Zuclopenthixol

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Zuclopenthixol
Zuclopenthixol.svg
Names
Trade namesClopixol, Cisordinol, others
Other namesZuclopentixol
  • cis-(Z)-2-(4-(3-(2-chloro-9H-thioxanthen-9-ylidene)propyl)piperazin-1-yl)ethanol
Clinical data
Drug classTypical antipsychotic[1]
Main usesSchizophrenia and other psychoses.[1]
Side effectsAnxiety, depression, high blood sugar, liver problems, sexual dysfunction, trouble sleeping[1]
Pregnancy
category
  • AU: C
Routes of
use
By mouth, IM[1]
External links
AHFS/Drugs.comInternational Drug Names
Legal
Legal status
  • AU: S4 (Prescription only) [2]
  • BR: Class C1 (Other controlled substances) [3]
  • UK: POM (Prescription only)
  • In general: ℞ (Prescription only)
Pharmacokinetics
Bioavailability49% (by mouth)
Protein binding98%
MetabolismLiver (CYP2D6 and CYP3A4-mediated)
Elimination half-life20 hours (by mouth), 19 days (IM)
ExcretionFeces
Chemical and physical data
FormulaC22H25ClN2OS
Molar mass400.97 g·mol−1
3D model (JSmol)
  • Clc2cc1C(\c3c(Sc1cc2)cccc3)=C/CCN4CCN(CCO)CC4
  • InChI=1S/C22H25ClN2OS/c23-17-7-8-22-20(16-17)18(19-4-1-2-6-21(19)27-22)5-3-9-24-10-12-25(13-11-24)14-15-26/h1-2,4-8,16,26H,3,9-15H2/b18-5- checkY
  • Key:WFPIAZLQTJBIFN-DVZOWYKESA-N checkY

Zuclopenthixol , sold under the brand names Clopixol among others, is a medication used to treat schizophrenia and other psychoses.[1] Depending on the formulation it may be taken by mouth or by injection into a muscle.[1]

Side effects may include anxiety, depression, high blood sugar, liver problems, sexual dysfunction, and trouble sleeping.[1] Lower doses should be used in those with liver or kidney problems.[1] It is a typical antipsychotic.[1] It may be possible to use the medication while breastfeeding.[4]

Zuclopenthixol was isolated in 1962 and came into medical use in 1978.[5][6] It is approved for use in Australia, Canada, New Zealand, and the UK; though not the United States.[5][7][8] Some forms are available as a generic medication.[1] The long acting decanoate formulation is on the World Health Organization's List of Essential Medicines as an alternative to fluphenazine.[9] In the United Kingdom it is relatively inexpensive as of 2022.[1]

Medical uses

It is primarily used to treat schizophrenia and other psychoses.[1] It is also used in the treatment of acute bipolar mania.

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.[10] There is some evidence it may be more helpful in managing aggressive behaviour.[11]
  • 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.[12]
  • As zuclopenthixol dihydrochloride (Clopixol, Cisordinol), it is a tablet used in the treatment of schizophrenia in those who are compliant with oral medication.[13]

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.

It is available in 2, 10, 25 and 40 mg tablets, with a dose range of 20–60 mg daily.[14]

Side effects

Long term zuclopenthixol (30 mg/kg/day for two years) in rats results in a small increases in 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.[1] Archived 2023-08-26 at the Wayback Machine[2] Archived 2023-08-26 at the Wayback Machine

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.[13] Zuclopenthixol is thought to be more sedating than the related flupentixol, though possibly less likely to induce extrapyramidal symptoms than other typical depots.[10] 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.[15]

Very common (≥10% incidence) [16]
Common (1%≤incidence≤10%) [16]
Uncommon (0.1%≤incidence≤1%)[16]
Rare (0.01%≤incidence≤0.1%)[16]
Very rare (incidence<0.01%)[16]

Pharmacology

Pharmacodynamics

Cisordinol 10 mg tablet

It is a D1 and D2 antagonist, α1-adrenergic and 5-HT2 antagonist.[17]

It has no affinity for muscarinic acetylcholine receptors. It weakly antagonises the histamine (H1) receptor but has no α2-adrenoceptor blocking activity[citation needed].

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.[18]

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

Chemistry

Chemically it is a thioxanthene. It is the cis-isomer of clopenthixol.[29]

History

Zuclopenthixol was introduced by Lundbeck in 1978.[30]

References

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  3. 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 português do Brasil). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
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External links

Identifiers: