View source for Chlorpromazine

{{Short description|Antipsychotic medication}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Distinguish|Chlorpropamide}}
{{Use dmy dates|date=March 2024}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 443519547
| image = Chlorpromazine.svg
| alt = Skeletal formula of chlorpromazine
| width = 222
| image2 = Chlorpromazine-3D-balls.png
| alt2 = Ball-and-stick model of the chlorpromazine molecule
| width2 = 
| caption =

<!-- Clinical data -->
| pronounce = 
| tradename = Largactil, Thorazine, Sonazine, others
| Drugs.com = {{drugs.com|monograph|chlorpromazine}}
| MedlinePlus = a682040
| DailyMedID = Chlorpromazine
| pregnancy_AU = C
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Chlorpromazine Pregnancy and Breastfeeding Warnings | website=Drugs.com | date=5 February 2020 | url=https://www.drugs.com/pregnancy/chlorpromazine.html | access-date=21 August 2020}}</ref>
| pregnancy_category= 
| routes_of_administration = [[Oral administration|By mouth]], [[Rectal administration|rectal]], [[intramuscular injection|intramuscular]], [[intravenous therapy|intravenous]]
| class = [[Typical antipsychotic]]
| ATC_prefix = N05
| ATC_suffix = AA01
| ATC_supplemental =

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = 
| legal_BR = C1
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |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=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment = 
| legal_NZ = Prescription only
| legal_UK = POM
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = 
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web|url=https://www.ema.europa.eu/documents/psusa/chlorpromazine-list-nationally-authorised-medicinal-products-psusa/00000715/202005_en.pdf |title=List of nationally authorised medicinal products - Active substance: chlorpromazine: Procedure no.: PSUSA/00000715/202005|website=Ema.europa.eu|access-date=3 March 2022}}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment = 
| legal_status = Rx-only

<!-- Pharmacokinetic data -->
| bioavailability = 10–80% (Oral; large interindividual variation)<ref name=TGA>{{cite web|title=Australian Product Information – Largactil (chlorpromazine hydrochloride)|work=[[Therapeutic Goods Administration]] (TGA) |publisher=Sanofi Aventis Pty Ltd|date=28 August 2012|access-date=8 December 2013|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05882-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20170330162812/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05882-3|archive-date=30 March 2017}}</ref>
| protein_bound = 90–99%<ref name = TGA/>
| metabolism = [[Liver]], mostly [[CYP2D6]]-mediated<ref name = TGA/>
| metabolites = 
| onset = 
| elimination_half-life = 30 hours<ref name=AHFS2015/>
| duration_of_action = 
| excretion = [[Kidney]] (43–65% in 24 hrs)<ref name = TGA/>

<!-- Identifiers -->
| index2_label = as HCl
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 50-53-3
| CAS_supplemental = (free base)<br />{{CAS|69-09-0}} (hydrochloride)
| PubChem = 2726
| IUPHAR_ligand = 83
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00477
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2625
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = U42B7VYA4P
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00270
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D00789
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 3647
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 71
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms =

<!-- Chemical and physical data -->
| IUPAC_name = 3-(2-chloro-10''H''-phenothiazin-10-yl)-''N'',''N''-dimethylpropan-1-amine
| C=17 | H=19 | Cl=1 | N=2 | S=1
| SMILES = CN(C)CCCN1c2ccccc2Sc2ccc(Cl)cc21
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C17H19ClN2S/c1-19(2)10-5-11-20-14-6-3-4-7-16(14)21-17-9-8-13(18)12-15(17)20/h3-4,6-9,12H,5,10-11H2,1-2H3
| StdInChI_comment = 
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = ZPEIMTDSQAKGNT-UHFFFAOYSA-N
| density = 
| density_notes = 
| melting_point = 
| melting_high = 
| melting_notes = 
| boiling_point = 
| boiling_notes = 
| solubility = 
| sol_units = 
| specific_rotation = 
}}
<!-- Definition and medical uses -->
'''Chlorpromazine''' ('''CPZ'''), marketed under the brand names '''Thorazine''' and '''Largactil''' among others, is an [[antipsychotic]] medication.<ref name=AHFS2015/> It is primarily used to treat [[psychotic disorder]]s such as [[schizophrenia]].<ref name=AHFS2015/> Other uses include the treatment of [[bipolar disorder]], severe behavioral problems in children including those with [[attention deficit hyperactivity disorder]], [[nausea]] and [[vomiting]], anxiety before surgery, and [[hiccups]] that do not improve following other measures.<ref name=AHFS2015/> It can be given [[Oral administration|orally]] (by mouth), by [[intramuscular|intramuscular injection]] (injection into a muscle), or [[intravenously]] (injection into a vein).<ref name=AHFS2015/>

<!-- Mechanism -->
Chlorpromazine is in the [[typical antipsychotic]] class,<ref name=AHFS2015/> and, chemically, is one of the [[phenothiazines]]. Its [[mechanism of action]] is not entirely clear but is believed to be related to its ability as a [[dopamine antagonist]].<ref name=AHFS2015/> It has [[antiserotonergic]] and [[antihistaminergic]] properties.<ref name=AHFS2015>{{cite web|title=Chlorpromazine Hydrochloride|url=https://www.drugs.com/monograph/chlorpromazine-hydrochloride.html|publisher=The American Society of Health-System Pharmacists|access-date=1 December 2015|url-status=live|archive-url=https://web.archive.org/web/20151208163938/http://www.drugs.com/monograph/chlorpromazine-hydrochloride.html|archive-date=8 December 2015}}</ref>

<!-- Side effects -->
Common side effects include [[extrapyramidal symptoms|movement problems]], [[sedation|sleepiness]], dry mouth, [[orthostatic hypotension|low blood pressure upon standing]], and [[weight gain | increased weight]].<ref name=AHFS2015/> Serious side effects may include the potentially permanent movement disorder [[tardive dyskinesia]], [[neuroleptic malignant syndrome]], severe lowering of the [[seizure threshold]], and [[leukopenia|low white blood cell levels]].<ref name=AHFS2015/> In older people with psychosis as a result of [[dementia]], it may increase the [[all-cause mortality |risk of death]].<ref name=AHFS2015/> It is unclear if it is safe for use in [[pregnancy]].<ref name=AHFS2015/>

<!-- History, society and culture -->
Chlorpromazine was developed in 1950 and was the first antipsychotic on the market.<ref name="history05">{{cite journal | vauthors = López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G | title = History of the discovery and clinical introduction of chlorpromazine | journal = Annals of Clinical Psychiatry | volume = 17 | issue = 3 | pages = 113–135 | year = 2005 | pmid = 16433053 | doi = 10.1080/10401230591002002 }}</ref><ref name=Ban2007>{{cite journal | vauthors = Ban TA | title = Fifty years chlorpromazine: a historical perspective | journal = Neuropsychiatric Disease and Treatment | volume = 3 | issue = 4 | pages = 495–500 | date = August 2007 | pmid = 19300578 | pmc = 2655089 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> Its introduction has been labeled as one of the great advances in the [[history of psychiatry]].<ref>{{cite journal | vauthors = López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G | title = History of the discovery and clinical introduction of chlorpromazine | journal = Annals of Clinical Psychiatry | volume = 17 | issue = 3 | pages = 113–135 | date = 2005 | pmid = 16433053 | doi = 10.1080/10401230591002002 }}</ref><ref>{{cite book| vauthors = Shorter E |title=A historical dictionary of psychiatry|date=2005|publisher=Oxford University Press|location=New York|isbn=9780198039235|page=6|url=https://books.google.com/books?id=M49pEDoEpl0C&pg=PA6|url-status=live|archive-url=https://web.archive.org/web/20170214213428/https://books.google.com/books?id=M49pEDoEpl0C&pg=PA6|archive-date=14 February 2017}}</ref> It is available as a [[generic medication]].<ref name=AHFS2015/>

==Medical uses==
Chlorpromazine is used in the treatment of both acute and chronic [[psychosis|psychoses]], including [[schizophrenia]] and the manic phase of [[bipolar disorder]], as well as [[amphetamine]]-induced psychosis.

