Chemistry:Fluphenazine

From HandWiki

Fluphenazine, sold under the brand name Prolixin among others, is a high-potency typical antipsychotic medication of the phenothiazine class.[1] It is used in the treatment of chronic psychoses such as schizophrenia,[1][2] and is about equal in effectiveness to low-potency antipsychotics like chlorpromazine.[3] It is also used to treat depression in combination with nortriptyline.[4][5] In addition to the oral form, fluphenazine comes in decanoate and enanthate depot injection versions for increased adherence.[6] Fluphenazine is given by mouth, intramuscularly, or just under the skin.[1]

Common side effects include movement problems, sleepiness, depression and increased weight.[1] Serious side effects may include neuroleptic malignant syndrome, low white blood cell levels, and the potentially permanent movement disorder tardive dyskinesia.[1] In older people with psychosis as a result of dementia it may increase the risk of dying.[1] It may also increase prolactin levels which may result in milk production, enlarged breasts in males, impotence, and the absence of menstrual periods.[1] It is unclear if it is safe for use in pregnancy.[1] Fluphenazine decanoate should not be used by people with severe depression.[7][8] In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal.[9]

Fluphenazine is a dopamine antagonist, blocking mesolimbic dopamine receptors.[1][4] Fluphenazine inhibits tubulin polymerization, a property shared with other phenothiazine derivatives including perphenazine, chlorpromazine, trifluoperazine, and triflupromazine.[10]

Fluphenazine was the third antipsychotic FDA approved in the United States in 1959, and 9 years later was the first FDA approved injectable antipsychotic.[11][12] The injectable form is on the World Health Organization's List of Essential Medicines.[13] It is available as a generic medication.[1] It was discontinued in Australia in 2017.[14]

Medical use

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.[15] Another 2018 Cochrane review found that there was limited evidence that newer atypical antipsychotics were more tolerable than fluphenazine.[16] Intramuscular depot injection forms are available as both the decanoate and enanthate esters.[17]

Side effects

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[18] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[19] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[19] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[19] Symptoms generally resolve after a short period of time.[19]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[20] It may also result in reoccurrence of the condition that is being treated.[21] Rarely tardive dyskinesia can occur when the medication is stopped.[19]

Pharmacology

Pharmacodynamics

Fluphenazine acts primarily by blocking post-synaptic dopaminergic D2 and D1 receptors in the basal ganglia, cortical and limbic system.[4] It also blocks α1 adrenergic receptors, muscarinic M1 receptors, and histaminergic H1 receptors, and like other phenothiazines, it competitively inhibits calmodulin.[22][23][24] Fluphenazine depresses both the release of hypothalamic and hypophyseal hormones and the reticular activating system.[4]

Target Ki (nM) Action
D2 0.89 Antagonist
D1 14.45 Antagonist
5-HT2A 3.8–98 Antagonist
5-HT1B 334 Modulator
5-HT2C 174–2,570 Antagonist
AR ND Antagonist
α1A 6.4–9 Antagonist
H1 7.3–70 Antagonist
M1 1,095-3,235.93 Antagonist
Calmodulin ND Inhibitor
The smaller the Ki, the more strongly the drug binds to the site. All data are for human cloned proteins, except 5-HT3 (rat).[25]

Pharmacokinetics

Oral fluphenazine rapidly absorbs and plasma levels peak at about 1.0-2.5 ng/mL 2 hours post-ingestion.[26][27] The volume of distribution is about 298 L due to extensive tissue uptake, and it crosses the blood brain barrier.[27] Bioavailability is low at 2.7% due to first pass metabolism,[28] and the half-life is about 14–16 hours.[26][29] Steady state concentrations vary considerably across individuals, which indicates variability in absorption, metabolism, or excretion.[26] Additionally, the dose-level relationship is curvilinear with plasma levels of 0.2 - 2.8 ng/mL being optimal for clinical improvement.[26] Fluphenazine is primarily metabolized to fluphenazine sulfoxide by the cytochrome P450 2D6.[4] Benztropine mesylate did not indicate any major drug-drug interactions.[26] Fluphenazine is exreted primarily through urine and feces.

