imported>Monkbot: Monkbot/task 21: Replace page(s) with article-number;

2025-09-28T17:09:28Z

Monkbot/task 21: Replace page(s) with article-number;

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{{Short description|Antipsychotic medication}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 408581688
| image = Loxapine.svg
| image_class = skin-invert-image
| width = 200
| alt =
| image2 = Loxapine ball-and-stick model from xtal 1977.png
| width2 = 200
| alt2 =


| tradename = Loxitane, Adasuve
| Drugs.com = {{drugs.com|monograph|loxapine-succinate}}
| MedlinePlus = a682311
| licence_EU = yes
| DailyMedID = Loxapine
| licence_US = Loxapine
| routes_of_administration = [[Oral administration|By mouth]], [[inhalation]], [[Intramuscular injection|intramuscular]]
| class = [[Antipsychotic]]
| ATC_prefix = N05
| ATC_suffix = AH01
| ATC_supplemental =

| legal_AU = S4
| legal_BR = C1
| legal_BR_comment = <ref>{{Cite web | vauthors = Anvisa | title = RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial | date = 2023-03-31 | 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_US = Rx-only
| legal_EU = Rx-only


| bioavailability =
| protein_bound = 96.8%<ref name="DrugPoint">Truven Health Analytics, Inc. DrugPoint System (Internet) [cited 2013 Sep 21]. Greenwood Village, CO: Thomsen Healthcare; 2013.</ref>
| metabolism = Extensive [[Liver]]; active metabolites include [[amoxapine]] and 8-hydroxyloxapine. Inhibits [[P-glycoprotein|P-gp]] and is a substrate of [[CYP1A2]], [[CYP3A4]] and [[CYP2D6]]<ref name="DrugPoint" />
| elimination_half-life = 4 hours (oral); 7.61 hours (inhalation)<ref name="DrugPoint" />
| excretion = Majority are excreted within 24 hours, main route through urine (conjugated metabolites), small amounts through the feces (unconjugated metabolites)


| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 1977-10-2
| PubChem = 3964
| IUPHAR_ligand = 205
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB00408
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3827
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = LER583670J
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02340
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 50841
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 831


| IUPAC_name = 8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepine
| C=18 | H=18 | Cl=1 | N=3 | O=1
| SMILES = Clc2ccc1Oc4c(/N=C(\c1c2)N3CCN(C)CC3)cccc4
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C18H18ClN3O/c1-21-8-10-22(11-9-21)18-14-12-13(19)6-7-16(14)23-17-5-3-2-4-15(17)20-18/h2-7,12H,8-11H2,1H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = XJGVXQDUIWGIRW-UHFFFAOYSA-N
| melting_point = 109
| melting_high = 110
}}

[[Image:Loxapine.jpg|thumb|right|Bottle containing loxapine capsules, a mid-potency antipsychotic.]]

'''Loxapine''', sold under the brand names '''Loxitane''' and '''Adasuve''' (''inhalation'' only) among others, is a [[tricyclic]]<ref>{{cite journal | vauthors = Popovic D, Nuss P, Vieta E | title = Revisiting loxapine: a systematic review | journal = Annals of General Psychiatry | volume = 14 | article-number = 15 | date = 2015-04-01 | pmid = 25859275 | pmc = 4391595 | doi = 10.1186/s12991-015-0053-3 | doi-access = free }}</ref> [[antipsychotic]] medication used primarily in the treatment of [[schizophrenia]]. The medicine is a member of the [[dibenzoxazepine]] class and structurally very similar to [[clozapine]]. Several researchers have argued that loxapine, initially classified as a [[typical antipsychotic]], behaves as an [[atypical antipsychotic]].<ref name="Glazer_1999">{{cite journal | vauthors = Glazer WM | title = Does loxapine have "atypical" properties? Clinical evidence | journal = The Journal of Clinical Psychiatry | volume = 60 Suppl 10 | issue = Suppl 10 | pages = 42–46 | year = 1999 | pmid = 10340686 | url = https://www.psychiatrist.com/jcp/psychopharmacology/does-loxapine-atypical-properties-clinical-evidence/ }}</ref>