Controversially, some [[Psychiatric hospital|psychiatric ward]] patients may be given Chlorpromazine by force, even if they do not suffer any of the typical conditions the drug is prescribed for.<ref>{{cite journal | vauthors = Douglas-Hall P, Whicher EV | title = 'As required' medication regimens for seriously mentally ill people in hospital | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 12 | pages = CD003441 | date = December 2015 | pmid = 26689942 | doi = 10.1002/14651858.CD003441.pub3 | collaboration = Cochrane Schizophrenia Group | pmc = 7052742 }}</ref>

In a 2013 comparison of fifteen antipsychotics in schizophrenia, chlorpromazine demonstrated mild-standard effectiveness. It was 13% more effective than [[lurasidone]] and [[iloperidone]], approximately as effective as [[ziprasidone]] and [[asenapine]], and 12–16% less effective than [[haloperidol]], [[quetiapine]], and [[aripiprazole]].<ref>{{cite journal | vauthors = Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM | title = Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis | journal = Lancet | volume = 382 | issue = 9896 | pages = 951–962 | date = September 2013 | pmid = 23810019 | doi = 10.1016/S0140-6736(13)60733-3 | s2cid = 32085212 }}</ref>

A 2014 systematic review carried out by Cochrane included 55 trials that compared the effectiveness of chlorpromazine versus placebo for the treatment of schizophrenia. Compared to the placebo group, patients under chlorpromazine experienced less relapse during 6 months to 2 years follow-up. No difference was found between the two groups beyond two years of follow-up. Patients under chlorpromazine showed a global improvement in symptoms and functioning. The systematic review also highlighted the fact that the side effects of the drug were 'severe and debilitating', including sedation, considerable weight gain, a lowering of blood pressure, and an increased risk of [[extrapyramidal symptoms|acute movement disorders]]. They also noted that the quality of evidence of the 55 included trials was very low and that 315 trials could not be included in the systematic review due to their poor quality. They called for further research on the subject, as chlorpromazine is a cheap benchmark drug and one of the most used treatments for schizophrenia worldwide.<ref>{{cite journal | vauthors = Adams CE, Awad GA, Rathbone J, Thornley B, Soares-Weiser K | title = Chlorpromazine versus placebo for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD000284 | date = January 2014 | pmid = 24395698 | doi = 10.1002/14651858.CD000284.pub3 | pmc = 10640712 | collaboration = Cochrane Schizophrenia Group }}</ref>

Chlorpromazine has also been used in [[porphyria]] and as part of [[tetanus]] treatment. It still is recommended for short-term management of severe anxiety and psychotic aggression. Resistant and severe [[hiccups]], severe [[nausea]]/[[emesis]], and [[preanesthetic]] conditioning are other uses.<ref name="GG" /><ref name="ashp">{{Cite web |author=American Society of Health-System Pharmacists |author-link=American Society of Health-System Pharmacists |date=1 November 2008 |title=Chlorpromazine |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000553 |work=PubMed Health |publisher=[[National Center for Biotechnology Information]] |url-status=live |archive-url=https://web.archive.org/web/20100706075413/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000553 |archive-date=6 July 2010}}</ref> Symptoms of [[delirium]] in hospitalized [[AIDS]] patients have been effectively treated with low doses of chlorpromazine.<ref name="Breitbart">{{cite journal | vauthors = Breitbart W, Marotta R, Platt MM, Weisman H, Derevenco M, Grau C, Corbera K, Raymond S, Lund S, Jacobson P | title = A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients | journal = The American Journal of Psychiatry | volume = 153 | issue = 2 | pages = 231–237 | date = February 1996 | pmid = 8561204 | doi = 10.1176/ajp.153.2.231 }}</ref>

===Other uses===
Chlorpromazine is occasionally used off-label for treatment of severe [[migraine]].<ref name = MD/><ref>{{cite journal | vauthors = Logan P, Loga P, Lewis D | title = Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Chlorpromazine in migraine | journal = Emergency Medicine Journal | volume = 24 | issue = 4 | pages = 297–300 | date = April 2007 | pmid = 17384391 | pmc = 2658244 | doi = 10.1136/emj.2007.047860 }}</ref> It is often, particularly as [[palliation]], used in small doses to reduce nausea by [[opioid]]-treated cancer patients and to intensify and prolong the analgesia of the opioids as well.<ref name = MD>{{cite book | chapter = Chlorpromazine| title =  Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|date=30 January 2013|access-date=8 December 2013|location= London | chapter-url= http://www.medicinescomplete.com/mc/martindale/current/ms-7021-g.htm}}</ref><ref>{{cite journal | vauthors = Richter PA, Burk MP | title = The potentiation of narcotic analgesics with phenothiazines | journal = The Journal of Foot Surgery | volume = 31 | issue = 4 | pages = 378–380 | date = July–August 1992 | pmid = 1357024 }}</ref> Efficacy has been shown in treatment of symptomatic [[hypertensive emergency]].

In Germany, chlorpromazine still carries label indications for [[insomnia]], severe [[pruritus]], and preanesthesia.<ref>{{Cite web |url=http://www.epgonline.org/drugs/de/propaphenin/ |title=Propaphenin, Medicine and Disease information |work=EPG Online |date=14 July 2001 |url-status=live |access-date=26 November 2013 |archive-url= https://web.archive.org/web/20131202235156/http://www.epgonline.org/drugs/de/propaphenin/ |archive-date=2 December 2013}}</ref>

Chlorpromazine has been used as a [[trip killer|hallucinogen antidote or "trip killer"]] to block the effects of [[serotonergic psychedelic]]s like [[psilocybin]], [[lysergic acid diethylamide]] (LSD), and [[mescaline]].<ref name="HalmanKongSarris2024">{{cite journal | vauthors = Halman A, Kong G, Sarris J, Perkins D | title = Drug-drug interactions involving classic psychedelics: A systematic review | journal = J Psychopharmacol | volume = 38 | issue = 1 | pages = 3–18 | date = January 2024 | pmid = 37982394 | pmc = 10851641 | doi = 10.1177/02698811231211219 | url = }}</ref><ref name="YatesMelon2024">{{cite journal | vauthors = Yates G, Melon E | title = Trip-killers: a concerning practice associated with psychedelic drug use | journal = Emerg Med J | volume = 41 | issue = 2 | pages = 112–113 | date = January 2024 | pmid = 38123961 | doi = 10.1136/emermed-2023-213377 | url = }}</ref><ref name="Suran2024">{{cite journal | vauthors = Suran M | title = Study Finds Hundreds of Reddit Posts on "Trip-Killers" for Psychedelic Drugs | journal = JAMA | volume = 331 | issue = 8 | pages = 632–634 | date = February 2024 | pmid = 38294772 | doi = 10.1001/jama.2023.28257 | url = }}</ref> However, the results of clinical studies of chlorpromazine for this use have been inconsistent, with reduced effects, no change in effects, and even enhanced effects all reported.<ref name="HalmanKongSarris2024" />

