Editing Doxylamine

{{Short description|First-generation antihistamine used as a short-term sedative and hypnotic (sleep aid)}}
{{Use dmy dates|date=April 2023}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 456483386
| IUPAC_name = (''RS'')-''N'',''N''-dimethyl-2-[1-phenyl-1-(pyridin-2-yl)ethoxy]ethan-1-amine
| image = Doxylamine structure.svg
| image_class = skin-invert-image
| width = 200px
| alt = Skeletal formula of the doxylamine molecule
| image2 = Doxylamine 3D ball.png
| width2 = 200px
| alt2 = Ball-and-stick model of the doxylamine molecule

<!--Clinical data-->
| tradename = Unisom, [[Vicks]] Formula 44 (in combination with [[Dextromethorphan]]), others
| Drugs.com = {{drugs.com|monograph|doxylamine-succinate}}
| MedlinePlus = a682537
| pregnancy_US = B
| pregnancy_AU = A
| pregnancy_category = A (Briggs)
| legal_AU = S3
| legal_US = OTC
| routes_of_administration = [[Oral administration|By mouth]]

<!--Pharmacokinetic data-->
| bioavailability = [[Oral administration|Oral]]: 24.7%<ref name=pmid12214324/><br/>[[Intranasal administration|Intranasal]]: 70.8%<ref name=pmid12214324/>
| metabolism = [[Liver|Hepatic]] ([[CYP2D6]], [[CYP1A2]], [[CYP2C9]])<ref name=KrygerRoth2010/>
| elimination_half-life = 10–12 hours (range 7–15 hours)<ref name="KrygerRoth2010" /><ref name="pmid29671128" /><ref name="pmid27057416" />
| excretion = [[Urine]] (60%), [[feces]] (40%)<ref name=NZlabel>{{cite web|title=New Zealand Datasheet: Doxylamine Succinate|url=http://www.medsafe.govt.nz/profs/datasheet/d/Dozilecap.pd|publisher=Medsafe, New Zealand Medicines and Medical Devices Safety Authority|archive-url=https://web.archive.org/web/20160322211016/http://www.medsafe.govt.nz/profs/datasheet/d/Dozilecap.pdf|archive-date=22 March 2016|date=16 July 2008|url-status=dead}}</ref>

<!--Identifiers-->
| IUPHAR_ligand = 7171
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 469-21-6
| ATC_prefix = R06
| ATC_suffix = AA09
| PubChem = 3162
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00366
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3050
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 95QB77JKPL
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07878
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 51380
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1004
| synonyms =

<!--Chemical data-->
| C=17 | H=22 | N=2 | O=1
| SMILES = n1ccccc1C(c1ccccc1)(C)OCCN(C)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C17H22N2O/c1-17(20-14-13-19(2)3,15-9-5-4-6-10-15)16-11-7-8-12-18-16/h4-12H,13-14H2,1-3H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = HCFDWZZGGLSKEP-UHFFFAOYSA-N
}}
'''Doxylamine''' is an [[antihistamine]] medication used to treat [[insomnia]] and [[allergy|allergies]], and—in combination with [[pyridoxine]] ([[vitamin B6|vitamin B<sub>6</sub>]])—to treat [[morning sickness]] in [[pregnant]] women. It is available [[over-the-counter]] and is sold under such brand names as '''Equate''' or '''Unisom''', among others; and it is used in nighttime [[cold medicine]]s (e.g., [[NyQuil]]) and [[pain medication]]s containing [[paracetamol]] (acetaminophen) or [[codeine]] to help with [[sleep]]. The medication is delivered chemically by the salt doxylamine succinate and is taken [[oral administration|by mouth]]. Doxylamine and other [[first-generation antihistamine]]s are the most widely used sleep medications in the world.<ref name="SimonsSimons2011" /> Typical [[side effect]]s of doxylamine include [[dizziness]], [[drowsiness]], [[grogginess]], and [[dry mouth]], among others.<ref name="pmid17824496">{{cite journal | vauthors = Neubauer DN | title = The evolution and development of insomnia pharmacotherapies | journal = Journal of Clinical Sleep Medicine | volume = 3 | issue = 5 Suppl | pages = S11–S15 | date = August 2007 | pmid = 17824496 | pmc = 1978321 | doi = 10.5664/jcsm.26930 }}</ref><ref name="pmid27057416" /> 