Injectable fluphenazine is dissolved in sesame oil which forms a localized oil depot in the muscle.[30] Due to the lipophilicity of the added decanoate or enanthate group, the drug remains in the oil causing the rate-limiting step for drug being diffusion out, resulting in flip-flop kinetics.[30] Fluphenazine decanoate and enanthate are prodrugs which are hydrolyzed by esterases to fluphenazine.[31] The fluphenazine decanoate acts within 1–3 days, and its effect lasts an average of 2 weeks.[27] The half-life of fluphenazine decanoate is about 6.8-9.6 days,[27][29] and plasma levels peak at about 2.18 ng/mL about 4–6 hours post injection.[31] Fluphenazine enanthate has a lower half life of about 3.6-3.7 days, reflecting its decreased lipophilicity.[27][29]

v · d · e Pharmacokinetics of long-acting injectable antipsychotics
Medication Brand name Class Vehicle Dosage Tmax t1/2 single t1/2 multiple logPc Ref
Aripiprazole lauroxil Aristada Atypical Watera 441–1064 mg/4–8 weeks 24–35 days ? 54–57 days 7.9–10.0
Aripiprazole monohydrate Abilify Maintena Atypical Watera 300–400 mg/4 weeks 7 days ? 30–47 days 4.9–5.2
Bromperidol decanoate Impromen Decanoas Typical Sesame oil 40–300 mg/4 weeks 3–9 days ? 21–25 days 7.9 [32]
Clopentixol decanoate Sordinol Depot Typical Viscoleob 50–600 mg/1–4 weeks 4–7 days ? 19 days 9.0 [33]
Flupentixol decanoate Depixol Typical Viscoleob 10–200 mg/2–4 weeks 4–10 days 8 days 17 days 7.2–9.2 [33][34]
Fluphenazine decanoate Prolixin Decanoate Typical Sesame oil 12.5–100 mg/2–5 weeks 1–2 days 1–10 days 14–100 days 7.2–9.0 [35][36][37]
Fluphenazine enanthate Prolixin Enanthate Typical Sesame oil 12.5–100 mg/1–4 weeks 2–3 days 4 days ? 6.4–7.4 [36]
Fluspirilene Imap, Redeptin Typical Watera 2–12 mg/1 week 1–8 days 7 days ? 5.2–5.8 [38]
Haloperidol decanoate Haldol Decanoate Typical Sesame oil 20–400 mg/2–4 weeks 3–9 days 18–21 days 7.2–7.9 [39][40]
Olanzapine pamoate Zyprexa Relprevv Atypical Watera 150–405 mg/2–4 weeks 7 days ? 30 days –
Oxyprothepin decanoate Meclopin Typical ? ? ? ? ? 8.5–8.7
Paliperidone palmitate Invega Sustenna Atypical Watera 39–819 mg/4–12 weeks 13–33 days 25–139 days ? 8.1–10.1
Perphenazine decanoate Trilafon Dekanoat Typical Sesame oil 50–200 mg/2–4 weeks ? ? 27 days 8.9
Perphenazine enanthate Trilafon Enanthate Typical Sesame oil 25–200 mg/2 weeks 2–3 days ? 4–7 days 6.4–7.2 [41]
Pipotiazine palmitate Piportil Longum Typical Viscoleob 25–400 mg/4 weeks 9–10 days ? 14–21 days 8.5–11.6 [34]
Pipotiazine undecylenate Piportil Medium Typical Sesame oil 100–200 mg/2 weeks ? ? ? 8.4
Risperidone Risperdal Consta Atypical Microspheres 12.5–75 mg/2 weeks 21 days ? 3–6 days –
Zuclopentixol acetate Clopixol Acuphase Typical Viscoleob 50–200 mg/1–3 days 1–2 days 1–2 days 4.7–4.9
Zuclopentixol decanoate Clopixol Depot Typical Viscoleob 50–800 mg/2–4 weeks 4–9 days ? 11–21 days 7.5–9.0
Note: All by intramuscular injection. Footnotes: a = Microcrystalline or nanocrystalline aqueous suspension. b = Low-viscosity vegetable oil (specifically fractionated coconut oil with medium-chain triglycerides). c = Predicted, from PubChem and DrugBank. Sources: Main: See template.

