Fluphenazine

Fluphenazine

Clinical data
Trade names	Prolixin, Modecate, Moditen others
AHFS/Drugs.com	Monograph
MedlinePlus	a682172
License data	US  DailyMed:  Fluphenazine
Pregnancy category	AU:C
Routes of administration	By mouth, Intramuscular injection, depot injection (fluphenazine decanoate)
Drug class	Typical antipsychotic
ATC code	N05AB02 ( WHO )
Legal status
Legal status	BR: Class C1 (Other controlled substances) [1] CA: ℞-only UK: POM (Prescription only) US: ℞-only
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
Identifiers
IUPAC name 2-[4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]piperazin-1-yl]ethanol
CAS Number	69-23-8  Y
PubChem CID	3372
IUPHAR/BPS	204
DrugBank	DB00623  Y
ChemSpider	3255  Y
UNII	S79426A41Z
KEGG	D07977  Y
ChEBI	CHEBI:5123  Y
ChEMBL	ChEMBL726  Y
CompTox Dashboard (EPA)	DTXSID2023068
ECHA InfoCard	100.000.639
Chemical and physical data
Formula	C22H26F3N3OS
Molar mass	437.53 g·mol−1
3D model (JSmol)	Interactive image
SMILES FC(F)(F)c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCN(CCO)CC4
InChI InChI=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 Y Key:PLDUPXSUYLZYBN-UHFFFAOYSA-N Y
(verify)

Fluphenazine, sold under the brand name Prolixin among others, is a high-potency typical antipsychotic medication. ^[2] It is used in the treatment of chronic psychoses such as schizophrenia, ^{[2] [3]} and appears to be about equal in effectiveness to low-potency antipsychotics like chlorpromazine. ^[4] It is given by mouth, injection into a muscle, or just under the skin. ^[2] There is also a long acting injectable version that may last for up to four weeks. ^[2] Fluphenazine decanoate, the depot injection form of fluphenazine, should not be used by people with severe depression. ^{[5] [6]}

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 is a typical antipsychotic of the phenothiazine class. ^[2] Its mechanism of action is not entirely clear but believed to be related to its ability to block dopamine receptors. ^[2] In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal. ^[7]

Fluphenazine inhibits tubulin polymerization, a property shared with other phenothiazine derivatives including perphenazine, chlorpromazine, trifluoperazine, and triflupromazine. ^[8]

Fluphenazine came into use in 1959. ^[9] The injectable form is on the World Health Organization's List of Essential Medicines. ^[10] It is available as a generic medication. ^[2] It was discontinued in Australia in 2017. ^[11]

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. ^[12] Another 2018 Cochrane review found that there was limited evidence that newer atypical antipsychotics were more tolerable than fluphenazine. ^[13] Intramuscular depot injection forms are available as both the decanoate and enanthate esters. ^[14]

Side effects

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. ^[15] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. ^[16] Other symptoms may include restlessness, increased sweating, and trouble sleeping. ^[16] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. ^[16] Symptoms generally resolve after a short period of time. ^[16]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. ^[17] It may also result in reoccurrence of the condition that is being treated. ^[18] Rarely tardive dyskinesia can occur when the medication is stopped. ^[16]

Pharmacology

Pharmacodynamics

See also: Antipsychotic § Pharmacodynamics, and 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. ^{[19] [20]}

Binding Affinities of Fluphenazine ^{[21] [22] [23]}

Target	Ki (nM)	Action
5-HT1A	145–2829	ND
5-HT1B	334	Modulator
5-HT1D	334	ND
5-HT1E	540	ND
5-HT2A	3.8–98	Antagonist
5-HT2C	174–2,570	Antagonist
5-HT3	4,265– >10,000	ND
5-HT5A	145	ND
5-HT6	7.9–38	ND
5-HT7	8	ND
D1	14.45	Antagonist
D2	0.89	Antagonist
D2L	0.50	ND
D3	1.412	ND
D4	89.12	ND
D5	95–2,590	ND
α1A	6.4–9	Antagonist
α1B	13	ND
α2A	304–314	ND
α2B	181.6–320	ND
α2C	28.8–122	ND
β1	>10,000	ND
β2	>10,000	ND
H1	7.3–70	Antagonist
H2	560	ND
H3	1,000	ND
H4	>10,000	ND
M1	1,095-3,235.93	Antagonist
M2	2,187.76–7,163	ND
M3	1441–1445.4	ND
M4	5,321	ND
M5	357	ND
SERT Tooltip Serotonin transporter	5,950	ND
NET Tooltip Norepinephrine transporter	3,076–4,100	ND
DAT Tooltip Dopamine transporter	10,000–11,000	ND
NMDA (PCP)	>10,000	ND
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). [21]

Pharmacokinetics

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

Oral fluphenazine rapidly absorbs with plasma levels peaking at 2 hours post-ingestion. ^[24] The half-life is about 15-16 hours. ^{[24] [25]} Steady state concentrations vary considerably across individuals, which indicates variability in absorption, metabolism, or excretion. ^[24] Additionally, the dose-level relationship is curvilinear with plasma levels of 0.2 - 2.8 ng/mL being optimal for clinical improvement. ^[24] Benztropine mesylate did not indicate any major drug-drug interactions. ^[24]

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Pharmacokinetics of long-acting injectable antipsychotics

Medication	Brand name	Class	Vehicle	Dosage	Tmax	t1/2 single	t1/2 multiple	logPc	Ref
Aripiprazole lauroxil	Aristada	Atypical	Water a	441–1064 mg/4–8 weeks	24–35 days	?	54–57 days	7.9–10.0
Aripiprazole monohydrate	Abilify Maintena	Atypical	Water a	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	[26]
Clopentixol decanoate	Sordinol Depot	Typical	Viscoleo b	50–600 mg/1–4 weeks	4–7 days	?	19 days	9.0	[27]
Flupentixol decanoate	Depixol	Typical	Viscoleo b	10–200 mg/2–4 weeks	4–10 days	8 days	17 days	7.2–9.2	[27] [28]
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	[29] [30] [31]
Fluphenazine enanthate	Prolixin Enanthate	Typical	Sesame oil	12.5–100 mg/1–4 weeks	2–3 days	4 days	?	6.4–7.4	[30]
Fluspirilene	Imap, Redeptin	Typical	Water a	2–12 mg/1 week	1–8 days	7 days	?	5.2–5.8	[32]
Haloperidol decanoate	Haldol Decanoate	Typical	Sesame oil	20–400 mg/2–4 weeks	3–9 days	18–21 days		7.2–7.9	[33] [34]
Olanzapine pamoate	Zyprexa Relprevv	Atypical	Water a	150–405 mg/2–4 weeks	7 days	?	30 days	–
Oxyprothepin decanoate	Meclopin	Typical	?	?	?	?	?	8.5–8.7
Paliperidone palmitate	Invega Sustenna	Atypical	Water a	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	[35]
Pipotiazine palmitate	Piportil Longum	Typical	Viscoleo b	25–400 mg/4 weeks	9–10 days	?	14–21 days	8.5–11.6	[28]
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	Viscoleo b	50–200 mg/1–3 days	1–2 days	1–2 days		4.7–4.9
Zuclopentixol decanoate	Clopixol Depot	Typical	Viscoleo b	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.

History

Fluphenazine came into use in 1959. ^[9]

Availability

The injectable form is on the World Health Organization's List of Essential Medicines. ^[10] It is available as a generic medication. ^[2] It was discontinued in Australia in 2017. ^[11]

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. ^[36]

References

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