782
Chemical Formula
C7H6ClN3O4S2
InChI Key
JBMKAUGHUNFTOL-UHFFFAOYSA-N
InChI
InChI=1S/C7H6ClN3O4S2/c8-4-1-5-7(2-6(4)16(9,12)13)17(14,15)11-3-10-5/h1-3H,(H,10,11)(H2,9,12,13)
IUPAC Name
6-chloro-1,1-dioxo-4H-1λ⁶,2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=C(Cl)C=C2NC=NS(=O)(=O)C2=C1

Pharmacology

Indication

Chlorothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It 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.

Associated Conditions
Pharmacodynamics

Like other thiazides, chlorothiazide promotes water loss from the body (diuretics). It inhibits 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. Chlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosages, all thiazides are approximately equal in their diuretic efficacy. Chlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral doses, 10-15 percent of the dose is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Mechanism of action

As a diuretic, chlorothiazide 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 chlorothiazide 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 chlorothiazide 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
ACarbonic anhydrase 1
inhibitor
Human
ACarbonic anhydrase 2
inhibitor
Human
Absorption

Rapidly absorbed following oral administration.

Volume of distribution
Not Available
Protein binding

Approximately 40% bound to plasma proteins.

Metabolism

Chlorothiazide is not metabolized but is eliminated rapidly by the kidney.

Route of elimination

Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. After oral doses, 10 to 15 percent of the dose is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Half life

45-120 minutes

Clearance
Not Available
Toxicity

Oral, rat LD50: > 10 g/kg. Signs of overdose include those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered hypokalemia may accentuate cardiac arrhythmias.

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

Interactions

Drug Interactions
DrugInteraction
(2-benzhydryloxyethyl)diethyl-methylammonium iodideThe serum concentration of Chlorothiazide can be increased when it is combined with (2-benzhydryloxyethyl)diethyl-methylammonium iodide.
1alpha-Hydroxyvitamin D5The risk or severity of hypercalcemia can be increased when Chlorothiazide is combined with 1alpha-Hydroxyvitamin D5.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Chlorothiazide.
AbediterolAbediterol may increase the hypokalemic activities of Chlorothiazide.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Chlorothiazide.
AcebutololChlorothiazide may increase the hypotensive activities of Acebutolol.
AceclofenacThe therapeutic efficacy of Chlorothiazide can be decreased when used in combination with Aceclofenac.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Chlorothiazide.
AcetyldigitoxinThe risk or severity of adverse effects can be increased when Chlorothiazide is combined with Acetyldigitoxin.
AcetyldigoxinThe risk or severity of adverse effects can be increased when Chlorothiazide is combined with Acetyldigoxin.
Food Interactions
Not Available

References

Synthesis Reference

Eugene S. Barabas, "Water soluble complex of a poly (vinyl lactam) and chlorothiazide and process for producing same." U.S. Patent US4713238, issued December, 1985.

US4713238
General References
Not Available
External Links
Human Metabolome Database
HMDB0015018
KEGG Drug
D00519
KEGG Compound
C07461
PubChem Compound
2720
PubChem Substance
46507032
ChemSpider
2619
BindingDB
39351
ChEBI
3640
ChEMBL
CHEMBL842
Therapeutic Targets Database
DAP000605
PharmGKB
PA448953
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Chlorothiazide
ATC Codes
C03AA04 — ChlorothiazideC03AB04 — Chlorothiazide and potassiumC03AH01 — Chlorothiazide, combinationsG01AE10 — Combinations of sulfonamides
MSDS
Download (72.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedPreventionCardiovascular Disease (CVD) / Heart Diseases / High Blood Pressure (Hypertension) / Vascular Diseases1
4Active Not RecruitingTreatmentHeart Failure, Unspecified1
4Enrolling by InvitationTreatmentAcute Heart Failure (AHF) / Cardiovascular Disease (CVD) / Heart Failure With Reduced Ejection Fraction (HFrEF) / Heart Failure, Unspecified1
Not AvailableCompletedScreeningDiabetes Insipidus, Nephrogenic1
Not AvailableRecruitingDiagnosticHeart Failure, Unspecified1

