Zuclopenthixol: Difference between revisions

{{Short description|Typical antipsychotic medication}}

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 419456332

| IUPAC_name = ''cis''-(''Z'')-2-(4-(3-(2-chloro-9''H''-thioxanthen-9-ylidene)propyl)piperazin-1-yl)ethanol

| image = Zuclopenthixol.svg

| width = 250

<!--Clinical data-->

| tradename = Clopixol

| Drugs.com = {{drugs.com|international|zuclopenthixol}}

| pregnancy_AU = C

| legal_AU = S4

| legal_AU_comment = <ref>{{Cite web |url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05705-3 |title= Clopixol (Zuclopenthixol Hydrochloride) Film-coated tablets | work = Australian Product Information | publisher = The Therapeutics Goods Administration | location = Australia |access-date=2013-08-08 |archive-date=2018-06-15 |archive-url=https://web.archive.org/web/20180615111308/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05705-3 |url-status=live }}</ref>

| legal_BR = C1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_UK = POM

| legal_status = Rx-only

| routes_of_administration = [[oral administration|Oral]], [[Intramuscular injection|IM]]

| class = [[Typical antipsychotic]]

<!--Pharmacokinetic data-->

| bioavailability = 49% (oral)

| protein_bound = 98%

| metabolism = [[Liver]] ([[CYP2D6]] and [[CYP3A4]]-mediated)

| elimination_half-life = 20 hours (oral), 19 days (IM)

| excretion = Feces

<!--Identifiers-->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 53772-83-1

| CAS_supplemental = <br />{{CAS|85721-05-7}} ([[acetate]])<br />{{CAS|64053-00-5}} ([[decanoic acid|decanoate]])

| ATC_prefix = N05

| ATC_suffix = AF05

| PubChem = 5311507

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB01624

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D03556

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 51364

<!--Chemical data-->

| C=22 | H=25 | Cl=1 | N=2 | O=1 | S=1

| smiles = Clc2cc1C(\c3c(Sc1cc2)cccc3)=C/CCN4CCN(CCO)CC4

'''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-trans isomerism|cis]]''-[[isomer]] of [[clopenthixol]] (Sordinol, Ciatyl).<ref name="isbn0-471-89980-1">{{cite book | author = Sneader, Walter | title = Drug discovery: a history | publisher = Wiley | location = New York | year = 2005 | page = 410 | isbn = 0-471-89980-1 | url = https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA410 | access-date = 2020-10-07 | archive-date = 2023-04-29 | archive-url = https://web.archive.org/web/20230429054434/https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA410 | url-status = live }}</ref> Clopenthixol was introduced in 1961, while zuclopenthixol was introduced in 1978.

Zuclopenthixol is a [[Dopamine receptor|D₁ and D₂]] antagonist, [[adrenergic receptor|α₁-adrenergic]] and [[serotonin receptor|5-HT₂]] antagonist.<ref>{{cite journal | vauthors = Christensen AV, Arnt J, Hyttel J, Larsen JJ, Svendsen O | title = Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics | journal = Life Sciences | volume = 34 | issue = 16 | pages = 1529–1540 | date = April 1984 | doi = 10.1016/0024-3205(84)90607-6 | pmid = 6144029 }}</ref> 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.<ref name="GreenNoordsy2008">{{cite journal | vauthors = Green AI, Noordsy DL, Brunette MF, O'Keefe C | title = Substance abuse and schizophrenia: pharmacotherapeutic intervention | journal = Journal of Substance Abuse Treatment | volume = 34 | issue = 1 | pages = 61–71 | date = January 2008 | pmid = 17574793 | pmc = 2930488 | doi = 10.1016/j.jsat.2007.01.008 }}</ref><ref name=Martindale>{{Cite book|editor=Sweetman, Sean C. |chapter=Anxiolytic Sedatives Hypnotics and Antipsychotics|title=Martindale: The complete drug reference |edition=36th |year=2009 |pages=1040–1|publisher=Pharmaceutical Press |location=London|isbn=978-0-85369-840-1|title-link=Martindale: The complete drug reference}}</ref>

