Zuclopenthixol

Zuclopenthixol (brand names Cisordinol, Clopixol and others), also known as zuclopentixol, is a medication used to treat schizophrenia and other psychoses. It is classed, pharmacologically, as a typical antipsychotic. Chemically it is a thioxanthene. It is the cis-isomer of clopenthixol (Sordinol, Ciatyl).[1] Clopenthixol was introduced in 1961, while zuclopenthixol was introduced in 1978.[2]

Zuclopenthixol
Clinical data
Trade namesClopixol
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • AU: C
    Routes of
    administration    		Oral, IM
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Bioavailability49% (oral)
    Protein binding98%
    MetabolismHepatic (CYP2D6 and CYP3A4-mediated)
    Elimination half-life20 hours (oral), 19 days (IM)
    ExcretionFeces
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.053.398
    Chemical and physical data
    FormulaC22H25ClN2OS
    Molar mass400.97 g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Zuclopenthixol is a D1 and D2 antagonist, α1-adrenergic and 5-HT2 antagonist. While it is approved for use in Australia, Canada, Ireland, India, New Zealand, Singapore, South Africa and the UK it is not approved for use in the United States.[3][4]

    Medical uses

    Available forms

    Zuclopenthixol is available in three major preparations:

    • As zuclopenthixol decanoate (Clopixol Depot, Cisordinol Depot), it is a long-acting intramuscular injection. Its main use is as a long-acting injection given every two or three weeks to people with schizophrenia who have a poor compliance with medication and suffer frequent relapses of illness.[5] There is some evidence it may be more helpful in managing aggressive behaviour.[6]
    • As zuclopenthixol acetate (Clopixol-Acuphase, Cisordinol-Acutard), it is a shorter-acting intramuscular injection used in the acute sedation of psychotic inpatients. The effect peaks at 48–72 hours providing 2–3 days of sedation.[7]
    • As zuclopenthixol dihydrochloride (Clopixol, Cisordinol), it is a tablet used in the treatment of schizophrenia in those who are compliant with oral medication.[8]

    It is also used in the treatment of acute bipolar mania.

    Dosing

    As a long-acting injection, zuclopenthixol decanoate comes in a 200 mg and 500 mg ampoule. Doses can vary from 50 mg weekly to the maximum licensed dose of 600 mg weekly. In general, the lowest effective dose to prevent relapse is preferred. The interval may be shorter as a patient starts on the medication before extending to 3 weekly intervals subsequently. The dose should be reviewed and reduced if side effects occur, though in the short-term an anticholinergic medication benztropine may be helpful for tremor and stiffness, while diazepam may be helpful for akathisia. 100 mg of zuclopenthixol decanoate is roughly equivalent to 20 mg of flupentixol decanoate or 12.5 mg of fluphenazine decanoate.

    In acutely psychotic and agitated inpatients, 50 – 200 mg of zuclopenthixol acetate may be given for a calming effect over the subsequent three days, with a maximum dose of 400 mg in total to be given. As it is a long-acting medication, care must be taken not to give an excessive dose.

    In oral form zuclopenthixol is available in 10, 25 and 40 mg tablets, with a dose range of 20–60 mg daily.

    Side effects

    Chronic administration of zuclopenthixol (30 mg/kg/day for two years) in rats resulted in small, but significant, increases in the incidence of thyroid parafollicular carcinomas and, in females, of mammary adenocarcinomas and of pancreatic islet cell adenomas and carcinomas. An increase in the incidence of mammary adenocarcinomas is a common finding for D2 antagonists which increase prolactin secretion when administered to rats. An increase in the incidence of pancreatic islet cell tumours has been observed for some other D2 antagonists. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear.

    Withdrawal syndrome: Abrupt cessation of therapy may cause acute withdrawal symptoms (eg, nausea, vomiting, or insomnia). Symptoms usually begin in 1 to 4 days of withdrawal and subside within 1 to 2 weeks.

    Other permanent side effects are similar to many other typical antipsychotics, namely extrapyramidal symptoms as a result of dopamine blockade in subcortical areas of the brain. This may result in symptoms similar to those seen in Parkinson's disease and include a restlessness and inability to sit still known as akathisia, a slow tremor and stiffness of the limbs.[8] Zuclopenthixol is thought to be more sedating than the related flupentixol, though possibly less likely to induce extrapyramidal symptoms than other typical depots.[5] As with other dopamine antagonists, zuclopenthixol may sometimes elevate prolactin levels; this may occasionally result in amenorrhoea or galactorrhoea in severe cases. Neuroleptic malignant syndrome is a rare but potentially fatal side effect. Any unexpected deterioration in mental state with confusion and muscle stiffness should be seen by a physician.

