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Identification
NameMethyclothiazide
Accession NumberDB00232  (APRD01104)
TypeSmall Molecule
GroupsApproved
Description

A thiazide diuretic with properties similar to those of hydrochlorothiazide. (From Martindale, The Extra Pharmacopoeia, 30th ed, p825)

Structure
Thumb
Synonyms
Enduron
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Duretic 5mgtablet5 mgoralAbbott Laboratories, Limited1960-12-311999-08-09Canada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Methyclothiazidetablet5 mg/1oralMylan Pharmaceuticals Inc.1982-08-17Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AquatensenNot Available
DureticNot Available
EnduronNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIL3H46UAC61
CAS number135-07-9
WeightAverage: 360.237
Monoisotopic: 358.956802649
Chemical FormulaC9H11Cl2N3O4S2
InChI KeyInChIKey=CESYKOGBSMNBPD-UHFFFAOYSA-N
InChI
InChI=1S/C9H11Cl2N3O4S2/c1-14-9(4-10)13-6-2-5(11)7(19(12,15)16)3-8(6)20(14,17)18/h2-3,9,13H,4H2,1H3,(H2,12,15,16)
IUPAC Name
6-chloro-3-(chloromethyl)-2-methyl-1,1-dioxo-3,4-dihydro-2H-1λ⁶,2,4-benzothiadiazine-7-sulfonamide
SMILES
CN1C(CCl)NC2=CC(Cl)=C(C=C2S1(=O)=O)S(N)(=O)=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as 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).
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassThiadiazines
Sub ClassBenzothiadiazines
Direct ParentBenzothiadiazines
Alternative Parents
Substituents
  • Benzothiadiazine
  • Benzenesulfonamide
  • Secondary aliphatic/aromatic amine
  • Chlorobenzene
  • Benzenoid
  • Aryl halide
  • Aryl chloride
  • Aminosulfonyl compound
  • Sulfonyl
  • Sulfonic acid derivative
  • Sulfonamide
  • Azacycle
  • Secondary amine
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Amine
  • Alkyl halide
  • Alkyl chloride
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor use in the management of hypertension either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in the more severe forms of hypertension. Also used as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.
PharmacodynamicsMethyclothiazide, a diuretic-antihypertensive agent, is a member of the benzothiadiazine (thiazide) class of drugs. Methyclothiazide has a per mg natriuretic activity approximately 100 times that of the prototype thiazide, chlorothiazide. At maximal therapeutic dosages, all thiazides are approximately equal in their diuretic/natriuretic effects. Like other benzothiadiazines, methyclothiazide also has antihypertensive properties, and may be used for this purpose either alone or to enhance the antihypertensive action of other drugs.
Mechanism of actionMethyclothiazide 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, methyclothiazide 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 methyclothiazide 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 methyclothiazide 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.
Related Articles
AbsorptionRapidly absorbed following oral administration.
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityAcute oral toxicity (LD50): >4000 mg/kg [Rat]. Symptoms of overdosage include electrolyte imbalance and signs of potassium deficiency such as confusion, dizziness, muscular weakness, and gastrointestinal disturbances.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Methyclothiazide Action PathwayDrug actionSMP00081
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9834
Blood Brain Barrier-0.6866
Caco-2 permeable-0.6992
P-glycoprotein substrateSubstrate0.5317
P-glycoprotein inhibitor INon-inhibitor0.8518
P-glycoprotein inhibitor IINon-inhibitor0.8888
Renal organic cation transporterNon-inhibitor0.8177
CYP450 2C9 substrateNon-substrate0.631
CYP450 2D6 substrateNon-substrate0.8261
CYP450 3A4 substrateNon-substrate0.532
CYP450 1A2 substrateNon-inhibitor0.6883
CYP450 2C9 inhibitorNon-inhibitor0.6493
CYP450 2D6 inhibitorNon-inhibitor0.858
CYP450 2C19 inhibitorNon-inhibitor0.808
CYP450 3A4 inhibitorInhibitor0.5094
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7345
Ames testNon AMES toxic0.8905
CarcinogenicityNon-carcinogens0.82
BiodegradationNot ready biodegradable0.9971
Rat acute toxicity1.9853 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9384
hERG inhibition (predictor II)Non-inhibitor0.9318
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Medpointe pharmaceuticals medpointe healthcare inc
  • Abbott laboratories pharmaceutical products div
  • Ivax pharmaceuticals inc
  • Mylan pharmaceuticals inc
  • Par pharmaceutical inc
  • Sandoz inc
  • Usl pharma inc
  • Watson laboratories inc
Packagers
Dosage forms
FormRouteStrength
Tabletoral5 mg
Tabletoral5 mg/1
Prices
Unit descriptionCostUnit
Methyclothiazide powder11.32USD g
Enduron 5 mg tablet0.77USD tablet
Methyclothiazide 5 mg tablet0.77USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point225 °CPhysProp
water solubility11.2 mg/LNot Available
logP1.42HANSCH,C ET AL. (1995)
pKa9.4MERCK INDEX (2001)
Predicted Properties
PropertyValueSource
Water Solubility0.824 mg/mLALOGPS
logP0.93ALOGPS
logP0.53ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)9.29ChemAxon
pKa (Strongest Basic)-3.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area109.57 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity77.28 m3·mol-1ChemAxon
Polarizability31.65 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesC03AA08C03AB08
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (74.8 KB)
Interactions
Drug Interactions
Drug
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Methyclothiazide.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Methyclothiazide.