Loxapine may be metabolized by ''N''-demethylation to [[amoxapine]], a [[tricyclic antidepressant]].<ref name="Cheung_1991">{{cite journal | vauthors = Cheung SW, Tang SW, Remington G | title = Simultaneous quantitation of loxapine, amoxapine and their 7- and 8-hydroxy metabolites in plasma by high-performance liquid chromatography | journal = Journal of Chromatography | volume = 564 | issue = 1 | pages = 213–221 | date = March 1991 | pmid = 1860915 | doi = 10.1016/0378-4347(91)80083-O }}</ref>

==Medical uses==
The [[US Food and Drug Administration]] (FDA) has approved loxapine inhalation powder for the acute treatment of agitation associated with schizophrenia or [[bipolar I disorder]] in adults.<ref name="ADASUVE PI" />

A brief review of loxapine found no conclusive evidence that it was particularly effective in patients with [[schizophrenia]].<ref name="pmid1747161">{{cite journal | title = Clozapine and loxapine for schizophrenia | journal = Drug and Therapeutics Bulletin | volume = 29 | issue = 11 | pages = 41–42 | date = May 1991 | pmid = 1747161 | doi = 10.1136/dtb.29.11.41 | s2cid = 27613339 }}</ref> A subsequent systematic review considered that the limited evidence did not indicate a clear difference in its effects from other antipsychotics.<ref name="Chakrabarti_2007">{{cite journal | vauthors = Chakrabarti A, Bagnall A, Chue P, Fenton M, Palaniswamy V, Wong W, Xia J | veditors = Chakrabarti A | title = Loxapine for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2007 | issue = 4 | article-number = CD001943 | date = October 2007 | pmid = 17943763 | pmc = 7017975 | doi = 10.1002/14651858.CD001943.pub2 }}</ref>

===Available forms===
Loxapine can be taken [[Oral administration|by mouth]].<ref name="LOXITANE PI">{{cite web | title = LOXITANE Package Insert | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017525s051,017658s038,018039s024lbl.pdf | publisher = Watson Laboratories, Inc. }}</ref> It is also available as an intramuscular injection and as a powder for inhalation.<ref name="ADASUVE PI" /><ref name="LOXITANE PI" />

