Fluphenazine

{{Drugbox

| Watchedfields = changed

| verifiedrevid = 443824001

| image = Fluphenazine.svg

| image_class = skin-invert-image

| width = 250

| alt =

| image2 = Fluphenazine-xtal-2012-ball-and-stick.png

| width2 = 250

| alt2 =

| tradename = Prolixin, Modecate, Moditen others

| Drugs.com = {{drugs.com|monograph|fluphenazine-decanoate}}

| MedlinePlus = a682172

| DailyMedID = Fluphenazine

| pregnancy_AU = C

| pregnancy_category =

| routes_of_administration = By mouth, Intramuscular injection, depot injection (fluphenazine decanoate)

| class = Typical antipsychotic

| ATC_prefix = N05

| ATC_suffix = AB02

| legal_AU =

| legal_BR = C1

| legal_BR_comment = {{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=Diário Oficial da União |language=pt-BR |publication-date=4 April 2023}}

| legal_CA = Rx-only

| legal_UK = POM

| legal_US = Rx-only

| bioavailability = 2.7% (by mouth)

| metabolism = unclear

| elimination_half-life = IM 15 hours (HCl), 7–10 days (decanoate)

| excretion = Urine, feces

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 69-23-8

| PubChem = 3372

| IUPHAR_ligand = 204

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00623

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 3255

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = S79426A41Z

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D07977

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 5123

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 726

| IUPAC_name = 2-[4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]piperazin-1-yl]ethanol

| C=22 | H=26 | F=3 | N=3 | O=1 | S=1

| SMILES = FC(F)(F)c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCN(CCO)CC4

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C22H26F3N3OS/c23-22(24,25)17-6-7-21-19(16-17)28(18-4-1-2-5-20(18)30-21)9-3-8-26-10-12-27(13-11-26)14-15-29/h1-2,4-7,16,29H,3,8-15H2

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = PLDUPXSUYLZYBN-UHFFFAOYSA-N

}}

Fluphenazine, sold under the brand name Prolixin among others, is a high-potency typical antipsychotic medication.{{cite web|title=fluphenazine decanoate|url=https://www.drugs.com/monograph/fluphenazine-decanoate.html|publisher=The American Society of Health-System Pharmacists|access-date=1 December 2015|url-status=live|archive-url=https://web.archive.org/web/20151208191534/http://www.drugs.com/monograph/fluphenazine-decanoate.html|archive-date=8 December 2015}} It is used in the treatment of chronic psychoses such as schizophrenia,{{cite web |title=Product Information: Modecate (Fluphenazine Decanoate Oily Injection )|work=TGA eBusiness Services|publisher=Bristol-Myers Squibb Australia Pty Ltd|date=1 November 2012 |access-date=9 December 2013 |url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-02643-3|format=PDF|url-status=live|archive-url= https://web.archive.org/web/20170802135209/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-02643-3|archive-date=2 August 2017}} and appears to be about equal in effectiveness to low-potency antipsychotics like chlorpromazine.{{cite journal | vauthors = Tardy M, Huhn M, Engel RR, Leucht S | title = Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 8 | pages = CD009230 | date = August 2014 | pmid = 25087165 | doi = 10.1002/14651858.CD009230.pub2 | pmc = 10898219 }} 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.{{Cite web|url=http://www.medicines.org.uk/emc/medicine/15355/PIL/Modecate+Injection+25mg+ml|title=Modecate Injection 25mg/ml - Patient Information Leaflet (PIL) - (eMC)|website=www.medicines.org.uk|language=en|access-date=6 November 2017|archive-date=7 November 2017|archive-url=https://web.archive.org/web/20171107012917/http://www.medicines.org.uk/emc/medicine/15355/PIL/Modecate+Injection+25mg+ml|url-status=dead}}

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.{{Cite journal|url=https://livertox.nih.gov/Fluphenazine.htm|title=Fluphenazine|website=livertox.nih.gov|date=2012 |pmid=31643176 |access-date=6 November 2017}}

