Trifluoperazine

Trifluoperazine

Systematic (IUPAC) name
10-[3-(4-methylpiperazin-1-yl)propyl]- 2-(trifluoromethyl)-10H-phenothiazine
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a682121
Pregnancy cat.	C(AU) C(US)
Legal status	POM (UK) ℞-only (US)
Routes	oral, IM
Pharmacokinetic data
Metabolism	Hepatic
Half-life	10–20 hours
Identifiers
CAS number	117-89-5 Y
ATC code	N05AB06
PubChem	CID 5566
IUPHAR ligand	214
DrugBank	DB00831
ChemSpider	5365 Y
UNII	214IZI85K3 Y
ChEBI	CHEBI:45951 N
ChEMBL	CHEMBL422 Y
Chemical data
Formula	C21H24F3N3S
Mol. mass	407.497
SMILES	eMolecules & PubChem
InChI InChI=1S/C21H24F3N3S/c1-25-11-13-26(14-12-25)9-4-10-27-17-5-2-3-6-19(17)28-20-8-7-16(15-18(20)27)21(22,23)24/h2-3,5-8,15H,4,9-14H2,1H3 Y Key:ZEWQUBUPAILYHI-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Trifluoperazine (Eskazinyl, Eskazine, Jatroneural, Modalina, Stelazine, Terfluzine, Trifluoperaz, Triftazin) is a typical antipsychotic of the phenothiazine chemical class.

Uses

The primary application of trifluoperazine is for schizophrenia. Other official indications may vary country by country, but generally it is also indicated for use in agitation and patients with behavioural problems, severe nausea and vomiting as well as severe anxiety. Its use in many parts of the world has declined because of highly frequent and severe early and late tardive dyskinesia, a type of extrapyramidal symptom. The annual development rate of tardive dyskinesia may be as high as 4%.^{[citation needed]}

A 2006 study suggested that trifluoperazine may be able to reverse addiction to opioids.^[1]

A multi-year UK study by the Alzheimer's Research Trust suggested that this and other antipsychotic drugs commonly given to Alzheimer's patients with mild behavioural problems often make their condition worse.^[2] 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.

”

Pharmacology

Trifluoperazine has central antiadrenergic,^[3] antidopaminergic,^[4][5] and minimal anticholinergic effects.^[6] It is believed to work by blockading dopamine D₁ and D₂ receptors in the mesocortical and mesolimbic pathways, relieving or minimizing such symptoms of schizophrenia as hallucinations, delusions, and disorganized thought and speech.^[7]

Side effects

A 2004 meta-analysis of the studies on trifluoperazine found that it is more likely than placebo to cause extrapyramidal side effects such as akathisia, dystonia, and Parkinsonism.^[7] It is also more likely to cause somnolence and anticholinergic side effects such as blurred vision and xerostomia (dry mouth).^[7] All phenothiazines can cause the rare and sometimes fatal neuroleptic malignant syndrome.^[8] Trifluoperazine can lower the seizure threshold.^[9] The antimuscarinic action of trifluoperazine can cause excessive dilation of the pupils (mydriasis), which increases the chances of patients with hyperopia developing glaucoma.^[10]

Contraindications

Trifluoperazine is contraindicated in CNS depression, coma, and blood dyscrasias. Trifluoperazine should be used with caution in patients suffering from renal or hepatic impairment.

Formulations

In the United Kingdom and some other countries, Trifluoperazine is sold and marketed under the brand 'Stelazine'.

The drug is sold as tablet, liquid and 'Trifluoperazine-injectable USP' for deep intramuscular short-term use.

In the past, trifluoperazine was used in fixed combinations with the MAO inhibitor (antidepressant) tranylcypromine to attenuate the strong stimulating effects of this antidepressant. This combination was sold under the brand name Jatrosom N. Likewise a combination with amobarbital (potent sedative/hypnotic agent) for the amelioration of psychoneurosis and insomnia existed under the brand name Jalonac. In Italy the first combination is still available, sold under the brand name Parmodalin (10 mg of Tranylcypromine and 1 mg of Trifluoperazine).

