Fluphenazine

Template:Drugbox Fluphenazine, sold under the brand name Prolixin among others, is a high-potency typical antipsychotic medication of the phenothiazine class.<ref name=AHFS2015>Template:Cite web</ref> It is used in the treatment of chronic psychoses such as schizophrenia,<ref name="AHFS2015" /><ref name=TGA>Template:Cite web</ref> and is about equal in effectiveness to low-potency antipsychotics like chlorpromazine.<ref>Template:Cite journal</ref> It is also used to treat depression in combination with nortriptyline.<ref name=":0" /><ref>Template:Cite book</ref> In addition to the oral form, fluphenazine comes in decanoate and enanthate depot injection versions for increased adherence.<ref>Template:Cite journal</ref> Fluphenazine is given by mouth, intramuscularly, or just under the skin.<ref name="AHFS2015" />

Common side effects include movement problems, sleepiness, depression and increased weight.<ref name="AHFS2015" /> Serious side effects may include neuroleptic malignant syndrome, low white blood cell levels, and the potentially permanent movement disorder tardive dyskinesia.<ref name="AHFS2015" /> In older people with psychosis as a result of dementia it may increase the risk of dying.<ref name="AHFS2015" /> It may also increase prolactin levels which may result in milk production, enlarged breasts in males, impotence, and the absence of menstrual periods.<ref name="AHFS2015" /> It is unclear if it is safe for use in pregnancy.<ref name="AHFS2015" /> Fluphenazine decanoate should not be used by people with severe depression.<ref>Template:Cite web</ref><ref>Template:Cite web</ref>

Fluphenazine is a dopamine antagonist, blocking mesolimbic dopamine receptors.<ref name="AHFS2015" /><ref name=":0" /> In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal.<ref>Template:Cite journal</ref>

Fluphenazine inhibits tubulin polymerization, a property shared with other phenothiazine derivatives including perphenazine, chlorpromazine, trifluoperazine, and triflupromazine.<ref>Template:Cite journal</ref>

Fluphenazine was the third antipsychotic FDA approved in the United States in 1959, and 9 years later was the first FDA approved injectable antipsychotic.<ref>Template:Cite web</ref><ref name="McPherson_2007">Template:Cite book</ref> The injectable form is on the World Health Organization's List of Essential Medicines.<ref name="World_Health_Organization_2019">Template:Cite book</ref> It is available as a generic medication.<ref name="AHFS2015" /> It was discontinued in Australia in 2017.<ref name=Au2017>Template:Cite web</ref>

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.<ref>Template:Cite journal</ref> Another 2018 Cochrane review found that there was limited evidence that newer atypical antipsychotics were more tolerable than fluphenazine.<ref name="Sampford_2016">Template:Cite journal</ref> Intramuscular depot injection forms are available as both the decanoate and enanthate esters.<ref name="Maayan_2015">Template:Cite journal</ref>

Side effects

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.<ref name="Group 2009 192">Template:Cite book</ref> Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.<ref name="Haddad_2004">Template:Cite book</ref> Other symptoms may include restlessness, increased sweating, and trouble sleeping.<ref name="Haddad_2004" /> Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.<ref name="Haddad_2004" /> Symptoms generally resolve after a short period of time.<ref name="Haddad_2004" />

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.<ref>Template:Cite journal</ref> It may also result in reoccurrence of the condition that is being treated.<ref>Template:Cite book</ref> Rarely tardive dyskinesia can occur when the medication is stopped.<ref name="Haddad_2004" />

Pharmacology

Pharmacodynamics

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.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref>

Binding Affinities of Fluphenazine<ref name="PDSP">Template:Cite web</ref> <ref name=":0">Template:Cite web</ref><ref>Template:Cite book</ref>

Target	Ki (nM)	Action
5-HT1A	145–2829	Template:Abbr
5-HT1B	334	Modulator
5-HT1D	334	Template:Abbr
5-HT1E	540	Template:Abbr
5-HT2A	3.8–98	Antagonist
5-HT2C	174–2,570	Antagonist
5-HT3	4,265– >10,000	Template:Abbr
5-HT5A	145	Template:Abbr
5-HT6	7.9–38	Template:Abbr
5-HT7	8	Template:Abbr
D1	14.45	Antagonist
D2	0.89	Antagonist
D2L	0.50	Template:Abbr
D3	1.412	Template:Abbr
D4	89.12	Template:Abbr
D5	95–2,590	Template:Abbr
α1A	6.4–9	Antagonist
α1B	13	Template:Abbr
α2A	304–314	Template:Abbr
α2B	181.6–320	Template:Abbr
α2C	28.8–122	Template:Abbr
β1	>10,000	Template:Abbr
β2	>10,000	Template:Abbr
H1	7.3–70	Antagonist
H2	560	Template:Abbr
H3	1,000	Template:Abbr
H4	>10,000	Template:Abbr
M1	1,095-3,235.93	Antagonist
M2	2,187.76–7,163	Template:Abbr
M3	1441–1445.4	Template:Abbr
M4	5,321	Template:Abbr
M5	357	Template:Abbr
Template:Abbrlink	5,950	Template:Abbr
Template:Abbrlink	3,076–4,100	Template:Abbr
Template:Abbrlink	10,000–11,000	Template:Abbr
[[NMDA receptor|Template:Abbr (Template:Abbr)]]	>10,000	Template:Abbr
The smaller the Ki, 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).<ref name="PDSP" />

Pharmacokinetics

Oral fluphenazine rapidly absorbs with plasma levels peaking at 2 hours post-ingestion.<ref name="Dysken_1981">Template:Cite journal</ref> The half-life is about 15-16 hours.<ref name="Dysken_1981" /><ref>Template:Cite journal</ref> Steady state concentrations vary considerably across individuals, which indicates variability in absorption, metabolism, or excretion.<ref name="Dysken_1981" /> Additionally, the dose-level relationship is curvilinear with plasma levels of 0.2 - 2.8 ng/mL being optimal for clinical improvement.<ref name="Dysken_1981" /> Benztropine mesylate did not indicate any major drug-drug interactions.<ref name="Dysken_1981" />Template:Pharmacokinetics of long-acting injectable antipsychotics

History

Fluphenazine came into use in 1959.<ref name="McPherson_2007" />

Availability

The injectable form is on the World Health Organization's List of Essential Medicines.<ref name="World_Health_Organization_2019" /> It is available as a generic medication.<ref name="AHFS2015" /> It was discontinued in Australia in 2017.<ref name="Au2017" />

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.<ref>Template:Cite web</ref>