Chlorpromazine and other phenothiazines have been demonstrated to possess antimicrobial properties, but are not currently used for this purpose except for a very small number of cases. For example, Miki ''et al.'' 1992 trialed daily doses of chlorpromazine, reversing [[chloroquine resistance]] in ''[[Plasmodium chabaudi]]'' isolates in [[mice]].<ref name="Miki-et-al-1992-bundle">
   {{Unbulleted list citebundle
      |{{cite journal | vauthors = Henry M, Alibert S, Rogier C, Barbe J, Pradines B | title = Inhibition of efflux of quinolines as new therapeutic strategy in malaria | journal = Current Topics in Medicinal Chemistry | volume = 8 | issue = 7 | pages = 563–578 | date = 1 April 2008 | pmid = 18473883 | doi = 10.2174/156802608783955593 | publisher = [[Bentham Science Publishers|Bentham]] | s2cid = 13127221 }}
      |{{cite journal | vauthors = Miki A, Tanabe K, Nakayama T, Kiryon C, Ohsawa K | title = Plasmodium chabaudi: association of reversal of chloroquine resistance with increased accumulation of chloroquine in resistant parasites | journal = Experimental Parasitology | volume = 74 | issue = 2 | pages = 134–142 | date = March 1992 | pmid = 1740175 | doi = 10.1016/0014-4894(92)90040-h | publisher = [[Academic Press|AP]] | s2cid = 37364349 }}
   }}
</ref> Weeks ''et al.'', 2018 find that it also possesses a wide spectrum [[anthelmintic]] effect.<ref name="Repurposing">
   {{Unbulleted list citebundle
      |{{*}} {{cite journal | vauthors = Mangoni AA, Tuccinardi T, Collina S, Vanden Eynde JJ, Muñoz-Torrero D, Karaman R, Siciliano C, de Sousa ME, Prokai-Tatrai K, Rautio J, Guillou C, Gütschow M, Galdiero S, Liu H, Agrofoglio LA, Sabatier JM, Hulme C, Kokotos G, You Q, Gomes PA | title = Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-3 | journal = Molecules | volume = 23 | issue = 7 | page = 1596 | date = June 2018 | pmid = 29966350 | pmc = 6099979 | doi = 10.3390/molecules23071596 | publisher = [[MDPI AG]] | s2cid = 49644934 | doi-access = free }}<!--- Published by MDPI but highly cited including by Jimenez-Lopez et al., 2020, Elmaaty et al., 2021, and Sridhar et al., 2020. --->
      |{{*}} {{cite journal | vauthors = Weeks JC, Roberts WM, Leasure C, Suzuki BM, Robinson KJ, Currey H, Wangchuk P, Eichenberger RM, Saxton AD, Bird TD, Kraemer BC, Loukas A, Hawdon JM, Caffrey CR, Liachko NF | title = Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 975 | date = January 2018 | pmid = 29343694 | pmc = 5772060 | doi = 10.1038/s41598-017-18457-w | publisher = [[Springer Science and Business Media LLC]] | bibcode = 2018NatSR...8..975W | s2cid = 205636792 }}
   }}
</ref>

Chlorpromazine is an [[receptor antagonist|antagonist]] of several insect [[monoamine receptor]]s.<ref name="Verlinden-et-al-2010">{{cite journal | vauthors = Verlinden H, Vleugels R, Marchal E, Badisco L, Pflüger HJ, Blenau W, Broeck JV | title = The role of octopamine in locusts and other arthropods | journal = Journal of Insect Physiology | volume = 56 | issue = 8 | pages = 854–867 | date = August 2010 | pmid = 20621695 | doi = 10.1016/j.jinsphys.2010.05.018 | publisher = [[Elsevier]] | bibcode = 2010JInsP..56..854V }}</ref> It is the most active antagonist known of silk moth (''[[Bombyx mori]]'') [[octopamine receptor α]], intermediate for ''Bm'' tyramine receptors [[tyramine receptors 1|1]] & [[tyramine receptors 2|2]], weak for ''[[Drosophila melanogaster|Drosophila]]'' [[octopamine receptor β]], high for ''Drosophila'' tyramine receptor 1, intermediate for migratory locust (''[[Locusta migratoria]]'') tyramine receptor 1, and high for American cockroach (''[[Periplaneta americana]]'') octopamine receptor α and tyramine receptor 1.<ref name="Verlinden-et-al-2010" />

{| class="wikitable"
|+ Comparison of chlorpromazine to placebo<ref name=Adams>{{cite journal | vauthors = Adams CE, Awad GA, Rathbone J, Thornley B, Soares-Weiser K | title = Chlorpromazine versus placebo for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD000284 | date = January 2014 | pmid = 24395698 | doi = 10.1002/14651858.CD000284.pub3 | pmc = 10640712 | url = http://www.cochrane.org/CD000284/SCHIZ_chlorpromazine-versus-placebo-schizophrenia | url-status = live | archive-url = https://web.archive.org/web/20151001054010/http://www.cochrane.org/CD000284/SCHIZ_chlorpromazine-versus-placebo-schizophrenia | archive-date = 1 October 2015 }}</ref>
|-
! Measured outcome !! Findings summary!! Findings range!! Quality of evidence
|-
! colspan="4" style="text-align:left;"| '''Global effects'''
|-
| No improvement (9 weeks – 6 months) || 30% less risk of having no improvement in mental state, behaviour and functioning || [[relative risk|RR]] 0.7 [[confidence interval|CI]] 0.6 to 0.9 || rowspan="2" style="text-align:center;" | Very low <small>(estimate of effect uncertain)</small>
|-
| Relapse (6 months – 2 years) || 35% less risk of relapse || RR 0.7 CI 0.5 to 0.9
|-
|}

==Adverse effects==
{{See also|List of adverse effects of chlorpromazine}}

There appears to be a dose-dependent risk for seizures with chlorpromazine treatment.<ref>{{cite journal | vauthors = Pisani F, Oteri G, Costa C, Di Raimondo G, Di Perri R | title = Effects of psychotropic drugs on seizure threshold | journal = Drug Safety | volume = 25 | issue = 2 | pages = 91–110 | year = 2002 | pmid = 11888352 | doi = 10.2165/00002018-200225020-00004 | s2cid = 25290793 }}</ref> [[Tardive dyskinesia]] (involuntary, repetitive body movements) and [[akathisia]] (a feeling of inner restlessness and inability to stay still) are less commonly seen with chlorpromazine than they are with high potency typical antipsychotics such as [[haloperidol]]<ref name="Leucht">{{cite journal | vauthors = Leucht C, Kitzmantel M, Chua L, Kane J, Leucht S | title = Haloperidol versus chlorpromazine for schizophrenia | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD004278 | date = January 2008 | pmid = 18254045 | doi = 10.1002/14651858.CD004278.pub2 | veditors = Leucht C | pmc = 11528413 }}</ref> or [[trifluoperazine]], and some evidence suggests that, with conservative dosing, the incidence of such effects for chlorpromazine may be comparable to that of newer agents such as [[risperidone]] or [[olanzapine]].<ref name="fn_36">{{cite journal | vauthors = Leucht S, Wahlbeck K, Hamann J, Kissling W | title = New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis | journal = Lancet | volume = 361 | issue = 9369 | pages = 1581–1589 | date = May 2003 | pmid = 12747876 | doi = 10.1016/S0140-6736(03)13306-5 | s2cid = 40851775 }}</ref>

Chlorpromazine may deposit in ocular tissues when taken in high dosages for long periods of time.

