Thioridazine

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Thioridazine
Thioridazine.svg
Systematic (IUPAC) name
10-{2-[(RS)-1-Methylpiperidin-2-yl]ethyl}-
2-methylsulfanylphenothiazine
Clinical data
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a682119
Licence data US Daily Med:link
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Legal status
  • Withdrawn by the manufacturer worldwide[1]
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability incomplete
Metabolism hepatic (at least partly mediated by CYP2D6)
Biological half-life 21-24 hours[2]
Excretion faeces
Identifiers
CAS Number 50-52-2 YesY
ATC code N05AC02 (WHO)
PubChem CID: 5452
IUPHAR/BPS 100
DrugBank DB00679 YesY
ChemSpider 5253 YesY
UNII N3D6TG58NI YesY
KEGG D00373 YesY
ChEBI CHEBI:9566 YesY
ChEMBL CHEMBL479 YesY
Chemical data
Formula C21H26N2S2
Molecular mass 370.577
  (verify)

Thioridazine (Mellaril or Melleril) is a piperidine typical 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drug group and was previously widely used in the treatment of schizophrenia and psychosis; the branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias, however, generic versions are available in the US.[1]

In older references, it is sometimes described as atypical,[3] but more recently it is usually described as typical,[4] with the term "atypical" usually reserved for agents showing D4 selectivity or serotonin antagonism. The atypicality of second generation agents is not clearly defined. Some believe it's low D2 affinity, quick dissociation, 5-HT2A receptor antagonism, or all of the above. Its perceived atypical effects (namely its comparatively low propensity for extrapyramidal side effects) are likely the result of its potent anticholinergic effects.

Indications

The drug was voluntarily discontinued by its manufacturer, Novartis, worldwide because it caused severe cardiac arrhythmias.[5][1][6][7]

Its primary use in medicine was the treatment of schizophrenia.[8] It was also tried with some success as a treatment for various psychiatric symptoms seen in people with dementia,[9] but chronic use of thioridazine and other anti-psychotics in people with dementia is not recommended.[10]

Side effects

For further information see: Phenothiazine

Thioridazine prolongs the QTc interval in a dose-dependent manner.[11] It produces significantly less extrapyramidal side effects than most first-generation antipsychotics.[12][13] Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies.[14] 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.[15] 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.[16] 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).[11] Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia are possible with thioridazine treatment.[11]

Pharmacology

Thioridazine has the following binding profile:[17]

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.[8]
5-HT2C 53 157 ND Believed to play a role in the weight gain-promoting effects of antipsychotics.[8]
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.[8]
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.[8]
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.[8]
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,[18] and into (S)- and (R)-thioridazine-5-sulfoxide.[19] Mesoridazine is in turn metabolized into sulforidazine.[20] Thioridazine is an inhibitor of CYP1A2 and CYP3A2.[21]

History

The manufacturer Novartis/Sandoz/Wander of the brands of thioridazine, Mellaril in the USA and Canada and Melleril in Europe, discontinued the drug worldwide in June 2005.[1][5]

Antibiotic activity

Thioridazine is known to kill XDR-TB[22][23] and to make MRSA sensitive to β-lactam antibiotics.[24][25] A possible mechanism of action for the drug's antibiotic activity is via the inhibition of bacterial efflux pumps.[23]

References

  1. 1.0 1.1 1.2 1.3 "SHARED CARE PROTOCOL Thioridazine" (PDF). NHS Lothian Joint Formulary. March 2012.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
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  6. "WHO Pharmaceuticals Newsletter 2005, No. 04: REGULATORY MATTERS: Thioridazine - Sale discontinued in Canada". Essential Medicines and Health Products Information Portal. 4 (2). World Health Organization. 2005. p. 5. Retrieved 28 October 2013.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  7. "Withdrawal of thioridazine" (PDF). Australian Prescriber. Vol. 30 no. 3. June 2007. p. 82.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  8. 8.0 8.1 8.2 8.3 8.4 8.5 Brunton, L. L.; Chabner, B.; Knollmann, B. C., eds. (2011). Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill. ISBN 978-0-07-162442-8.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  9. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  10. Declercq T et al. Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. Cochrane Database Syst Rev. 2013 Mar 28;3:CD007726. PMID 23543555
  11. 11.0 11.1 11.2 "THIORIDAZINE HYDROCHLORIDE tablet, film coated [Mutual Pharmaceutical]". DailyMed. Mutual Pharmaceutical. September 2010. Retrieved 28 October 2013.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
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  15. "Martindale: The Complete Drug Reference". Medicines Complete. The Pharmaceutical Press. 18 August 2010. Retrieved 28 October 2013.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  16. "Selected adverse effects of antipsychotic medications for schizophrenia". UpToDate. Wolters Kluwer Health. Retrieved 24 October 2013.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  17. Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 28 October 2013. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  18. PubChem Substance Summary: Mesoridazine National Center for Biotechnology Information.
  19. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  20. PubChem Substance Summary: Sulforidazine National Center for Biotechnology Information.
  21. Daniel WA, Syrek M, Ryłko Z, Kot M (2001). "Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver" (PDF). Pol J Pharmacol. 53 (6): 615–21. PMID 11985335. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
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External links