- Molecular FormulaC22H26F3N3OS
- Average mass437.522 Da
- SQ 10733
- Squibb 16144
Fluphenazine is a phenothiazine used to treat patients requiring long-term neuroleptic therapy.
A phenothiazine used in the treatment of psychoses. Its properties and uses are generally similar to those of chlorpromazine.
Fluphenazine, sold under the brand names Prolixin among others, is a high-potency typical antipsychotic medication. It is used in the treatment of chronic psychoses such as schizophrenia, and appears to be about equal in effectiveness to low-potency antipsychotics like chlorpromazine. It is given by mouth, injection into a muscle, or just under the skin. There is also a long acting injectable version that may last for up to four weeks. Fluphenazine decanoate, the depot injection form of fluphenazine, should not be used by people with severe depression.
Common side effects include movement problems, sleepiness, depression and increased weight. Serious side effects may include neuroleptic malignant syndrome, low white blood cell levels, and the potentially permanent movement disorder tardive dyskinesia. In older people with psychosis as a result of dementia it may increase the risk of dying. It may also increase prolactin levels which may result in milk production, enlarged breasts in males, impotence, and the absence of menstrual periods. It is unclear if it is safe for use in pregnancy.
Fluphenazine is a typical antipsychotic of the phenothiazine class. Its mechanism of action is not entirely clear but believed to be related to its ability to block dopamine receptors. In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal.
Fluphenazine came into use in 1959. The injectable form is on the World Health Organization’s List of Essential Medicines. It is available as a generic medication. It was discontinued in Australia around mid 2017.
Ullyot, G.E.; U.S. Patent 3,058,979; October 16, 1962; assigned to Smith Kline & French Laboratories.
R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006
Fluphenazine, 4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]-1-piperazineethanol (6.1.8), is synthesized by any of the methods described above [21–27]. Alkylation of 2-trifluoromethylphenothiazine using 4-formyl-1-piperazineylpropylchlo-ride in the presence of sodium amide synthesizes 2-trifluoromethyl-10-[3-(4-formyl-1-piperazinyl)propyl]phenothizine (6.1.6). Further alkaline hydrolysis removes the N-formyl group, giving 2-trifluoromethyl-10-[3-(1-piperazinyl)propyl]phenothiazine (6.1.7). This is alkylated by 2-bromethanol-1 acetate, which upon further acidic hydrolysis removes the protecting acetyl group, yielding fluphenazine (6.1.8) [27,28].
Fluphenazine is an extremely strong antipsychotic drug. A stimulatory effect accompanies the neuroleptic effect. It is used in psychiatry for treating various forms of schizophrenia and other mental illnesses. The most common synonyms are fluorphenazine, moditen, dapotum, motival, permitil, and others.
A suspension of 69.0 grams of 2-trifluoromethylphenothiazine in 1 liter of toluene with 10.9 grams of sodium amide is heated at reflux with high speed stirring for 15 minutes. A solution of 54.1 grams of 1-formyl-4-(3’chloropropyl)-piperazine, [prepared by formylating 1-(3′-hydroxypropyl)piperazine by refluxing in an excess of methyl formate, purifying the 1-formyl4-(3′-hydroxypropyl)-piperazine by vacuum distillation, reacting this compound with an excess of thionyl chloride at reflux and isolating the desired 1-formyl-4(3′-chloropropyl)-piperazine by neutralization with sodium carbonate solution followed by distillation] in 200 ml of toluene is added. The reflux period is continued for 4 hours. The cooled reaction mixture is treated with 200 ml of water. The organic layer is extracted twice with dilute hydrochloric acid. The acid extracts are made basic with ammonia and extracted with benzene. The volatiles are taken off in vacuo at the steam bath to leave a dark brown oil which is 10-[3′-(N-formylpiperazinyl)-propyl]-2trifluoromethylphenothiazine. It can be distilled at 260°C at 10 microns, or used directly without distillation if desired.
