Flupentixol

Page semi-protected
Source: Wikipedia, the free encyclopedia.

Flupentixol
Clinical data
Trade namesDepixol, Fluanxol
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • AU: C
IM (including a depot)
Drug classTypical 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)
Renal (negligible)[3]
Identifiers
  • (EZ)-2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1-yl]ethanol
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- checkY
  • Key:NJMYODHXAKYRHW-DVZOWYKESA-N checkY
 ☒NcheckY (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
Russian Federation,[7] South Africa, New Zealand, Philippines, Iran, Germany
, and various other countries.

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
  • Extrapyramidal side effects such as: (which usually become apparent soon after therapy is begun or soon after an increase in dose is made)
  • Dry mouth
  • Constipation
  • Hypersalivation – excessive salivation
  • Blurred vision
  • Diaphoresis – excessive sweating
  • Nausea
  • Dizziness
  • Somnolence
  • Restlessness
  • Insomnia
  • Overactivity
  • Headache
  • Nervousness
  • Fatigue
  • Myalgia
  • Hyperprolactinemia
    and its complications such as: (acutely)
    • Sexual dysfunction
    • Amenorrhea – cessation of menstrual cycles
    • Gynecomastia – enlargement of breast tissue in males
    • Galactorrhea – the expulsion of breast milk that's not related to breastfeeding or pregnancy
and if the hyperprolactinemia persists chronically, the following adverse effects may be seen:
  • Reduced bone mineral density leading to osteoporosis (brittle bones)
  • Infertility
  • Dyspepsia – indigestion
  • Abdominal pain
  • Flatulence
  • Nasal congestion
  • Polyuria – passing more urine than usual
Uncommon (0.1–1% incidence) adverse effects include
  • Fainting
  • Palpitations
Rare (<0.1% incidence) adverse effects include
  • Blood dyscrasias (abnormalities in the cell composition of blood), such as:
    • Agranulocytosis – a drop in white blood cell counts that leaves one open to potentially life-threatening infections
    • neutrophils
      (white blood cells that specifically fight bacteria) in one's blood
    • Leucopenia
      – a less severe drop in white blood cell counts than agranulocytosis
    • Thrombocytopenia – a drop in the number of platelets in the blood. Platelets are responsible for blood clotting and hence this leads to an increased risk of bruising and other bleeds
  • D2 receptor
    blockade. The symptoms include:
    • Hyperthermia
    • Muscle rigidity
    • Rhabdomyolysis
    • Autonomic instability (e.g., tachycardia, diarrhea, diaphoresis, etc.)
    • Mental status changes (e.g., coma, agitation, anxiety, confusion, etc.)
Unknown incidence adverse effects include
  • Jaundice
  • Abnormal liver function test results
  • typical antipsychotics
    like flupenthixol. It presents with repetitive, involuntary, purposeless and slow movements; TD can be triggered by a fast dose reduction in any antipsychotic.
  • Hypotension
  • Confusional state
  • Seizures
  • Mania
  • Hypomania
  • Depression
  • Hot flush
  • Anergia
  • Appetite changes
  • Weight changes
  • Hyperglycemia – high blood glucose (sugar) levels
  • Abnormal glucose tolerance
  • Pruritus – itchiness
  • Rash
  • Dermatitis
  • Photosensitivity – sensitivity to light
  • Oculogyric crisis
  • Accommodation disorder
  • Sleep disorder
  • Impaired concentration
  • Tachycardia
  • electrical activity of the heart that can lead to potentially fatal changes in heart rhythm (only in overdose or <10 ms increases in QTc)[18][19]
  • Torsades de pointes
  • Miosis – constriction of the pupil of the eye
  • Paralytic ileus – paralysis of the bowel muscles leading to severe constipation, inability to pass wind, etc.
  • Mydriasis
  • Glaucoma

Interactions

It should not be used concomitantly with medications known to prolong the QTc interval (e.g.,

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]

Protein cis-flupentixol trans-flupentixol
5-HT1A 8028 —
5-HT2A 87.5 (HFC) —
5-HT2C 102.2 (RC) —
mAChRs[21] Neg. Neg.
D1
 3.5 474 (MB)
D2
 0.35 120
D3
 1.75 162.5
D4
 66.3 >1000
H1 0.86 5.73

