Chlorprothixene

{{Drugbox

| Watchedfields = changed

| verifiedrevid = 460033773

| IUPAC_name = (Z)-3-(2-chlorothioxanthen-9-ylidene)-N,N-dimethyl-propan-1-amine

| image = Chlorprothixene structure.svg

| image_class = skin-invert-image

| width = 200px

| image2 = Chlorprothixene3Dan.gif

| width2 = 180px

| tradename = Truxal, others

| Drugs.com = {{drugs.com|CONS|chlorprothixene}}

| pregnancy_category =

| legal_AU =

| legal_BR = C1

| legal_BR_comment = {{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}}

| legal_CA =

| legal_DE =

| legal_NZ =

| legal_UK =

| legal_US =

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| legal_status = Rx-only

| routes_of_administration = Oral, intramuscular injection

| class = Typical antipsychotic

| bioavailability =

| protein_bound =

| metabolism = Hepatic

| elimination_half-life = 8–12 hours

| excretion = Feces, urine

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

| CAS_number = 113-59-7

| ATC_prefix = N05

| ATC_suffix = AF03

| PubChem = 667467

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

| DrugBank = DB01239

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 580849

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 9S7OD60EWP

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

| KEGG = D00790

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 50931

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 908

| C=18 | H=18 | Cl=1 | N=1 | S=1

| SMILES = Clc2cc1C(\c3c(Sc1cc2)cccc3)=C/CCN(C)C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C18H18ClNS/c1-20(2)11-5-7-14-15-6-3-4-8-17(15)21-18-10-9-13(19)12-16(14)18/h3-4,6-10,12H,5,11H2,1-2H3/b14-7-

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = WSPOMRSOLSGNFJ-AUWJEWJLSA-N

}}

Chlorprothixene, sold under the brand name Truxal among others, is a typical antipsychotic of the thioxanthene group.

Medical uses

Chlorprothixene's principal indications are the treatment of psychotic disorders (e.g. schizophrenia) and of acute mania occurring as part of bipolar disorders.

Other uses are pre- and postoperative states with anxiety and insomnia, severe nausea / emesis (in hospitalized patients), the amelioration of anxiety and agitation due to use of selective serotonin reuptake inhibitors for depression and, off-label, the amelioration of alcohol and opioid withdrawal. It may also be used cautiously to treat nonpsychotic irritability, aggression, and insomnia in pediatric patients.

An intrinsic antidepressant effect of chlorprothixene has been discussed, but not proven. Likewise, it is unclear if chlorprothixene has genuine (intrinsic) analgesic effects. However, chlorprothixene can be used as co-medication in severe chronic pain. Also, like most antipsychotics, chlorprothixene has antiemetic effects.

Side effects

Chlorprothixene has a strong sedative activity with a high incidence of anticholinergic side effects. The types of side effects encountered (dry mouth, massive hypotension and tachycardia, hyperhidrosis, substantial weight gain etc.) normally do not allow a full effective dose for the remission of psychotic disorders to be given. So cotreatment with another, more potent, antipsychotic agent is needed.

Chlorprothixene is structurally related to chlorpromazine, with which it shares, in principle, all side effects. Allergic side effects and liver damage seem to appear with an appreciable lower frequency. The elderly are particularly sensitive to anticholinergic side effects of chlorprothixene (precipitation of narrow angle glaucoma, severe obstipation, difficulties in urinating, confusional and delirant states). In patients >60 years the doses should be particularly low.

Early and late extrapyramidal side effects may occur but have been noted with a low frequency (one study with a great number of participants has delivered a total number of only 1%).{{Citation needed|date=October 2021}}

Overdose

Overdose symptoms can be confusion, hypotension, and tachycardia, and several fatalities have been reported with concentrations in postmortem blood ranging from 0.1 to 7.0 mg/L compared to non-toxic levels in postmortem blood which can extend to 0.4 mg/kg.{{cite journal | vauthors = Skov L, Johansen SS, Linnet K | title = Postmortem femoral blood reference concentrations of aripiprazole, chlorprothixene, and quetiapine | journal = Journal of Analytical Toxicology | volume = 39 | issue = 1 | pages = 41–44 | date = Jan 2015 | pmid = 25342720 | doi = 10.1093/jat/bku121 | doi-access = free }}

Interactions

Chlorprothixene may increase the plasma-level of concomitantly given lithium. In order to avoid lithium intoxication, lithium plasma levels should be monitored closely.

