- a tranquilizer (trade name Mellaril) used to treat schizophrenia and other psychotic disorders (同)Mellaril
|AHFS/Drugs.com||Consumer Drug Information|
|Metabolism||hepatic (at least partly mediated by CYP2D6)|
|Biological half-life||21-24 hours|
|Chemical and physical data|
|3D model (Jmol)||
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 The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias.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 still available in the US.
- 1 Indications
- 2 Side effects
- 3 Pharmacology
- 4 Metabolism
- 5 History
- 6 Antibiotic activity
- 7 References
- 8 External links
Thioridazine was voluntarily discontinued by its manufacturer, Novartis, worldwide because it caused severe cardiac arrhythmias.
Its primary use in medicine was the treatment of schizophrenia. It was also tried with some success as a treatment for various psychiatric symptoms seen in people with dementia, but chronic use of thioridazine and other anti-psychotics in people with dementia is not recommended.
For further information see: Phenothiazine
Thioridazine prolongs the QTc interval in a dose-dependent manner. It produces significantly less extrapyramidal side effects than most first-generation antipsychotics. Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies. 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. 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. 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). Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia are possible with thioridazine treatment.
Thioridazine has the following binding profile:
|Biologic Protein||Binding affinity (Ki[nM])||Binding affinity of Mesoridazine (Ki [nM])||Binding affinity of Sulforidazine (Ki [nM])||Notes|
|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.|
|5-HT2C||53||157||ND||Believed to play a role in the weight gain-promoting effects of antipsychotics.|
|α1A||3.15||2 (HB)||ND||Likely the receptor responsible for the orthostatic hypotension known to occur in individuals on thioridazine.|
|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.|
|D2||0.4||4.3||0.25||Believed to be the receptor responsible for the therapeutic effects of antipsychotics.|
|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.|
Note: The Binding affinities given are towards cloned human receptors unless otherwise specified
HB — Human brain receptor
RC — Cloned rat receptor
ND — No data
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, and into (S)- and (R)-thioridazine-5-sulfoxide. Mesoridazine is in turn metabolized into sulforidazine. Thioridazine is an inhibitor of CYP1A2 and CYP3A2.
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.
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Thioridazine is known to kill XDR-TB and to make MRSA sensitive to β-lactam antibiotics. A possible mechanism of action for the drug's antibiotic activity is via the inhibition of bacterial efflux pumps.
- "SHARED CARE PROTOCOL Thioridazine" (PDF). NHS Lothian Joint Formulary. March 2012.
- Shvartsburd, A; Sajadi, C; Morton, V; Mirabi, M; Gordon, J; Smith, RC (August 1984). "Blood levels of haloperidol and thioridazine during maintenance neuroleptic treatment of schizophrenic outpatients". Journal of Clinical Psychopharmacology. 4 (4): 194–198. PMID 6470190. doi:10.1097/00004714-198408000-00004.
- Purhonen, M; Koponen, H; Tiihonen, J; Tanskanen, A (November 2012). "Outcome of patients after market withdrawal of thioridazine: A retrospective analysis in a nationwide cohort". Pharmacoepidemiology and Drug Safety. 21 (11): 1227–1231. PMID 22941581. doi:10.1002/pds.3346.
- "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.
- "Withdrawal of thioridazine" (PDF). Australian Prescriber. Vol. 30 no. 3. June 2007. p. 82.
- 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.
- Kirchner, V; Kelly, CA; Harvey, RJ (2001). "Thioridazine for dementia". The Cochrane Database of Systematic Reviews (3): CD000464. PMID 11686961. doi:10.1002/14651858.CD000464.
- Declercq T; et al. (Mar 2013). "Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia". Cochrane Database Syst Rev. 3: CD007726. PMID 23543555. doi:10.1002/14651858.CD007726.pub2.
- "THIORIDAZINE HYDROCHLORIDE tablet, film coated [Mutual Pharmaceutical]". DailyMed. Mutual Pharmaceutical. September 2010. Retrieved 28 October 2013.
- Fenton, M; Rathbone, J; Reilly, J; Sultana, A (July 2007). "Thioridazine for schizophrenia". The Cochrane Database of Systematic Reviews (3): CD001944. PMID 17636691. doi:10.1002/14651858.CD001944.pub2.
- Keks, N; McGrath, J; Lambert, T; Catts, S; Vaddadi, K; Burrows, G; Varghese, F; George, T; Hustig, H; Burnett, P; et al. (November 1994). "The Australian multicentre double-blind comparative study of remoxipride and thioridazine in schizophrenia". Acta Psychiatrica Scandinavica. 90 (5): 358–365. PMID 7872041. doi:10.1111/j.1600-0447.1994.tb01607.x.
- Fornaro, P; Calabria, G; Corallo, G; Picotti, GB (July 2002). "Pathogenesis of degenerative retinopathies induced by thioridazine and other antipsychotics: a dopamine hypothesis". Documenta Ophthalmologica. 105 (1): 41–49. PMID 12152801. doi:10.1023/A:1015768114192.