As an antihistamine, doxylamine is an [[inverse agonist]] of the [[histamine]] [[H1 receptor|H<sub>1</sub> receptor]]. As a first-generation antihistamine, it typically crosses the [[blood–brain barrier]] into the [[brain]], thereby producing a suite of [[sedative]] and [[hypnotic]] effects that are mediated by the [[central nervous system]].  

Doxylamine is also a potent [[anticholinergic]], meaning that it [[deliriant|causes delirum]] at high doses (i.e., at much higher doses than recommended).<ref>{{cite web | url=https://psychonautwiki.org/wiki/Doxylamine | title=Doxylamine - PsychonautWiki }}</ref> Specifically, it is an [[receptor antagonist|antagonist]] of the [[muscarinic acetylcholine receptor]]s [[muscarinic acetylcholine receptor M1|M<sub>1</sub>]] through [[muscarinic acetylcholine receptor M5|M<sub>5</sub>]]. These sedative and deliriant effects have in some cases led to the drug being used recreationally. Doxylamine was first described in 1948 or 1949.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=546 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA546 }}</ref>

==Medical uses==
Doxylamine is an antihistamine used to treat [[sneezing]], [[runny nose]], [[watery eyes]], [[hives]], [[skin rash]], [[itching]], and other [[common cold|cold]] or [[allergy]] symptoms. It is also used as a short-term treatment for insomnia.<ref>{{Cite web|url=https://medlineplus.gov/druginfo/meds/a682537.html|title = Doxylamine: MedlinePlus Drug Information}}</ref>

===Insomnia===
The first-generation sedating antihistamines [[diphenhydramine]], [[doxepin]], doxylamine, and [[pyrilamine]] are the most widely used medications in the world for preventing and treating insomnia.<ref name="SimonsSimons2011" /> As of 2004, doxylamine and diphenhydramine, which are both over-the-counter medications, were the agents most commonly used to treat short-term insomnia.<ref>{{cite journal | vauthors = Ringdahl EN, Pereira SL, Delzell JE | title = Treatment of primary insomnia | journal = The Journal of the American Board of Family Practice | volume = 17 | issue = 3 | pages = 212–219 | date = 2004 | pmid = 15226287 | doi = 10.3122/jabfm.17.3.212 | doi-access = free }}</ref> As of 2008 and 2017, over-the-counter antihistamines were not recommended by the [[American Academy of Sleep Medicine]] for treatment of chronic insomnia "due to the relative lack of efficacy and safety data".<ref name="pmid18853708">{{cite journal | vauthors = Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M | title = Clinical guideline for the evaluation and management of chronic insomnia in adults | journal = Journal of Clinical Sleep Medicine | volume = 4 | issue = 5 | pages = 487–504 | date = October 2008 | pmid = 18853708 | pmc = 2576317 | doi = 10.5664/jcsm.27286 }}</ref><ref name="pmid27998379">{{cite journal | vauthors = Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL | title = Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline | journal = Journal of Clinical Sleep Medicine | volume = 13 | issue = 2 | pages = 307–349 | date = February 2017 | pmid = 27998379 | pmc = 5263087 | doi = 10.5664/jcsm.6470 }}</ref> Neither version of their guidelines explicitly included or mentioned doxylamine, although diphenhydramine was discussed.<ref name="pmid18853708" /><ref name="pmid27998379" /> A 2015 systematic review of over-the-counter sleep aids including doxylamine found little evidence to inform the use of doxylamine for treatment of insomnia.<ref name="pmid27057416" />

