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Identification
NameHydrochlorothiazide
Accession NumberDB00999  (APRD00092)
Typesmall molecule
Groupsapproved
Description

A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It has been used in the treatment of several disorders including edema, hypertension, diabetes insipidus, and hypoparathyroidism. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
EsidrixNot AvailableNot Available
HCTZNot AvailableNot Available
MicrozideNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
Apo-hydroApotex
DichlotrideM & H
EsidrexNovartis
HydrodiurilMerck
HydroDIURILMerck
MicrozideWatson
Brand mixtures
Brand NameIngredients
Accureticquinapril + hydrochlorothiazide
Aldactazidespironolactone + hydrochlorothiazide
Aldorilmethyldopa + hydrochlorothiazide
Atacand HCTcandesartan + hydrochlorothiazide
Avalideirbesartan + hydrochlorothiazide
Benicar HCTolmesartan + hydrochlorothiazide
Capozidecaptopril + hydrochlorothiazide
Diovan HCTvalsartan + hydrochlorothiazide
Dyazidetriamterene + hydrochlorothiazide
Hydra-Zidehydralazine + hydrochlorothiazide
Hyzaarlosartan + hydrochlorothiazide
Inderidepropranolol + hydrochlorothiazide
Lopressor HCTmetoprolol + hydrochlorothiazide
Lotensin HCTbenazepril + hydrochlorothiazide
Maxzidetriamterene + hydrochlorothiazide
MAXZIDE-25Triamterene + Hydrochlorothiazide
Micardis HCTtelmisartan + hydrochlorothiazide
Modureticamiloride + hydrochlorothiazide
Monopril-HCTfosinopril + hydrochlorothiazide
Prinzidelisinopril + hydrochlorothiazide
Teveten HCTeprosartan + hydrochlorothiazide
Timolidetimolol + hydrochlorothiazide
TribenzorOlmesartan + Amlodipine + Hydrochlorothiazide
Uniretic HCTmoexipril + hydrochlorothiazide
Vasereticenalapril + hydrochlorothiazide
Zestoreticlisinopril + hydrochlorothiazide
Ziacbisoprolol + hydrochlorothiazide
Categories
CAS number58-93-5
WeightAverage: 297.739
Monoisotopic: 296.964474846
Chemical FormulaC7H8ClN3O4S2
InChI KeyJZUFKLXOESDKRF-UHFFFAOYSA-N
InChI
InChI=1S/C7H8ClN3O4S2/c8-4-1-5-7(2-6(4)16(9,12)13)17(14,15)11-3-10-5/h1-2,10-11H,3H2,(H2,9,12,13)
IUPAC Name
6-chloro-1,1-dioxo-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=C(Cl)C=C2NCNS(=O)(=O)C2=C1
Mass Specshow(11.5 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassThiadiazines
SubclassBenzothiadiazines
Direct parentBenzothiadiazines
Alternative parentsBenzenesulfonamides; Chlorobenzenes; Aryl Chlorides; Sulfonyls; Sulfonamides; Polyamines; Secondary Amines; Organochlorides
Substituentschlorobenzene; aryl halide; aryl chloride; benzene; sulfonamide; sulfonic acid derivative; sulfonyl; polyamine; secondary amine; organochloride; amine; 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
IndicationFor the treatment of high blood pressure and management of edema.
PharmacodynamicsThiazides such as hydrochlorothiazide promote 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 actionHydrochlorothiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, hydrochlorothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.
Absorption50-60%
Volume of distributionNot Available
Protein binding67.9%
Metabolism

Hydrochlorothiazide is not metabolized.