If chlorprothixene is given concomitantly with opioids, the opioid dose should be reduced (by approx. 50%), because chlorprothixene amplifies the therapeutic actions and side effects of opioids considerably.

Avoid the concomitant use of chlorprothixene and tramadol (Ultram). Seizures may be encountered with this combination.

Consider additive sedative effects and confusional states to emerge, if chlorprothixene is given with benzodiazepines or barbiturates. Choose particular low doses of these drugs.

Exert particular caution in combining chlorprothixene with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma .

Pharmacology

=Pharmacodynamics=

Site	K_i (nM)	Species	Ref
class="wikitable floatright" style="font-size:small;" \|+ Chlorprothixene{{cite web \| title = PDSP K_i Database \| work = Psychoactive Drug Screening Program (PDSP) \| vauthors = Roth BL, BL, Driscol J \| publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health \| access-date = 14 August 2017 \| url = https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=chlorprothixene&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}
{{abbrlink\|SERT\|Serotonin transporter}}	110	{{abbr\|ND\|No data}}	{{cite journal \| vauthors = Silvestre JS, Prous J \| title = Research on adverse drug events. I. Muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes \| journal = Methods and Findings in Experimental and Clinical Pharmacology \| volume = 27 \| issue = 5 \| pages = 289–304 \| date = June 2005 \| pmid = 16082416 \| doi = 10.1358/mf.2005.27.5.908643 }}
{{abbrlink\|NET\|Norepinephrine transporter}}	21–532	Human	{{cite journal \| vauthors = Haunsø A, Buchanan D \| title = Pharmacological characterization of a fluorescent uptake assay for the noradrenaline transporter \| journal = Journal of Biomolecular Screening \| volume = 12 \| issue = 3 \| pages = 378–384 \| date = April 2007 \| pmid = 17379857 \| doi = 10.1177/1087057107299524 \| doi-access = free }}
{{abbrlink\|DAT\|Dopamine transporter}}	1,699	{{abbr\|ND\|No data}}
5-HT_1A	138–230	Human	{{cite journal \| vauthors = Wander TJ, Nelson A, Okazaki H, Richelson E \| title = Antagonism by neuroleptics of serotonin 5-HT1A and 5-HT2 receptors of normal human brain in vitro \| journal = European Journal of Pharmacology \| volume = 143 \| issue = 2 \| pages = 279–282 \| date = November 1987 \| pmid = 2891550 \| doi = 10.1016/0014-2999(87)90544-9 }}
5-HT_2A	0.30–0.43	Human
5-HT_2B	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}
5-HT_2C	4.5	{{abbr\|ND\|No data}}
5-HT₃	398	{{abbr\|ND\|No data}}
5-HT₆	3.0–3.2	Rat	{{cite journal \| vauthors = Roth BL, Craigo SC, Choudhary MS, Uluer A, Monsma FJ, Shen Y, Meltzer HY, Sibley DR \| display-authors = 6 \| title = Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors \| journal = The Journal of Pharmacology and Experimental Therapeutics \| volume = 268 \| issue = 3 \| pages = 1403–1410 \| date = March 1994 \| pmid = 7908055 \| author1-link = Bryan Roth }}{{cite journal \| vauthors = Glusa E, Pertz HH \| title = Further evidence that 5-HT-induced relaxation of pig pulmonary artery is mediated by endothelial 5-HT(2B) receptors \| journal = British Journal of Pharmacology \| volume = 130 \| issue = 3 \| pages = 692–698 \| date = June 2000 \| pmid = 10821800 \| pmc = 1572101 \| doi = 10.1038/sj.bjp.0703341 }}
5-HT₇	5.0–5.6	Rat
α₁	1.0	{{abbr\|ND\|No data}}
α₂	186	{{abbr\|ND\|No data}}
β	>10,000	Mammal	{{cite journal \| vauthors = Bylund DB, Snyder SH \| title = Beta adrenergic receptor binding in membrane preparations from mammalian brain \| journal = Molecular Pharmacology \| volume = 12 \| issue = 4 \| pages = 568–580 \| date = July 1976 \| pmid = 8699 }}
D₁	12–18	Human	{{cite journal \| vauthors = von Coburg Y, Kottke T, Weizel L, Ligneau X, Stark H \| title = Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics \| journal = Bioorganic & Medicinal Chemistry Letters \| volume = 19 \| issue = 2 \| pages = 538–542 \| date = January 2009 \| pmid = 19091563 \| doi = 10.1016/j.bmcl.2008.09.012 }}
D₂	3.0–5.6	Human	{{cite journal \| vauthors = Seeman P, Tallerico T \| title = Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors \| journal = Molecular Psychiatry \| volume = 3 \| issue = 2 \| pages = 123–134 \| date = March 1998 \| pmid = 9577836 \| doi = 10.1038/sj.mp.4000336 \| s2cid = 16484752 \| doi-access = }}
D₃	1.9–4.6	Human
D₄	0.65	Human
D₅	9.0	Human
H₁	0.89–3.8	Human
H₃	>1,000	Human
{{abbrlink\|mACh\|Muscarinic acetylcholine receptor}}	41	{{abbr\|ND\|No data}}
M₁	11–26	Human	{{cite journal \| vauthors = Bolden C, Cusack B, Richelson E \| title = Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells \| journal = The Journal of Pharmacology and Experimental Therapeutics \| volume = 260 \| issue = 2 \| pages = 576–580 \| date = February 1992 \| pmid = 1346637 }}
M₂	28–79	Human
M₃	22	Human
M₄	18	Human
M₅	25	Human
σ	603	{{abbr\|ND\|No data}}
class="sortbottom" \| colspan="4" style="width: 1px;" \| Values are K_i (nM). The smaller the value, the more strongly the drug binds to the site.