A major [[systematic review]] and [[network meta-analysis]] of medications for the treatment of insomnia published in 2022 found that doxylamine had an [[effect size]] ([[standardized mean difference]] (SMD)) against [[placebo]] for treatment of insomnia at 4{{nbsp}}weeks of 0.47 (95% {{Abbrlink|CI|confidence interval}} 0.06 to 0.89).<ref name="pmid35843245">{{cite journal | vauthors = De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A | display-authors = 6 | title = Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis | journal = Lancet | volume = 400 | issue = 10347 | pages = 170–184 | date = July 2022 | pmid = 35843245 | doi = 10.1016/S0140-6736(22)00878-9 | s2cid = 250536370 | doi-access = free | hdl = 11380/1288245 | hdl-access = free }}</ref> The [[quality of evidence|certainty of evidence]] was rated as moderate.<ref name="pmid35843245" /> No data were available for doxylamine in terms of longer-term treatment (3{{nbsp}}months).<ref name="pmid35843245" /> For comparison, the other sedating medicines assessed, [[doxepin]] and [[trimipramine]] (both of which are tricyclic antidepressants)  had effect sizes (SMD) at 4{{nbsp}}weeks of 0.30 (95% CI –0.05 to 0.64) (very low certainty evidence) and 0.55 (95% CI –0.11 to 1.21) (very low certainty evidence), respectively.<ref name="pmid35843245" />

Doses of doxylamine that have been used for sleep range from 5 to 50{{nbsp}}mg, with 25{{nbsp}}mg being the typical dose.<ref name="Perry2007">{{Cite book|url=https://books.google.com/books?id=h7lva61Muq4C&pg=PA377|title = Psychotropic Drug Handbook|isbn = 9780781762731| vauthors = Perry PJ |year = 2007|publisher=Lippincott Williams & Wilkins}}</ref><ref name="pmid30879783">{{cite journal | vauthors = Dupuis G, Vaugeois JM | title = [The interesting anti-H1 effects in maintenance insomnia: A reflection on the comparative advantages of doxylamine and doxepin] | language = French | journal = L'Encephale | volume = 46 | issue = 1 | pages = 80–82 | date = February 2020 | pmid = 30879783 | doi = 10.1016/j.encep.2019.01.006 | trans-title = The interesting anti-H1 effects in maintenance insomnia: A reflection on the comparative advantages of doxylamine and doxepin | s2cid = 151085176 | doi-access = free }}</ref><ref name="pmid26609210">{{cite journal | vauthors = Lie JD, Tu KN, Shen DD, Wong BM | title = Pharmacological Treatment of Insomnia | journal = P & T | volume = 40 | issue = 11 | pages = 759–771 | date = November 2015 | pmid = 26609210 | pmc = 4634348 }}</ref><ref name="pmid31913218" />

===Morning sickness===
Doxylamine is used in the [[combination drug]] [[pyridoxine/doxylamine]] to treat [[morning sickness]] (nausea and vomiting of pregnancy).<ref name="pmid24748822" /><ref name="pmid24574047" /><ref name=pmid24421551>{{cite journal | vauthors = Cada DJ, Demaris K, Levien TL, Baker DE | title = Doxylamine succinate/pyridoxine hydrochloride | journal = Hospital Pharmacy | volume = 48 | issue = 9 | pages = 762–766 | date = October 2013 | pmid = 24421551 | pmc = 3857125 | doi = 10.1310/hpj4809-762 }}</ref> It is the only medication approved by the United States [[Food and Drug Administration]] for the treatment of morning sickness.<ref name="pmid24748822" /><ref name="pmid24574047" />