==Medical uses==

===Available forms===

* 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.<ref name = "Cochzuclo2">{{cite journal | vauthors = da Silva Freire Coutinho E, Fenton M, Quraishi SN | title = Zuclopenthixol decanoate for schizophrenia | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD001164 | publisher = John Wiley and Sons, Ltd. | year = 1999 | volume = 1999 | url = http://www.cochrane.org/reviews/en/ab001164.html | doi = 10.1002/14651858.CD001164 | pmid = 10796607 | pmc = 7032616 | access-date = 2007-06-12 | archive-date = 2007-06-13 | archive-url = https://web.archive.org/web/20070613153843/http://www.cochrane.org/reviews/en/ab001164.html | url-status = live }}</ref> There is some evidence it may be more helpful in managing aggressive behaviour.<ref>{{Cite journal |vauthors=Haessler F, Glaser T, Beneke M, Pap AF, Bodenschatz R, Reis O | title = Zuclopenthixol in adults with intellectual disabilities and aggressive behaviours | journal = [[British Journal of Psychiatry]] | volume = 190 | issue = 5 | pages = 447&ndash;448 | year = 2007 | doi = 10.1192/bjp.bp.105.016535 | pmid = 17470962 | doi-access = free }}</ref>

* 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.<ref>{{cite web | author = Lundbeck P/L | title = Clopixol Acuphase 50 mg/mL Injection Clopixol Acuphase 100 mg / 2 mL Injection | publisher = Lundbeck P/L | year = 1991 | url = http://home.intekom.com/pharm/lundbeck/clopixac.html | access-date = 2007-06-12 | archive-date = 2007-06-09 | archive-url = https://web.archive.org/web/20070609192828/http://home.intekom.com/pharm/lundbeck/clopixac.html | url-status = live }}</ref>

* As '''zuclopenthixol dihydrochloride''' ('''Clopixol''', '''Cisordinol'''), it is a tablet used in the treatment of schizophrenia in those who are compliant with oral medication.<ref name=":0">{{cite journal | vauthors = Bryan EJ, Purcell MA, Kumar A | title = Zuclopenthixol dihydrochloride for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | issue = 11 | pages = CD005474 | date = November 2017 | pmid = 29144549 | pmc = 6486001 | doi = 10.1002/14651858.CD005474.pub2 }}</ref>

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

===Dosing===

As a long-acting injection, zuclopenthixol decanoate comes in a 200&nbsp;mg and 500&nbsp;mg ampoule. Doses can vary from 50&nbsp;mg weekly to the maximum licensed dose of 600&nbsp;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&nbsp;mg of zuclopenthixol decanoate is roughly equivalent to 20&nbsp;mg of flupentixol decanoate or 12.5&nbsp;mg of [[fluphenazine]] decanoate.

In oral form zuclopenthixol is available in 2, 10, 25 and 40&nbsp;mg tablets, with a dose range of 20&ndash;60&nbsp;mg daily.<ref>{{Cite web |title=Clopixol 2 mg film-coated tablets - Summary of Product Characteristics (SmPC) - (emc) |url=https://www.medicines.org.uk/emc/product/994/#gref |access-date=2023-03-28 |website=www.medicines.org.uk |archive-date=2023-03-28 |archive-url=https://web.archive.org/web/20230328180621/https://www.medicines.org.uk/emc/product/994/#gref |url-status=live }}</ref>

==Side effects==

Chronic administration of zuclopenthixol (30&nbsp;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.

[[Drug withdrawal|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.<ref>[https://www.medicines.org.uk/emc/product/994/smpc]</ref><ref>[https://www.uptodate.com/contents/zuclopenthixol-united-states-not-available-drug-information?search=Zuclopenthixol&topicRef=15250&source=see_link#F236382]</ref>

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.<ref name=":0" /> Zuclopenthixol is thought to be more sedating than the related [[flupentixol]], though possibly less likely to induce extrapyramidal symptoms than other typical depots.<ref name = "Cochzuclo2"/> 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.<ref>{{Cite web|url=https://www.hpra.ie/img/uploaded/swedocuments/LicenseSPC_PA0115-005-007_03062015110150.pdf|title=Summary of Product Characteristics|access-date=2017-03-28|archive-date=2017-03-28|archive-url=https://web.archive.org/web/20170328105635/https://www.hpra.ie/img/uploaded/swedocuments/LicenseSPC_PA0115-005-007_03062015110150.pdf|url-status=live}}</ref>

;Very common Adverse Effects (≥10% incidence) <ref name = "TGA">{{Cite web|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05705-3|title=TGA eBS - Product and Consumer Medicine Information Licence|access-date=2013-08-08|archive-date=2018-06-15|archive-url=https://web.archive.org/web/20180615111308/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05705-3|url-status=live}}</ref>

* Dry Mouth

* [[Somnolence]]

* [[Akathisia]]

* [[Hyperkinesia]]

* [[Hypokinesia]]