Availability

The injectable form is on the World Health Organization's List of Essential Medicines.[13] It is available as a generic medication.[1] It was discontinued in Australia in 2017.[14]

Veterinary

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.[42]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 "fluphenazine decanoate". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/fluphenazine-decanoate.html. 
  2. ↑ "Product Information: Modecate (Fluphenazine Decanoate Oily Injection )" (PDF). TGA eBusiness Services. Bristol-Myers Squibb Australia Pty Ltd. 1 November 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-02643-3. 
  3. ↑ "Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia". The Cochrane Database of Systematic Reviews 2014 (8). August 2014. doi:10.1002/14651858.CD009230.pub2. PMID 25087165. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Cite error: Invalid <ref> tag; no text was provided for refs named DB00623
  5. ↑ "Fluphenazine" (in en-US). XPharm: The Comprehensive Pharmacology Reference. 2007-01-01. pp. 1–7. doi:10.1016/B978-008055232-3.61772-6. ISBN 978-0-08-055232-3. https://www.sciencedirect.com/science/chapter/referencework/abs/pii/B9780080552323617726. 
  6. ↑ "Historical perspective on antipsychotic long-acting injections". The British Journal of Psychiatry. Supplement 52 (S52): S7-12. November 2009. doi:10.1192/bjp.195.52.s7. PMID 19880921. 
  7. ↑ "Modecate Injection 25mg/ml - Patient Information Leaflet (PIL) - (eMC)" (in en). http://www.medicines.org.uk/emc/medicine/15355/PIL/Modecate+Injection+25mg+ml. 
  8. ↑ "Depot Neuroleptika: Umrechnung der oralen Dosis in eine Depot-Dosis" (in de-DE). 2013-03-28. https://psychiatrietogo.de/2013/03/28/depot-neuroleptika-umrechnung-der-oralen-dosis-in-eine-depot-dosis/. 
  9. ↑ Fluphenazine. 2012. PMID 31643176. https://livertox.nih.gov/Fluphenazine.htm. Retrieved 6 November 2017. 
  10. ↑ "NanoDSF Screening for Anti-tubulin Agents Uncovers New Structure-Activity Insights". Journal of Medicinal Chemistry 68 (16): 17485–17498. August 2025. doi:10.1021/acs.jmedchem.5c01008. PMID 40815226. 
  11. ↑ "fluphenazine (Permitil, Prolixin): Antipsychotic Side Effects & Dosage" (in en). https://www.medicinenet.com/fluphenazine-oral/article.htm. 
  12. ↑ Pharmaceutical Manufacturing Encyclopedia. (3rd ed.). Burlington: Elsevier. 2007. p. 1680. ISBN 978-0-8155-1856-3. https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1680. 
  13. ↑ 13.0 13.1 World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  14. ↑ 14.0 14.1 "Fluphenazine - Australian Medicines Handbook". Australian Medicines Handbook. Australian Medicines Handbook Pty Ltd. July 2017. https://amhonline.amh.net.au/chapters/chap-18/antipsychotics/fluphenazine. 
  15. ↑ "Fluphenazine (oral) versus placebo for schizophrenia". The Cochrane Database of Systematic Reviews 6 (6). June 2018. doi:10.1002/14651858.CD006352.pub3. PMID 29893410. 
  16. ↑ "Fluphenazine (oral) versus atypical antipsychotics for schizophrenia". The Cochrane Database of Systematic Reviews 2016 (7). July 2016. doi:10.1002/14651858.CD010832.pub2. PMID 27370402. 
  17. ↑ "Fluphenazine decanoate (depot) and enanthate for schizophrenia". The Cochrane Database of Systematic Reviews 2015 (2). February 2015. doi:10.1002/14651858.CD000307.pub2. PMID 25654768. 
  18. ↑ 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." 
  19. ↑ 19.0 19.1 19.2 19.3 19.4 (in en) Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. 2004. pp. 207–216. ISBN 978-0-19-852748-0. https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207. 
  20. ↑ "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatrica Scandinavica 114 (1): 3–13. July 2006. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655. 