===Available forms===
{{See also|Pyridoxine/doxylamine}}

Doxylamine is used medically as doxylamine succinate, the [[succinate]] [[salt (chemistry)|salt]] of doxylamine, and is available both alone (brand names Decapryn, Doxy-Sleep-Aid, Unisom) and in combination with [[pyridoxine]] (a form of [[vitamin B6|vitamin B<sub>6</sub>]]) (brand names Bendectin, Bonjesta, Diclegis).<ref name="Drugs@FDA">{{cite web | title=Drugs@FDA: FDA-Approved Drugs | website=accessdata.fda.gov | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | archive-url=https://web.archive.org/web/20161104020633/http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | url-status=dead | archive-date=4 November 2016 | access-date=23 August 2022}}</ref> Doxylamine is available alone as [[immediate-release]] [[oral administration|oral]] [[tablet (pharmacy)|tablet]]s containing 25{{nbsp}}mg doxylamine succinate.<ref name="Drugs@FDA" /> Oral tablets containing 12.5{{nbsp}}mg doxylamine succinate as well as oral [[capsule (pharmacy)|capsule]]s containing 25{{nbsp}}mg doxylamine succinate were also previously available but were discontinued.<ref name="Drugs@FDA" /> The [[pyridoxine/doxylamine|combination of doxylamine and pyridoxine]] is available in the form of [[extended-release|extended-]] and [[delayed-release (pharmacy)|delayed-release]] oral tablets containing 10 to 20{{nbsp}}mg doxylamine succinate and 10 to 20{{nbsp}}mg pyridoxine hydrochloride.<ref name="Drugs@FDA" /> Doxylamine alone is available [[over-the-counter]], whereas doxylamine in combination with pyridoxine is a [[prescription-only medication]].<ref name="Drugs@FDA" /> Doxylamine is also available in over-the-counter nighttime [[cold medicine]] products such as NyQuil Cold & Flu (contains [[acetaminophen]], doxylamine succinate 6.25 to 12.5{{nbsp}}mg, and [[dextromethorphan hydrobromide]]), where it serves as the sedating component.<ref name="DailyMed-NyQuil">{{cite web | url=https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=620bc3dc-099b-40bd-be22-e4c3f9c8e09d | work = DailyMed | title = VICKS NYQUIL COLD AND FLU - acetaminophen, dextromethorphan hydrobromide, and doxylamine succinate capsule, liquid filled | publisher = U.S. National Library of Medicine }}</ref><ref name="GoodRx-NyQuil">{{cite web | url=https://www.goodrx.com/nyquil/what-is | title=Nyquil Cold and Flu: Basics, Side Effects & Reviews }}</ref>

==Contraindications==
The [[fetal]] [[Pregnancy category|safety rating]] of doxylamine is "A" (no evidence of risk).<ref name=BriggsFreeman2008>{{cite book | vauthors = Briggs GG, Freeman RK, Yaffe SJ |title=Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk | series = Obstetric Medicine |volume=2 |issue=2 |pages=89 |url=https://books.google.com/books?id=YOEV2w3XTxsC |year=2008 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-7876-3 |doi=10.1258/om.2009.090002 |pmc=4989726}}</ref>

==Side effects==
[[Side effect]]s of doxylamine include [[dizziness]], [[drowsiness]], and [[dry mouth]], among others.<ref name="pmid27057416" /> Doxylamine is a potent [[anticholinergic]] and has a [[adverse drug reaction|side-effect]] profile common to such drugs, including [[blurred vision]], dry mouth, [[constipation]], [[ataxia|muscle incoordination]], [[urinary retention]], [[mental confusion]], and [[delirium]].<ref name="pmid31913218">{{cite journal | vauthors = Shirley DW, Sterrett J, Haga N, Durham C | title = The therapeutic versatility of antihistamines: A comprehensive review | journal = The Nurse Practitioner | volume = 45 | issue = 2 | pages = 8–21 | date = February 2020 | pmid = 31913218 | doi = 10.1097/01.NPR.0000651112.76528.ed | s2cid = 210086511 | doi-access = free }}</ref><ref name="pmid17824496" />

Because of its relatively long [[elimination half-life]] (10–12{{nbsp}}hours), doxylamine is associated with next-day effects including [[sedation]], [[drowsiness]], [[grogginess]], [[dry mouth]], and [[tiredness]] when used as a [[hypnotic]].<ref name=Avidan2017>{{cite book | vauthors = Avidan AY |title=Review of Sleep Medicine E-Book |url=https://books.google.com/books?id=hpwqDwAAQBAJ&pg=PA394 |date= 2017 |publisher=Elsevier Health Sciences |isbn=978-0-323-47349-1 |page=394}}</ref><ref name="pmid31913218" /> This may be described as a "[[hangover effect]]".<ref name="pmid31913218" /> The shorter elimination half-life of diphenhydramine (4–8{{nbsp}}hours) compared to doxylamine may give it an advantage over doxylamine as a sleep aid in this regard.<ref name=RutterNewby2015>{{cite book | vauthors = Rutter P, Newby D |title=Community Pharmacy ANZ – eBook: Symptoms, Diagnosis and Treatment |url=https://books.google.com/books?id=NbjVCgAAQBAJ&pg=PA99 |date=11 September 2015 |publisher=Elsevier Health Sciences |isbn=978-0-7295-8345-9 |page=99}}</ref>

