Thioridazine

Systematic (IUPAC) name
10-{2-[(RS)-1-Methylpiperidin-2-yl]ethyl}- 2-methylsulfanylphenothiazine
Clinical data
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a682119
Pregnancy cat.	Only if clearly needed
Legal status	RX-only-medication, non-narcotic
Routes	oral (tablets, concentration, sometimes syrup)
Pharmacokinetic data
Bioavailability	incomplete
Metabolism	hepatic
Half-life	7–13 hours (up to 20 hours)
Excretion	feces
Identifiers
CAS number	50-52-2 Y
ATC code	N05AC02
PubChem	CID 5452
IUPHAR ligand	100
DrugBank	DB00679
ChemSpider	5253 Y
UNII	N3D6TG58NI Y
KEGG	D00373 Y
ChEBI	CHEBI:9566 Y
ChEMBL	CHEMBL479 Y
Chemical data
Formula	C21H26N2S2
Mol. mass	370.577
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 Y Key:KLBQZWRITKRQQV-UHFFFAOYSA-N Y
Y (what is this?)  (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]}

Autonomic 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

^[13]

This section requires expansion.

  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).
• Bourquin, J.-P.; Schwarb, G.; Gamboni, G.; Fischer, R.; Ruesch, L.; Guldimann, S.; Theus, V.; Schenker, E. et al. (1958). "Synthesen auf dem Phenothiazin-Gebiet. 2. Mitteilung. N-substituierte Mercaptophenothiazin-Derivate". Helvetica Chimica Acta 41: 1072. DOI:10.1002/hlca.19580410420.  edit

  References

  External links

• PubChem Substance Summary: Thioridazine National Center for Biotechnology Information,.
• Antipsychotic Mellaril Removed from Market Schizophrenia Daily News Blog.
• U.S. National Library of Medicine: Drug Information Portal - Thioridazine