Chemistry:Thioridazine

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Short description: Typical antipsychotic medication
Thioridazine
Thioridazine.svg
Clinical data
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa682119
License data
Pregnancy
category
  • AU: C
  • US: N (Not classified yet)
Routes of
administration		Oral
Drug classTypical antipsychotic
ATC code
Legal status
Legal status
  • BR: Class C1 (Other controlled substances)
  • Withdrawn by the manufacturer worldwide;[1] generic formulations are still available by prescription
Pharmacokinetic data
BioavailabilityIncomplete
MetabolismHepatic (at least partly mediated by CYP2D6)
Elimination half-life21–24 hours[2]
ExcretionFeces
Identifiers
CAS Number
PubChem CID
PubChem SID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H26N2S2
Molar mass370.57 g·mol−1
3D model (JSmol)
  (verify)

Thioridazine (Mellaril or Melleril) is a first generation antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis. The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias. However, generic versions are still available in the US.[1]

Indications

Thioridazine was voluntarily discontinued by its manufacturer, Novartis, worldwide because it caused severe cardiac arrhythmias. However, generics remain on the market.[1][3][4][5]

Its primary use in medicine is for the treatment of schizophrenia.[6] It was also tried with some success as a treatment for various psychiatric symptoms seen in people with dementia,[7] but chronic use of thioridazine and other anti-psychotics in people with dementia is not recommended.[8] Generic forms of thioridazine remain on the market in a few countries, usually with restrictions due to the risk of arrhythmias. For example, in the US, it is restricted to patients who have taken at least 2 other antipsychotics that either failed or caused serious side effects. [9]

Side effects

Further information: Chemistry:Phenothiazine

Thioridazine prolongs the QTc interval in a dose-dependent manner.[10] It produces significantly less extrapyramidal side effects than most first-generation antipsychotics, likely due to its potent anticholinergic effect.[11][12] Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies (specifically retinitis pigmentosa).[13] It has a higher propensity for causing anticholinergic side effects coupled with a lower propensity for causing extrapyramidal side effects and sedation than chlorpromazine, but also has a higher incidence of hypotension and cardiotoxicity.[14] It is also known to possess a relatively high liability for causing orthostatic hypotension compared to other antipsychotics. Similarly to other first-generation antipsychotics it has a relatively high liability for causing prolactin elevation. It is moderate risk for causing weight gain.[15] As with all antipsychotics thioridazine has been linked to cases of tardive dyskinesia (an often permanent neurological disorder characterised by slow, repetitive, purposeless and involuntary movements, most often of the facial muscles, that is usually brought on by years of continued treatment with antipsychotics, especially the first-generation (or typical) antipsychotics such as thioridazine) and neuroleptic malignant syndrome (a potentially fatal complication of antipsychotic treatment).[10] Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia are possible with thioridazine treatment.[10] Thioridazine is also associated with abnormal retinal pigmentation after many years of use.[16] Thioridazine has been correlated to rare instances of clinically apparent acute cholestatic liver injury. [17]

Pharmacology

Thioridazine has the following binding profile:[18]

Biologic Protein Binding affinity (Ki[nM]) Binding affinity of Mesoridazine (Ki [nM]) Binding affinity of Sulforidazine (Ki [nM]) Notes
SERT 1259 ND ND
NET 842 ND ND
DAT 1684 ND ND
5-HT1A 144.35 500 (HB) ND
5-HT1B 109 ND ND
5-HT1D 579 ND ND
5-HT1E 194 ND ND
5-HT2A 27.67 4.76 (HB) ND The ratio of 5-HT2A to D2 receptor binding is believed to dictate whether or not most antipsychotics are atypical or typical. In thioridazine's case its ratio of 5-HT2A to D2 receptor binding is below the level that's believed to be required for atypicality despite its relatively low extrapyramidal side effect liability in practice.[6]
5-HT2C 53 157 ND Believed to play a role in the weight gain-promoting effects of antipsychotics.[6]
5-HT3 >10000 ND ND
5-HT5A 364 ND ND
5-HT6 57.05 380 ND
5-HT7 99 73 (RC) ND
α1A 3.15 2 (HB) ND Likely the receptor responsible for the orthostatic hypotension known to occur in individuals on thioridazine.[6]
α1B 2.4 ND ND
α2A 134.15 1612.9 (HB) ND
α2B 341.65 ND ND
α2C 74.9 ND ND
β1 >10000 ND ND
β2 >10000 ND ND
M1 12.8 10 ND This receptor is believed to be the chief receptor responsible for the anticholinergic side effects of thioridazine (e.g. dry mouth, constipation, blurred vision, etc.). Likely plays a role in thioridazine's low extrapyramidal side effect liability as anticholinergic drugs such as benzatropine are routinely given to treat extrapyramidal side effects resulting from antipsychotic treatment.[6]
M2 286.33 15 ND
M3 29 90 ND
M4 310.33 19 ND
M5 12.67 60 ND
D1 94.5 ND ND
D2 0.4 4.3 0.25 Believed to be the receptor responsible for the therapeutic effects of antipsychotics.[6]
D3 1.5 2.6 0.7
D4 1.5 9.1 ND
D5 258 ND ND
hERG 191 ND ND Likely involved in thioridazine's cardiac effects.
H1 16.5 1.81 (HB) ND Likely responsible for the sedating effects of thioridazine.
H2 136 ND ND Regulates the release of hydrochloric acid into the stomach.
H4 2400 ND ND