    Zuclopenthixol decanoate induces a transient dose-dependent sedation. However, if the patient is switched to maintenance treatment with zuclopenthixol decanoate from oral zuclopenthixol or from i.m. zuclopenthixol acetate the sedation will be no problem. Tolerance to the unspecific sedative effect develops rapidly.[9]

    Very common Adverse Effects (≥10% incidence) [10]
    • Dry Mouth
    • Somnolence
    • Akathisia
    • Hyperkinesia
    • Hypokinesia
    Common (1%≤incidence≤10%) [10]
    • Tachycardia
    • Palpitations
    • Vertigo
    • Accommodation disorder
    • Vision abnormal
    • Salivary hypersecretion
    • Constipation
    • Vomiting
    • Dyspepsia
    • Diarrhoea
    • Asthenia
    • Fatigue
    • Malaise
    • Pain (at the injection site)
    • Increased appetite
    • Weight gain
    • Myalgia
    • Tremor
    • Dystonia
    • Hypertonia
    • Dizziness
    • Headache
    • Paraesthesia
    • Disturbance in attention
    • Amnesia
    • Gait abnormal
    • Insomnia
    • Depression
    • Anxiety
    • Nervousness
    • Abnormal dreams
    • Agitation,
    • Libido decreased
    • Nasal congestion
    • Dyspnoea
    • Hyperhidrosis
    • Pruritus
    Uncommon (0.1%≤incidence≤1%)[10]
    • Hyperacusis
    • Tinnitus
    • Oculogyration
    • Mydriasis
    • Abdominal pain
    • Nausea
    • Flatulence
    • Thirst
    • Injection site reaction
    • Hypothermia
    • Pyrexia
    • Liver function test abnormal
    • Decreased appetite
    • Weight loss
    • Muscle rigidity
    • Trismus
    • Torticollis
    • Tardive dyskinesia
    • Hyperreflexia
    • Dyskinesia
    • Parkinsonism
    • Syncope
    • Ataxia
    • Speech disorder
    • Hypotonia
    • Convulsion
    • Migraine
    • Apathy
    • Nightmare
    • Libido increased
    • Confusional state
    • Ejaculation failure
    • Erectile dysfunction
    • Female orgasmic disorder
    • Vulvovaginal
    • Dryness
    • Rash
    • Photosensitivity reaction
    • Pigmentation disorder
    • Seborrhoea
    • Dermatitis
    • Purpura
    • Hypotension
    • Hot flush
    Rare (0.01%≤incidence≤0.1%)[10]
    • Thrombocytopenia
    • Neutropenia
    • Leukopenia
    • Agranulocytosis
    • Electrocardiogram QT prolonged
    • Hyperprolactinaemia
    • Hypersensitivity
    • Anaphylactic reaction
    • Hyperglycaemia
    • Glucose tolerance impaired
    • Hyperlipidaemia
    • Gynaecomastia
    • Galactorrhoea
    • Amenorrhoea
    • Priapism
    • Withdrawal symptoms
    Very rare (incidence<0.01%)[10]
    • Cholestatic hepatitis
    • Jaundice
    • Neuroleptic malignant syndrome
    • Venous thromboembolism

    Pharmacology

    Pharmacodynamics
    Cisordinol 10 mg tablet

    Zuclopenthixol antagonises both dopamine D1 and D2 receptors, α1-adrenoceptors and 5-HT2 receptors with a high affinity, but has no affinity for cholinergic muscarine receptors. It weakly antagonises the histamine (H1) receptor but has no α2-adrenoceptor blocking activity .

    Evidence from in vitro work and clinical sources (i.e. therapeutic drug monitoring databases) suggests that both CYP2D6 and CYP3A4 play important roles in zuclopenthixol metabolism.[11]