Fluphenazine came into use in 1959.{{cite book| vauthors = McPherson EM |title=Pharmaceutical Manufacturing Encyclopedia. |date=2007 |publisher=Elsevier |location=Burlington |isbn=9780815518563|page=1680 |edition=3rd |url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1680 }} The injectable form is on the World Health Organization's List of Essential Medicines.{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }} It is available as a generic medication. It was discontinued in Australia in 2017.{{cite web |title=Fluphenazine - Australian Medicines Handbook|work=Australian Medicines Handbook|place=Adelaide, Australia|publisher=Australian Medicines Handbook Pty Ltd|veditors = Rossi S |date=July 2017 |access-date=8 August 2017 |url=https://amhonline.amh.net.au/chapters/chap-18/antipsychotics/fluphenazine }}

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.{{cite journal | vauthors = Matar HE, Almerie MQ, Sampson SJ | title = Fluphenazine (oral) versus placebo for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 6 | issue = 6 | pages = CD006352 | date = June 2018 | pmid = 29893410 | pmc = 6513420 | doi = 10.1002/14651858.CD006352.pub3 }} Another 2018 Cochrane review found that there was limited evidence that newer atypical antipsychotics were more tolerable than fluphenazine.{{cite journal | vauthors = Sampford JR, Sampson S, Li BG, Zhao S, Xia J, Furtado VA | title = Fluphenazine (oral) versus atypical antipsychotics for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 7 | issue = 7 | pages = CD010832 | date = July 2016 | pmid = 27370402 | pmc = 6474115 | doi = 10.1002/14651858.CD010832.pub2 | doi-access = free }} Intramuscular depot injection forms are available as both the decanoate and enanthate esters.{{cite journal | vauthors = Maayan N, Quraishi SN, David A, Jayaswal A, Eisenbruch M, Rathbone J, Asher R, Adams CE | title = Fluphenazine decanoate (depot) and enanthate for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 2 | pages = CD000307 | date = February 2015 | pmid = 25654768 | pmc = 10388394 | doi = 10.1002/14651858.CD000307.pub2 | doi-access = free }}

Side effects

=Discontinuation=

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.{{cite book |editor1-first=BMJ | editor = Joint Formulary Committee | title = British National Formulary | edition = 57 | date = March 2009 |publisher=Royal Pharmaceutical Society of Great Britain |location=United Kingdom |isbn=978-0-85369-845-6 |page=192 |chapter=4.2.1 |quote=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.}} Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.{{cite book | vauthors = Haddad P, Haddad PM, Dursun S, Deakin B |title=Adverse Syndromes and Psychiatric Drugs: A Clinical Guide |date=2004 |publisher=OUP Oxford |isbn=9780198527480 |pages=207–216 |url=https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207 |language=en}} 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.{{cite journal | vauthors = Moncrieff J | title = Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse | journal = Acta Psychiatrica Scandinavica | volume = 114 | issue = 1 | pages = 3–13 | date = July 2006 | pmid = 16774655 | doi = 10.1111/j.1600-0447.2006.00787.x | s2cid = 6267180 }} It may also result in reoccurrence of the condition that is being treated.{{cite book | vauthors = Sacchetti E, Vita A, Siracusano A, Fleischhacker W |title=Adherence to Antipsychotics in Schizophrenia |date=2013 |publisher=Springer Science & Business Media |isbn=9788847026797 |page=85 |url=https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85 |language=en}} Rarely tardive dyskinesia can occur when the medication is stopped.