Chlorprothixene is an antagonist of the following receptors:

5-HT₂, 5-HT₆, 5-HT₇: antipsychotic effects, sedation/anxiolysis, antidepressant effect, weight gain
D₁, D₂, D₃, D₄, D₅: antipsychotic effects, sedation, extrapyramidal side effects, prolactin increase, depression, apathy/anhedonia, weight gain
H₁: sedation, weight gain
Muscarinic acetylcholine receptors: anticholinergic effects, inhibition of extrapyramidal side effects
α₁-Adrenergic: hypotension, sedation, anxiolysis

Because of its potent serotonin 5-HT_2A and muscarinic acetylcholine receptor antagonism, chlorprothixene causes relatively mild extrapyramidal symptoms.{{cite book| vauthors = Csernansky JG |title=Antipsychotics|url=https://books.google.com/books?id=hiz6CAAAQBAJ&pg=PA360|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-61007-3|pages=360–}} This is in contrast to most other typical antipsychotics. For this reason, chlorprothixene has sometimes been described instead as an atypical antipsychotic.

Chlorprothixene has also been found to act as FIASMA (functional inhibitor of acid sphingomyelinase).{{cite journal | vauthors = Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer TW, Spitzer GM, Liedl KR, Gulbins E, Tripal P | display-authors = 6 | title = Identification of novel functional inhibitors of acid sphingomyelinase | journal = PLOS ONE | volume = 6 | issue = 8 | pages = e23852 | year = 2011 | pmid = 21909365 | pmc = 3166082 | doi = 10.1371/journal.pone.0023852 | doi-access = free | bibcode = 2011PLoSO...623852K }}

= Pharmacokinetics =

One metabolite of chlorprothixene is N-desmethylchlorprothixene.{{Citation needed|date=April 2022}}

File:Desmethylchlorprothixene.svg

History

Chlorprothixene was the first of the thioxanthene antipsychotics to be synthesized.{{cite book | vauthors = Healy D | title = The antidepressant era | publisher = Harvard University Press | location = Cambridge | year = 1997 | page = [https://archive.org/details/antidepressanter00heal/page/182 182] | isbn = 978-0-674-03958-2 | url = https://archive.org/details/antidepressanter00heal| url-access = registration | quote = chlorprothixene antidepressant. }} It was introduced in 1959 by Lundbeck.{{cite book | vauthors = Sneader W | title = Drug discovery: a history | publisher = Wiley | location = New York | year = 2005 | page = 410 | isbn = 978-0-471-89980-8 | url = https://books.google.com/books?id=Cb6BOkj9fK4C&q=chlorprothixene+introduced+1958&pg=PA410}}

Lometraline, tametraline, and sertraline were reportedly derived via structural modification of chlorprothixene.{{Citation needed|date=August 2017}}

Society and culture

=Brand names=

Chlorprothixene is sold mainly under the brand name Truxal.{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA224|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=224–}}{{Cite web|url=https://www.drugs.com/international/chlorprothixene.html|title = Truxal}}

=Availability=

Chlorprothixene is widely available throughout Europe and elsewhere in the world. The drug was previously available in the United States under the brand name Taractan, but this formulation has since been discontinued and the drug is no longer available in this country.{{Cite web | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=012486 | title=Drugs@FDA: FDA Approved Drug Products}}