Route of eliminationHydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Half life5.6 and 14.8 hours
ClearanceNot Available
ToxicityThe most common signs and symptoms observed are 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. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in the mouse and rat.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Hydrochlorothiazide Action PathwayDrug actionSMP00100
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9202
Blood Brain Barrier - 0.9659
Caco-2 permeable - 0.8956
P-glycoprotein substrate Non-substrate 0.6533
P-glycoprotein inhibitor I Non-inhibitor 0.8624
P-glycoprotein inhibitor II Non-inhibitor 0.8688
Renal organic cation transporter Non-inhibitor 0.8416
CYP450 2C9 substrate Non-substrate 0.7664
CYP450 2D6 substrate Non-substrate 0.8333
CYP450 3A4 substrate Non-substrate 0.6217
CYP450 1A2 substrate Non-inhibitor 0.9401
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9252
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.9569
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9036
Ames test Non AMES toxic 0.9133
Carcinogenicity Non-carcinogens 0.7986
Biodegradation Not ready biodegradable 0.9964
Rat acute toxicity 2.0666 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9576
hERG inhibition (predictor II) Non-inhibitor 0.9135
Pharmacoeconomics
Manufacturers
  • Apotex inc
  • Aurobindo pharma ltd
  • Cadista pharmaceuticals inc
  • Ipca laboratories ltd
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mylan pharmaceuticals inc
  • Unichem laboratories ltd
  • Vintage pharmaceuticals inc
  • West ward pharmaceutical corp
  • Watson laboratories inc
  • Morton grove pharmaceuticals inc
  • Roxane laboratories inc
  • Novartis pharmaceuticals corp
  • Abc holding corp
  • Actavis elizabeth llc
  • Alra laboratories inc
  • Ascot hosp pharmaceuticals inc div travenol laboratories inc
  • Barr laboratories inc
  • Caraco pharmaceutical laboratories ltd
  • Dava pharmaceuticals inc
  • Elkins sinn div ah robins co inc
  • Excellium pharmaceutical inc
  • Heather drug co inc
  • Heritage pharmaceuticals inc
  • Impax laboratories inc
  • Inwood laboratories inc sub forest laboratories inc
  • Lannett holdings inc
  • Mm mast and co
  • Mutual pharmaceutical co inc
  • Private formulations inc
  • Sandoz inc
  • Solvay pharmaceuticals
  • Superpharm corp
  • Teva pharmaceuticals usa inc
  • Tg united labs llc
  • Usl pharma inc
  • Vangard laboratories inc div midway medical co
  • Warner chilcott div warner lambert co
  • Whiteworth towne paulsen inc
  • Halsey drug co inc
  • Merck and co inc
  • Abbott laboratories pharmaceutical products div
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Niferex-150 Forte 100 80-70 mg capsule Box109.86USDbox
Niferex 100 mg/5ml Elixir 236ml Bottle80.55USDbottle
Niferex 100 40-20 mg capsule Box77.99USDbox
Capozide 50-25 mg tablet3.63USDtablet
Ziac 10-6.25 mg tablet3.6USDtablet
Ziac 2.5-6.25 mg tablet3.6USDtablet
Ziac 5-6.25 mg tablet3.6USDtablet
Capozide 50-15 tablet3.49USDtablet
Capozide 50-25 tablet3.49USDtablet
Capozide 50-15 mg tablet2.59USDtablet
Lotensin 20 mg tablet2.25USDtablet
Lotensin 10 mg tablet2.09USDtablet
Lotensin 40 mg tablet2.09USDtablet
Lotensin 5 mg tablet2.09USDtablet
Accuretic 20-12.5 mg tablet2.04USDtablet
Capozide 25-15 tablet2.03USDtablet
Capozide 25-25 tablet2.03USDtablet
Accuretic 10-12.5 mg tablet2.0USDtablet
Accuretic 20-25 mg tablet2.0USDtablet
Lotensin HCT 20-12.5 mg tablet1.97USDtablet
Lotensin HCT 10-12.5 mg tablet1.95USDtablet
Lotensin HCT 20-25 mg tablet1.94USDtablet
Lotensin hct 10-12.5 tablet1.9USDtablet
Lotensin hct 20-12.5 tablet1.9USDtablet
Lotensin hct 20-25 tablet1.9USDtablet
Lotensin hct 5-6.25 tablet1.9USDtablet
Niferex-150 150-50-50 mg capsule1.62USDcapsule
Capozide 25-15 mg tablet1.51USDtablet
Lotensin HCT 5-6.25 mg tablet1.31USDtablet
Hydrochlorothiazide powder1.1USDg
Hydrochlorothiazide 12.5 mg tablet0.82USDtablet
Moduretic 5-50 mg tablet0.68USDtablet
Hydrochlorothiazide 12.5 mg capsule0.5USDcapsule
Hydrochlorothiazide 50 mg tablet0.16USDtablet
Apo-Hydro 100 mg Tablet0.13USDtablet
Hydrochlorothiazide 25 mg tablet0.11USDtablet
Apo-Hydro 50 mg Tablet0.06USDtablet
Novo-Hydrazide 50 mg Tablet0.06USDtablet
Apo-Hydro 25 mg Tablet0.04USDtablet
Novo-Hydrazide 25 mg Tablet0.04USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point266-268U.S. Patent 3,163,645.
water solubility722 mg/L (at 25 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP-0.07HANSCH,C ET AL. (1995)
logS-2.62ADME Research, USCD
Caco2 permeability-6.06ADME Research, USCD
pKa7.9SANGSTER (1994)
Predicted Properties
PropertyValueSource
water solubility2.24e+00 g/lALOGPS
logP-0.16ALOGPS
logP-0.58ChemAxon
logS-2.1ALOGPS
pKa (strongest acidic)9.09ChemAxon
pKa (strongest basic)-2.7ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count3ChemAxon
polar surface area118.36ChemAxon
rotatable bond count1ChemAxon
refractivity63.11ChemAxon
polarizability25.35ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraMS/MS1D NMR2D NMR
References
Synthesis Reference