Note: The Binding affinities given are towards cloned human receptors unless otherwise specified

Acronyms used
HB – Human brain receptor
RC – Cloned rat receptor
ND – No data

Metabolism

Thioridazine is a racemic compound with two enantiomers, both of which are metabolized, according to Eap et al., by CYP2D6 into (S)- and (R)-thioridazine-2-sulfoxide, better known as mesoridazine,[19] and into (S)- and (R)-thioridazine-5-sulfoxide.[20] Mesoridazine is in turn metabolized into sulforidazine.[21] Thioridazine is an inhibitor of CYP1A2 and CYP3A4.[22]

History

The manufacturer Novartis/Sandoz/Wander of the brands of thioridazine, Mellaril in the US and Canada and Melleril in Europe, discontinued the drug worldwide in June 2005.[1][3]

Generic forms of thioridazine however remain on the market in a few countries usually with restrictions for example in the US its restricted to patients who have taken at least 2 other antipsychotics that either failed or caused serious side effects [23]

Antibiotic activity

Thioridazine is known to kill extensively drug-resistant tuberculosis[24][25] and to make methicillin-resistant Staphylococcus aureus sensitive to β-lactam antibiotics.[26][27] A possible mechanism of action for the drug's antibiotic activity is via the inhibition of bacterial secretion pumps. The β-lactam antibiotic resistance is due to the secretion β-lactamase a protein that destroys antibiotics. If the bacteria cannot secrete the β-lactamase, then the antibiotic will be effective.[25] The drug has been successfully used in the treatment of granulomatous amoebic encephalitis in conjunction with more conventional amoebicidal medications.

Synthesis

Note: Same sidechain used for mesoridazine and sulforidazine.

Thieme Synthesis:[28] Patent:[29] Sidechain:[30] Enantiomers:[31]

The alkylation of 2-Picoline [109-06-8] (1) with formaldehyde gives 2-Pyridineethanol [103-74-2] (2). Forming the quat salt with methyl iodide [74-88-4] leads to 2-(2-hydroxyethyl)-1-methyl-pyridinium iodide [56622-15-2] (3). Catalytic hydrogenation in the presence of hydrochloric acid leads to 2-(2-Chloroethyl)-1-Methylpiperidine [50846-01-0] (4). Alkylation of 2-Methylthiophenothiazine [7643-08-5] (5) in the presence of sodium hydride base completed the synthesis of Thioridazine (6).