  21. ↑ (in en) Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. 2013. p. 85. ISBN 978-88-470-2679-7. https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85. 
  22. ↑ "Fluphenazine". StatPearls. 2020. PMID 29083807. https://www.ncbi.nlm.nih.gov/books/NBK459194/. 
  23. ↑ "Fluphenazine" (in en). PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/3372. 
  24. ↑ "Inhibition by phenothiazine antipsychotic drugs of calcium-dependent phosphorylation of cerebral cortex proteins regulated by phospholipid or calmodulin". Life Sciences 29 (7): 725–733. August 1981. doi:10.1016/0024-3205(81)90026-6. PMID 7278508. 
  25. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named PDSP
  26. ↑ 26.0 26.1 26.2 26.3 26.4 "Fluphenazine pharmacokinetics and therapeutic response". Psychopharmacology 73 (3): 205–210. 1981-05-01. doi:10.1007/BF00422403. PMID 6787637. 
  27. ↑ 27.0 27.1 27.2 27.3 27.4 "Hazardous Substances Data Bank (HSDB) : 3334" (in en). PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3334#section=Absorption-Distribution-and-Excretion-(Complete). 
  28. ↑ "Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers". European Journal of Clinical Pharmacology 51 (2): 183–187. 1996-10-01. doi:10.1007/s002280050182. PMID 8911886. 
  29. ↑ 29.0 29.1 29.2 "Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man". British Journal of Clinical Pharmacology 7 (4): 325–331. April 1979. doi:10.1111/j.1365-2125.1979.tb00941.x. PMID 444352. 
  30. ↑ 30.0 30.1 "Studies on the mechanism of absorption of depot neuroleptics: fluphenazine decanoate in sesame oil". Pharmaceutical Research 14 (8): 1079–1084. August 1997. doi:10.1023/a:1012165731390. PMID 9279892. 
  31. ↑ 31.0 31.1 Luo JP (March 1999). Pharmacokinetic studies of fluphenazine and four ester prodrugs (Ph.D. thesis). University of Saskatchewan.
  32. ↑ "Long-term treatment of chronic psychotics with bromperidol decanoate: clinical and pharmacokinetic evaluation.". Current Therapeutic Research 34 (1): 1–6. 1983. 
  33. ↑ 33.0 33.1 "Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels". Acta Psychiatrica Scandinavica. Supplementum 279: 41–54. 1980. doi:10.1111/j.1600-0447.1980.tb07082.x. PMID 6931472. 
  34. ↑ 34.0 34.1 "Anxiolytic sedatives, hypnotics and neuroleptics.". Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. 1993. pp. 364–623. 
  35. ↑ "Future of depot neuroleptic therapy: pharmacokinetic and pharmacodynamic approaches". The Journal of Clinical Psychiatry 45 (5 Pt 2): 50–9. May 1984. PMID 6143748. 
  36. ↑ 36.0 36.1 "Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man". British Journal of Clinical Pharmacology 7 (4): 325–31. April 1979. doi:10.1111/j.1365-2125.1979.tb00941.x. PMID 444352. 
  37. ↑ "Explaining the pharmacokinetics of fluphenazine through computer simulations. (Abstract.)". 19th Annual Midyear Clinical Meeting of the American Society of Hospital Pharmacists.. Dallas, Texas. 1984. 
  38. ↑ "The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug". Arzneimittel-Forschung 20 (11): 1689–98. November 1970. PMID 4992598. 
  39. ↑ "Haloperidol decanoate. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis". Drugs 33 (1): 31–49. January 1987. doi:10.2165/00003495-198733010-00002. PMID 3545764. 
  40. ↑ "Pharmacokinetics of haloperidol decanoate. A 2-year follow-up". International Pharmacopsychiatry 17 (4): 238–46. 1982. doi:10.1159/000468580. PMID 7185768. 
  41. ↑ "On the pharmacokinetics of perphenazine: a clinical study of perphenazine enanthate and decanoate.". Current Therapeutic Research 36 (6): 1071–88. 1984. 
  42. ↑ "Effects of Behavior-Modifying Drug Investigated (AAEP 2011)". The Horse Media Group. 31 March 2012. http://www.thehorse.com/articles/28907/effects-of-behavior-modifying-drug-investigated-aaep-2011. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Fluphenazine&oldid=4238255"