{| class="wikitable"
|+ Comparison of chlorpromazine to placebo<ref name=Adams/>
|-
! Measured outcome !! Findings summary!! Findings range!! Quality of evidence
|-
! colspan="4" style="text-align:left;"| Adverse effects
|-
| Weight gain || 5 times more likely to have considerable weight gain, around 40% with chlorpromazine gaining weight || RR 4.9 CI 2.3 to 10.4 || rowspan="5" style="text-align:center;" | Very low <small>(estimate of effect uncertain)</small>
|-
| Sedation || 3 times more likely to cause sedation, around 30% with chlorpromazine || RR 2.8 CI 2.3 to 3.5
|-
| Acute movement disorder || 3.5 times more likely to cause easily reversible but unpleasant severe stiffening of muscles, around 6% with chlorpromazine || RR 3.5 CI 1.5 to 8.0
|-
| Parkinsonism || 2 times more likely to cause parkinsonism (symptoms such as tremor, hesitancy of movement, decreased facial expression), around 17% with chlorpromazine || RR 2.1 CI 1.6 to 2.8
|-
| Decreased blood pressure with dizziness ||  3 times more likely to cause decreased blood pressure and dizziness, around 15% with chlorpromazine || RR 2.4 CI 1.7 to 3.3
|}

===Contraindications===

Absolute contraindications include:<ref name = TGA/>
{{div col|colwidth=22em}}
* Circulatory depression
* [[CNS depression]]
* Coma
* Drug intoxication
* Bone marrow suppression
* [[Phaeochromocytoma]]
* [[Hepatic failure]]
* Active liver disease
{{div col end}}
* Previous [[hypersensitivity]] (including jaundice, agranulocytosis, etc.) to phenothiazines, especially chlorpromazine, or any of the excipients in the formulation being used.

Relative contraindications include:<ref name = TGA/>
{{div col|colwidth=30em}}
* Epilepsy
* [[Parkinson's disease]]
* [[Myasthenia gravis]]
* [[Hypoparathyroidism]]
* Prostatic hypertrophy
{{div col end}}

Very rarely, elongation of the QT interval, due to [[hERG]] blockade, may occur, increasing the risk of potentially fatal arrhythmias.<ref>{{cite journal | vauthors = Thomas D, Wu K, Kathöfer S, Katus HA, Schoels W, Kiehn J, Karle CA | title = The antipsychotic drug chlorpromazine inhibits HERG potassium channels | journal = British Journal of Pharmacology | volume = 139 | issue = 3 | pages = 567–574 | date = June 2003 | pmid = 12788816 | pmc = 1573882 | doi = 10.1038/sj.bjp.0705283 }}</ref>

===Interactions===
{{cleanup section|reason=Too much use of "also"; unclear structure/organization, especially due to heavy reliance on one source.|date=January 2022}}
Consuming food prior to taking chlorpromazine orally limits its absorption; likewise, cotreatment with [[benztropine]] can also reduce chlorpromazine absorption.<ref name = TGA/> [[alcohol (drug)|Alcohol]] can also reduce chlorpromazine absorption.<ref name = TGA/> Antacids slow chlorpromazine absorption.<ref name = TGA/> [[Lithium (medication)|Lithium]] and chronic treatment with [[barbiturates]] can increase chlorpromazine clearance significantly.<ref name = TGA/> [[Tricyclic antidepressants]] (TCAs) can decrease chlorpromazine clearance and hence increase chlorpromazine exposure.<ref name = TGA/> Cotreatment with [[CYP1A2]] inhibitors like [[ciprofloxacin]], [[fluvoxamine]] or [[vemurafenib]] can reduce chlorpromazine clearance and hence increase exposure and potentially also adverse effects.<ref name = TGA/> Chlorpromazine can also potentiate the CNS depressant effects of drugs like [[barbiturates]], [[benzodiazepines]], [[opioids]], lithium and anesthetics and hence increase the potential for adverse effects such as [[respiratory depression]] and [[sedation]].<ref name =TGA/>

Chlorprozamine is also a moderate inhibitor of [[CYP2D6]] and a substrate for [[CYP2D6]], and hence can inhibit its own metabolism.<ref name =GG/> It can also inhibit the clearance of [[CYP2D6]] substrates such as [[dextromethorphan]], potentiating their effects.<ref name = GG/> Other drugs like [[codeine]] and [[tamoxifen]], which require [[CYP2D6]]-mediated activation into their respective active metabolites, may have their therapeutic effects attenuated.<ref name = GG/> Likewise, [[CYP2D6]] inhibitors such as [[paroxetine]] or [[fluoxetine]] can reduce chlorpromazine clearance, increasing serum levels of chlorpromazine and potentially its adverse effects.<ref name = TGA/> Chlorpromazine also reduces [[phenytoin]] levels and increases [[valproic acid]] levels.<ref name =TGA/> It also reduces [[propranolol]] clearance and antagonizes the therapeutic effects of [[antidiabetic]] agents, [[levodopa]] (a [[Parkinson's]] medication. This is likely due to the fact that chlorpromazine antagonizes the D<sub>2</sub> receptor which is one of the receptors dopamine, a levodopa metabolite, activates), [[amphetamine]]s and [[anticoagulant]]s.<ref name = TGA/> It may also interact with anticholinergic drugs such as [[orphenadrine]] to produce [[hypoglycaemia]] (low blood sugar).<ref name = TGA/>

Chlorpromazine may also interact with [[epinephrine]] (adrenaline) to produce a paradoxical fall in blood pressure.<ref name = TGA/> [[Monoamine oxidase inhibitors]] (MAOIs) and [[thiazide]] diuretics may also accentuate the orthostatic hypotension experienced by those receiving chlorpromazine treatment.<ref name = TGA/> Quinidine may interact with chlorpromazine to increase [[myocardium|myocardial]] depression.<ref name = TGA/> Likewise, it may also antagonize the effects of [[clonidine]] and [[guanethidine]].<ref name = TGA/> It also may reduce the seizure threshold and hence a corresponding titration of anticonvulsant treatments should be considered.<ref name = TGA/> [[Prochlorperazine]] and [[desferrioxamine]] may also interact with chlorpromazine to produce transient metabolic [[encephalopathy]].<ref name = TGA/>

Other drugs that prolong the QT interval, such as [[quinidine]], [[verapamil]], [[amiodarone]], [[sotalol]] and [[methadone]], may also interact with chlorpromazine to produce additive [[QT interval]] prolongation.<ref name = TGA/>

===Discontinuation===
The [[British National Formulary]] recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.<ref name="Group 2009 192">{{cite book |editor1-first=BMJ | editor =  Joint Formulary Committee  | title = British National Formulary | edition = 57 | date = March 2009 |publisher=Royal Pharmaceutical Society of Great Britain |location=United Kingdom |isbn=978-0-85369-845-6 |page=192 |chapter=4.2.1 |quote=Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.}}</ref> Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.<ref name=Had2004>{{cite book | vauthors = Haddad PM, Dursun S, Deakin B |title=Adverse Syndromes and Psychiatric Drugs: A Clinical Guide |date=2004 |publisher=OUP Oxford |isbn=9780198527480 |pages=207–16 |url=https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207 |language=en}}</ref> Other symptoms may include restlessness, increased sweating, and trouble sleeping.<ref name=Had2004/> Less commonly, there may be a feeling of the world spinning, numbness, or muscle pains.<ref name=Had2004/> Symptoms generally resolve after a short period of time.<ref name=Had2004/>

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.<ref>{{cite journal | vauthors = Moncrieff J | title = Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse | journal = Acta Psychiatrica Scandinavica | volume = 114 | issue = 1 | pages = 3–13 | date = July 2006 | pmid = 16774655 | doi = 10.1111/j.1600-0447.2006.00787.x | s2cid = 6267180 }}</ref> It may also result in reoccurrence of the condition that is being treated.<ref>{{cite book | vauthors = Sacchetti E, Vita A, Siracusano A, Fleischhacker W |title=Adherence to Antipsychotics in Schizophrenia |date=2013 |publisher=Springer Science & Business Media |isbn=9788847026797 |page=85 |url=https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85 |language=en}}</ref> Rarely, tardive dyskinesia can occur when the medication is stopped.<ref name=Had2004/>

