Thioridazine
This article's lead section may be too short to adequately summarize the key points. (September 2021) |
Clinical data | |
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AHFS/Drugs.com | Professional Drug Facts |
MedlinePlus | a682119 |
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Pregnancy category |
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Routes of administration | Oral |
Drug class | Typical antipsychotic |
ATC code | |
Legal status | |
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Pharmacokinetic data | |
Bioavailability | Incomplete |
Metabolism | Hepatic (at least partly mediated by CYP2D6) |
Elimination half-life | 21–24 hours[3] |
Excretion | Feces |
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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 The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias.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.[2]
Indications
Thioridazine was voluntarily discontinued by its manufacturer, Novartis, worldwide because it caused severe cardiac arrhythmias. However, generics remain on the market in some countries.[2][4][5][6]
Its primary use in medicine is for the treatment of schizophrenia.[7] It was also tried with some success as a treatment for various psychiatric symptoms seen in people with dementia,[8] but chronic use of thioridazine and other anti-psychotics in people with dementia is not recommended.[9] 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. [10]
Side effects
Thioridazine prolongs the
Pharmacology
Thioridazine has the following binding profile:[19]
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.[7] |
5-HT2C | 53 | 157 | ND | Believed to play a role in the weight gain-promoting effects of antipsychotics.[7] |
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.[7] |
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 extrapyramidal side effects resulting from antipsychotic treatment.[7]
|
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.[7] |
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
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.[2][4]
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 [24]
Antibiotic activity
Thioridazine is known to kill
Synthesis
Note: Same sidechain used for mesoridazine and sulforidazine.
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
- ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
- ^ a b c d "SHARED CARE PROTOCOL Thioridazine" (PDF). NHS Lothian Joint Formulary. March 2012. Archived from the original (PDF) on 18 May 2015.
- S2CID 33161119.
- ^ S2CID 19560432.
- ^ "WHO Pharmaceuticals Newsletter 2005, No. 04: REGULATORY MATTERS: Thioridazine - Sale discontinued in Canada". Essential Medicines and Health Products Information Portal. Vol. 4, no. 2. World Health Organization. 2005. p. 5. Archived from the original on 28 May 2011. Retrieved 28 October 2013.
- ^ "Withdrawal of thioridazine" (PDF). Australian Prescriber. Vol. 30, no. 3. June 2007. p. 82.
- ^ ISBN 978-0-07-162442-8.
- PMID 11686961.
- PMID 23543555.
- ^ "Thioridazine: MedlinePlus Drug Information". medlineplus.gov. Retrieved 7 June 2023.
- ^ a b c "THIORIDAZINE HYDROCHLORIDE tablet, film coated [Mutual Pharmaceutical]". DailyMed. Mutual Pharmaceutical. September 2010. Retrieved 28 October 2013.
- PMID 17636691.
- S2CID 40042606.
- S2CID 23618581.
- ^ "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.
- PMID 14065014.
- PMID 31643669.
- ^ 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. Archived from the original on 8 November 2013. Retrieved 28 October 2013.
- ^ PubChem Substance Summary: Mesoridazine National Center for Biotechnology Information.
- S2CID 45135063.
- ^ PubChem Substance Summary: Sulforidazine National Center for Biotechnology Information.
- PMID 11985335.
- ^ "Thioridazine: MedlinePlus Drug Information". medlineplus.gov. Retrieved 7 June 2023.
- PMID 20188526.
- ^ PMID 22445204.
- PMID 17764469.
- PMID 23691239.
- .
- ^ US 3239514, Renz J, Bourquin JP, "Phenothiazine derivatives substituted by a monovalent sulfur function in 3-position", issued 1966, assigned to Sandoz KK
- PMID 20994984.
- .
Further reading
- Dean L (2017). "Thioridazine Therapy and CYP2D6 Genotypes". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. PMID 28520378. Bookshelf ID: NBK424018.
External links
- "Thioridazine". Drug Information Portal. U.S. National Library of Medicine.
- Antipsychotic Mellaril Removed from Market Schizophrenia Daily News Blog.