AlfuzosinAlfuzosin may increase the hypotensive activities of Methyclothiazide.
AllopurinolThe risk of a hypersensitivity reaction to Allopurinol is increased when it is combined with Methyclothiazide.
AlogliptinThe therapeutic efficacy of Alogliptin can be decreased when used in combination with Methyclothiazide.
AmifostineMethyclothiazide may increase the hypotensive activities of Amifostine.
BrimonidineBrimonidine may increase the antihypertensive activities of Methyclothiazide.
ButabarbitalButabarbital may increase the orthostatic hypotensive activities of Methyclothiazide.
ButethalButethal may increase the orthostatic hypotensive activities of Methyclothiazide.
CanagliflozinThe therapeutic efficacy of Canagliflozin can be decreased when used in combination with Methyclothiazide.
CarbamazepineThe risk or severity of adverse effects can be increased when Methyclothiazide is combined with Carbamazepine.
ChlorpropamideThe therapeutic efficacy of Chlorpropamide can be decreased when used in combination with Methyclothiazide.
ColesevelamColesevelam can cause a decrease in the absorption of Methyclothiazide resulting in a reduced serum concentration and potentially a decrease in efficacy.
CyclophosphamideThe risk or severity of adverse effects can be increased when Methyclothiazide is combined with Cyclophosphamide.
DexketoprofenThe risk or severity of adverse effects can be increased when Dexketoprofen is combined with Methyclothiazide.
DiazoxideThe risk or severity of adverse effects can be increased when Methyclothiazide is combined with Diazoxide.
DigoxinThe risk or severity of adverse effects can be increased when Methyclothiazide is combined with Digoxin.
DihydrotachysterolMethyclothiazide may increase the hypercalcemic activities of Dihydrotachysterol.
DofetilideMethyclothiazide may increase the QTc-prolonging activities of Dofetilide.
DuloxetineMethyclothiazide may increase the orthostatic hypotensive activities of Duloxetine.
EthanolEthanol may increase the orthostatic hypotensive activities of Methyclothiazide.
FludrocortisoneFludrocortisone may increase the hypokalemic activities of Methyclothiazide.
FlunisolideFlunisolide may increase the hypokalemic activities of Methyclothiazide.
GliclazideThe therapeutic efficacy of Gliclazide can be decreased when used in combination with Methyclothiazide.
GlimepirideThe therapeutic efficacy of Glimepiride can be decreased when used in combination with Methyclothiazide.
GliquidoneThe therapeutic efficacy of Gliquidone can be decreased when used in combination with Methyclothiazide.
GlyburideThe therapeutic efficacy of Glyburide can be decreased when used in combination with Methyclothiazide.
HeptabarbitalHeptabarbital may increase the orthostatic hypotensive activities of Methyclothiazide.
HexobarbitalHexobarbital may increase the orthostatic hypotensive activities of Methyclothiazide.
InfliximabThe therapeutic efficacy of Methyclothiazide can be decreased when used in combination with Infliximab.
Insulin AspartThe therapeutic efficacy of Insulin Aspart can be decreased when used in combination with Methyclothiazide.
Insulin DetemirThe therapeutic efficacy of Insulin Detemir can be decreased when used in combination with Methyclothiazide.
Insulin GlargineThe therapeutic efficacy of Insulin Glargine can be decreased when used in combination with Methyclothiazide.
Insulin GlulisineThe therapeutic efficacy of Insulin Glulisine can be decreased when used in combination with Methyclothiazide.
Insulin HumanThe therapeutic efficacy of Insulin Regular can be decreased when used in combination with Methyclothiazide.
Insulin LisproThe therapeutic efficacy of Insulin Lispro can be decreased when used in combination with Methyclothiazide.
IvabradineMethyclothiazide may increase the arrhythmogenic activities of Ivabradine.
LevodopaMethyclothiazide may increase the orthostatic hypotensive activities of Levodopa.
LicoriceLicorice may increase the hypokalemic activities of Methyclothiazide.