    Pharmacokinetics
    Pharmacokinetics of long-acting injectable antipsychotics
    MedicationBrand nameClassVehicleDosageTmaxt1/2 singlet1/2 multiplelogPcRef
    Aripiprazole lauroxilAristadaAtypicalWatera441–1064 mg/4–8 weeks24–35 days?54–57 days7.9–10.0
    Aripiprazole monohydrateAbilify MaintenaAtypicalWatera300–400 mg/4 weeks7 days?30–47 days4.9–5.2
    Bromperidol decanoateImpromen DecanoasTypicalSesame oil40–300 mg/4 weeks3–9 days?21–25 days7.9[12]
    Clopentixol decanoateSordinol DepotTypicalViscoleob50–600 mg/1–4 weeks4–7 days?19 days9.0[13]
    Flupentixol decanoateDepixolTypicalViscoleob10–200 mg/2–4 weeks4–10 days8 days17 days7.2–9.2[13][14]
    Fluphenazine decanoateProlixin DecanoateTypicalSesame oil12.5–100 mg/2–5 weeks1–2 days1–10 days14–100 days7.2–9.0[15][16][17]
    Fluphenazine enanthateProlixin EnanthateTypicalSesame oil12.5–100 mg/1–4 weeks2–3 days4 days?6.4–7.4[16]
    FluspirileneImap, RedeptinTypicalWatera2–12 mg/1 week1–8 days7 days?5.2–5.8[18]
    Haloperidol decanoateHaldol DecanoateTypicalSesame oil20–400 mg/2–4 weeks3–9 days18–21 days7.2–7.9[19][20]
    Olanzapine pamoateZyprexa RelprevvAtypicalWatera150–405 mg/2–4 weeks7 days?30 days–
    Oxyprothepin decanoateMeclopinTypical?????8.5–8.7
    Paliperidone palmitateInvega SustennaAtypicalWatera39–819 mg/4–12 weeks13–33 days25–139 days?8.1–10.1
    Perphenazine decanoateTrilafon DekanoatTypicalSesame oil50–200 mg/2–4 weeks??27 days8.9
    Perphenazine enanthateTrilafon EnanthateTypicalSesame oil25–200 mg/2 weeks2–3 days?4–7 days6.4–7.2[21]
    Pipotiazine palmitatePiportil LongumTypicalViscoleob25–400 mg/4 weeks9–10 days?14–21 days8.5–11.6[14]
    Pipotiazine undecylenatePiportil MediumTypicalSesame oil100–200 mg/2 weeks???8.4
    RisperidoneRisperdal ConstaAtypicalMicrospheres12.5–75 mg/2 weeks21 days?3–6 days–
    Zuclopentixol acetateClopixol AcuphaseTypicalViscoleob50–200 mg/1–3 days1–2 days1–2 days4.7–4.9
    Zuclopentixol decanoateClopixol DepotTypicalViscoleob50–800 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.

    References
    1. Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 410. ISBN 0-471-89980-1.
    2. William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 1102–. ISBN 978-0-8155-1856-3.
    3. Green, Alan I.; Noordsy, Douglas L.; Brunette, Mary F.; O'Keefe, Christopher (2008). "Substance abuse and schizophrenia: Pharmacotherapeutic intervention". Journal of Substance Abuse Treatment. 34 (1): 61–71. doi:10.1016/j.jsat.2007.01.008. ISSN 0740-5472. PMC 2930488. PMID 17574793.
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    6. Haessler F, Glaser T, Beneke M, Pap AF, Bodenschatz R, Reis O (2007). "Zuclopenthixol in adults with intellectual disabilities and aggressive behaviours". British Journal of Psychiatry. 190 (5): 447–448. doi:10.1192/bjp.bp.105.016535. PMID 17470962.
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    8. Bryan, Edward J.; Purcell, Marie Ann; Kumar, Ajit (16 November 2017). "Zuclopenthixol dihydrochloride for schizophrenia". The Cochrane Database of Systematic Reviews. 11: CD005474. doi:10.1002/14651858.CD005474.pub2. ISSN 1469-493X. PMC 6486001. PMID 29144549.
    9. "Summary of Product Characteristics" (PDF).
    10. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05705-3
    11. Davies SJ, Westin AA, Castberg I, Lewis G, Lennard MS, Taylor S, Spigset O (2010). "Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies". Acta Psychiatrica Scandinavica. 122 (6): 445–453. doi:10.1111/j.1600-0447.2010.01619.x. PMID 20946203.
    12. 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. https://scholar.google.com/scholar?cites=10379409109713994773
    13. Jørgensen A, Overø KF (1980). "Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels". Acta Psychiatr Scand Suppl. 279: 41–54. doi:10.1111/j.1600-0447.1980.tb07082.x. PMID 6931472.
    14. Reynolds, J. E. F. (1993). Anxiolytic sedatives, hypnotics and neuroleptics. Martindale: The Extra Pharmacopoeia, 30th Edition (pp. 364–623). Pharmaceutical Press, London. https://scholar.google.com/scholar?cluster=8335042449033257176
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    16. Curry SH, Whelpton R, de Schepper PJ, Vranckx S, Schiff AA (April 1979). "Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man". Br J Clin Pharmacol. 7 (4): 325–31. doi:10.1111/j.1365-2125.1979.tb00941.x. PMC 1429660. PMID 444352.
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    19. Beresford R, Ward A (January 1987). "Haloperidol decanoate. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis". Drugs. 33 (1): 31–49. doi:10.2165/00003495-198733010-00002. PMID 3545764.
    20. Reyntigens AJ, Heykants JJ, Woestenborghs RJ, Gelders YG, Aerts TJ (1982). "Pharmacokinetics of haloperidol decanoate. A 2-year follow-up". Int Pharmacopsychiatry. 17 (4): 238–46. doi:10.1159/000468580. PMID 7185768.
    21. 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), 1071–1088. https://scholar.google.com/scholar?cluster=12503004172250709786
    1. Product information for Zuclopenthixol (CLOPIXOL), provided by the Therapeutic Goods Administration — https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05705-3
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