Fluphenazine
High-potency antipsychotic used for chronic psychoses.
Last updated
Fluphenazine (brand name Prolixin) is a high-potency typical antipsychotic from the phenothiazine class. It is prescribed for chronic psychoses like schizophrenia and works about as well as lower-potency options such as chlorpromazine.
It can also be combined with nortriptyline to treat depression. Besides an oral form, it comes as depot injections (decanoate and enanthate) to help with medication adherence. It can be taken by mouth, injected into a muscle, or given just under the skin.
Common side effects include movement problems, drowsiness, depression, and weight gain. Serious risks include neuroleptic malignant syndrome, low white blood cell counts, and tardive dyskinesia, a potentially permanent movement disorder. In older adults with dementia-related psychosis, it may raise the risk of death. It can also increase prolactin levels, leading to milk production, breast enlargement in men, impotence, or missed menstrual periods.
It is not known whether it is safe during pregnancy. The decanoate form should not be used by people with severe depression. Up to 40% of people on long-term phenothiazines develop mildly abnormal liver function tests.
Pharmacodynamics
Fluphenazine works by blocking dopamine receptors in the mesolimbic pathway. It also inhibits tubulin polymerization, a trait shared with other phenothiazines like perphenazine, chlorpromazine, trifluoperazine, and triflupromazine.
Availability
It was the third antipsychotic approved by the FDA in the United States in 1959, and nine years later became the first injectable antipsychotic approved. The injectable version is on the World Health Organization’s List of Essential Medicines and is available as a generic. It was discontinued in Australia in 2017.
Medical use
A 2018 Cochrane review found fluphenazine to be an imperfect treatment; other inexpensive drugs with fewer side effects may be equally effective for schizophrenia. Another 2018 Cochrane review found limited evidence that newer atypical antipsychotics are more tolerable. Depot injections are available as decanoate and enanthate esters.
Discontinuation
The British National Formulary recommends gradual withdrawal to avoid acute withdrawal syndrome or rapid relapse. Withdrawal symptoms often include nausea, vomiting, and loss of appetite, and may also involve restlessness, increased sweating, or trouble sleeping. Less common symptoms include dizziness, numbness, or muscle pain.
These usually resolve quickly. There is tentative evidence that stopping antipsychotics can trigger psychosis or a relapse of the treated condition. Rarely, tardive dyskinesia may appear after discontinuation.
Fluphenazine primarily blocks postsynaptic D2 and D1 dopamine receptors in the basal ganglia, cortex, and limbic system. It also blocks α1 adrenergic, muscarinic M1, and histaminergic H1 receptors, and, like other phenothiazines, competitively inhibits calmodulin. It depresses the release of hypothalamic and hypophyseal hormones and the reticular activating system.
Oral fluphenazine is absorbed quickly, with plasma levels peaking at about 1.0–2.5 ng/mL two hours after ingestion. Its volume of distribution is around 298 L due to extensive tissue uptake, and it crosses the blood-brain barrier. Bioavailability is low (2.7%) because of first-pass metabolism, and the half-life is about 14–16 hours. Steady-state concentrations vary widely between individuals, suggesting differences in absorption, metabolism, or excretion.
The dose-level relationship is curvilinear, with plasma levels of 0.2–2.8 ng/mL being optimal for clinical improvement. It is mainly metabolized to fluphenazine sulfoxide by cytochrome P450 2D6. Benztropine mesylate does not show major drug interactions. Fluphenazine is excreted mostly in urine and feces.
Injectable fluphenazine is dissolved in sesame oil, forming a localized depot in the muscle. The added decanoate or enanthate group makes the drug lipophilic, keeping it in the oil so that diffusion out is the rate-limiting step, producing flip-flop kinetics. These esters are prodrugs, hydrolyzed by esterases to fluphenazine.
Fluphenazine decanoate acts within 1–3 days and lasts about two weeks. Its half-life is about 6.8–9.6 days, with plasma levels peaking at about 2.18 ng/mL 4–6 hours after injection. Fluphenazine enanthate has a shorter half-life of about 3.6–3.7 days due to lower lipophilicity.
In veterinary use, fluphenazine is sometimes injected into horses to relieve anxiety, though it has many negative side effects and is banned by many equestrian organizations.
Lore & Background
Fluphenazine is a high-potency typical antipsychotic of the phenothiazine class, sold under the brand name Prolixin among others. It appears as an oral tablet, as well as injectable depot formulations—specifically the decanoate and enanthate esters—which are dissolved in sesame oil to form a localized muscle depot. These injectable versions act as prodrugs, hydrolyzed by esterases into active fluphenazine; the decanoate form takes effect within one to three days and lasts about two weeks, while the enanthate form has a shorter half-life.
The drug is administered by mouth, intramuscularly, or just under the skin. Its range of use includes treating chronic psychoses such as schizophrenia, where it is about as effective as low-potency antipsychotics like chlorpromazine, and it is also used for depression in combination with nortriptyline. Defining characteristics include its mechanism as a dopamine antagonist, primarily blocking post-synaptic D2 and D1 receptors in the basal ganglia, cortex, and limbic system, as well as blocking α1 adrenergic, muscarinic M1, and histaminergic H1 receptors.
It also inhibits tubulin polymerization, a property shared with other phenothiazines. Fluphenazine was the third antipsychotic approved by the FDA in the United States in 1959, and nine years later became the first FDA-approved injectable antipsychotic. The injectable form is on the World Health Organization's List of Essential Medicines and is available as a generic, though it was discontinued in Australia in 2017.
Reader's Guide
Fluphenazine is significant as a high-potency typical antipsychotic that remains on the World Health Organization's List of Essential Medicines in its injectable form. It was the third antipsychotic approved in the United States and the first injectable antipsychotic, offering depot formulations (decanoate and enanthate) that improve adherence in chronic psychosis treatment. 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 due to dementia, it may increase the risk of dying. It may also increase prolactin levels, leading to milk production, enlarged breasts in males, impotence, and absence of menstrual periods.
Frequently Asked Questions
What is Fluphenazine?
Fluphenazine is a high-potency typical antipsychotic in the phenothiazine class, best known by its brand name Prolixin. It is primarily prescribed to manage chronic psychotic disorders such as schizophrenia.
How does Fluphenazine differ from other phenothiazines?
It sits on the high-potency end of the typical antipsychotic spectrum, meaning lower doses are needed to achieve therapeutic effect compared to low-potency agents like chlorpromazine. This potency distinction made it a go-to choice for managing severe, chronic psychotic symptoms.
More in Addictive Substances & Medications
Sources
Compiled from Wikipedia and the sources listed below. Text from Wikipedia is available under CC BY-SA 4.0; this entry is adapted from it.
- Wikipedia: Fluphenazine (CC BY-SA 4.0).
Spotted an error? Know more?
Reader corrections go straight into our review queue. Suggest an edit · How this site is sourced