thioridazine thioridazine 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 the branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias.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. not to be confused with thorazine. thioridazineclinical dataahfs/drugs.comprofessional drug factsmedlineplusa682119license data us dailymed: thioridazine us fda: thioridazine pregnancycategory au: c routes ofadministrationoraldrug classtypical antipsychoticatc coden05ac02 (who) legal statuslegal status withdrawn by the manufacturer worldwide; generic formulations are still available by prescription pharmacokinetic databioavailabilityincompletemetabolismhepatic (at least partly mediated by cyp2d6)elimination half-life21–24 hoursexcretionfecesidentifiers iupac name 10--2-methylsulfanylphenothiazine cas number50-52-2 ypubchem cid5452pubchem sid148555iuphar/bps100drugbankdb00679 ychemspider5253 yuniin3d6tg58nikeggd00373 ychebichebi:9566 ychemblchembl479 ycomptox dashboard (epa)dtxsid6023656 echa infocard100.000.041 chemical and physical dataformulac21h26n2s2molar mass370.57 g·mol−13d 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 ykey:klbqzwritkrqqv-uhfffaoysa-n y (verify) 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 further information: phenothiazine 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: biologic proteinbinding affinity (ki)binding affinity of mesoridazine (ki )binding affinity of sulforidazine (ki )notes sert1259ndnd net842ndnd dat1684ndnd 5-ht1a144.35500 (hb)nd 5-ht1b109ndnd 5-ht1d579ndnd 5-ht1e194ndnd 5-ht2a27.674.76 (hb)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 (rc)nd α1a3.152 (hb)ndlikely the receptor responsible for the orthostatic hypotension known to occur in individuals on thioridazine. α1b2.4ndnd α2a134.151612.9 (hb)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 (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. 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 (hb)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 (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 (1) with formaldehyde gives 2-pyridineethanol (2). forming the quat salt with methyl iodide leads to 2-(2-hydroxyethyl)-1-methyl-pyridinium iodide (3). catalytic hydrogenation in the presence of hydrochloric acid leads to 2-(2-chloroethyl)-1-methylpiperidine (4). alkylation of 2-methylthiophenothiazine (5) in the presence of sodium hydride base completed the synthesis of thioridazine (6).