View source for Thioridazine

{{distinguish|Thorazine}}
{{drugbox | verifiedrevid = 470608946
| IUPAC_name = 10-{2-[(''RS'')-1-Methylpiperidin-2-yl]ethyl}-<BR>2-methylsulfanylphenothiazine
| image = Thioridazin Enantiomers Structural Formulae V.1.svg
| width = 250
| image2 = Thioridazine3d.png

<!--Clinical data-->
| Drugs.com = {{drugs.com|CDI|thioridazine}}
| MedlinePlus = a682119
| pregnancy_category = Only if clearly needed
| legal_status = RX-only-medication, non-narcotic
| routes_of_administration = oral (tablets, concentration, sometimes syrup)

<!--Pharmacokinetic data-->
| bioavailability = incomplete
| metabolism = hepatic
| elimination_half-life = 7–13 hours (up to 20 hours)
| excretion = feces

<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 50-52-2
| ATC_prefix = N05
| ATC_suffix = AC02
| PubChem = 5452
| IUPHAR_ligand = 100
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00679
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5253
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = N3D6TG58NI
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00373
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 9566
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 479

<!--Chemical data-->
| C=21 | H=26 | N=2 | S=2 
| molecular_weight = 370.577
| smiles = S(c2cc1N(c3c(Sc1cc2)cccc3)CCC4N(C)CCCC4)C
| InChI = 1/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
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KLBQZWRITKRQQV-UHFFFAOYSA-N
}}

'''Thioridazine''' ('''Mellaril''', '''Novoridazine''', '''Thioril''') is a [[piperidine]] typical (but see next paragraph, below) [[antipsychotic]] [[psychoactive drug|drug]] belonging to the [[phenothiazine]] drug group and was previously widely used in the treatment of [[schizophrenia]] and [[psychosis]]. Due to concerns about [[cardiotoxicity]] and [[retinopathy]] at high doses this drug is not commonly prescribed, reserved for patients who have failed to respond to, or have [[contraindication]]s for, more widely used antipsychotics. A serious side effect is the potentially fatal [[neuroleptic malignant syndrome]]. It exerts its actions through a central adrenergic-blocking, a [[dopamine]]-blocking, and minor [[anticholinergic]] activity.

In older references, it is sometimes described as [[atypical antipsychotic|atypical]],<ref name="pmid6540455">{{cite journal |author=Robertson A, MacDonald C |title=Atypical neuroleptics clozapine and thioridazine enhance amphetamine-induced stereotypy |journal=Pharmacol. Biochem. Behav. |volume=21 |issue=1 |pages=97–101 |year=1984 |month=July |pmid=6540455 |doi= 10.1016/0091-3057(84)90137-0|url=}}</ref> but more recently it is usually described as [[typical antipsychotics|typical]],<ref name="pmid11850147">{{cite journal |author=Ichikawa J, Dai J, O'Laughlin IA, Fowler WL, Meltzer HY |title=Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum |journal=Neuropsychopharmacology |volume=26 |issue=3 |pages=325–39 |year=2002 |month=March |pmid=11850147 |doi=10.1016/S0893-133X(01)00312-8}}</ref> with the term "atypical" usually reserved for agents showing [[Dopamine receptor D4|D4]] selectivity or [[Serotonin antagonist|serotonin antagonism]].

==Indications==
Previous additional indications were [[agitated depression]], [[stress (medicine)|tension]] and [[anxiety]] linked to [[alcohol withdrawal syndrome|alcohol withdrawal]] and [[dysphoria]] of [[epilepsy|epileptic]] patients. It was even indicated in Europe for the treatment of psychosis in children and adolescents as Melleretten (10&nbsp;mg to 60&nbsp;mg daily).

It was also given off-label for the treatment of [[insomnia]] and for alleviation of [[opiate]] withdrawal. {{Citation needed|date=July 2008}}

Thioridazine is known to kill multidrug-resistant ''[[Mycobacterium tuberculosis]]'' and [[MRSA]] at clinical concentrations.<ref>Amaral L, Viveiros M, Molnar J. "Antimicrobial activity of phenothiazines."</ref><ref>{{cite journal |author=Amaral L, Boeree MJ, Gillespie SH, Udwadia ZF, van Soolingen D |title=Thioridazine cures extensively drug-resistant tuberculosis (XDR-TB) and the need for global trials is now! |journal=Int. J. Antimicrob. Agents |volume=35 |issue=6 |pages=524–6 |year=2010 |month=June |pmid=20188526 |doi=10.1016/j.ijantimicag.2009.12.019 |url=}}</ref>