Frederic J. Nugent, John K. C. Yen, “Process for preparing the combination products of triamterene and hydrochlorothiazide.” U.S. Patent US4804540, issued July, 1987.

US4804540
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00340
BindingDB13076
Therapeutic Targets DatabaseDAP000750
PharmGKBPA449899
Drug Product Database2247386
RxListhttp://www.rxlist.com/cgi/generic/hctz.htm
Drugs.comhttp://www.drugs.com/hctz.html
WikipediaHydrochlorothiazide
ATC CodesNot Available
AHFS Codes
  • 40:28.20
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(72.7 KB)
Interactions
Drug Interactions
Drug
DeslanosidePossible electrolyte variations and arrhythmias
DiazoxideSignificant hyperglycemic effect
DigitoxinPossible electrolyte variations and arrhythmias
DigoxinPossible electrolyte variations and arrhythmias
DihydrocodeineDihydrocodeine may enhance the hypotensive effects of thiazide diuretics. It is recommended to monitor therapy.
DofetilideIncreased risk of cardiotoxicity and arrhythmias
IndacaterolConcomitant therapy may increase the risk of hypokalemia via intracellular shunting. Monitor for adverse effects and especially for cardiovascular effects associated with hypokalemia.
Insulin LisproConcomitant therapy with diuretics may reduce the blood-glucose-lowering effect of insulin lispro.
LithiumThe thiazide diuretic, hydrochlorothiazide, may increase serum levels of lithium.
TenoxicamTenoxicam may antagonize the blood pressure lowering effect of Hydrochlorothiazide. Monitor for changes in the therapeutic effect of Hydrochlorothiazide if Tenoxicam is initiated, discontinued or dose changed.
TrandolaprilThe thiazide diuretic, Hydrochlorothiazide, may increase the hypotensive effect of Trandolapril. Hydrochlorothiazide 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 Interactions
  • Avoid alcohol.
  • Avoid excess salt/sodium unless otherwise instructed by your physician.
  • Avoid natural licorice.
  • Do not take calcium, aluminum, magnesium or Iron supplements within 2 hours of taking this medication.
  • Increase potassium intake; add a banana or orange juice; unless instructed otherwise.
  • Take with food.

