Fluphenazine

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]

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)

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.^[6]

Fluphenazine came into use in 1959.^[7] The injectable form is on the World Health Organization's List of Essential Medicines.^[8] It is available as a generic medication.^[2] It was discontinued in Australia in 2017.^[9]

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.^[10] Another 2018 Cochrane review found that there was limited evidence that newer atypical antipsychotics were more tolerable than fluphenazine.^[11] Intramuscular depot injection forms are available as both the decanoate and enanthate esters.^[12]

Side effects

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.^[13] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.^[14] Other symptoms may include restlessness, increased sweating, and trouble sleeping.^[14] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.^[14] Symptoms generally resolve after a short period of time.^[14]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.^[15] It may also result in reoccurrence of the condition that is being treated.^[16] Rarely tardive dyskinesia can occur when the medication is stopped.^[14]

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.^[17][18]

Fluphenazine^[19]

Site	Ki (nM)	Action	Ref
5-HT1A	145–2829	ND	[19]
5-HT1B	334	ND	[19]
5-HT1D	334	ND	[19]
5-HT1E	540	ND	[19]
5-HT2A	3.8–98	ND	[19]
5-HT2B	ND	ND	[19]
5-HT2C	174–2,570	ND	[19]
5-HT3	4,265– >10,000	ND	[19]
5-HT5A	145	ND	[19]
5-HT6	7.9–38	ND	[19]
5-HT7	8	ND	[19]
D1	14.45	ND	[19]
D2	0.89	ND
D2L		ND	[19]
D3	1.412	ND	[19]
D4	89.12	ND	[19]
D5	95–2,590	ND	[19]
α1A	6.4–9	ND	[19]
α1B	13	ND	[19]
α2A	304–314	ND	[19]
α2B	181.6–320	ND	[19]
α2C	28.8–122	ND	[19]
β1	>10,000	ND	[19]
β2	>10,000	ND	[19]
H1	7.3–70	ND	[19]
H2	560	ND	[19]
H3	1,000	ND	[19]
H4	>10,000	ND	[19]
M1	1,095-3,235.93	ND	[19]
M2	2,187.76–7,163	ND	[19]
M3	1441–1445.4	ND	[19]
M4	5,321	ND	[19]
M5	357	ND	[19]
SERTTooltip Serotonin transporter	ND	ND	[19]
NETTooltip Norepinephrine transporter	ND	ND	[19]
DATTooltip Dopamine transporter	ND	ND	[19]
NMDA (PCP)	ND	ND	[19]
Values are Ki (nM). The smaller the value, 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).[19]

Pharmacokinetics

• v
• t
• e

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	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	[20]
Clopentixol decanoate	Sordinol Depot	Typical	Viscoleob	50–600 mg/1–4 weeks	4–7 days	?	19 days	9.0	[21]
Flupentixol decanoate	Depixol	Typical	Viscoleob	10–200 mg/2–4 weeks	4–10 days	8 days	17 days	7.2–9.2	[21][22]
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	[23][24][25]
Fluphenazine enanthate	Prolixin Enanthate	Typical	Sesame oil	12.5–100 mg/1–4 weeks	2–3 days	4 days	?	6.4–7.4	[24]
Fluspirilene	Imap, Redeptin	Typical	Watera	2–12 mg/1 week	1–8 days	7 days	?	5.2–5.8	[26]
Haloperidol decanoate	Haldol Decanoate	Typical	Sesame oil	20–400 mg/2–4 weeks	3–9 days	18–21 days		7.2–7.9	[27][28]
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	[29]
Pipotiazine palmitate	Piportil Longum	Typical	Viscoleob	25–400 mg/4 weeks	9–10 days	?	14–21 days	8.5–11.6	[22]
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.

History

Fluphenazine came into use in 1959.^[7]

Availability

The injectable form is on the World Health Organization's List of Essential Medicines.^[8] It is available as a generic medication.^[2] It was discontinued in Australia in 2017.^[9]

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.^[30]