Flupentixol

Last updated

Flupentixol
Flupentixol structure.svg
Clinical data
Trade names Depixol, Fluanxol
AHFS/Drugs.com Micromedex Detailed Consumer Information
Pregnancy
category
  • AU:C
Routes of
administration 		Oral, IM (including a depot)
Drug class Typical antipsychotic
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • BR: Class C1 (Other controlled substances) [1]
  • CA: ℞-only
  • UK: POM (Prescription only)
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 40–55% (oral) [2]
Metabolism Gut wall, hepatic [3]
Elimination half-life 35 hours [2]
Excretion Renal (negligible) [4]
Identifiers
  • (EZ)-2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1-yl]ethanol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.018.459 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H25F3N2OS
Molar mass 434.52 g·mol−1
3D model (JSmol)
  • FC(F)(F)c2cc1C(\c3c(Sc1cc2)cccc3)=C/CCN4CCN(CCO)CC4
  • InChI=1S/C23H25F3N2OS/c24-23(25,26)17-7-8-22-20(16-17)18(19-4-1-2-6-21(19)30-22)5-3-9-27-10-12-28(13-11-27)14-15-29/h1-2,4-8,16,29H,3,9-15H2/b18-5- Yes check.svgY
  • Key:NJMYODHXAKYRHW-DVZOWYKESA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Flupentixol (INN), also known as flupenthixol (former BAN), marketed under brand names such as Depixol and Fluanxol is a typical antipsychotic drug of the thioxanthene class. It was introduced in 1965 by Lundbeck. In addition to single drug preparations, it is also available as flupentixol/melitracen—a combination product containing both melitracen (a tricyclic antidepressant) and flupentixol (marketed as Deanxit). Flupentixol is not approved for use in the United States. It is, however, approved for use in the UK, [5] Australia, [6] Canada, Russian Federation, [7] South Africa, New Zealand, Philippines, Iran, Germany, and various other countries.

Contents

Medical uses

Flupentixol's main use is as a long-acting injection given once in every two or three weeks to individuals with schizophrenia who have poor compliance with medication and have frequent relapses of illness, though it is also commonly given as a tablet. There is little formal evidence to support its use for this indication but it has been in use for over fifty years. [5] [8]

Flupentixol is also used in low doses as an antidepressant. [5] [9] [10] [11] [12] [13] [14] There is tentative evidence that it reduces the rate of deliberate self-harm, among those who self-harm repeatedly. [15]

Adverse effects

Adverse effect incidence [2] [5] [6] [16] [17]

Common (>1% incidence) adverse effects include
and if the hyperprolactinemia persists chronically, the following adverse effects may be seen:
  • Reduced bone mineral density leading to osteoporosis (brittle bones)
  • Infertility
Uncommon (0.1–1% incidence) adverse effects include
Rare (<0.1% incidence) adverse effects include
Unknown incidence adverse effects include

Interactions

It should not be used concomitantly with medications known to prolong the QTc interval (e.g., 5-HT3 antagonists, tricyclic antidepressants, citalopram, etc.) as this may lead to an increased risk of QTc interval prolongation. [17] [2] Neither should it be given concurrently with lithium (medication) as it may increase the risk of lithium toxicity and neuroleptic malignant syndrome. [5] [6] [17] It should not be given concurrently with other antipsychotics due to the potential for this to increase the risk of side effects, especially neurological side effects such as neuroleptic malignant syndrome. [5] [6] [17] It should be avoided in patients on CNS depressants such as opioids, alcohol and barbiturates. [17]

Contraindications

It should not be given in the following disease states: [2] [5] [6] [17]

Pharmacology

Pharmacodynamics

Binding profile [20]

Proteincis-flupentixoltrans-flupentixol
5-HT1A 8028—
5-HT2A 87.5 (HFC)—
5-HT2C 102.2 (RC)—
mAChRs [21] Neg.Neg.
D1 3.5474 (MB)
D2 0.35120
D3 1.75162.5
D4 66.3>1000
H1 0.865.73

Acronyms used:
HFC – Human frontal cortex receptor
MB – Mouse brain receptor
RC – Cloned rat receptor

A study measuring the in vivo receptor occupancies of 13 schizophrenic patients treated with 5.7 ± 1.4 mg/day of flupentixol found 50-70% receptor occupancy for D2, 20 ± 5% for D1, and 20 ± 10% for 5-HT2A. [22]

Its antipsychotic effects are predominantly a function of D2 antagonism.