==Side effects==

Loxapine can cause side effects that are generally similar to that of other antipsychotic medications. These include, e.g., gastrointestinal problems (like constipation and abdominal pain), cardiovascular problems (like tachycardia), moderate likelihood of drowsiness (relative to other antipsychotics),<ref name="Taylor_2012">{{cite book | vauthors = Taylor D, Paton C, Kapur S, Taylor D | title = The Maudsley prescribing guidelines in psychiatry | location = Chichester, West Sussex | date = 2012 | publisher = Wiley-Blackwell | isbn = 978-0-470-97948-8 | edition = 11th }}</ref> and movement problems (i.e. [[extrapyramidal symptoms]] [EPS]).<ref name="Chakrabarti Cochrane 2007">{{cite journal | vauthors = Chakrabarti A, Bagnall A, Chue P, Fenton M, Palaniswamy V, Wong W, Xia J | title = Loxapine for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2007 | issue = 4 | article-number = CD001943 | date = October 2007 | pmid = 17943763 | pmc = 7017975 | doi = 10.1002/14651858.CD001943.pub2 }}</ref> At lower dosages its propensity for causing EPS appears to be similar to that of atypical antipsychotics.<ref name="Nordstrom_2012">{{Cite journal | vauthors = Nordstrom K | title = Inhaled loxapine for rapid treatment of agitation in schizophrenia and bipolar disorder: An update | journal = Neuropsychiatry | volume = 2 | issue = 3 | pages = 253–260 | year = 2012 | doi = 10.2217/npy.12.23 | s2cid = 39718567 }}</ref> Although it is structurally similar to [[clozapine]], it has much lower risk of [[agranulocytosis]] (which, even with clozapine, is 0.8%); however, mild and temporary fluctuations in blood leukocyte levels can occur.<ref name="DePaulo review 1982">{{cite journal | vauthors = DePaulo JR, Ayd FJ | title = Loxapine: fifteen years' clinical experience | journal = Psychosomatics | volume = 23 | issue = 3 | pages = 261–271 | date = March 1982 | pmid = 7041162 | doi = 10.1016/S0033-3182(82)73416-4 }}</ref><ref name="Singh et al 1996">{{cite journal | vauthors = Singh AN, Barlas C, Singh S, Franks P, Mishra RK | title = A neurochemical basis for the antipsychotic activity of loxapine: interactions with dopamine D1, D2, D4 and serotonin 5-HT2 receptor subtypes | journal = Journal of Psychiatry & Neuroscience | volume = 21 | issue = 1 | pages = 29–35 | date = January 1996 | pmid = 8580115 | pmc = 1188731 }}</ref> Abuse of loxapine has been reported.<ref name="Sperry et al 1984">{{cite journal | vauthors = Sperry L, Hudson B, Chan CH | title = Loxapine abuse | journal = The New England Journal of Medicine | volume = 310 | issue = 9 | page = 598 | date = March 1984 | pmid = 6694719 | doi = 10.1056/NEJM198403013100920 }}</ref>

The inhaled formulation of loxapine carries a low risk for a type of airway adverse reaction called [[bronchospasm]] that is not thought to occur when loxapine is taken by mouth.<ref name="ADASUVE PI">{{cite web | title = ADASUVE Package Insert | url = https://www.adasuve.com/PDF/AdasuvePI.pdf | publisher = Galen US Inc }}</ref>

==Pharmacology==
===Mechanism of action===
Some scientists say loxapine is a "[[Typical antipsychotic#Potency|mid-potency]]" typical antipsychotic.<ref name="Singh et al 1996" /> However, unlike most other typical antipsychotics, it has significant potency at the 5HT2A receptor (6.6 nM), which is similar to atypical antipsychotics like [[clozapine]] (5.35 nM). The higher likelihood of EPS with loxapine, compared to clozapine, may be due to its higher affinity for the D2 receptor compared to [[clozapine]], which has one of the lowest binding affinities at the D2 receptor of any antipsychotic.<ref name="Singh et al 1996" />