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
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 [29]
Clopentixol decanoate
 Sordinol Depot Typical Viscoleob 50–600 mg/1–4 weeks 4–7 days ? 19 days 9.0 [30]
Flupentixol decanoate Depixol Typical Viscoleob 10–200 mg/2–4 weeks 4–10 days 8 days 17 days 7.2–9.2 [30][31]
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 [32][33][34]
Fluphenazine enanthate
 Prolixin Enanthate Typical Sesame oil 12.5–100 mg/1–4 weeks 2–3 days 4 days ? 6.4–7.4 [33]
Fluspirilene Imap, Redeptin Typical Watera 2–12 mg/1 week 1–8 days 7 days ? 5.2–5.8 [35]
Haloperidol decanoate Haldol Decanoate Typical Sesame oil 20–400 mg/2–4 weeks 3–9 days 18–21 days 7.2–7.9 [36][37]
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 [38]
Pipotiazine palmitate
 Piportil Longum Typical Viscoleob 25–400 mg/4 weeks 9–10 days ? 14–21 days 8.5–11.6 [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 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
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]

References

  1. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ^ a b c d e "Depixol Tablets 3mg - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Lundbeck Ltd. 27 December 2012. Retrieved 20 October 2013.
  3. S2CID 24707620
    .
  4. S2CID 12848774
    .
  5. ^
    ISBN 978-0-85711-084-8
    .
  6. ^
    ISBN 978-0-9805790-9-3
    .
  7. ^ "Fluanxol® (flupentixol) Tablets Registration Certificate". Russian State Register of Medicinal Products. Retrieved 29 July 2014.
  8. PMID 23152280
    .
  9. PMID 7291129
    .
  10. PMID 6674820
    .
  11. S2CID 144717662
    .
  12. PMID 773506
    .
  13. S2CID 25364795
    .
  14. S2CID 30537435
    .
  15. PMID 26147958
    .
  16. S2CID 25981099
    .
  17. ^ a b c d e f "FLUANXOL® DEPOT FLUANXOL® CONCENTRATED DEPOT". TGA eBusiness Services. Lundbeck Australia Pty Ltd. 28 June 2013. Retrieved 20 October 2013.
  18. ^ "Guidelines for the Management of QTc Prolongation in Adults Prescribed Antipsychotics" (PDF). nhs.uk.
  19. PMID 31463053
    .
  20. ^ Roth, BL, Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 8 November 2013. Retrieved 20 October 2013.
  21. PMID 7052344
    .
  22. S2CID 2231884
    .
  23. S2CID 22801301
    .
  24. PMID 22308204
    .
  25. PMID 11229973
    .
  26. PMID 10740989
    .
  27. S2CID 31885144
    .
  28. PMID 26905976
    .
  29. ^ Parent M, Toussaint C, Gilson H (1983). "Long-term treatment of chronic psychotics with bromperidol decanoate: clinical and pharmacokinetic evaluation". Current Therapeutic Research. 34 (1): 1–6.
  30. ^
    PMID 6931472
    .
  31. ^ a b Reynolds JE (1993). "Anxiolytic sedatives, hypnotics and neuroleptics.". Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. pp. 364–623.
  32. PMID 6143748
    .
  33. ^
    PMID 444352
    .
  34. ^ Young D, Ereshefsky L, Saklad SR, Jann MW, Garcia N (1984). Explaining the pharmacokinetics of fluphenazine through computer simulations. (Abstract.). 19th Annual Midyear Clinical Meeting of the American Society of Hospital Pharmacists. Dallas, Texas.
  35. PMID 4992598
    .
  36. PMID 3545764
    .
  37. PMID 7185768
    .
  38. ^ Larsson M, Axelsson R, Forsman A (1984). "On the pharmacokinetics of perphenazine: a clinical study of perphenazine enanthate and decanoate". Current Therapeutic Research. 36 (6): 1071–88.
  39. S2CID 145021607
    .
  40. S2CID 42657501
    .