Its antidepressant effects at lower doses are not well understood; however, it may be mediated by functional selectivity and/or preferentially binding to D2 autoreceptors at low doses, resulting in increased postsynaptic activation via higher dopamine levels. Flupentixol's demonstrated ability to raise dopamine levels in mice [23] and flies [24] lends credibility to the supposition of autoreceptor bias. Functional selectivity may be responsible through causing preferential autoreceptor binding or other means. The effective dosage guideline for an antipsychotic is very closely related to its receptor residency time (i.e., where drugs like aripiprazole take several minutes or more to disassociate from a receptor while drugs like quetiapine and clozapine—with guideline dosages in the hundreds of milligrams—take under 30s) [25] [26] [27] and long receptor residency time is strongly correlated with likehood of pronounced functional selectivity; [28] thus, with a maximum guideline dose of only 18 mg/day for schizophrenia, there is a significant possibility of this drug possessing unique signalling characteristics that permit counterintuitive dopaminergic action at low doses.

Pharmacokinetics

Pharmacokinetics of long-acting injectable antipsychotics
MedicationBrand nameClassVehicleDosageTmaxt1/2 singlet1/2 multiplelogPcRef
Aripiprazole lauroxil Aristada Atypical Water a441–1064 mg/4–8 weeks24–35 days ?54–57 days7.9–10.0
Aripiprazole monohydrate Abilify Maintena Atypical Water a300–400 mg/4 weeks7 days ?30–47 days4.9–5.2
Bromperidol decanoate Impromen Decanoas Typical Sesame oil 40–300 mg/4 weeks3–9 days ?21–25 days7.9 [29]
Clopentixol decanoate Sordinol Depot Typical Viscoleo b50–600 mg/1–4 weeks4–7 days ?19 days9.0 [30]
Flupentixol decanoateDepixol Typical Viscoleo b10–200 mg/2–4 weeks4–10 days8 days17 days7.2–9.2 [30] [31]
Fluphenazine decanoate Prolixin Decanoate Typical Sesame oil 12.5–100 mg/2–5 weeks1–2 days1–10 days14–100 days7.2–9.0 [32] [33] [34]
Fluphenazine enanthate Prolixin Enanthate Typical Sesame oil 12.5–100 mg/1–4 weeks2–3 days4 days ?6.4–7.4 [33]
Fluspirilene Imap, Redeptin Typical Water a2–12 mg/1 week1–8 days7 days ?5.2–5.8 [35]
Haloperidol decanoate Haldol Decanoate Typical Sesame oil 20–400 mg/2–4 weeks3–9 days18–21 days7.2–7.9 [36] [37]
Olanzapine pamoate Zyprexa Relprevv Atypical Water a150–405 mg/2–4 weeks7 days ?30 days–
Oxyprothepin decanoate Meclopin Typical  ? ? ? ? ?8.5–8.7
Paliperidone palmitate Invega Sustenna Atypical Water a39–819 mg/4–12 weeks13–33 days25–139 days ?8.1–10.1
Perphenazine decanoate Trilafon Dekanoat Typical Sesame oil 50–200 mg/2–4 weeks ? ?27 days8.9
Perphenazine enanthate Trilafon Enanthate Typical Sesame oil 25–200 mg/2 weeks2–3 days ?4–7 days6.4–7.2 [38]
Pipotiazine palmitate Piportil Longum Typical Viscoleo b25–400 mg/4 weeks9–10 days ?14–21 days8.5–11.6 [31]
Pipotiazine undecylenate Piportil Medium Typical Sesame oil 100–200 mg/2 weeks ? ? ?8.4
Risperidone Risperdal Consta Atypical Microspheres 12.5–75 mg/2 weeks21 days ?3–6 days–
Zuclopentixol acetate Clopixol Acuphase Typical Viscoleo b50–200 mg/1–3 days1–2 days1–2 days4.7–4.9
Zuclopentixol decanoate Clopixol Depot Typical Viscoleo b50–800 mg/2–4 weeks4–9 days ?11–21 days7.5–9.0
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

In March 1963 the Danish pharmaceutical company Lundbeck began research into further agents for schizophrenia, having already developed the thioxanthene derivatives clopenthixol and chlorprothixene. By 1965 the promising agent flupenthixol had been developed and trialled in two hospitals in Vienna by Austrian psychiatrist Heinrich Gross. [39] The long- acting decanoate preparation was synthesised in 1967 and introduced into hospital practice in Sweden in 1968, with a reduction in relapses among patients who were put on the depot. [40]

Related Research Articles

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Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations from alcohol withdrawal. It may be used by mouth or injection into a muscle or a vein. Haloperidol typically works within 30 to 60 minutes. A long-acting formulation may be used as an injection every four weeks by people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.

