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Thioridazine

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Not to be confused with Thorazine.
Thioridazine
Clinical data
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa682119
Pregnancy
category
  • Only if clearly needed
Routes of
administration		oral (tablets, concentration, sometimes syrup)
ATC code
Legal status
Legal status
  • RX-only-medication, non-narcotic
Pharmacokinetic data
Bioavailabilityincomplete
Metabolismhepatic
Elimination half-life7–13 hours (up to 20 hours)
Excretionfeces
Identifiers
  • 10-{2-[(RS)-1-Methylpiperidin-2-yl]ethyl}-
    2-methylsulfanylphenothiazine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.041 Edit this at Wikidata
Chemical and physical data
FormulaC21H26N2S2
Molar mass370.577 g·mol−1
3D model (JSmol)
  • S(c2cc1N(c3c(Sc1cc2)cccc3)CCC4N(C)CCCC4)C
  • 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 checkY
  • Key:KLBQZWRITKRQQV-UHFFFAOYSA-N checkY
  (verify)

Thioridazine (Mellaril, Novoridazine, Thioril) is a piperidine typical (but see next paragraph, below) antipsychotic 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 contraindications 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,[1] but more recently it is usually described as typical,[2] with the term "atypical" usually reserved for agents showing D4 selectivity or serotonin antagonism.

Indications

Previous additional indications were agitated depression, tension and anxiety linked to alcohol withdrawal and dysphoria of epileptic patients. It was even indicated in Europe for the treatment of psychosis in children and adolescents as Melleretten (10 mg to 60 mg daily).

It was also given off-label for the treatment of insomnia and for alleviation of opiate withdrawal. [citation needed]

Thioridazine is known to kill multidrug-resistant Mycobacterium tuberculosis and MRSA at clinical concentrations.[3][4]

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,[5] and into (S)- and (R)-thioridazine-5-sulfoxide.[6] Mesoridazine is in turn metabolized into sulforidazine.[7] Thioridazine is an inhibitor of CYP1A2 and CYP3A2.[8]

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-blocking activity. Painful ejaculation or no ejaculation at all is also sometimes seen.[citation needed]

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.[9]

It can also cause sialadenitis, which is more common in older individuals.[10]

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.[11] [citation needed]

Discontinuation

It is advisable to withdraw thioridazine gradually and not abruptly to avoid unpleasant withdrawal symptoms (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 benzodiazepines lorazepam (Ativan) 1 mg—2 mg, alprazolam (Xanax) 0,5 mg prn or clonazepam (Klonopin, Rivotril) 0,5 mg to 2 mg prn (as needed)or Diazepam (Valium)5 – 10 mg prn for up to 2 weeks (not longer to avoid addiction). [citation needed]

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 mg per day for mild cases to 600–800 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][12] The study concluded that

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.

[13]

Chemistry

Thioridazine, (±)-(10-[2-(1-methyl-2-piperidyl)ethyl]-2-(methylthio)phenothiazine) is synthesized by alkylating 2-methylthiophenothiazine with 2-(2-chloroethyl)-1-methylpiperidine.

  • J. Renz, J.P. Bourquin, G. Gamboni, G. Schwarb, U.S. patent 3,239,514 (1966).
  • Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1002/hlca.19580410420, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1002/hlca.19580410420 instead.

References

  1. ^ Robertson A, MacDonald C (1984). "Atypical neuroleptics clozapine and thioridazine enhance amphetamine-induced stereotypy". Pharmacol. Biochem. Behav. 21 (1): 97–101. doi:10.1016/0091-3057(84)90137-0. PMID 6540455. {{cite journal}}: Unknown parameter |month= ignored (help)
  2. ^ Ichikawa J, Dai J, O'Laughlin IA, Fowler WL, Meltzer HY (2002). "Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum". Neuropsychopharmacology. 26 (3): 325–39. doi:10.1016/S0893-133X(01)00312-8. PMID 11850147. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Amaral L, Viveiros M, Molnar J. "Antimicrobial activity of phenothiazines."
  4. ^ Amaral L, Boeree MJ, Gillespie SH, Udwadia ZF, van Soolingen D (2010). "Thioridazine cures extensively drug-resistant tuberculosis (XDR-TB) and the need for global trials is now!". Int. J. Antimicrob. Agents. 35 (6): 524–6. doi:10.1016/j.ijantimicag.2009.12.019. PMID 20188526. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ PubChem Substance Summary: Mesoridazine National Center for Biotechnology Information.
  6. ^ Eap CB, Guentert TW, Schaublin-Loidl M, Stabl M, Koeb L, Powell K, Baumann P (1996). "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". Clinical Pharmacology & Therapy. 59 (3): 322–31. doi:10.1016/S0009-9236(96)80010-5. PMID 8653995. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ PubChem Substance Summary: Sulforidazine National Center for Biotechnology Information.
  8. ^ Daniel WA, Syrek M, Ryłko Z, Kot M (2001). "Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver" (PDF). Pol J Pharmacol. 53 (6): 615–21. PMID 11985335.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  9. ^ Heath A, Svensson C, Martensson E (1985). "Thioridazine toxicity--an experimental cardiovascular study of thioridazine and its major metabolites in overdose". Veterinary and Human Toxicology. 27 (2): 100–5. PMID 3992882. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ p229, Robbins and Cotran Review of Pathology, 3rd edition, Klatt and Kumar
  11. ^ AJ Giannini, PJ Mahar. An unusual ocular complication of thioridazine. International Journal of Psychiatry in Medicine. 10:217-219, 1980.
  12. ^ "Medication 'worsens Alzheimer's'". BBC News. 1 April 2008. Retrieved 1 April 2008. Neuroleptics provided no benefit for patients with mild behavioural problems, but were associated with a marked deterioration in verbal skills. {{cite news}}: Cite has empty unknown parameter: |coauthors= (help)
  13. ^ Ballard C, Lana MM, Theodoulou M, Douglas S, McShane R; et al. (2008). Brayne, Carol (ed.). "A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial)". PLOS Medicine. 5 (4, e76): e76. doi:10.1371/journal.pmed.0050076. PMC 2276521. PMID 18384230. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)

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