Thioridazine

Its primary use in medicine is for the treatment of schizophrenia.^[4] It was also tried with some success as a treatment for various psychiatric symptoms seen in people with dementia,^[5] but chronic use of thioridazine and other anti-psychotics in people with dementia is not recommended.^[6]

Thioridazine prolongs the QTc interval in a dose-dependent manner.^[7] It produces significantly less extrapyramidal side effects than most first-generation antipsychotics, likely due to its potent anticholinergic effect.^[8][9] Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies (specifically retinitis pigmentosa).^[10] 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.^[11] 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.^[12] 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).^[7] Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia are possible with thioridazine treatment.^[7] Thioridazine is also associated with abnormal retinal pigmentation after many years of use.^[13] Thioridazine has been correlated to rare instances of clinically apparent acute cholestatic liver injury.^[14]

Thioridazine has the following binding profile:^[15]

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

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,^[16] and into (S)- and (R)-thioridazine-5-sulfoxide.^[17] Mesoridazine is in turn metabolized into sulforidazine.^[18] Thioridazine is an inhibitor of CYP1A2 and CYP3A4.^[19]

Thioridazine was first synthesized in 1958 by Swiss pharmaceutical company Sandoz.^[20] It quickly entered widespread clinical use, as there were few alternatives for treating schizophrenia. In 2005, 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][21][22][23]} Generic forms of thioridazine however remain on the market in a few countries, usually with restrictions. 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.^[24]

Thioridazine is known to kill extensively drug-resistant tuberculosis^[25][26] and to make methicillin-resistant Staphylococcus aureus sensitive to β-lactam antibiotics.^[27][28] 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.^[26] Phenothiazines more broadly have also been used in combination with other drugs to treat infections caused by pathogenic free living amoeba (PFLA).^[29]

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).