LinagliptinThe therapeutic efficacy of Linagliptin can be decreased when used in combination with Methyclothiazide.
LithiumMethyclothiazide may decrease the excretion rate of Lithium which could result in a lower serum level and potentially a reduction in efficacy.
MecamylamineThe risk or severity of adverse effects can be increased when Methyclothiazide is combined with Mecamylamine.
MetforminThe therapeutic efficacy of Metformin can be decreased when used in combination with Methyclothiazide.
MethohexitalMethohexital may increase the orthostatic hypotensive activities of Methyclothiazide.
MethylphenidateMethylphenidate may decrease the antihypertensive activities of Methyclothiazide.
MolsidomineMolsidomine may increase the hypotensive activities of Methyclothiazide.
MorphineThe risk or severity of adverse effects can be increased when Morphine is combined with Methyclothiazide.
MoxonidineMoxonidine may increase the hypotensive activities of Methyclothiazide.
NicorandilNicorandil may increase the hypotensive activities of Methyclothiazide.
ObinutuzumabMethyclothiazide may increase the hypotensive activities of Obinutuzumab.
OrciprenalineOrciprenaline may increase the hypokalemic activities of Methyclothiazide.
OxcarbazepineThe risk or severity of adverse effects can be increased when Methyclothiazide is combined with Oxcarbazepine.
ParoxetineParoxetine may increase the activities of Methyclothiazide.
PentobarbitalPentobarbital may increase the orthostatic hypotensive activities of Methyclothiazide.
PentoxifyllinePentoxifylline may increase the hypotensive activities of Methyclothiazide.
PerindoprilMethyclothiazide may increase the hypotensive activities of Perindopril.
PhenelzinePhenelzine may increase the orthostatic hypotensive activities of Methyclothiazide.
PorfimerMethyclothiazide may increase the photosensitizing activities of Porfimer.
PrimidonePrimidone may increase the orthostatic hypotensive activities of Methyclothiazide.
ProcyclidineThe serum concentration of Methyclothiazide can be increased when it is combined with Procyclidine.
QuinineQuinine may increase the hypotensive activities of Methyclothiazide.
RepaglinideThe therapeutic efficacy of Repaglinide can be decreased when used in combination with Methyclothiazide.
RisperidoneMethyclothiazide may increase the hypotensive activities of Risperidone.
RituximabMethyclothiazide may increase the hypotensive activities of Rituximab.
SaxagliptinThe therapeutic efficacy of Saxagliptin can be decreased when used in combination with Methyclothiazide.
SecobarbitalSecobarbital may increase the orthostatic hypotensive activities of Methyclothiazide.
SulpirideThe risk or severity of adverse effects can be increased when Methyclothiazide is combined with Sulpiride.
TadalafilTadalafil may increase the antihypertensive activities of Methyclothiazide.
TolbutamideThe therapeutic efficacy of Tolbutamide can be decreased when used in combination with Methyclothiazide.
TopiramateMethyclothiazide may increase the hypokalemic activities of Topiramate.
ToremifeneMethyclothiazide may increase the hypercalcemic activities of Toremifene.
TranylcypromineTranylcypromine may increase the orthostatic hypotensive activities of Methyclothiazide.
TreprostinilTreprostinil may increase the hypotensive activities of Methyclothiazide.
ValsartanThe risk or severity of adverse effects can be increased when Valsartan is combined with Methyclothiazide.
VardenafilVardenafil may increase the antihypertensive activities of Methyclothiazide.
VerteporfinMethyclothiazide may increase the photosensitizing activities of Verteporfin.
VildagliptinThe therapeutic efficacy of Vildagliptin can be decreased when used in combination with Methyclothiazide.
YohimbineYohimbine may decrease the antihypertensive activities of Methyclothiazide.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Sodium:potassium:chloride symporter activity
Specific Function:
Electrically silent transporter system. Mediates sodium and chloride reabsorption. Plays a vital role in the regulation of ionic balance and cell volume.
Gene Name:
SLC12A1
Uniprot ID:
Q13621
Molecular Weight:
121449.13 Da
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:17139284 ]
  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:17016423 ]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
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
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. 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:9546276 ]
  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. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
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 into the anterior chamber of the eye. Contributes to intracellular pH regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption. Stimulates the chloride-bicarbonate ex...
Gene Name:
CA2
Uniprot ID:
P00918
Molecular Weight:
29245.895 Da
References
  1. 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:1901209 ]
  2. 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:2226620 ]
  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. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid.
Gene Name:
CA4
Uniprot ID:
P22748
Molecular Weight:
35032.075 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. 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. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014 ]
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Drug created on June 13, 2005 07:24 / Updated on September 25, 2013 14:48