Thioridazine

Thioridazine

Clinical data
AHFS/Drugs.com	Professional Drug Facts
MedlinePlus	a682119
License data	US DailyMed: Thioridazine US FDA: Thioridazine
Pregnancy category	AU: C
Routes of administration	Oral
Drug class	Typical antipsychotic
ATC code	N05AC02 (WHO)
Legal status
Legal status	Withdrawn by the manufacturer worldwide; generic formulations are still available by prescription
Pharmacokinetic data
Bioavailability	Incomplete
Metabolism	Hepatic (at least partly mediated by CYP2D6)
Elimination half-life	21–24 hours
Excretion	Feces
Identifiers
IUPAC name 10-{2-[(RS)-1-Methylpiperidin-2-yl]ethyl}- 2-methylsulfanylphenothiazine
CAS Number	50-52-2 Y
PubChem CID	5452
PubChem SID	148555
IUPHAR/BPS	100
DrugBank	DB00679 Y
ChemSpider	5253 Y
UNII	N3D6TG58NI
KEGG	D00373 Y
ChEBI	CHEBI:9566 Y
ChEMBL	ChEMBL479 Y
CompTox Dashboard (EPA)	DTXSID6023656
ECHA InfoCard	100.000.041
Chemical and physical data
Formula	C21H26N2S2
Molar mass	370.57 g·mol−1
3D model (JSmol)	Interactive image
SMILES S(c2cc1N(c3c(Sc1cc2)cccc3)CCC4N(C)CCCC4)C
InChI InChI=1S/C21H26N2S2/c1-22-13-6-5-7-16(22)12-14-23-18-8-3-4-9-20(18)25-21-11-10-17(24-2)15-19(21)23/h3-4,8-11,15-16H,5-7,12-14H2,1-2H3 Y Key:KLBQZWRITKRQQV-UHFFFAOYSA-N Y
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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 The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias.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.

While it had some success treating psychiatric symptoms in dementia patients, its chronic use is not recommended. Thioridazine has various side effects, including QTc interval prolongation, extrapyramidal side effects, retinopathies, anticholinergic effects, hypotension, cardiotoxicity, orthostatic hypotension, prolactin elevation, weight gain, tardive dyskinesia, neuroleptic malignant syndrome, blood dyscrasias, and retinal pigmentation. It is metabolized by CYP2D6 into mesoridazine and thioridazine-5-sulfoxide, and it inhibits CYP1A2 and CYP3A4. The drug was discontinued in June 2005, but it has demonstrated antibiotic activity against drug-resistant tuberculosis and MRSA. Thioridazine synthesis involves multiple steps, starting with the alkylation of 2-picoline.

Indications

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.

Side effects

Thioridazine prolongs the QTc interval in a dose-dependent manner. It produces significantly less extrapyramidal side effects than most first-generation antipsychotics, likely due to its potent anticholinergic effect. Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies (specifically retinitis pigmentosa). 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 is also associated with abnormal retinal pigmentation after many years of use. Thioridazine has been correlated to rare instances of clinically apparent acute cholestatic liver injury.

Pharmacology

Thioridazine has the following binding profile:

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, and into (S)- and (R)-thioridazine-5-sulfoxide. Mesoridazine is in turn metabolized into sulforidazine. Thioridazine is an inhibitor of CYP1A2 and CYP3A4.

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.

Antibiotic activity

Thioridazine is known to kill extensively drug-resistant tuberculosis and to make methicillin-resistant Staphylococcus aureus sensitive to β-lactam antibiotics. 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. 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, & Sulforidazine.

Thieme Synthesis: Patent: Sidechain: Enantiomers:

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).

Further reading

• Dean L (2017). "Thioridazine Therapy and CYP2D6 Genotypes". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). 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.