Thioridazine


Thioridazine 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 The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias.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.

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

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 and neuroleptic malignant syndrome. 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.

Pharmacology

Thioridazine has the following binding profile:
Biologic ProteinBinding affinity Binding affinity of Mesoridazine Binding affinity of Sulforidazine Notes
SERT1259NDND
NET842NDND
DAT1684NDND
5-HT1A144.35500 ND
5-HT1B109NDND
5-HT1D579NDND
5-HT1E194NDND
5-HT2A27.674.76 NDThe 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-HT2C53157NDBelieved to play a role in the weight gain-promoting effects of antipsychotics.
5-HT3>10000NDND
5-HT5A364NDND
5-HT657.05380ND
5-HT79973 ND
α1A3.152 NDLikely the receptor responsible for the orthostatic hypotension known to occur in individuals on thioridazine.
α1B2.4NDND
α2A134.151612.9 ND
α2B341.65NDND
α2C74.9NDND
β1>10000NDND
β2>10000NDND
M112.810NDThis receptor is believed to be the chief receptor responsible for the anticholinergic side effects of thioridazine. 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.
M2286.3315ND
M32990ND
M4310.3319ND
M512.6760ND
D194.5NDND
D20.44.30.25Believed to be the receptor responsible for the therapeutic effects of antipsychotics.
D31.52.60.7
D41.59.1ND
D5258NDND
hERG191NDNDLikely involved in thioridazine's cardiac effects.
H116.51.81 NDLikely responsible for the sedating effects of thioridazine.
H2136NDNDRegulates the release of hydrochloric acid into the stomach.
H42400NDND

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 - and -thioridazine-2-sulfoxide, better known as mesoridazine, and into - and -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.