- "Martindale: The Complete Drug Reference". Medicines Complete. The Pharmaceutical Press. 18 August 2010. Retrieved 28 October 2013.
- "Selected adverse effects of antipsychotic medications for schizophrenia". UpToDate. Wolters Kluwer Health. Retrieved 24 October 2013.
- 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.
- PubChem Substance Summary: Mesoridazine National Center for Biotechnology Information.
- Eap CB, Guentert TW, Schaublin-Loidl M, Stabl M, Koeb L, Powell K, Baumann P (Mar 1996). "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 & Therapy. 59 (3): 322–31. PMID 8653995. doi:10.1016/S0009-9236(96)80010-5.
- PubChem Substance Summary: Sulforidazine National Center for Biotechnology Information.
- 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. CS1 maint: Multiple names: authors list (link)
- Amaral L, Boeree MJ, Gillespie SH, Udwadia ZF, van Soolingen D (June 2010). "Thioridazine cures extensively drug-resistant tuberculosis (XDR-TB) and the need for global trials is now!". Int. J. Antimicrob. Agents. 35 (6): 524–6. PMID 20188526. doi:10.1016/j.ijantimicag.2009.12.019.
- Amaral, L; Viveiros, M (May 2012). "Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections". International Journal of Antimicrobial Agents. 39 (5): 376–380. PMID 22445204. doi:10.1016/j.ijantimicag.2012.01.012.
- Thanacoody, HKR (November 2007). "Thioridazine: resurrection as an antimicrobial agent?". British Journal of Clinical Pharmacology. 64 (5): 566–574. PMC . PMID 17764469. doi:10.1111/j.1365-2125.2007.03021.x.
- Thorsing, M; Klitgaard, JK; Atilano, ML; Skov, MN; Kolmos, HJ; Filipe, SR; Kallipolitis, BH (May 2013). "Thioridazine Induces Major Changes in Global Gene Expression and Cell Wall Composition in Methicillin-Resistant Staphylococcus aureus USA300". PLOS ONE. 8 (5): e64518. PMC . PMID 23691239. doi:10.1371/journal.pone.0064518.
- PubChem Substance Summary: Thioridazine National Center for Biotechnology Information,.
- Antipsychotic Mellaril Removed from Market Schizophrenia Daily News Blog.
- U.S. National Library of Medicine: Drug Information Portal - Thioridazine
Antipsychotics (neuroleptics) (N05A)
Adrenergic receptor modulators
Acetylcholine receptor modulators
See also: Receptor/signaling modulators
Dopamine receptor modulators
Histamine receptor modulators
See also: Receptor/signaling modulators • Monoamine metabolism modulators • Monoamine reuptake and release modulators
(TCAs and TeCAs)
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- 大中 博晶,大津 史子,矢野 玲子,金田 典雄,政田 幹夫,後藤 伸之
- 医療薬学 33(10), 823-830, 2007-10-10
- … In addition, disopyramide, ritodrine, miconazole, halothane, thioridazine and sodium thiopental were found to significantly raise the risk of drug-induced arrhythmia. …
- NAID 110006419376
- Simple and simultaneous determination for twelve phenothiazines in human serum by reversed-phase high-performance liquid chromatography
- Tanaka Einosuke,Nakamura Takako,Terada Masaru,Shinozuka Tatsuo,Hashimoto Chikako,Kurihara Katsuyoshi,Honda Katsuya,田中 榮之介
- Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 854(1), 116-120, 2007-07-01
- … A high-performance liquid chromatographic method has been developed for the simultaneous analysis of the 12 phenothiazines (chlorpromazine, fluphenazine, levomepromazine, perazine, perphenazine, prochlorperazine, profenamine, promethazine, propericiazine, thioproperazine, thioridazine and trifluoperazine) in human serum using HPLC/UV. …
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- Journal of toxicological sciences 32(1), 1-7, 2007-02-16
- … This has led regulatory authorities in the United Kingdom to restrict the use of thioridazine. … These data indicate that legislative changes that restrict the use of thioridazine and other typical antipsychotics are associated with a measurable reduction in the number of hospital admissions due to overdose with these agents. …
- NAID 110006204874
- 概説 心の不調や不具合を調整するお薬です。神経の高ぶりや不安感をしずめ、気持ちをおだやかにします。いろいろな心の病気の治療に用います。 作用 【働き-1】 気分を落ち着ける作用があるので、統合失調症のほか、うつ病や ...
- Thioridazine hydrochloride, USP is available as tablets for oral administration containing 10 mg, 25 mg, 50 mg, or 100 mg. Each tablet for oral administration contains the following inactive ingredients: carnauba wax, colloidal silicon ...
- Thioridazine is used to treat the symptoms of schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions) in people who have already been treated with at least ...