Pharmacology

=Pharmacodynamics=

{{See also|Antipsychotic#Pharmacodynamics|Antipsychotic#Comparison of medications}}

Fluphenazine acts primarily by blocking post-synaptic dopaminergic D₂ receptors in the basal ganglia, cortical and limbic system. It also blocks α₁ adrenergic receptors, muscarinic M₁ receptors, and histaminergic H₁ receptors.{{cite journal |vauthors=Siragusa S, Saadabadi A |title=Fluphenazine |journal=StatPearls |year=2020 |pmid=29083807 |url=https://www.ncbi.nlm.nih.gov/books/NBK459194/}}{{Cite web |url= https://pubchem.ncbi.nlm.nih.gov/compound/3372 |title=Fluphenazine| work = PubChem | publisher = U.S. National Library of Medicine |language=en|access-date=30 September 2019}}

Site	K_i (nM)	Action
class="wikitable floatright" style="font-size:small;" \|+ Fluphenazine{{cite web\|author1-link=Bryan Roth \| title = PDSP K_i Database \| website = Psychoactive Drug Screening Program (PDSP) \| vauthors = Roth BL, Driscol J \| publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health \| access-date = 14 August 2017 \| url = https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=fluphenazine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}
5-HT_1A	145–2829	{{abbr\|ND\|No data}}
5-HT_1B	334	{{abbr\|ND\|No data}}
5-HT_1D	334	{{abbr\|ND\|No data}}
5-HT_1E	540	{{abbr\|ND\|No data}}
5-HT_2A	3.8–98	{{abbr\|ND\|No data}}
5-HT_2B	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}
5-HT_2C	174–2,570	{{abbr\|ND\|No data}}
5-HT₃	4,265– >10,000	{{abbr\|ND\|No data}}
5-HT_5A	145	{{abbr\|ND\|No data}}
5-HT₆	7.9–38	{{abbr\|ND\|No data}}
5-HT₇	8	{{abbr\|ND\|No data}}
D₁	14.45	{{abbr\|ND\|No data}}
D₂	0.89	{{abbr\|ND\|No data}}
D_2L		{{abbr\|ND\|No data}}
D₃	1.412	{{abbr\|ND\|No data}}
D₄	89.12	{{abbr\|ND\|No data}}
D₅	95–2,590	{{abbr\|ND\|No data}}
α_1A	6.4–9	{{abbr\|ND\|No data}}
α_1B	13	{{abbr\|ND\|No data}}
α_2A	304–314	{{abbr\|ND\|No data}}
α_2B	181.6–320	{{abbr\|ND\|No data}}
α_2C	28.8–122	{{abbr\|ND\|No data}}
β₁	>10,000	{{abbr\|ND\|No data}}
β₂	>10,000	{{abbr\|ND\|No data}}
H₁	7.3–70	{{abbr\|ND\|No data}}
H₂	560	{{abbr\|ND\|No data}}
H₃	1,000	{{abbr\|ND\|No data}}
H₄	>10,000	{{abbr\|ND\|No data}}
M₁	1,095-3,235.93	{{abbr\|ND\|No data}}
M₂	2,187.76–7,163	{{abbr\|ND\|No data}}
M₃	1441–1445.4	{{abbr\|ND\|No data}}
M₄	5,321	{{abbr\|ND\|No data}}
M₅	357	{{abbr\|ND\|No data}}
{{abbrlink\|SERT\|Serotonin transporter}}	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}
{{abbrlink\|NET\|Norepinephrine transporter}}	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}
{{abbrlink\|DAT\|Dopamine transporter}}	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}
NMDA receptor	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}
class="sortbottom" \| colspan="4" style="width: 1px;" \| Values are K_i (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).

=Pharmacokinetics=

History

Fluphenazine came into use in 1959.

Availability

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 in 2017.

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.{{cite web |url= http://www.thehorse.com/articles/28907/effects-of-behavior-modifying-drug-investigated-aaep-2011 |title=Effects of Behavior-Modifying Drug Investigated (AAEP 2011) | vauthors =Loving NS |date=31 March 2012 |publisher=The Horse Media Group |access-date=13 December 2016 |url-status=live |archive-url= https://web.archive.org/web/20170106203758/http://www.thehorse.com/articles/28907/effects-of-behavior-modifying-drug-investigated-aaep-2011 |archive-date=6 January 2017 }}