Fluphenazine

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]

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 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]}

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

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]

• 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	[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]