==Pharmacology==
Chlorpromazine is classified as a low-potency [[typical antipsychotic]]. Low-potency antipsychotics have more [[anticholinergic]] side effects, such as dry mouth, sedation, and constipation, and lower rates of [[Extrapyramidal symptoms|extrapyramidal]] side effects, while high-potency antipsychotics (such as [[haloperidol]]) have the reverse profile.<ref name =GG/>

===Pharmacodynamics===
{| class="wikitable" style = "float: right; margin-left:15px; text-align:center"
|+Chlorpromazine
!Site
!Ki
!Species
!Ref
|-
|[[5-HT1A receptor|5-HT<sub>1A</sub>]]
|3115
|Human
|<ref>{{cite journal | vauthors = Maheux J, Ethier I, Rouillard C, Lévesque D | title = Induction patterns of transcription factors of the nur family (nurr1, nur77, and nor-1) by typical and atypical antipsychotics in the mouse brain: implication for their mechanism of action | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 313 | issue = 1 | pages = 460–473 | date = April 2005 | pmid = 15615863 | doi = 10.1124/jpet.104.080184 | hdl-access = free | s2cid = 1436507 | hdl = 20.500.11794/17025 }}</ref>
|-
|[[5-HT1B receptor|5-HT<sub>1B</sub>]]
|1,489
|Human
|<ref name=":0">{{Cite web|title=Chlorpromazine|url=https://pdsp.unc.edu/databases/pdspImg.php|website=PDSP Database}}</ref>
|-
|[[5-HT1D receptor|5-HT<sub>1D</sub>]]
|452
|Human
|<ref name=":0" />
|-
|[[5-HT1E receptor|5-HT<sub>1E</sub>]]
|344
|Human
|<ref name=":0" />
|-
|[[5-HT2A receptor|5-HT<sub>2A</sub>]]
|2.75
|Human
|<ref>{{cite journal | vauthors = Gillman PK | title = Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity | journal = British Journal of Anaesthesia | volume = 95 | issue = 4 | pages = 434–441 | date = October 2005 | pmid = 16051647 | doi = 10.1093/bja/aei210 | doi-access = free }}</ref>
|-
|[[5-HT2C receptor|5-HT<sub>2C</sub>]]
|25
|Human
|<ref>{{cite journal | vauthors = Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL | title = H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs | journal = Neuropsychopharmacology | volume = 28 | issue = 3 | pages = 519–526 | date = March 2003 | pmid = 12629531 | doi = 10.1038/sj.npp.1300027 | author8-link = Herbert Y. Meltzer | doi-access = free | author9-link = Bryan Roth }}</ref>
|-
|[[5-HT3 receptor|5-HT<sub>3</sub>]]
|776
|Human
|<ref name=":1">{{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 }}</ref>
|-
|[[5-HT5A receptor|5-HT<sub>5A</sub>]]
|118
|Human
|<ref name=":0" />
|-
|[[5-HT6 receptor|5-HT<sub>6</sub>]]
|19.5
|Human
|<ref name=":1" />
|-
|[[5-HT7 receptor|5-HT<sub>7</sub>]]
|21
|Human
|<ref name=":0" />
|-
|[[Alpha-1A adrenergic receptor|α<sub>1A</sub>]]
|0.28
|Human
|<ref name=":0" />
|-
|[[Alpha-1B adrenergic receptor|α<sub>1B</sub>]]
|0.81
|Human
|<ref name=":0" />
|-
|[[Alpha-2A adrenergic receptor|α<sub>2A</sub>]]
|184
|Human
|<ref name=":0" />
|-
|[[Alpha-2B adrenergic receptor|α<sub>2B</sub>]]
|28
|Human
|<ref name=":0" />
|-
|[[Alpha-2C adrenergic receptor|α<sub>2C</sub>]]
|46
|Human
|<ref name=":0" />
|-
|[[Beta-1 adrenergic receptor|β<sub>1</sub>]]
|>10,000
|Human
|<ref name=":0" />
|-
|[[Beta-2 adrenergic receptor|β<sub>2</sub>]]
|>10,000
|Human
|<ref name=":0" />
|-
|[[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]]
|47
|Human
|<ref name=":0" />
|-
|[[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]]
|433
|Human
|<ref name=":0" />
|-
|[[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]]
|47
|Human
|<ref name=":0" />
|-
|[[Muscarinic acetylcholine receptor M4|M<sub>4</sub>]]
|151
|Human
|<ref name=":0" />
|-
|[[Dopamine receptor D1|D<sub>1</sub>]]
|114.8
|Human
|<ref name=":1" />
|-
|[[Dopamine receptor D2|D<sub>2</sub>]]
|7.244
|Human
|<ref name=":1" />
|-
|[[Dopamine receptor D3|D<sub>3</sub>]]
|6.9
|Human
|<ref name=":2">{{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 }}</ref>
|-
|[[Dopamine receptor D4|D<sub>4</sub>]]
|32.36
|Human
|<ref name=":1" />
|-
|[[Histamine H1 receptor|H<sub>1</sub>]]
|4.25
|Human
|<ref name=":2" />
|-
|[[Histamine H2 receptor|H<sub>2</sub>]]
|174
|Human
|<ref name=":0" />
|-
|[[Histamine H3 receptor|H<sub>3</sub>]]
|1,000
|Human
|<ref name=":2" />
|-
|[[Histamine H4 receptor|H<sub>4</sub>]]
|5,048
|Human
|<ref name=":0" />
|-
|[[Norepinephrine transporter|NET]]
|2,443
|Human
|<ref name=":0" />
|-
|[[Dopamine transporter|DAT]]
|>10,000
|Human
|<ref name=":0" />
|}

Chlorpromazine is a very effective antagonist of [[Dopamine receptor D2|D2]] [[dopamine]] receptors and similar receptors, such as [[Dopamine receptor D3|D3]] and [[Dopamine receptor D5|D5]]. Unlike most other drugs of this genre, it also has a high affinity for [[Dopamine receptor D1|D1]] receptors. Blocking these receptors causes diminished neurotransmitter binding in the forebrain, resulting in many different effects. [[Dopamine]], unable to bind with a receptor, causes a feedback loop that causes dopaminergic neurons to release more dopamine. Therefore, upon first taking the drug, patients will experience an increase in dopaminergic neural activity. Eventually, dopamine production of the neurons will drop substantially and dopamine will be removed from the [[synaptic cleft]]. At this point, neural activity decreases greatly; the continual blockade of receptors only compounds this effect.<ref name="GG"/>

Chlorpromazine acts as an [[receptor antagonist|antagonist]] (blocking agent) on different postsynaptic and presynaptic receptors:

*[[Dopamine receptor]]s (subtypes D<sub>1</sub>, D<sub>2</sub>, D<sub>3</sub> and D<sub>4</sub>), which account for its different antipsychotic properties on productive and unproductive symptoms, in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects
*[[Serotonin receptor]]s (5-HT<sub>2</sub>, 5-HT<sub>6</sub> and 5-HT<sub>7</sub>), with anxiolytic, antidepressant and antiaggressive properties as well as an attenuation of [[extrapyramidal side effect]]s, but also leading to weight gain and ejaculation difficulties.
*[[Histamine receptor]]s ([[histamine H1 receptor|H<sub>1</sub> receptor]]s, accounting for sedation, antiemetic effect, vertigo, and weight gain)
*[[Adrenergic receptor|α<sub>1</sub>- and α<sub>2</sub>-adrenergic receptor]]s (accounting for sympatholytic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism – controversial. Also associated with weight gain as a result of blockage of the adrenergic alpha 1 receptor as well as with [[intraoperative floppy iris syndrome]] due to its effect on the iris dilator muscle.<ref>{{cite book | vauthors = Tsai LM |title=Lens and cataract |date=2021 |publisher= American Academy of Ophthalmology |location=San Francisco |isbn=978-1681044491 |pages=162}}</ref>
*[[Muscarinic acetylcholine receptor|M<sub>1</sub> and M<sub>2</sub> muscarinic acetylcholine receptor]]s (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, [[sinus tachycardia]], [[electrocardiogram|electrocardiographic]] changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects).{{medcn|date=March 2023}}