A solution of 103.5 grams of 10-[3′-(N-formylpiperazinyl)-propyl]-2trifluoromethylphenothiazine in 400 ml of ethanol and 218 ml of water containing 26 ml of 40% sodium hydroxide solution is heated at reflux for 2 hours. The alcohol is taken off in vacuo on the steam bath. The residue is swirled with benzene and water. The dried benzene layer is evaporated in vacuo. The residue is vacuum distilled to give a viscous, yellow oil, 10(3’piperazinylpropyl)-2-trifluoromethylphenothiazine, distilling at 210° to235°C at 0.5 to 0.6 mm.
A suspension of 14.0 grams of 10-(3′-piperazinylpropyl)-2trifluoromethylphenothiazine, 6.4 grams of β-bromoethyl acetate and 2.6 grams of potassium carbonate in 100 ml of toluene is stirred at reflux for 16 hours. Water (50 ml) is added to the cooled mixture. The organic layer is extracted into dilute hydrochloric acid. After neutralizing the extracts and taking the separated base up in benzene, a viscous, yellow residue is obtained by evaporating the organic solvent in vacuo. This oil is chromatographed on alumina. The purified fraction of 7.7 grams of 10-[3′-(Nacetoxyethylpiperazinyl)-propyl] -2-trifluoromethylphenothiazine is taken up in ethyl acetate and mixed with 25 ml of alcoholic hydrogen chloride. Concentration in vacuo separates white crystals of the dihydrochloride salt, MP 225° to 227°C.
A solution of 1.0 gram of 10-[3′-(N-acetoxyethylpiperazinyl)-propyl]-2trifluoromethylphenothiazine in 25 ml of 1 N hydrochloric acid is heated at reflux briefly. Neutralization with dilute sodium carbonate solution and extraction with benzene gives the oily base, 10-[3′-(N-βhydroxyethylpiperazinyl)-propyl]-2-trifluoromethylphenothiazine. The base is reacted with an excess of an alcoholic hydrogen chloride solution. Trituration with ether separates crystals of the dihydrochloride salt, MP 224° to 226°C, (from US Patent 3,058,979).
Fluphenazine, 4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]-1- piperazineethanol (6.1.8), is synthesized by any of the methods described above [21–27]. Alkylation of 2-trifluoromethylphenothiazine using 4-formyl-1-piperazineylpropylchloride in the presence of sodium amide synthesizes 2-trifluoromethyl-10-[3-(4-formyl- 1-piperazinyl)propyl]phenothizine (6.1.6). Further alkaline hydrolysis removes the N-formyl group, giving 2-trifluoromethyl-10-[3-(1-piperazinyl)propyl]phenothiazine (6.1.7). This is alkylated by 2-bromethanol-1 acetate, which upon further acidic hydrolysis removes the protecting acetyl group, yielding fluphenazine (6.1.8) [27,28].
Indian Pat. Appl., 2014MU02033,
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A 2018 Cochrane review found that fluphenazine was an imperfect treatment and other inexpensive drugs less associated with side effects may be an equally effective choice for people with schizophrenia.
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Fluphenazine acts primarily by blocking post-synaptic D2 receptors in the basal ganglia, cortical and limbic system. It also blocks alpha-1 adrenergic receptors, muscarinic-1 receptors, and histamine-1 receptors.
|5-HT3||4,265- > 10,000||ND|||
|5-HT6||7.9 – 38||ND|||
|Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except 5-HT3 (rat), D4 (human/rat), H3 (guinea pig), and NMDA/PCP (rat).|
Fluphenazine came into use in 1959.
The injectable form is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. It is available as a generic medication. It was discontinued in Australia around mid 2017.
In horses, it is sometimes given by injection as an anxiety-relieving medication, though there are many negative common side effects and it is forbidden by many equestrian competition organizations.
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- World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
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- Joint Formulary Committee, BMJ, ed. (March 2009). “4.2.1”. British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6.
Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
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|Trade names||Prolixin, Modecate, Moditen others|
|By mouth, Intramuscular injection, depot injection (fluphenazine decanoate)|
|Drug class||Typical antipsychotic|
|Bioavailability||2.7% (by mouth)|
|Elimination half-life||IM 15 hours (HCL), 7–10 days (decanoate)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||437.53 g·mol−1|
|3D model (JSmol)|
////////////Fluphenazine, فلوفينازين , 氟奋乃静 , SQ 10733, Squibb 16144