Thioridazine

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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 The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias.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.<ref name = NHS/>

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.<ref name=NHS>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=PDS2012>Template:Cite journal</ref><ref>Template:Cite news</ref><ref>Template:Cite magazine</ref>

Its primary use in medicine is for the treatment of schizophrenia.<ref name = GG>Template:Cite book</ref> It was also tried with some success as a treatment for various psychiatric symptoms seen in people with dementia,<ref>Template:Cite journal</ref> but chronic use of thioridazine and other anti-psychotics in people with dementia is not recommended.<ref>Template:Cite journal</ref> 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.<ref name="medlineplus.gov">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Side effects

Thioridazine prolongs the QTc interval in a dose-dependent manner.<ref name = DM>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It produces significantly less extrapyramidal side effects than most first-generation antipsychotics, likely due to its potent anticholinergic effect.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies (specifically retinitis pigmentosa).<ref>Template:Cite journal</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name = UpToDate>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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).<ref name = DM/> Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia are possible with thioridazine treatment.<ref name = DM/> Thioridazine is also associated with abnormal retinal pigmentation after many years of use.<ref>Template:Cite journal</ref> Thioridazine has been correlated to rare instances of clinically apparent acute cholestatic liver injury.<ref>Template:Cite book</ref>

Pharmacology

Thioridazine has the following binding profile:<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name = GG/>
5-HT2C	53	157	ND	Believed to play a role in the weight gain-promoting effects of antipsychotics.<ref name = GG/>
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.<ref name = GG/>
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.<ref name = GG/>
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.<ref name = GG/>
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,<ref>PubChem Substance Summary: Mesoridazine National Center for Biotechnology Information.</ref> and into (S)- and (R)-thioridazine-5-sulfoxide.<ref>Template:Cite journal</ref> Mesoridazine is in turn metabolized into sulforidazine.<ref>PubChem Substance Summary: Sulforidazine National Center for Biotechnology Information.</ref> Thioridazine is an inhibitor of CYP1A2 and CYP3A4.<ref>Template:Cite journal</ref>

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.<ref name = NHS/><ref name=PDS2012/>

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 <ref name="medlineplus.gov"/>

Antimicrobial activity

Thioridazine is known to kill extensively drug-resistant tuberculosis<ref>Template:Cite journal</ref><ref name = XDR>Template:Cite journal</ref> and to make methicillin-resistant Staphylococcus aureus sensitive to β-lactam antibiotics.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name = XDR/> Phenothiazines more broadly have also been used in combination with other drugs to treat infections caused by pathogenic free living ameoba (PFLA).<ref name="DeetzSawyer2003">Template:Cite journal</ref>

Synthesis

Note: Same sidechain used for mesoridazine and sulforidazine.

File:Thioridazine synthesis.svg

Thieme Synthesis:<ref>Template:Cite journal</ref> Patent:<ref>Template:Cite patent</ref> Sidechain:<ref name="pmid20994984">Template:Cite journal</ref> Enantiomers:<ref>Template:Cite journal</ref>

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

• Template:Cite book

External links

• {{#invoke:citation/CS1|citation

|CitationClass=web }}

• Antipsychotic Mellaril Removed from Market Schizophrenia Daily News Blog.