The presumed effectiveness of the antipsychotic drugs relied on their ability to block dopamine receptors. This assumption arose from the dopamine hypothesis that maintains that both schizophrenia and bipolar disorder are a result of excessive dopamine activity. Furthermore, psychomotor stimulants like cocaine that increase dopamine levels can cause psychotic symptoms if taken in excess.<ref name="Girault, 2004">{{cite journal | vauthors = Girault JA, Greengard P | title = The neurobiology of dopamine signaling | journal = Archives of Neurology | volume = 61 | issue = 5 | pages = 641–644 | date = May 2004 | pmid = 15148138 | doi = 10.1001/archneur.61.5.641 | doi-access = free }}</ref>

Chlorpromazine and other typical [[antipsychotics]] are primarily blockers of [[D2 receptors]]. In fact an almost perfect correlation exists between the therapeutic dose of a typical antipsychotic and the drug's affinity for the D2 receptor. Therefore, a larger dose is required if the drug's affinity for the D2 receptor is relatively weak. A correlation exists between average clinical potency and affinity of the antipsychotics for [[dopamine]] receptors.<ref name="Kin">{{Cite book| vauthors = McKim WA | title=Drugs and behavior: an introduction to behavioral pharmacology| edition=6th| publisher=Prentice Hall| location=Upper Saddle River, New Jersey| year=2007| page=416| isbn=978-0-13-219788-5}}</ref>
Chlorpromazine tends to have greater effect at [[serotonin]] receptors than at [[Dopamine receptor D2|D2]] receptors, which is notably the opposite effect of the other typical antipsychotics. Therefore, chlorpromazine with respect to its effects on dopamine and serotonin receptors is more similar to the atypical antipsychotics than to the typical antipsychotics.<ref name="Kin"/>

Chlorpromazine and other antipsychotics with [[sedative]] properties such as [[promazine]] and [[thioridazine]] are among the most potent agents at [[α-adrenergic receptor]]s. Furthermore, they are also among the most potent antipsychotics at [[histamine]] [[Histamine H1 receptor|H1]] receptors. This finding is in agreement with the pharmaceutical development of chlorpromazine and other antipsychotics as anti-histamine agents. Furthermore, the brain has a higher density of histamine H1 receptors than any body organ examined which may account for why chlorpromazine and other [[phenothiazine]] antipsychotics are as potent at these sites as the most potent classical [[antihistamines]].<ref name="Per">{{cite journal | vauthors = Peroutka SJ, Synder SH | title = Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency | journal = The American Journal of Psychiatry | volume = 137 | issue = 12 | pages = 1518–1522 | date = December 1980 | pmid = 6108081 | doi = 10.1176/ajp.137.12.1518 }}</ref>

In addition to influencing the neurotransmitters dopamine, serotonin, [[epinephrine]], [[norepinephrine]], and [[acetylcholine]] it has been reported that antipsychotic drugs could achieve glutamatergic effects. This mechanism involves direct effects on antipsychotic drugs on [[glutamate]] receptors. By using the technique of functional neurochemical assay chlorpromazine and phenothiazine derivatives have been shown to have inhibitory effects on [[NMDA]] receptors that appeared to be mediated by action at the Zn site. It was found that there is an increase of NMDA activity at low concentrations and suppression at high concentrations of the drug. No significant difference in [[glycine]] activity from the effects of chlorpromazine were reported. Further work will be necessary to determine if the influence in NMDA receptors by antipsychotic drugs contributes to their effectiveness.<ref name="Lid">{{cite journal | vauthors = Lidsky TI, Yablonsky-Alter E, Zuck LG, Banerjee SP | title = Antipsychotic drug effects on glutamatergic activity | journal = Brain Research | volume = 764 | issue = 1–2 | pages = 46–52 | date = August 1997 | pmid = 9295192 | doi = 10.1016/S0006-8993(97)00423-X | s2cid = 37454572 }}</ref>

Chlorpromazine does also act as a [[FIASMA]] (functional inhibitor of [[Sphingomyelin phosphodiesterase|acid sphingomyelinase]]).<ref name="pmid18504571">{{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 | 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 | veditors = Riezman H | doi-access = free | bibcode = 2011PLoSO...623852K }}</ref>

===Peripheral effects===
Chlorpromazine is an antagonist to [[histamine H1 receptor|H<sub>1</sub> receptor]]s (provoking antiallergic effects), [[histamine H2 receptor|H<sub>2</sub> receptor]]s (reduction of forming of gastric juice), [[muscarinic acetylcholine receptor|M<sub>1</sub> and M<sub>2</sub> receptor]]s (dry mouth, reduction in forming of gastric juice) and some [[5-HT receptor]]s (different anti-allergic/gastrointestinal actions).{{medcn|date=March 2023}}

Because it acts on so many receptors, chlorpromazine is often referred to as a "[[Dirty Drug|dirty drug]]".<ref name="Falkai">{{cite journal | vauthors = Falkai P, Vogeley K | title = [The chances of new atypical substances] | journal = Fortschritte der Neurologie-Psychiatrie | volume = 68 | issue = Suppl 1 | pages = S32–S37 | date = April 2000 | pmid = 10907611 | url = http://www.biopsychiatry.com/antipsychotics.htm | access-date = 6 July 2010 | publisher = biopsychiatry.com | url-status = live | archive-url = https://web.archive.org/web/20100724041027/http://www.biopsychiatry.com/antipsychotics.htm | archive-date = 24 July 2010 }}</ref>

===Pharmacokinetics===
{| class = wikitable
|+ <big>Pharmacokinetic parameters of chlorpromazine</big><ref name = TGA/><ref name = GG/><ref name=EMCS>{{cite web|title=Chlorpromazine Hydrochloride 100mg/5ml Oral Syrup – Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Rosemont Pharmaceuticals Limited|date=6 August 2013|access-date=8 December 2013|url=http://www.medicines.org.uk/emc/medicine/10751/SPC/Chlorpromazine+Hydrochloride+100mg+5ml+Oral+Syrup/|url-status=live|archive-url=https://web.archive.org/web/20131211235858/http://www.medicines.org.uk/emc/medicine/10751/SPC/Chlorpromazine+Hydrochloride+100mg+5ml+Oral+Syrup/|archive-date=11 December 2013}}</ref>
! Bioavailability !! t<sub>max</sub> !! C<sub>SS</sub> !!  Protein bound !! V<sub>d</sub> !! t<sub>1/2</sub> !! Details of metabolism !! Excretion !! Notes
|-
| 10–80% || 1–4 hours (Oral); 6–24 hours (IM) || 100–300&nbsp;ng/mL || 90–99% || 10–35 L/kg (mean: 22 L/kg) || 30±7 hours || [[CYP2D6]], [[CYP1A2]]—mediated into over 10 major metabolites.<ref name = GG/> The major routes of metabolism include hydroxylation, N-oxidation, sulfoxidation, demethylation, deamination and conjugation. There is little evidence supporting the development of metabolic tolerance or an increase in the metabolism of chlorpromazine due to microsomal liver enzymes following multiple doses of the drug.<ref name="Dahl">{{cite journal | vauthors = Dahl SG, Strandjord RE | title = Pharmacokinetics of chlorpromazine after single and chronic dosage | journal = Clinical Pharmacology and Therapeutics | volume = 21 | issue = 4 | pages = 437–448 | date = April 1977 | pmid = 849674 | doi = 10.1002/cpt1977214437 | s2cid = 6645825 }}</ref> || Urine (43–65% after 24 hours) || Its high degree of [[lipophilicity]] (fat solubility) allows it to be detected in the urine for up to 18 months.<ref name =TGA/><ref name = "Yeu"/> Less than 1% of the unchanged drug is excreted via the kidneys in the urine, in which 20–70% is excreted as conjugated or unconjugated metabolites, whereas 5–6% is excreted in feces.<ref name="Yeu">{{cite journal | vauthors = Yeung PK, Hubbard JW, Korchinski ED, Midha KK | title = Pharmacokinetics of chlorpromazine and key metabolites | journal = European Journal of Clinical Pharmacology | volume = 45 | issue = 6 | pages = 563–569 | year = 1993 | pmid = 8157044 | doi = 10.1007/BF00315316 | s2cid = 6410850 }}</ref>
|}