<span class="mw-page-title-main">Fluphenazine</span> Typical antipsychotic medication

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

<span class="mw-page-title-main">Typical antipsychotic</span> Class of drugs

Typical antipsychotics are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis. Typical antipsychotics may also be used for the treatment of acute mania, agitation, and other conditions. The first typical antipsychotics to come into medical use were the phenothiazines, namely chlorpromazine which was discovered serendipitously. Another prominent grouping of antipsychotics are the butyrophenones, an example of which is haloperidol. The newer, second-generation antipsychotics, also known as atypical antipsychotics, have largely supplanted the use of typical antipsychotics as first-line agents due to the higher risk of movement disorders in the latter.

<span class="mw-page-title-main">Atypical antipsychotic</span> Class of pharmaceutical drugs

The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval for schizophrenia, bipolar disorder, irritability in autism, and as an adjunct in major depressive disorder.

<span class="mw-page-title-main">Perphenazine</span> Antipsychotic medication

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<span class="mw-page-title-main">Haloperidol decanoate</span> Typical antipsychotic medication

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<span class="mw-page-title-main">Pipotiazine</span> Typical antipsychotic medication

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<span class="mw-page-title-main">Aripiprazole lauroxil</span> Chemical compound

Aripiprazole lauroxil, sold under the brand name Aristada, is a long-acting injectable atypical antipsychotic that was developed by Alkermes. It is an N-acyloxymethyl prodrug of aripiprazole that is administered via intramuscular injection once every four to eight weeks for the treatment of schizophrenia. Aripiprazole lauroxil was approved by the U.S. Food and Drug Administration (FDA) on 5 October 2015.

Viscoleo is a thin or low-viscosity vegetable oil. It is specifically a proprietary form of fractionated coconut oil and a medium-chain triglyceride (MCT) oil. It is prepared from the dried, solid endosperm of the fruit Cocos nucifera via hydrolysis, fractionation, and purification. Viscoleo is composed of the medium-chain fatty acids caprylic acid (C8) (55–60%), capric acid (C10) (40%), lauric acid (C12) (1–5%), and caproic acid (C6) (0.5%). It is used as an oil vehicle for several depot antipsychotics including clopentixol decanoate, flupentixol decanoate, pipotiazine palmitate, zuclopentixol acetate, and zuclopentixol decanoate. Injectable antipsychotics using Viscoleo as a carrier may be absorbed more rapidly and have shorter durations than preparations using sesame oil.

<span class="mw-page-title-main">Bromperidol decanoate</span> Chemical compound

Bromperidol decanoate, sold under the brand names Bromidol Depot, Bromodol Decanoato, and Impromen Decanoas, is an antipsychotic which has been marketed in Europe and Latin America. It is an antipsychotic ester and long-acting prodrug of bromperidol which is administered by depot intramuscular injection once every 4 weeks.

<span class="mw-page-title-main">Perphenazine enanthate</span> Typical antipsychotic medication

Perphenazine enanthate, sold under the brand name Trilafon Enantat among others, is a typical antipsychotic and a depot antipsychotic ester which is used in the treatment of schizophrenia and has been marketed in Europe. It is formulated in sesame oil and administered by intramuscular injection and acts as a long-lasting prodrug of perphenazine. Perphenazine enanthate is used at a dose of 25 to 200 mg once every 2 weeks by injection, with a time to peak levels of 2 to 3 days and an elimination half-life of 4 to 7 days.

<span class="mw-page-title-main">Oxyprothepin decanoate</span> Antipsychotic medication

Oxyprothepin decanoate, sold under the brand name Meclopin, is a typical antipsychotic which was used in the treatment of schizophrenia in the Czech Republic but is no longer marketed. It is administered by depot injection into muscle. The medication has an approximate duration of 2 to 3 weeks. The history of oxyprothepin decanoate has been reviewed.

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