Pharmacoeconomics

Manufacturers
  • Salix pharmaceuticals inc
  • Abc holding corp
  • Lederle laboratories div american cyanamid co
  • Mylan pharmaceuticals inc
  • Sandoz inc
  • Watson laboratories inc
  • West ward pharmaceutical corp
  • Lundbeck inc
  • App pharmaceuticals llc
Packagers
  • APP Pharmaceuticals
  • Ben Venue Laboratories Inc.
  • Endo Pharmaceuticals Inc.
  • Lundbeck Inc.
  • Major Pharmaceuticals
  • Merck & Co.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • PD-Rx Pharmaceuticals Inc.
  • Physicians Total Care Inc.
  • Salix Pharmaceuticals
  • Sandhills Packaging Inc.
  • UDL Laboratories
  • Watson Pharmaceuticals
  • West-Ward Pharmaceuticals
Dosage forms
FormRouteStrength
TabletOral250 mg/1
TabletOral500 mg/1
InjectionIntravenous500 mg/1
Injection, powder, lyophilized, for solutionIntravenous500 mg/18mL
SuspensionOral250 mg/5mL
Injection, powder, lyophilized, for solutionIntravenous0.5 g/18mL
InjectionIntravenous0.5 mg/18mL
TabletOral
Prices
Unit descriptionCostUnit
Diuril sodium 500 mg vial519.62USD vial
Chlorothiazide sod 500 mg vial357.24USD vial
Microzide 12.5 mg capsule0.95USD capsule
Aldoclor 250-250 mg tablet0.67USD tablet
Chlorothiazide 500 mg tablet0.36USD tablet
Chlorothiazide 250 mg tablet0.28USD tablet
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)342.5-343Novello, F.C.; US. Patent 2,809,194; October 8,1957; assigned to Merck & Co.,Inc. Hinkley, D.F.; US. Patent 2,937,169; May 17,1960; assigned to Merck & Co., Inc.
water solubility266 mg/L (at 30 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP-0.24HANSCH,C ET AL. (1995)
logS-3.05ADME Research, USCD
Caco2 permeability-6.72ADME Research, USCD
pKa6.85MERCK INDEX (1996)
Predicted Properties
PropertyValueSource
Water Solubility0.398 mg/mLALOGPS
logP0.41ALOGPS
logP-0.44ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)9.1ChemAxon
pKa (Strongest Basic)1.15ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area118.69 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity62.51 m3·mol-1ChemAxon
Polarizability24.55 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9119
Blood Brain Barrier-0.9506
Caco-2 permeable-0.7368
P-glycoprotein substrateNon-substrate0.706
P-glycoprotein inhibitor INon-inhibitor0.8482
P-glycoprotein inhibitor IINon-inhibitor0.8381
Renal organic cation transporterNon-inhibitor0.8177
CYP450 2C9 substrateNon-substrate0.755
CYP450 2D6 substrateNon-substrate0.8379
CYP450 3A4 substrateNon-substrate0.6308
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.923
CYP450 2C19 inhibitorNon-inhibitor0.9382
CYP450 3A4 inhibitorNon-inhibitor0.8901
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8658
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.7792
BiodegradationNot ready biodegradable1.0
Rat acute toxicity1.5023 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9654
hERG inhibition (predictor II)Non-inhibitor0.9352
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (10.1 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-QFT , negativeLC-MS/MSsplash10-0006-0090000000-e74dd6446e0284a7f0aa
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0006-0090000000-baf93e639a13c39dc1d6
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-01ox-0090000000-473477518be3f6c8ddcd
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-03di-0290000000-0e599c26917ade291ca0
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-03di-0890000000-ad270ef1247ce9a114ad
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-004i-0920000000-3c4bb920bb8316022718
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-004i-2900000000-eca13dbca70054de3470
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-02vr-9700000000-9261e1bf4e212aee7d84
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0i09-9100000000-491baf01fc6ef9ca39e1
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0002-0090000000-388cb4ff11dc0a41ad99
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-002b-0090000000-5645eee512f78cd689a7
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0udi-0390000000-a39ffe78224ed4cacc13
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0pbl-0920000000-eb979e3c4ecd1f12fb71
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-059f-2900000000-4c2eb27958fba0102431
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-05tk-5900000000-b42b446bc2b9f6216af1
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-00kk-9400000000-b4b975e3c1fabe09f4a7
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-03di-9100000000-f8f80586b12a43c2a667
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-03di-9000000000-9d41a0f061f998097c17

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
Organosulfonamides / Benzenoids / Aryl chlorides / Aminosulfonyl compounds / Propargyl-type 1,3-dipolar organic compounds / Formamidines / Azacyclic compounds / Organopnictogen compounds / Organochlorides / Organic oxides
show 1 more
Substituents
1,2,4-benzothiadiazine-1,1-dioxide / Aryl chloride / Aryl halide / Organosulfonic acid amide / Benzenoid / Organic sulfonic acid or derivatives / Organosulfonic acid or derivatives / Sulfonyl / Aminosulfonyl compound / Propargyl-type 1,3-dipolar organic compound
show 14 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
benzothiadiazine (CHEBI:3640)

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
Kind
Protein
Organism
Human
Pharmacological action
Yes
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. Puscas I, Coltau M, Baican M, Domuta G, Hecht A: Vasodilatory effect of diuretics is dependent on inhibition of vascular smooth muscle carbonic anhydrase by a direct mechanism of action. Drugs Exp Clin Res. 1999;25(6):271-9. [PubMed:10713865]
  2. Puscas I, Coltau M, Baican M, Pasca R, Domuta G: The inhibitory effect of diuretics on carbonic anhydrases. Res Commun Mol Pathol Pharmacol. 1999;105(3):213-36. [PubMed:10954127]
Kind
Protein
Organism
Human
Pharmacological action
Yes
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. Weiner ID, Verlander JW: Renal and hepatic expression of the ammonium transporter proteins, Rh B Glycoprotein and Rh C Glycoprotein. Acta Physiol Scand. 2003 Dec;179(4):331-8. [PubMed:14656370]
  2. Puscas I, Coltau M, Baican M, Pasca R, Domuta G: The inhibitory effect of diuretics on carbonic anhydrases. Res Commun Mol Pathol Pharmacol. 1999;105(3):213-36. [PubMed:10954127]
  3. Verlander JW, Miller RT, Frank AE, Royaux IE, Kim YH, Weiner ID: Localization of the ammonium transporter proteins RhBG and RhCG in mouse kidney. Am J Physiol Renal Physiol. 2003 Feb;284(2):F323-37. Epub 2002 Oct 8. [PubMed:12388412]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. Uwai Y, Saito H, Hashimoto Y, Inui KI: Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1. J Pharmacol Exp Ther. 2000 Oct;295(1):261-5. [PubMed:10991988]

Drug created on June 13, 2005 07:24 / Updated on October 01, 2018 16:30