[[Image:MetabsofChlorpromazine.svg|thumb|left|600px|Three common metabolites of chlorpromazine]]
{{clear}}

==History==
[[File:Thorazine advert.jpg|thumb|Advertisement for Thorazine (chlorpromazine) from the early 1960s<ref>{{cite web| url=https://commons.wikimedia.org/wiki/File:Thorazine_advert.jpg#/media/File:Thorazine_advert.jpg |title= Thorazine advertisement| publisher= Smith Kline & French | year= c. 1963| quote=When the patient lashes out against 'them' –  Thorazine (brand of chlorpromazine) quickly puts an end to his violent outburst. 'Thorazine' is especially effective when the psychotic episode is triggered by delusions or hallucinations. At the outset of treatment, Thorazine's combination of antipsychotic and sedative effects provides both emotional and physical calming. Assaultive or destructive behavior is rapidly controlled. As therapy continues, the initial sedative effect gradually disappears. But the antipsychotic effect continues, helping to dispel or modify delusions, hallucinations and confusion, while keeping the patient calm and approachable. Smith Kline and French Laboratories}}</ref>]]

In 1933, the French pharmaceutical company [[Laboratoires Rhône-Poulenc]] began to search for new [[antihistamine]]s. In 1947, it synthesized [[promethazine]], a [[phenothiazine]] derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs.<ref name = "Healy_2004">{{Cite book | vauthors = Healy D |title = The creation of psychopharmacology |year = 2004 |publisher = Harvard University Press |isbn = 978-0-674-01599-9 |page = 77 |chapter = Explorations in a new world |url = https://books.google.com/books?id=6O2rPJnyhj0C |url-status = live |access-date = 26 November 2013 |archive-url = https://web.archive.org/web/20170908170912/https://books.google.com/books?id=6O2rPJnyhj0C&printsec=frontcover&dq=isbn=978-0-674-01599-9&cd=1 |archive-date = 8 September 2017}}</ref>{{rp|77}} A year later, the French surgeon Pierre Huguenard used promethazine together with [[pethidine]] as part of a cocktail to induce relaxation and indifference in surgical patients. Another surgeon, [[Henri Laborit]], believed the compound stabilized the central nervous system by causing "artificial hibernation" and described this state as "sedation without [[narcotic|narcosis]]". He suggested to Rhône-Poulenc that they develop a compound with better stabilizing properties.<ref>{{Cite book| vauthors = Healy D | title=The creation of psychopharmacology| year=2004| publisher=Harvard University Press| isbn=978-0-674-01599-9| page=80| chapter=Explorations in a new world}}</ref> In December 1950, the chemist Paul Charpentier produced a series of compounds that included RP4560 or chlorpromazine.<ref name="history05"/>

Chlorpromazine was distributed for testing to physicians between April and August 1951. Laborit trialled the medicine on at the [[Val-de-Grâce]] military hospital in Paris, using it as an anaesthetic booster in intravenous doses of 50 to 100&nbsp;mg on surgery patients and confirming it as the best drug to date in calming and reducing shock, with patients reporting improved well being afterwards. He also noted its [[hypothermic]] effect and suggested it may induce artificial hibernation. Laborit thought this would allow the body to better tolerate major surgery by reducing [[circulatory shock | shock]], a novel idea at the time. Known colloquially as "Laborit's drug", chlorpromazine was released onto the market in 1953 by Rhône-Poulenc and given the trade name ''Largactil'', derived from ''large'' "broad" and ''acti*'' "activity".<ref name="history05"/><!-- cites previous four sentences -->

Following on, Laborit considered whether chlorpromazine may have a role in managing patients with severe [[burn]]s, [[Raynaud's phenomenon]], or psychiatric disorders. At the Villejuif Mental Hospital in November 1951, he and Montassut administered an [[intravenous]] dose to psychiatrist Cornelia Quarti, who was acting as a volunteer. Quarti noted the indifference, but fainted upon getting up to go to the toilet, and so further testing was discontinued. ([[Orthostatic hypotension]] is a known side effect of chlorpromazine). Despite this, Laborit continued to push for testing in psychiatric patients during early 1952. Psychiatrists were reluctant initially, but on 19 January 1952, it was administered (alongside pethidine, [[pentothal]] and ECT) to Jacques Lh., a 24-year-old [[mania| manic]] patient, who responded dramatically; he was discharged after three weeks, having received 855&nbsp;mg of the drug in total.<ref name="history05"/><!-- cites previous four sentences -->

[[Pierre Deniker]] had heard about Laborit's work from his brother-in-law, who was a surgeon, and ordered chlorpromazine for a clinical trial at the [[Sainte-Anne Hospital Center]] in Paris where he was chief of the men's service.<ref name="history05"/> Together with the hospital director [[Jean Delay]], they published their first clinical trial in 1952, in which they treated thirty-eight [[psychosis|psychotic]] patients with daily injections of chlorpromazine without the use of other sedating agents.<ref name="Turner2007"/> The response was dramatic; treatment with chlorpromazine went beyond simple sedation, with patients showing improvements in [[cognition| thinking]] and [[emotion]]al behaviour.<ref name="healy1">{{Cite book |url=https://books.google.com/books?id=6O2rPJnyhj0C |title=The Creation of Psychopharmacology | vauthors = Healy D |year=2004 |publisher=Harvard University Press |pages=37–73 |isbn=978-0-674-01599-9 |url-status=live |access-date=26 November 2013 |archive-url=https://web.archive.org/web/20170908170912/https://books.google.com/books?id=6O2rPJnyhj0C&printsec=frontcover&dq=isbn=978-0-674-01599-9&cd=1#v=onepage&q=chlorpromazie |archive-date=8 September 2017}}</ref> They also found that doses higher than those used by Laborit were required, giving patients 75–100&nbsp;mg daily.<ref name="history05"/>

