Fluphenazine
Watchedfieldschanged
Verifiedrevid443824001
Width250
Width 2250
TradenameProlixin, Modecate, Moditen others
Medlineplusa682172
DailymedidFluphenazine
Pregnancy auC
Routes of administrationBy mouth, Intramuscular injection, depot injection (fluphenazine decanoate)
ClassTypical antipsychotic
Atc prefixN05
Atc suffixAB02
Legal brC1
Legal br comment[1]
Legal caRx-only
Legal ukPOM
Legal usRx-only
Bioavailability2.7% (by mouth)
Metabolismunclear[2]
Elimination half-lifeIM 15 hours (HCl), 7–10 days (decanoate)[2]
ExcretionUrine, feces
Cas number69-23-8
Pubchem3372
Iuphar ligand204
DrugbankDB00623
Chemspiderid3255
UniiS79426A41Z
KeggD07977
Chebi5123
Chembl726
Iupac name2-[4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]piperazin-1-yl]ethanol
C22
H26
F3
N3
O1
S1
SmilesFC(F)(F)c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCN(CCO)CC4
Stdinchi1S/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
StdinchikeyPLDUPXSUYLZYBN-UHFFFAOYSA-N

Fluphenazine, sold under the brand name Prolixin among others, is a high-potency typical antipsychotic medication of the phenothiazine class.[2] It is used in the treatment of chronic psychoses such as schizophrenia,[2][3] and is about equal in effectiveness to low-potency antipsychotics like chlorpromazine.[4] It is also used to treat depression in combination with nortriptyline.[5][6] In addition to the oral form, fluphenazine comes in decanoate and enanthate depot injection versions for increased adherence.[7] Fluphenazine is given by mouth, intramuscularly, or just under the skin.[2]

Common side effects include movement problems, sleepiness, depression and increased weight.[2] Serious side effects may include neuroleptic malignant syndrome, low white blood cell levels, and the potentially permanent movement disorder tardive dyskinesia.[2] In older people with psychosis as a result of dementia it may increase the risk of dying.[2] It may also increase prolactin levels which may result in milk production, enlarged breasts in males, impotence, and the absence of menstrual periods.[2] It is unclear if it is safe for use in pregnancy.[2] Fluphenazine decanoate should not be used by people with severe depression.[8][9] In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal.[10]

Fluphenazine is a dopamine antagonist, blocking mesolimbic dopamine receptors.[2][5] Fluphenazine inhibits tubulin polymerization, a property shared with other phenothiazine derivatives including perphenazine, chlorpromazine, trifluoperazine, and triflupromazine.[11]

Fluphenazine was the third antipsychotic FDA approved in the United States in 1959, and 9 years later was the first FDA approved injectable antipsychotic.[12][13] The injectable form is on the World Health Organization's List of Essential Medicines.[14] It is available as a generic medication.[2] It was discontinued in Australia in 2017.[15]

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.[16] Another 2018 Cochrane review found that there was limited evidence that newer atypical antipsychotics were more tolerable than fluphenazine.[17] Intramuscular depot injection forms are available as both the decanoate and enanthate esters.[18]

Side effects

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[19] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[20] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[20] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[20] Symptoms generally resolve after a short period of time.[20]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[21] It may also result in reoccurrence of the condition that is being treated.[22] Rarely tardive dyskinesia can occur when the medication is stopped.[20]

Pharmacology

Pharmacodynamics

See also: Antipsychotic#Pharmacodynamics and Antipsychotic#Comparison of medications

Fluphenazine acts primarily by blocking post-synaptic dopaminergic D2 and D1 receptors in the basal ganglia, cortical and limbic system.[5] It also blocks α1 adrenergic receptors, muscarinic M1 receptors, and histaminergic H1 receptors, and like other phenothiazines, it competitively inhibits calmodulin.[23][24][25] Fluphenazine depresses both the release of hypothalamic and hypophyseal hormones and the reticular activating system.[5]

Binding Affinities of Fluphenazine[25][26][5][27]
TargetKi (nM)Action
D20.89Antagonist
D114.45Antagonist
5-HT2A3.8–98Antagonist
5-HT1B334Modulator
5-HT2C174–2,570Antagonist
ARNDAntagonist
α1A6.4–9Antagonist
H17.3–70Antagonist
M11,095-3,235.93Antagonist
CalmodulinNDInhibitor
The smaller the Ki, the more strongly the drug binds to the site. All data are for human cloned proteins, except 5-HT3 (rat).[26]

Pharmacokinetics

See also: Antipsychotic#Pharmacokinetics and Antipsychotic#Pharmacokinetics of long-lasting injectable antipsychotics

Oral fluphenazine rapidly absorbs and plasma levels peak at about 1.0-2.5 ng/mL 2 hours post-ingestion.[28][29] The volume of distribution is about 298 L due to extensive tissue uptake, and it crosses the blood brain barrier.[29] Bioavailability is low at 2.7% due to first pass metabolism,[30] and the half-life is about 14–16 hours.[28][31] Steady state concentrations vary considerably across individuals, which indicates variability in absorption, metabolism, or excretion.[28] Additionally, the dose-level relationship is curvilinear with plasma levels of 0.2 - 2.8 ng/mL being optimal for clinical improvement.[28] Fluphenazine is primarily metabolized to fluphenazine sulfoxide by the cytochrome P450 2D6.[5] Benztropine mesylate did not indicate any major drug-drug interactions.[28] Fluphenazine is exreted primarily through urine and feces.

Injectable fluphenazine is dissolved in sesame oil which forms a localized oil depot in the muscle.[32] 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.[32] Fluphenazine decanoate and enanthate are prodrugs which are hydrolyzed by esterases to fluphenazine.[33] The fluphenazine decanoate acts within 1–3 days, and its effect lasts an average of 2 weeks.[29] The half-life of fluphenazine decanoate is about 6.8-9.6 days,[29][31] and plasma levels peak at about 2.18 ng/mL about 4–6 hours post injection.[33] Fluphenazine enanthate has a lower half life of about 3.6-3.7 days, reflecting its decreased lipophilicity.[29][31]

Availability

The injectable form is on the World Health Organization's List of Essential Medicines.[14] It is available as a generic medication.[2] It was discontinued in Australia in 2017.[15]

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.[34]

References

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