Antihistamines like doxylamine are sedating initially but [[drug tolerance|tolerance]] occurs with repeated use and can result in [[rebound insomnia]] upon [[drug discontinuation|discontinuation]].<ref name="pmid17824496" /><ref name="pmid19179941">{{cite journal | vauthors = Stahl SM | title = Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines | journal = CNS Spectrums | volume = 13 | issue = 12 | pages = 1027–1038 | date = December 2008 | pmid = 19179941 | doi = 10.1017/s1092852900017089 | s2cid = 6849261 }}</ref>

Occasional [[case report]]s of [[coma]] and [[rhabdomyolysis]] have been reported with doxylamine overdose.<ref name="KrygerRoth2010" /> This is in contrast to diphenhydramine.<ref name="KrygerRoth2010" />

Studies of doxylamine's [[carcinogenicity]] in mice and rats have produced positive results for both [[liver cancer|liver]] and [[thyroid cancer]], especially in the mouse.<ref>[http://potency.berkeley.edu/chempages/DOXYLAMINE%20SUCCINATE.html Doxylamine succinate (CAS 562-10-7)] {{Webarchive|url=https://web.archive.org/web/20120501174456/http://potency.berkeley.edu/chempages/DOXYLAMINE%20SUCCINATE.html |date=1 May 2012 }}. berkeley.edu.</ref> The carcinogenicity of the drug in humans is not well-studied, and the [[International Agency for Research on Cancer]] lists the drug as "not classifiable as to its carcinogenicity to humans".<ref>[http://www.inchem.org/documents/iarc/vol79/79-05.html DOXYLAMINE SUCCINATE]. International Agency for Research on Cancer (IARC) – Summaries & Evaluations.</ref>

Continuous and/or cumulative use of [[anticholinergic]] medications, including first-generation antihistamines, is associated with a higher risk of cognitive decline and dementia in older people.<ref>{{cite journal | vauthors = Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB | display-authors = 6 | title = Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study | journal = JAMA Internal Medicine | volume = 175 | issue = 3 | pages = 401–407 | date = March 2015 | pmid = 25621434 | pmc = 4358759 | doi = 10.1001/jamainternmed.2014.7663 | author5-link = Rebecca Hubbard }}</ref><ref>{{cite journal | vauthors = Carrière I, Fourrier-Reglat A, Dartigues JF, Rouaud O, Pasquier F, Ritchie K, Ancelin ML | title = Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study | journal = Archives of Internal Medicine | volume = 169 | issue = 14 | pages = 1317–1324 | date = July 2009 | pmid = 19636034 | pmc = 2933398 | doi = 10.1001/archinternmed.2009.229 }}</ref>