==Metabolism==
Thioridazine is a [[racemic]] compound with two [[enantiomer]]s, both of which are metabolized, according to Eap et al., by [[CYP2D6]] into (S)- and (R)-thioridazine 2-sulfoxide, better known as [[mesoridazine]],<ref>[http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=447728 PubChem Substance Summary: Mesoridazine] National Center for Biotechnology Information.</ref> and into (S)- and (R)-thioridazine-5-sulfoxide.<ref>{{cite journal | author = Eap CB, Guentert TW, Schaublin-Loidl M, Stabl M, Koeb L, Powell K, Baumann P | year = 1996 | month = Mar | title = Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin | url = | journal = Clinical Pharmacology & Therapy | volume = 59 | issue = 3| pages = 322–31 | pmid = 8653995 | doi=10.1016/S0009-9236(96)80010-5}}</ref> Mesoridazine is in turn metabolized into [[sulforidazine]].<ref>[http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=300587&namedisopt=&ncount=12#Synonyms PubChem Substance Summary: Sulforidazine] National Center for Biotechnology Information.</ref> Thioridazine is an inhibitor of [[CYP1A2]] and CYP3A2.<ref>{{cite journal | url = http://www.if-pan.krakow.pl/pjp/pdf/2001/6_615.pdf | pmid = 11985335 | volume=53 | issue=6 | title=Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver | year=2001 | journal=Pol J Pharmacol | pages=615–21 | author=Daniel WA, Syrek M, Ry&#x142;ko Z, Kot M}}</ref>

==Side effects==
For further information see: [[Phenothiazine]]

The most commonly complained about side effect is [[akathisia]] which is the main reason for low patient compliance

[[Tardive dyskinesia]] characterized by involuntary movements of the lips, mouth, and tongue can be long lasting or irreversible, tremor of the mouth and lips without tongue involvement constitutes [[Rabbit syndrome]]. [[Neuroleptic malignant syndrome]] is potentially fatal.

Central nervous system side effects occur. These are mainly drowsiness, dizziness, fatigue, and vertigo. Early and late [[extrapyramidal]] side effects are seen only infrequently (less than 1% altogether). There is no clear dose-effect relationship, as with higher doses anticholinergic effects of thioridazine become more prominent.

Thioridazine causes also an unusual high incidence of [[impotence]] and [[anorgasmia]] due to a strong [[alpha blocker|alpha-blocking]] activity. Painful ejaculation or no ejaculation at all is also sometimes seen.{{Citation needed|date=July 2008}}

Autonomous side effects ([[dry mouth]], [[urination]] difficulty, [[obstipation]], induction of [[glaucoma]], [[postural hypotension]], and [[sinus tachycardia]]) occur obviously less often than with most other mildly potent antipsychotics.

Thioridazine is no longer recommended as first-line treatment due its side effect of prolonging the [[QT interval]] on the [[EKG]]. Thioridazine-5-sulfoxide is associated with [[ventricular tachycardia]] and [[torsades de pointes]].<ref>{{cite journal | author = Heath A, Svensson C, Martensson E | year = 1985 | month = Apr | title = Thioridazine toxicity--an experimental cardiovascular study of thioridazine and its major metabolites in overdose | url = | journal = Veterinary and Human Toxicology | volume = 27 | issue = 2| pages = 100–5 | pmid = 3992882 }}</ref>

It can also cause [[sialadenitis]], which is more common in older individuals.<ref>p229, Robbins and Cotran ''Review of Pathology'', 3rd edition, Klatt and Kumar</ref>

Also, the serious and sometimes fatal blood damage [[agranulocytosis]] is seen more frequently (approximately 1/500 to 1/1,000 patients) with thioridazine than with other typical phenothiazines (1/2,000 to 1/10,000 patients).

