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Identification
NameChlorothiazide
Accession NumberDB00880  (APRD00721)
Typesmall molecule
Groupsapproved
Description

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

Structure
Thumb
Synonyms
SynonymLanguageCode
ChlorothiazidNot AvailableNot Available
ChlorothiazidumNot AvailablePH: Ph. Eur. 7, Ph. Int. 2
ChlorthiazideNot AvailableNot Available
MechlozidNot AvailableIS
UrofluxNot AvailableIS
Salts
Name/CAS Structure Properties
Chlorothiazide Sodium
Thumb Not applicable DBSALT000926
Brand names
NameCompany
DiurilMerck, Lundbeck
Brand mixtures
Brand NameIngredients
Supres 150 TabChlorothiazide + Methyldopa
Supres 250 TabChlorothiazide + Methyldopa
Categories
CAS number58-94-6
WeightAverage: 295.723
Monoisotopic: 294.948824782
Chemical FormulaC7H6ClN3O4S2
InChI KeyJBMKAUGHUNFTOL-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-1$l^{6},2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=C(Cl)C=C2NC=NS(=O)(=O)C2=C1
Mass Specshow(10.1 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassThiadiazines
SubclassBenzothiadiazines
Direct parentBenzothiadiazines
Alternative parentsBenzenesulfonamides; Chlorobenzenes; Aryl Chlorides; Sulfonyls; Sulfonamides; Polyamines; Organochlorides
Substituentschlorobenzene; aryl chloride; aryl halide; benzene; sulfonamide; sulfonyl; sulfonic acid derivative; polyamine; organochloride; organohalogen; organonitrogen compound
Classification descriptionThis compound belongs to the benzothiadiazines. These are organic compounds containing a benzene fused to a thiadiazine ring (a six-member ring with two nitrogen atoms and a sulfur atom).
Pharmacology
IndicationChlorothiazide 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.
PharmacodynamicsLike 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 actionAs 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.
AbsorptionRapidly absorbed following oral administration.
Volume of distributionNot Available
Protein bindingApproximately 40% bound to plasma proteins.
Metabolism