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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Ran XW, Wang C, Dai F, Jiang JJ, Tong NW, Li XJ, Liang JZ: [A case of Gitelman’s syndrome presenting with severe hypocalcaemia and hypokalemic periodic paralysis] Sichuan Da Xue Xue Bao Yi Xue Ban. 2005 Jul;36(4):583-7. Pubmed
  3. Turner ST, Schwartz GL, Chapman AB, Boerwinkle E: WNK1 kinase polymorphism and blood pressure response to a thiazide diuretic. Hypertension. 2005 Oct;46(4):758-65. Epub 2005 Sep 19. Pubmed
  4. Abuladze N, Yanagawa N, Lee I, Jo OD, Newman D, Hwang J, Uyemura K, Pushkin A, Modlin RL, Kurtz I: Peripheral blood mononuclear cells express mutated NCCT mRNA in Gitelman’s syndrome: evidence for abnormal thiazide-sensitive NaCl cotransport. J Am Soc Nephrol. 1998 May;9(5):819-26. Pubmed
  5. Barry EL, Gesek FA, Kaplan MR, Hebert SC, Friedman PA: Expression of the sodium-chloride cotransporter in osteoblast-like cells: effect of thiazide diuretics. Am J Physiol. 1997 Jan;272(1 Pt 1):C109-16. Pubmed
  6. Kurschat C, Heering P, Grabensee B: [Gitelman’s syndrome: an important differential diagnosis of hypokalemia] Dtsch Med Wochenschr. 2003 May 30;128(22):1225-8. Pubmed
  7. Monroy A, Plata C, Hebert SC, Gamba G: Characterization of the thiazide-sensitive Na(+)-Cl(-) cotransporter: a new model for ions and diuretics interaction. Am J Physiol Renal Physiol. 2000 Jul;279(1):F161-9. Pubmed

2. Carbonic anhydrase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

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. Couloigner V, Loiseau A, Sterkers O, Amiel C, Ferrary E: Effect of locally applied drugs on the endolymphatic sac potential. Laryngoscope. 1998 Apr;108(4 Pt 1):592-8. Pubmed
  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. Epub 2008 Dec 24. Pubmed

3. Carbonic anhydrase 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 2 P00918 Details

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
  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
  3. Meyerson LR, Nesta D: [3H]acetazolamide binding to carbonic anhydrase in normal and transformed cells. Biochem Pharmacol. 1991 Mar 15-Apr 1;41(6-7):995-1000. Pubmed
  4. Schaeffer P, Vigne P, Frelin C, Lazdunski M: Identification and pharmacological properties of binding sites for the atypical thiazide diuretic, indapamide. Eur J Pharmacol. 1990 Jul 17;182(3):503-8. Pubmed
  5. 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

4. Carbonic anhydrase 4

Kind: protein

Organism: Human

Pharmacological action: unknown

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. 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

5. Carbonic anhydrase 9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 9 Q16790 Details

References:

  1. 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

6. Carbonic anhydrase 12

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 12 O43570 Details

References:

  1. 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

7. Calcium-activated potassium channel subunit alpha-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other/unknown

Components

Name UniProt ID Details
Calcium-activated potassium channel subunit alpha-1 Q12791 Details

References:

  1. Tricarico D, Barbieri M, Mele A, Carbonara G, Camerino DC: Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats. FASEB J. 2004 Apr;18(6):760-1. Epub 2004 Feb 6. 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. Race JE, Grassl SM, Williams WJ, Holtzman EJ: Molecular cloning and characterization of two novel human renal organic anion transporters (hOAT1 and hOAT3). Biochem Biophys Res Commun. 1999 Feb 16;255(2):508-14. Pubmed
  2. 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

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