Fluphenazine
Typical antipsychotic medication
From Wikipedia, the free encyclopedia
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]
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| Trade names | Prolixin, Modecate, Moditen others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682172 |
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| Routes of administration | By mouth, Intramuscular injection, depot injection (fluphenazine decanoate) |
| Drug class | Typical antipsychotic |
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| Pharmacokinetic data | |
| Bioavailability | 2.7% (by mouth) |
| Metabolism | unclear[2] |
| Elimination half-life | IM 15 hours (HCl), 7–10 days (decanoate)[2] |
| Excretion | Urine, feces |
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| ECHA InfoCard | 100.000.639 |
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| Formula | C22H26F3N3OS |
| Molar mass | 437.53 g·mol−1 |
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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
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]
| 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).[26] | ||
Pharmacokinetics
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]
| 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 | [34] |
| Clopentixol decanoate | Sordinol Depot | Typical | Viscoleob | 50–600 mg/1–4 weeks | 4–7 days | ? | 19 days | 9.0 | [35] |
| Flupentixol decanoate | Depixol | Typical | Viscoleob | 10–200 mg/2–4 weeks | 4–10 days | 8 days | 17 days | 7.2–9.2 | [35][36] |
| 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 | [37][38][39] |
| Fluphenazine enanthate | Prolixin Enanthate | Typical | Sesame oil | 12.5–100 mg/1–4 weeks | 2–3 days | 4 days | ? | 6.4–7.4 | [38] |
| Fluspirilene | Imap, Redeptin | Typical | Watera | 2–12 mg/1 week | 1–8 days | 7 days | ? | 5.2–5.8 | [40] |
| Haloperidol decanoate | Haldol Decanoate | Typical | Sesame oil | 20–400 mg/2–4 weeks | 3–9 days | 18–21 days | 7.2–7.9 | [41][42] | |
| 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 | [43] |
| Pipotiazine palmitate | Piportil Longum | Typical | Viscoleob | 25–400 mg/4 weeks | 9–10 days | ? | 14–21 days | 8.5–11.6 | [36] |
| 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.[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.[44]