References

  1. ↑ 1.0 1.1 1.2 1.3 "SHARED CARE PROTOCOL Thioridazine". NHS Lothian Joint Formulary. March 2012. http://www.ljf.scot.nhs.uk/SharedCareofMedicines/Shared%20Care%20Agreements/SCA/SCA%20Thioridazine%20v1%200%20Final.pdf. 
  2. ↑ "Blood levels of haloperidol and thioridazine during maintenance neuroleptic treatment of schizophrenic outpatients". Journal of Clinical Psychopharmacology 4 (4): 194–198. August 1984. doi:10.1097/00004714-198408000-00004. PMID 6470190. 
  3. ↑ 3.0 3.1 "Outcome of patients after market withdrawal of thioridazine: a retrospective analysis in a nationwide cohort". Pharmacoepidemiology and Drug Safety 21 (11): 1227–1231. November 2012. doi:10.1002/pds.3346. PMID 22941581. 
  4. ↑ "WHO Pharmaceuticals Newsletter 2005, No. 04: REGULATORY MATTERS: Thioridazine - Sale discontinued in Canada". Essential Medicines and Health Products Information Portal (World Health Organization) 4 (2): p. 5. 2005. http://apps.who.int/medicinedocs/en/d/Js8119e/1.12.html. 
  5. ↑ "Withdrawal of thioridazine". Australian Prescriber 30 (3): 82. June 2007. http://www.australianprescriber.com/magazine/30/3/article/891.pdf. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill. 2011. ISBN 978-0-07-162442-8. 
  7. ↑ "Thioridazine for dementia". The Cochrane Database of Systematic Reviews (3): CD000464. 2001. doi:10.1002/14651858.CD000464. PMID 11686961. 
  8. ↑ "Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia". The Cochrane Database of Systematic Reviews 3 (3): CD007726. March 2013. doi:10.1002/14651858.CD007726.pub2. PMID 23543555. 
  9. ↑ "Thioridazine: MedlinePlus Drug Information" (in en). https://medlineplus.gov/druginfo/meds/a682119.html. 
  10. ↑ 10.0 10.1 10.2 "THIORIDAZINE HYDROCHLORIDE tablet, film coated [Mutual Pharmaceutical"]. DailyMed. Mutual Pharmaceutical. September 2010. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9c4bedb4-2d59-4fcd-aad7-fce988cd96d8. 
  11. ↑ "Thioridazine for schizophrenia". The Cochrane Database of Systematic Reviews 2007 (3): CD001944. July 2007. doi:10.1002/14651858.CD001944.pub2. PMID 17636691. 
  12. ↑ "The Australian multicentre double-blind comparative study of remoxipride and thioridazine in schizophrenia". Acta Psychiatrica Scandinavica 90 (5): 358–365. November 1994. doi:10.1111/j.1600-0447.1994.tb01607.x. PMID 7872041. 
  13. ↑ "Pathogenesis of degenerative retinopathies induced by thioridazine and other antipsychotics: a dopamine hypothesis". Documenta Ophthalmologica. Advances in Ophthalmology 105 (1): 41–49. July 2002. doi:10.1023/A:1015768114192. PMID 12152801. 
  14. ↑ "Martindale: The Complete Drug Reference". Medicines Complete. The Pharmaceutical Press. 18 August 2010. https://www.medicinescomplete.com/mc/martindale/current/login.htm?uri=http%3A%2F%2Fwww.medicinescomplete.com%2Fmc%2Fmartindale%2Fcurrent%2F. 
  15. ↑ "Selected adverse effects of antipsychotic medications for schizophrenia". UpToDate. Wolters Kluwer Health. http://www.uptodate.com/contents/pharmacotherapy-for-schizophrenia-side-effect-management?detectedLanguage=en&source=search_result&search=Selected+adverse+effects+of+antipsychotic+medications+for+schizophrenia&selectedTitle=1%7E150&provider=noProvider#subscribeMessage. 
  16. ↑ "Retinal Pigmentation in a Patient Receiving Thioridazine". Archives of Ophthalmology 70 (6): 775–778. December 1963. doi:10.1001/archopht.1963.00960050777009. PMID 14065014. 
  17. ↑ "Thioridazine". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. https://www.ncbi.nlm.nih.gov/books/n/livertox/Thioridazine/. 
  18. ↑ "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. 12 January 2011. http://pdsp.med.unc.edu/pdsp.php. 
  19. ↑ PubChem Substance Summary: Mesoridazine National Center for Biotechnology Information.
  20. ↑ "Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin". Clinical Pharmacology and Therapeutics 59 (3): 322–331. March 1996. doi:10.1016/S0009-9236(96)80010-5. PMID 8653995. 
  21. ↑ PubChem Substance Summary: Sulforidazine National Center for Biotechnology Information.
  22. ↑ "Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver". Polish Journal of Pharmacology 53 (6): 615–621. 2001. PMID 11985335. http://www.if-pan.krakow.pl/pjp/pdf/2001/6_615.pdf. 
  23. ↑ "Thioridazine: MedlinePlus Drug Information" (in en). https://medlineplus.gov/druginfo/meds/a682119.html. 
  24. ↑ "Thioridazine cures extensively drug-resistant tuberculosis (XDR-TB) and the need for global trials is now!". International Journal of Antimicrobial Agents 35 (6): 524–526. June 2010. doi:10.1016/j.ijantimicag.2009.12.019. PMID 20188526. https://hal.archives-ouvertes.fr/hal-00585817/file/PEER_stage2_10.1016%252Fj.ijantimicag.2009.12.019.pdf. 
  25. ↑ 25.0 25.1 "Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections". International Journal of Antimicrobial Agents 39 (5): 376–380. May 2012. doi:10.1016/j.ijantimicag.2012.01.012. PMID 22445204. 
  26. ↑ "Thioridazine: resurrection as an antimicrobial agent?". British Journal of Clinical Pharmacology 64 (5): 566–574. November 2007. doi:10.1111/j.1365-2125.2007.03021.x. PMID 17764469. 
  27. ↑ "Thioridazine induces major changes in global gene expression and cell wall composition in methicillin-resistant Staphylococcus aureus USA300". PLOS ONE 8 (5): e64518. May 2013. doi:10.1371/journal.pone.0064518. PMID 23691239. Bibcode: 2013PLoSO...864518T. 
  28. ↑ "Synthesen auf dem Phenothiazin-Gebiet. 2. Mitteilung. N-substituierte Mercaptophenothiazin-Derivate". Helvetica Chimica Acta 41 (4): 1072–1108. 1958. doi:10.1002/hlca.19580410420. 
  29. ↑ Renz J, Bourquin JP, "Phenothiazine derivatives substituted by a monovalent sulfur function in 3-position", US patent 3239514, issued 1966, assigned to Sandoz KK
  30. ↑ "The synthesis of some substituted 8-aminoquinolines". Journal of the American Chemical Society 68 (8): 1572–6. August 1946. doi:10.1021/ja01212a058. PMID 20994984. 
  31. ↑ "Synthesis of the enantiomers of thioridazine.". SynOpen 4 (1): 12–16. 2020. doi:10.1055/s-0039-1690834. 

Further reading

External links



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