;Common (1–10%) <ref name = "TGA" />

* [[Tachycardia]]

* [[Heart palpitations]]

* [[Vertigo]]

* [[Accommodative insufficiency|Accommodation disorder]]

* Abnormal vision

* 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]]

* Abnormal gait

* [[Insomnia]]

* [[Depression (mood)|Depression]]

* [[Anxiety]]

* Abnormal dreams

* Agitation

* Decreased libido

* Nasal congestion

* [[Dyspnoea]]

* [[Hyperhidrosis]]

* [[Pruritus]]

;Uncommon (0.1–1%)<ref name = "TGA" />

* [[Hyperacusis]]

* [[Tinnitus]]

* [[Mydriasis]]

* Abdominal pain

* Nausea

* Flatulence

* Thirst

* [[Injection site reaction]]

* [[Hypothermia]]

* [[Pyrexia]]

* Abnormal liver function tests

* Decreased appetite

* Weight loss

* Muscle rigidity

* [[Trismus]]

* [[Torticollis]]

* [[Tardive dyskinesia]]

* [[Hyperreflexia]]

* [[Dyskinesia]]

* [[Parkinsonism]]

* [[Syncope (medicine)|Syncope]]

* [[Ataxia]]

* Speech disorder

* [[Hypotonia]]

* Convulsion

* [[Migraine]]

* Apathy

* Nightmares

* Libido increased

* Confused state

* Ejaculation failure

* Erectile dysfunction

* Female orgasmic disorder

* Vulvovaginal

* Dryness

* Rash

* [[Photosensitivity]]

* Pigmentation disorder

* [[Seborrhoea]]

* Dermatitis

* [[Purpura]]

* [[Hypotension]]

* Hot flush

;Rare (0.01–0.1%)<ref name = "TGA" />

* [[Thrombocytopenia]]

* [[Neutropenia]]

* [[Leukopenia]]

* [[Agranulocytosis]]

* [[QT prolongation]]

* [[Hyperprolactinaemia]]

* Hypersensitivity

* [[Anaphylactic reaction]]

* [[Hyperglycaemia]]

* Glucose tolerance impaired

* [[Hyperlipidaemia]]

* [[Gynaecomastia]]

* [[Galactorrhoea]]

* [[Amenorrhoea]]

* [[Priapism]]

* Withdrawal symptoms

;Very rare (<0.01%)<ref name = "TGA" />

* [[Cholestatic hepatitis]]

* [[Jaundice]]

* [[Neuroleptic malignant syndrome]]

* [[Venous thromboembolism]]

==Pharmacology==

===Pharmacodynamics===

[[File:Cisordinol.jpg|thumb|150px|Cisordinol 10 mg tablet]]

Zuclopenthixol antagonises both dopamine [[Dopamine receptor D1|D₁]] and [[Dopamine receptor_D2|D₂]] receptors, [[alpha 1 receptor|α₁-adrenoceptors]] and [[5-HT2 receptor|5-HT₂]] receptors with a high affinity, but has no affinity for [[muscarinic acetylcholine receptors]]. It weakly antagonises the [[Histamine H1 receptor|histamine (H₁)]] receptor but has no [[alpha 2 receptor|α₂-adrenoceptor]] blocking activity {{Citation needed|date=August 2020}}.

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.<ref>{{Cite journal |vauthors=Davies SJ, Westin AA, Castberg I, Lewis G, Lennard MS, Taylor S, Spigset O | title = Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies. | journal = [[Acta Psychiatrica Scandinavica]] | volume = 122 | issue = 6 | pages = 445&ndash;453 | year = 2010 | doi = 10.1111/j.1600-0447.2010.01619.x | pmid = 20946203 | s2cid = 41869401 }}</ref>

===Pharmacokinetics===

{{Pharmacokinetics of long-acting injectable antipsychotics}}

==History==

Zuclopenthixol was introduced by Lundbeck in 1978.<ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1102|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1102–|access-date=27 September 2017|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114123157/https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1102|url-status=live}}</ref>

==References==

{{Reflist}}

{{Navboxes

| title = [[Pharmacodynamics]]

| titlestyle = background:#ccccff

| list1 =

{{Adrenergic receptor modulators}}

{{Dopamine receptor modulators}}

{{Histamine receptor modulators}}

{{Serotonin receptor modulators}}

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[[Category:Typical antipsychotics]]

[[Category:Alcohols]]

[[Category:Chloroarenes]]

[[Category:CYP2D6 inhibitors]]

[[Category:Enantiopure drugs]]