Thioridazine: Wikis

  

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Thioridazine
Systematic (IUPAC) name
10-{2-[(RS)-1-Methylpiperidin-2-yl]ethyl}-
2-methylsulfanyl-phenothiazine
Identifiers
CAS number 50-52-2
ATC code N05AC02
PubChem 5452
DrugBank APRD00596
Chemical data
Formula C 21H26N2S2  
Mol. mass 370.577
Pharmacokinetic data
Bioavailability incomplete
Metabolism hepatic
Half life 7–13 hours (up to 20 hours)
Excretion feces
Therapeutic considerations
Pregnancy cat. Only if clearly needed
Legal status RX-only-medication, non-narcotic
Routes oral (tablets, concentration, sometimes syrup)
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Thioridazine (Mellaril, Novoridazine, Thioril) is a piperidine 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.

Contents

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.

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

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

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.

Autonomous side-effects (dry mouth, urination-difficulties, 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 responsible for the ventricular tachycardia, torsades de pointes according to Heath, Svensson and Martensson.[8]

It can also cause sialadenitis, which is more common in older individuals[9].

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. [10]

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 - 10mg prn for up to 2 weeks (not longer to avoid addiction).

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.[11] 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.

[12]

References

  1. ^ Robertson A, MacDonald C (July 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.  
  2. ^ Ichikawa J, Dai J, O'Laughlin IA, Fowler WL, Meltzer HY (March 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.  
  3. ^ Amaral L, Viveiros M, Molnar J. "Antimicrobial activity of phenothiazines."
  4. ^ PubChem Substance Summary: Mesoridazine National Center for Biotechnology Information.
  5. ^ Eap CB, Guentert TW, Schaublin-Loidl M, Stabl M, Koeb L, Powell K, Baumann P. "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. 1996 Mar;59(3):322–31. PMID 8653995
  6. ^ PubChem Substance Summary: Sulforidazine National Center for Biotechnology Information.
  7. ^ Daniel WA, Syrek M, Rylko Z, Kot M. "Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver." Polish Journal of Pharmacology. 2001 Nov-Dec;53(6):615–21. PMID 11985335 Fulltext (PDF)
  8. ^ Heath A, Svensson C, Martensson E. "Thioridazine toxicity--an experimental cardiovascular study of thioridazine and its major metabolites in overdose." Veterinary and Human Toxicology. 1985 Apr;27(2):100–5. PMID 3992882
  9. ^ p229, Robbins and Cotran Review of Pathology, 3rd edition, Klatt and Kumar
  10. ^ AJ Giannini, PJ Mahar. An unusual ocular complication of thioridazine. International Journal of Psychiatry in Medicine. 10:217-219, 1980.
  11. ^ "Medication 'worsens Alzheimer's'". BBC News. 1 April 2008. http://news.bbc.co.uk/1/hi/health/7319393.stm. Retrieved 2008-04-01. "Neuroleptics provided no benefit for patients with mild behavioural problems, but were associated with a marked deterioration in verbal skills."  
  12. ^ Ballard C, Lana MM, Theodoulou M, Douglas S, McShane R, et al. (2008). "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.  

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