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

Route of eliminationChlorothiazide 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 life45-120 minutes
ClearanceNot Available
ToxicityOral, 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
PathwayCategorySMPDB ID
Chlorothiazide Action PathwayDrug actionSMP00078
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9119
Blood Brain Barrier - 0.9506
Caco-2 permeable - 0.7368
P-glycoprotein substrate Non-substrate 0.706
P-glycoprotein inhibitor I Non-inhibitor 0.8482
P-glycoprotein inhibitor II Non-inhibitor 0.8381
Renal organic cation transporter Non-inhibitor 0.8177
CYP450 2C9 substrate Non-substrate 0.755
CYP450 2D6 substrate Non-substrate 0.8379
CYP450 3A4 substrate Non-substrate 0.6308
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.923
CYP450 2C19 substrate Non-inhibitor 0.9382
CYP450 3A4 substrate Non-inhibitor 0.8901
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8658
Ames test Non AMES toxic 0.9132
Carcinogenicity Non-carcinogens 0.7792
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 1.5023 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9654
hERG inhibition (predictor II) Non-inhibitor 0.9352
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
Dosage forms
FormRouteStrength
SuspensionOral
Prices
Unit descriptionCostUnit
Diuril sodium 500 mg vial519.62USDvial
Chlorothiazide sod 500 mg vial357.24USDvial
Microzide 12.5 mg capsule0.95USDcapsule
Aldoclor 250-250 mg tablet0.67USDtablet
Chlorothiazide 500 mg tablet0.36USDtablet
Chlorothiazide 250 mg tablet0.28USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point342.5-343Novello, 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 solubility3.98e-01 g/lALOGPS
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 area118.69ChemAxon
rotatable bond count1ChemAxon
refractivity62.51ChemAxon
polarizability24.55ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot 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 ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00519
KEGG CompoundC07461
PubChem Compound2720
PubChem Substance46507032
ChemSpider2619
ChEBI3640
ChEMBLCHEMBL842
Therapeutic Targets DatabaseDAP000605
PharmGKBPA448953
Drug Product Database231169
RxListhttp://www.rxlist.com/cgi/generic2/chloroth.htm
Drugs.comhttp://www.drugs.com/cdi/chlorothiazide.html
WikipediaChlorothiazide
ATC CodesC03AA03C03AA04
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(72.7 KB)
Interactions
Drug Interactions
Drug
AmifostineAntihypertensives may enhance the hypotensive effect of amifostine. When amifostine is used at doses recommended for chemotherapy, antihypertensive medications should be withheld for 24 hours prior to amifostine administration to avoid excessive hypotension during or immediately after infusion. If antihypertensive therapy can not be withheld, then that patient should not receive amifostine. Caution is recommended when using amifostine at the lower doses recommended for radiotherapy, but routine interruption of antihypertensive therapy is not recommended in these patients.
CholestyramineBile acid sequestrants may decrease the absorption of thiazide diuretics such as chlorothiazide. The diuretic response is likewise decreased. Monitor for decreased therapeutic effects of thiazide diuretics if coadministered with a bile acid sequestrant. If these agents are used concomitantly, separate doses 2 or more hours to minimize the interaction.
ColestipolBile acid sequestrants may decrease the absorption of thiazide diuretics such as chlorothiazide. The diuretic response is likewise decreased. Monitor for decreased therapeutic effects of thiazide diuretics if coadministered with a bile acid sequestrant. If these agents are used concomitantly, separate doses 2 or more hours to minimize the interaction.
DigoxinPossible electrolyte variations and arrhythmias
DofetilideThiazide diuretics such as chlorothiazide may enhance the QTc-prolonging effect of dofetilide. Thiazide diuretics may increase the serum concentration of dofetilide. The concomitant use of hydrochlorothiazide and dofetilide is contraindicated by the manufacturer of dofetilide. Monitor for increased risk of QTc-prolongation and associated ventricular arrythmias during concomitant use of dofetilide and thiazide diuretics.
LithiumThe thiazide diuretic, chlorothiazide, may increase serum levels of lithium.
RituximabAntihypertensives such as chlorothiazide may enhance the hypotensive effect of Rituximab. Consider temporarily withholding antihypertensive medications for 12 hours prior to rituximab infusion to avoid excessive hypotension during or immediately after infusion.
TopiramateThiazide diuretics such as chlorothiazide may enhance the hypokalemic effect of topiramate. Thiazide diuretics may increase the serum concentration of topiramate. Monitor for increased topiramate concentrations/adverse effects (e.g., hypokalemia) with initiation/dose increase of a thiazide diuretic. Closely monitor serum potassium concentrations with concomitant therapy. Topiramate dose reductions may be necessary.
TrandolaprilThe thiazide diuretic, Chlorothiazide, may increase the hypotensive effect of Trandolapril. Chlorothiazide may also increase the nephrotoxicity of Trandolapril. Monitor for postural hypotension at initiation of concomitant therapy and renal dysfunction during chronic therapy.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food InteractionsNot Available

Targets

1. Solute carrier family 12 member 3

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier family 12 member 3 P55017 Details

References:

  1. Thakker RV: Molecular pathology of renal chloride channels in Dent’s disease and Bartter’s syndrome. Exp Nephrol. 2000 Nov-Dec;8(6):351-60. Pubmed
  2. Schmidt H, Kabesch M, Schwarz HP, Kiess W: Clinical, biochemical and molecular genetic data in five children with Gitelman’s syndrome. Horm Metab Res. 2001 Jun;33(6):354-7. Pubmed
  3. Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, Hebert SC, Gamba G, Lifton RP: Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):680-4. Epub 2003 Jan 6. Pubmed
  4. Maki N, Komatsuda A, Wakui H, Ohtani H, Kigawa A, Aiba N, Hamai K, Motegi M, Yamaguchi A, Imai H, Sawada K: Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman’s syndrome. Nephrol Dial Transplant. 2004 Jul;19(7):1761-6. Epub 2004 Apr 6. Pubmed
  5. Reinalter SC, Jeck N, Peters M, Seyberth HW: Pharmacotyping of hypokalaemic salt-losing tubular disorders. Acta Physiol Scand. 2004 Aug;181(4):513-21. Pubmed

2. Carbonic anhydrase 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 1 P00915 Details

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
  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

3. Carbonic anhydrase 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 2 P00918 Details

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
  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
  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
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

4. Carbonic anhydrase 4

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 4 P22748 Details

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
  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

Transporters

1. Solute carrier family 22 member 6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier family 22 member 6 Q4U2R8 Details

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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12