{| class="wikitable floatright sortable" style="font-size:small;"
|+ Loxapine (and metabolite)<ref name="PDSP">{{cite web | vauthors = Roth BL, Driscol J | title = PDSP Ki Database | website = Psychoactive Drug Screening Program (PDSP) | author1-link = Bryan Roth | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 14 August 2017 | url = https://kidbdev.med.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=loxapine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query }}</ref><ref name="Appl_2012">{{cite journal | vauthors = Appl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R | title = Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 385 | issue = 2 | pages = 145–170 | date = February 2012 | pmid = 22033803 | doi = 10.1007/s00210-011-0704-0 | s2cid = 14274150 }}</ref>
|-
! data-sortable | Site !! {{abbr|LOX|Loxapine}} !! {{abbrlink|AMX|Amoxapine}}
|-
| [[5-HT1A receptor|5-HT1A]] || 2460 || {{abbr|ND|No data}}
|-
| [[5-HT1B receptor|5-HT1B]] || 388 || {{abbr|ND|No data}}
|-
| [[5-HT1D receptor|5-HT1D]] || 3470 || {{abbr|ND|No data}}
|-
| [[5-HT1E receptor|5-HT1E]] || 1400 || {{abbr|ND|No data}}
|-
| [[5-HT2A receptor|5-HT2A]] || 6.6 || 0.5
|-
| [[5-HT2C receptor|5-HT2C]] || 13 || 2 (rat)
|-
| [[5-HT3 receptor|5-HT3]] || 190 || {{abbr|ND|No data}}
|-
| [[5-HT5A receptor|5-HT5A]] || 780 || {{abbr|ND|No data}}
|-
| [[5-HT6 receptor|5-HT6]] || 31 || 50
|-
| [[5-HT7 receptor|5-HT7]] || 88 || 40 (rat)
|-
| [[Alpha-1A adrenergic receptor|α1A]] || 31 || {{abbr|ND|No data}}
|-
| [[Alpha-1B adrenergic receptor|α1B]] || 53 || {{abbr|ND|No data}}
|-
| [[Alpha-2A adrenergic receptor|α2A]] || 151 || {{abbr|ND|No data}}
|-
| [[Alpha-2B adrenergic receptor|α2B]] || 108 || {{abbr|ND|No data}}
|-
| [[Alpha-2C adrenergic receptor|α2C]] || 80 || {{abbr|ND|No data}}
|-
| [[Beta-1 adrenergic receptor|β1]] || 10000+ || {{abbr|ND|No data}}
|-
| [[Beta-2 adrenergic receptor|β2]] || 10000+ || {{abbr|ND|No data}}
|-
| [[Muscarinic acetylcholine receptor M1|M1]] || 120 || {{abbr|ND|No data}}
|-
| [[Muscarinic acetylcholine receptor M2|M2]] || 445 || {{abbr|ND|No data}}
|-
| [[Muscarinic acetylcholine receptor M3|M3]] || 211 || {{abbr|ND|No data}}
|-
| [[Muscarinic acetylcholine receptor M4|M4]] || 1270 || {{abbr|ND|No data}}
|-
| [[Muscarinic acetylcholine receptor M5|M5]] || 166 || {{abbr|ND|No data}}
|-
| [[Dopamine D1 receptor|D1]] || 54 || {{abbr|ND|No data}}
|-
| [[Dopamine D2 receptor|D2]] || 11 || 21
|-
| [[Dopamine D3 receptor|D3]] || 19 || 21
|-
| [[Dopamine D4 receptor|D4]] || 8.4 || 21
|-
| [[Dopamine D5 receptor|D5]] || 75 || {{abbr|ND|No data}}
|-
| [[Histamine H1 receptor|H1]] || 2.2–4.9 || 7.9–25
|-
| [[Histamine H2 receptor|H2]] || 208 || {{abbr|ND|No data}}
|-
| [[Histamine H3 receptor|H3]] || 55000 || >100,000
|-
| [[Histamine H4 receptor|H4]] || 5050–8710 || 6,310
|-
| {{abbrlink|SERT|Serotonin transporter}} || 10000+ || 58
|-
| {{abbrlink|NET|Norepinephrine transporter}} || 5700 || 16
|-
| {{abbrlink|DAT|Dopamine transporter}} || 10000+ || 58
|- class="sortbottom"
| colspan="3" style="width: 1px;" | Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.
|}