Chemistry

Trifluoperazine (2-trifluoromethyl-10-[3-(4-methyl-1-piperazinyl)propyl]phenothazine) is synthesized in the manner described already for prochlorperazine, alkylation is performed using 2-trifluoromethylphenothazin-4-methyl-1-piperazinylpropylchloride as the substrate.

• Craig, P.; Nodiff, E.; Lafferty, J.; Ullyot, G. (1957). Journal of Organic Chemistry 22 (6): 709. doi:10.1021/jo01357a618.  edit
• G.E. Ullyot, U.S. Patent 2,921,069 (1960).
• Sharma, H.; Banerjee, S.; Sharma, V.; Mital, R. (1968). "Phenothiazines Exhibiting Lesser Extraparamidal Manifestations". Journal of Medicinal Chemistry 11 (6): 1244. doi:10.1021/jm00312a600. PMID 5680054.  edit
• P.N. Craig, G.E. Ullyot, DE 1165034  (1956).
• B.H. Chung, F. Zimalkowski, Arch. Pharm., 317, 323 (1984).

References

1. ^ Tang L, Shukla PK, Wang ZJ (2006). "Trifluoperazine, an orally available clinically used drug, disrupts opioid antinociceptive tolerance". Neuroscience Letters 397 (1–2): 1–4. doi:10.1016/j.neulet.2005.11.050. PMID 16380209. Lay summary – ScienceDaily (2006-02-13). 
2. ^ Ballard C, Lana MM, Theodoulou M, et al. (April 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. doi:10.1371/journal.pmed.0050076. PMC 2276521. PMID 18384230. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2276521. Lay summary – BBC News (2008-04-01). "Neuroleptics provided no benefit for patients with mild behavioural problems, but were associated with a marked deterioration in verbal skills" 
3. ^ Huerta-Bahena J, Villalobos-Molina R, García-Sáinz JA (January 1983). "Trifluoperazine and chlorpromazine antagonize alpha 1- but not alpha2- adrenergic effects". Molecular Pharmacology 23 (1): 67–70. PMID 6135146. http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=6135146. Retrieved 2009-06-21. 
4. ^ Seeman P, Lee T, Chau-Wong M, Wong K (June 1976). "Antipsychotic drug doses and neuroleptic/dopamine receptors". Nature 261 (5562): 717–9. Bibcode 1976Natur.261..717S. doi:10.1038/261717a0. PMID 945467. 
5. ^ Creese I, Burt DR, Snyder SH (1996). "Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs". The Journal of Neuropsychiatry and Clinical Neurosciences 8 (2): 223–6. PMID 9081563. http://neuro.psychiatryonline.org/cgi/content/abstract/8/2/223. Retrieved 2009-06-21. 
6. ^ Ebadi, Manuchair S (1998). "Trifluoperazine Hydrochloride". CRC desk reference of clinical pharmacology (illustrated ed.). CRC Press. ISBN 978-0-8493-9683-0. http://books.google.co.uk/books?id=-EAxShTKfGAC&lpg=PA580&dq=trifluoperazine%20anticholinergic. Retrieved 2009-06-21. 
7. ^ ^{a b c} Marques LO, Lima MS, Soares BG (2004). Marques, Luciana de Oliveira. ed. "Trifluoperazine for schizophrenia". Cochrane Database of Systematic Reviews (Online) (1): CD003545. doi:10.1002/14651858.CD003545.pub2. PMID 14974020. 
8. ^ Smego RA, Durack DT (June 1982). "The neuroleptic malignant syndrome". Archives of Internal Medicine 142 (6): 1183–5. doi:10.1001/archinte.142.6.1183. PMID 6124221. 
9. ^ Hedges D, Jeppson K, Whitehead P (July 2003). "Antipsychotic medication and seizures: a review". Drugs of Today (Barcelona, Spain : 1998) 39 (7): 551–7. doi:10.1358/dot.2003.39.7.799445. PMID 12973403. 
10. ^ Boet DJ (July 1970). "Toxic effects of phenothiazines on the eye". Documenta Ophthalmologica. Advances in Ophthalmology 28 (1): 1–69. doi:10.1007/BF00153873. PMID 5312274.