Deniker then visited America, where the publication of their work alerted the American psychiatric community that the new treatment might represent a real breakthrough. Heinz Lehmann of the [[Douglas Hospital|Verdun Protestant Hospital]] in Montreal trialled it in seventy patients and also noted its striking effects, with patients' symptoms resolving after many years of unrelenting psychosis.<ref>{{Cite web| vauthors = Dronsfield A |title=Chlorpromazine - unlocks the saylum|url=https://edu.rsc.org/feature/chlorpromazine-unlocks-the-saylum/2020118.article|access-date=13 January 2022|website=RSC Education|language=en}}</ref> By 1954, chlorpromazine was being used in the United States to treat [[schizophrenia]], [[mania]], [[psychomotor agitation|psychomotor excitement]], and other [[psychosis|psychotic]] disorders.<ref name="GG">{{cite book | isbn = 978-0-07-162442-8 | title = [[Goodman and Gilman's The Pharmacological Basis of Therapeutics]] | edition = 12th | vauthors = Brunton L, Chabner B, Knollman B | year = 2010 | publisher = McGraw-Hill Professional | location = New York }}</ref><ref>{{Cite book| vauthors = Long JW |title=The Essential guide to prescription drugs| publisher= HarperPerennial| location= New York|year=1992|pages=321–25|isbn=978-0-06-271534-0}}</ref><ref>{{Cite journal| vauthors = Reines BP | year= 1990| title= The Relationship Between Laboratory and Clinical Studies in Psychopharmacologic Discovery| journal= Perspectives on Medical Research| volume= 2| publisher= Medical Research Modernization Society| url= http://www.curedisease.net/reports/Perspectives/vol_2_1990/PsycholDisc.html| url-status= live| access-date= 26 November 2013| archive-url= https://web.archive.org/web/20150907024721/http://www.curedisease.net/reports/Perspectives/vol_2_1990/PsycholDisc.html| archive-date= 7 September 2015}}</ref>
Rhône-Poulenc licensed chlorpromazine to Smith Kline & French (today's [[GlaxoSmithKline]]) in 1953. In 1955 it was approved in the United States for the treatment of emesis (vomiting). The effect of this drug in emptying [[psychiatric hospitals]] has been compared to that of [[penicillin]] on [[infectious disease]]s.<ref name="Turner2007">{{cite journal | vauthors = Turner T | title = Chlorpromazine: unlocking psychosis | journal = BMJ | volume = 334 | issue = Suppl 1 | pages = s7 | date = January 2007 | pmid = 17204765 | doi = 10.1136/bmj.39034.609074.94 | s2cid = 33739419 }}</ref> 

But the popularity of the drug fell from the late 1960s as newer drugs came on the scene. From chlorpromazine a number of other similar antipsychotics were developed, leading to the discovery of [[antidepressants]].<ref name="healy3">{{Cite book| vauthors = Healy D | title= The Creation of Psychopharmacology| url= https://books.google.com/books?id=6O2rPJnyhj0C| year= 2004| publisher= Harvard University Press| isbn= 9780674015999| page= 2| chapter= Introduction| url-status= live| access-date= 26 November 2013| archive-url= https://web.archive.org/web/20170908170912/https://books.google.com/books?id=6O2rPJnyhj0C&printsec=frontcover&dq=isbn=978-0-674-01599-9&cd=1#v=onepage&q=chlorpromazine| archive-date= 8 September 2017}}</ref>

Chlorpromazine largely replaced [[electroconvulsive therapy]], [[hydrotherapy]],<ref>{{cite web |url= http://davidhealy.org/wp-content/uploads/2014/07/Psychopharmacology-and-The-Government-of-the-Self.pdf |title= Psychopharmacology and the Government of the Self | vauthors = Healy D |date= 2000 |website= davidhealy.org |access-date= 20 July 2015 |url-status= dead |archive-url= https://web.archive.org/web/20141006092443/http://davidhealy.org/wp-content/uploads/2014/07/Psychopharmacology-and-The-Government-of-the-Self.pdf |archive-date= 6 October 2014}}</ref> [[psychosurgery]], and [[insulin shock therapy]].<ref name="healy1"/> By 1964, about fifty million people worldwide had taken it.<ref>{{Cite web|url=https://www.pbs.org/wgbh/aso/databank/entries/dh52dr.html|title=Drug for treating schizophrenia identified|website=PBS.org|publisher=[[WGBH-TV]]|access-date=7 July 2010|url-status=live|archive-url=https://web.archive.org/web/20090918064700/http://www.pbs.org/wgbh/aso/databank/entries/dh52dr.html|archive-date=18 September 2009}}</ref> Chlorpromazine, in widespread use for fifty years, remains a "benchmark" drug in the treatment of [[schizophrenia]], an effective drug although not a perfect one.<ref name="Adams" />

== Society and culture ==
=== In literature ===
Thorazine was often depicted in Tom Wolfe's [[The Electric Kool-Aid Acid Test]] to abort bad trips on [[LSD]]. Thorazine is also mentioned in [[Fear and Loathing in Las Vegas]], where it was reported to negate the effects of LSD.

=== Names ===
Brand names include Thorazine, Largactil, Hibernal, and Megaphen (sold by [[Bayer]] in West-Germany since July 1953).<ref>Bangen, Hans (1992). Geschichte der medikamentösen Therapie der Schizophrenie. Verlag für Wissenschaft und Bildung. p.&nbsp;98. {{ISBN|3-927-408-82-4}}.</ref>

==Research==
Chlorpromazine has tentative benefit{{clarify|date=July 2024}} in animals infected with ''[[Naegleria fowleri]]''<ref>{{cite journal | vauthors = Kim JH, Jung SY, Lee YJ, Song KJ, Kwon D, Kim K, Park S, Im KI, Shin HJ | title = Effect of therapeutic chemical agents in vitro and on experimental meningoencephalitis due to Naegleria fowleri | journal = Antimicrobial Agents and Chemotherapy | volume = 52 | issue = 11 | pages = 4010–4016 | date = November 2008 | pmid = 18765686 | pmc = 2573150 | doi = 10.1128/AAC.00197-08 }}</ref> and shows [[antifungal]] and [[antibacterial]] activity [[in vitro]].<ref name="Afeltra Verweij pp. 397–407">{{cite journal | vauthors = Afeltra J, Verweij PE | title = Antifungal activity of nonantifungal drugs | journal = European Journal of Clinical Microbiology & Infectious Diseases | volume = 22 | issue = 7 | pages = 397–407 | date = July 2003 | pmid = 12884072 | doi = 10.1007/s10096-003-0947-x | publisher = Springer Nature | s2cid = 10489462 }}</ref>{{clarify|reason=In a specific species, or in general?|date=January 2022}}

==Veterinary use==
The veterinary use of chlorpromazine has generally been superseded by use of [[acepromazine]].<ref name="Plumb2015">{{cite book| vauthors = Plumb DC |title=Plumb's Veterinary Drug Handbook|year=2015|publisher=John Wiley & Sons|isbn=978-1118911921|edition=8th}}</ref>

Chlorpromazine may be used as an [[antiemetic]] in dogs and cats, or, less often, as sedative before anesthesia.<ref name="VetPharmTherap9">{{cite book| vauthors = Posner LA, Burns P | veditors = Riviere JE, Papich MG, Adams RH |title=Veterinary pharmacology and therapeutics.|date=2009|publisher=Wiley-Blackwell|location=Ames, Iowa|isbn=9780813820613|pages=337–80|edition=9|chapter=Chapter 13: Sedative agents: tranquilizers, alpha-2 agonists, and related agents}}</ref> In horses, it often causes [[ataxia]] and [[lethargy]] and is therefore seldom used.<ref name="Plumb2015" /><ref name="VetPharmTherap9" />

It is commonly used to decrease nausea in animals that are too young for other common antiemetics.{{Citation needed|date=February 2017}} It is sometimes used as a [[preanesthetic]] and [[muscle relaxant]] in cattle, swine, sheep, and goats.{{Citation needed|date=February 2017}}

The use of chlorpromazine in [[livestock| food-producing animal]]s is not permitted in the [[European Union]], as a [[maximum residue limit]] could not be determined following assessment by the [[European Medicines Agency]].<ref>{{cite web|title=Chlorpromazine: summary report|url=http://www.ema.europa.eu/docs/en_GB/document_library/Maximum_Residue_Limits_-_Report/2009/11/WC500012075.pdf|website=European Medicines Agency|publisher=Committee for Veterinary Medicinal Products|access-date=17 January 2017|date=June 1996|url-status=live|archive-url=https://web.archive.org/web/20170118140703/http://www.ema.europa.eu/docs/en_GB/document_library/Maximum_Residue_Limits_-_Report/2009/11/WC500012075.pdf|archive-date=18 January 2017}}</ref>

== References ==
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