Thioridazine if given over a prolonged time and in high doses can be stored in the ocula and the [[retina]] of the eyes and in the heart muscle. Clinical consequences (disturbed or blurred vision) are rare although chromatopsia has been reported.<ref>AJ Giannini, PJ Mahar. An unusual ocular complication of thioridazine. International Journal of Psychiatry in Medicine. 10:217-219, 1980.</ref> {{Citation needed|date=October 2008}}

==Discontinuation==
It is advisable to withdraw thioridazine gradually and not abruptly to avoid unpleasant withdrawal symptoms ([[Psychomotor agitation|agitation]], insomnia, anxiety). Another neuroleptic may be introduced to the therapeutic regime step by step (overlapping), if needed. If sudden withdrawal of thioridazine is necessary, withdrawal symptoms can also be alleviated with the [[benzodiazepine]]s [[lorazepam]] (Ativan) 1&nbsp;mg—2&nbsp;mg, [[alprazolam]] (Xanax) 0,5&nbsp;mg prn or [[clonazepam]] (Klonopin, Rivotril) 0,5&nbsp;mg  to 2&nbsp;mg prn (as needed)or [[Diazepam]] (Valium)5 – 10&nbsp;mg prn for up to 2 weeks (not longer to avoid addiction). {{Citation needed|date=July 2008}}

==History==
The manufacturer [[Novartis]]/Sandoz/Wander of the brands of thioridazine, Mellaril in the USA and Canada and Melleril in Europe, discontinued the drug worldwide in June 2005.

The usual dosage was 50&nbsp;mg per day for mild cases to 600–800&nbsp;mg per day for severely disturbed patients.

Thioridazine may still be available from other manufacturers as a generic drug with the precaution that it is used only in psychotic patients refractory to other forms of drug treatment. ECG-monitoring and frequent [[white blood cell]] counts are required before initiating therapy and in close intervals afterwards.

A multi-year UK study by the Alzheimer's Research Trust suggested that this and other [[neuroleptic]] [[anti-psychotic]] drugs commonly given to Alzheimer's patients with mild behavioural problems often make their condition worse. {{Citation needed|date=July 2008}}<ref>
{{cite news |first= |last=
 |authorlink=
 |author=
 |coauthors=
 |title=Medication 'worsens Alzheimer's' |url=http://news.bbc.co.uk/1/hi/health/7319393.stm
 |format=
 |work= |publisher=BBC News
 |location= |id= |pages= |page= |date= 1 April 2008
 |accessdate=2008-04-01
 |language=
 |quote=Neuroleptics provided no benefit for patients with mild behavioural problems, but were associated with a marked deterioration in verbal skills.
 |archiveurl=
 |archivedate=
}}</ref>  The study concluded that {{cquote|For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status and by some measures improved functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this possibility must be weighed against the unwanted effects of therapy. The current study helps to inform a clinical management strategy for current practice, but the considerable risks of maintenance therapy highlight the urgency of further work to find, develop, and implement safer and more effective treatment approaches for neuropsychiatric symptoms in people with AD.}}
<ref>{{cite journal
 |journal=PLOS Medicine
 |title=A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial)
 |author=Ballard C, Lana MM, Theodoulou M, Douglas S, McShane R, et al.
 |volume=5 |issue=4, e76
 |doi=10.1371/journal.pmed.0050076
 |year=2008
 |pages=e76
 |pmid=18384230
 |pmc=2276521
 |editor1-last=Brayne
 |editor1-first=Carol
}}</ref>
{{Expand section|date=June 2008}}
==Chemistry==
Thioridazine, (±)-(10-[2-(1-methyl-2-piperidyl)ethyl]-2-(methylthio)phenothiazine) is synthesized by alkylating 2-methylthiophenothiazine with 2-(2-chloroethyl)-1-methylpiperidine.
[[File:Thioridazine synthesis.png|600px|center]]
*J. Renz, J.P. Bourquin, G. Gamboni, G. Schwarb, {{US Patent|3239514}} (1966).
*{{Cite doi|10.1002/hlca.19580410420}}
== References ==
{{Reflist|2}}

== External links ==
* [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=148555 PubChem Substance Summary: Thioridazine] National Center for Biotechnology Information,.
* [http://www.schizophrenia.com/sznews/archives/001377.html Antipsychotic Mellaril Removed from Market] ''Schizophrenia Daily News Blog.''
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Thioridazine U.S. National Library of Medicine: Drug Information Portal - Thioridazine]

{{Antipsychotics}}
{{Adrenergics}}
{{Cholinergics}}
{{Dopaminergics}}
{{Histaminergics}}
{{Tricyclics}}
{{Use dmy dates|date=January 2011}}

[[Category:Typical antipsychotics]]
[[Category:Phenothiazines]]
[[Category:Piperidines]]
[[Category:Thioethers]]

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