|Systematic (IUPAC) name|
|Licence data||US Daily Med:|
|Metabolism||hepatic (at least partly mediated by CYP2D6)|
|Biological half-life||21-24 hours|
|CAS Registry Number|
|(what is this?)|
Thioridazine (Mellaril or Melleril) was a piperidine typical 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drug group and was previously widely used in the treatment of schizophrenia and psychosis; the branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias, however, generic versions are available in the US.
In older references, it is sometimes described as atypical, but more recently it is usually described as typical, with the term "atypical" usually reserved for agents showing D4 selectivity or serotonin antagonism. The atypicality of second generation agents is not clearly defined. Some believe it's low D2 affinity, quick dissociation, 5-HT2A receptor antagonism, or all of the above. Its perceived atypical effects (namely its comparatively low propensity for extrapyramidal side effects) are likely the result of its potent anticholinergic effects.
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.
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 (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 has the following binding profile:
|Biologic Protein||Binding affinity (Ki[nM])||Binding affinity of Mesoridazine (Ki [nM])||Binding affinity of Sulforidazine (Ki [nM])||Notes|
|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.|
|5-HT2C||53||157||ND||Believed to play a role in the weight gain-promoting effects of antipsychotics.|
|α1A||3.15||2 (HB)||ND||Likely the receptor responsible for the orthostatic hypotension known to occur in individuals on thioridazine.|
|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.|
|D2||0.4||4.3||0.25||Believed to be the receptor responsible for the therapeutic effects of antipsychotics.|
|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.|
Note: The Binding affinities given are towards cloned human receptors unless otherwise specified
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, and into (S)- and (R)-thioridazine-5-sulfoxide. Mesoridazine is in turn metabolized into sulforidazine. Thioridazine is an inhibitor of CYP1A2 and CYP3A2.
Thioridazine is known to kill intracellular extensively drug-resistant (XDR) Mycobacterium tuberculosis and both inhibit MRSA directly but also increase the susceptibility of MRSA to β-lactam antibiotics at clinical concentrations. It also appears to increase the efficacy of standard antimicrobial agents (even ones to which the strain in question is resistant) in treating XDR-tuberculosis (XDR-TB) via inhibiting bacterial efflux pumps.
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