====Use as an Inhaled Agitation Medication====
Loxapine has a relatively strong safety profile compared to similar antipsychotic drugs, such as quetiapine, olanzapine, and clozapine, with a relatively lower incidence of metabolic side-effects (although higher extrapyramial side-effects).<ref>{{Cite journal | vauthors = Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, Arndt T, Bäckers L, Rothe P, Cipriani A, Davis J, Salanti G, Leucht S | title = Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis | journal = Lancet | location = London, England | volume = 394 | issue = 10202 | pages = 939–951 | date = 2019-09-14 | pmid = 31303314 | pmc = 6891890 | doi = 10.1016/S0140-6736(19)31135-3 | language = English | issn = 0140-6736 }}</ref> Given its strong safety profile and speed/efficacy when given intramuscularly for acute agitation,<ref>{{Cite journal | vauthors = Lebel C, Endomba FT, Chabridon G, Chauvet-Gélinier JC | title = Efficacy and Safety of Loxapine in Acute Agitation: A Systematic Review of Interventional Studies | journal = The Primary Care Companion for CNS Disorders | volume = 25 | issue = 6 | date = 2023-12-19 | pmid = 38134395 | doi = 10.4088/PCC.23r03552 | url = https://www.psychiatrist.com/pcc/efficacy-safety-loxapine-acute-agitation-systematic-review-interventional-studies/ | issn = 2155-7780 | url-access = subscription }}</ref> an inhaled version of the drug (Adasuve) has been developed to be applied nasally for agitated patients needing to be rapidly de-escalated.<ref>{{Cite journal | vauthors = Popovic D, Nuss P, Vieta E | title = Revisiting loxapine: a systematic review | journal = Annals of General Psychiatry | volume = 14 | article-number = 15 | date = 2015 | pmid = 25859275 | pmc = 4391595 | doi = 10.1186/s12991-015-0053-3 | doi-access = free | issn = 1744-859X }}</ref>

===Pharmacokinetics===
Loxapine is metabolized to [[amoxapine]], as well as its 8-hydroxy metabolite (8-hydroxyloxapine).<ref name="DrugPoint" /> Amoxapine is further metabolized to its 8-hydroxy metabolite ([[8-hydroxyamoxapine]]), which is also found in the blood of people taking loxapine.<ref name="Simpson et al 1978">{{cite journal | vauthors = Simpson GM, Cooper TB, Lee JH, Young MA | title = Clinical and plasma level characteristics of intramuscular and oral loxapine | journal = Psychopharmacology | volume = 56 | issue = 2 | pages = 225–232 | date = March 1978 | pmid = 417377 | doi = 10.1007/BF00431855 | s2cid = 21795809 }}</ref> At [[Steady state (biochemistry)|steady-state]] after taking loxapine by mouth, the relative amounts of loxapine and its metabolites in the blood is as follows: 8-hydroxyloxapine > 8-hydroxyamoxapine > loxapine.<ref name="Simpson et al 1978" />

The pharmacokinetics of loxapine change depending on how it is given. Intramuscular injections of loxapine lead to higher blood levels and [[Area under the curve (pharmacokinetics)|area under the curve]] of loxapine than when it is taken by mouth.<ref name="Simpson et al 1978" />

==Chemistry==
Loxapine is a [[dibenzoxazepine]] and is structurally very similar to [[clozapine]], an [[atypical antipsychotic]].
[[File:Loxapine and clozapine.svg|class=skin-invert-image|thumb|center|400px|Chemical structures of loxapine and clozapine, with key differences highlighted.]]

== References ==
{{Reflist}}

== External links ==
* {{cite web | title = Loxapine | url = https://druginfo.nlm.nih.gov/drugportal/name/loxapine | archive-url = https://web.archive.org/web/20190628221417/https://druginfo.nlm.nih.gov/drugportal/name/loxapine | archive-date = June 28, 2019 | publisher = U.S. National Library of Medicine | work = Drug Information Portal }}

{{Antipsychotics}}
{{Antidepressants}}
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| title = [[Pharmacodynamics]]
| titlestyle = background:#ccccff
| list1 =
{{Adrenergic receptor modulators}}
{{Dopamine receptor modulators}}
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}}
{{Tricyclics}}
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[[Category:4-Methylpiperazin-1-yl compounds]]
[[Category:Alpha-1 blockers]]
[[Category:Alpha-2 blockers]]
[[Category:Chloroarenes]]
[[Category:Dibenzoxazepines]]
[[Category:M1 receptor antagonists]]
[[Category:M2 receptor antagonists]]
[[Category:M3 receptor antagonists]]
[[Category:M4 receptor antagonists]]
[[Category:M5 receptor antagonists]]
[[Category:Typical antipsychotics]]

Loxapine - Revision history

imported>Monkbot: Monkbot/task 21: Replace page(s) with article-number;