==Overdose==
Doxylamine is generally safe for administration to healthy adults. Doses of doxylamine of up to 1,600{{nbsp}}mg/day for 6{{nbsp}}months have been given to adults with [[schizophrenia]], with little [[toxicity]] encountered.<ref name="FederalRegister1978">{{cite book | date = 1978 | title = Federal Register, Volume 43, Issues 114-121 | publisher = Office of the Federal Register, National Archives and Records Service, General Services Administration |page=25584 | oclc = 1768512 | url = https://books.google.com/books?id=NTG_12_vTEEC&pg=PA25584}}</ref> The [[median lethal dose]] ({{LD50}}) is estimated to be 50–500{{nbsp}}mg/kg in humans.<ref>{{cite web |url=http://hazard.com/msds/mf/baker/baker/files/d8882.htm |title=DOXYLAMINE SUCCINATE |website=hazard.com |url-status=usurped |archive-url=https://web.archive.org/web/20220117012245/http://hazard.com/msds/mf/baker/baker/files/d8882.htm |archive-date=2022-01-17 }}</ref> Symptoms of [[overdose]] may include [[dry mouth]], [[dilated pupil]]s, [[insomnia]], [[night terror]]s, [[euphoria]], [[hallucination]]s, [[seizure]]s, [[rhabdomyolysis]], and death.<ref>{{cite journal | vauthors = Syed H, Som S, Khan N, Faltas W | title = Doxylamine toxicity: seizure, rhabdomyolysis and false positive urine drug screen for methadone | journal = BMJ Case Reports | volume = 2009 | issue = 90 | pages = 845 | date = 17 March 2009 | pmid = 21686586 | pmc = 3028279 | doi = 10.1136/bcr.09.2008.0879 }}</ref> Fatalities have been reported from doxylamine overdose. These have been characterized by [[coma]], [[tonic-clonic seizures|tonic-clonic (or grand mal) seizures]] and [[cardiopulmonary arrest]]. Children appear to be at a high risk for cardiopulmonary arrest. A toxic dose for children of more than 1.8{{nbsp}}mg/kg has been reported. A 3-year-old child died 18 hours after ingesting 1,000{{nbsp}}mg doxylamine succinate.<ref name=NZlabel/> Rarely, an overdose results in [[rhabdomyolysis]] and [[acute kidney injury]].<ref>{{cite journal | vauthors = Leybishkis B, Fasseas P, Ryan KF | title = Doxylamine overdose as a potential cause of rhabdomyolysis | journal = The American Journal of the Medical Sciences | volume = 322 | issue = 1 | pages = 48–49 | date = July 2001 | pmid = 11465247 | doi = 10.1097/00000441-200107000-00009 }}</ref>

==Pharmacology==

===Pharmacodynamics===
{| class="wikitable floatright sortable" style="font-size:small;"
|+ Doxylamine<ref name=PDSP>{{cite web |title= PDSP K<sub>i</sub> Database |work= Psychoactive Drug Screening Program (PDSP)|author1-link=Bryan Roth | vauthors = Roth 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=doxylamine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref>
|-
! Site !! K<sub>i</sub> (nM) !! Species !! Ref
|-
| {{abbrlink|SERT|Serotonin transporter}} || 10000+ || Human || <ref name=pmid23357028>{{cite journal | vauthors = Krystal AD, Richelson E, Roth T | title = Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications | journal = Sleep Medicine Reviews | volume = 17 | issue = 4 | pages = 263–272 | date = August 2013 | pmid = 23357028 | doi = 10.1016/j.smrv.2012.08.001 }}</ref>
|-
| {{abbrlink|NET|Norepinephrine transporter}} || 10000+ || Human || <ref name=pmid23357028/>
|-
| {{abbrlink|DAT|Dopamine transporter}} || 10000+ || Human || <ref name=pmid23357028/>
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 10000+ || Human || <ref name=pmid23357028/>
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 10000+ || Human || <ref name=pmid23357028/>
|-
| [[Alpha-1B adrenergic receptor|α<sub>1B</sub>]] || 10000+ || Human || <ref name=pmid23357028/>
|-
| [[Alpha-2A adrenergic receptor|α<sub>2A</sub>]] || 10000+ || Human || <ref name=pmid23357028/>
|-
| [[Alpha-2B adrenergic receptor|α<sub>2B</sub>]] || 10000+ || Human || <ref name=pmid23357028/>
|-
| [[Alpha-2C adrenergic receptor|α<sub>2C</sub>]] || 10000+ || Human || <ref name=pmid23357028/>
|-
| [[Histamine H1 receptor|H<sub>1</sub>]] || 42 || Human || <ref name=pmid23357028/>
|-
| [[Histamine H2 receptor|H<sub>2</sub>]] || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Histamine H3 receptor|H<sub>3</sub>]] || 10000+ || Human || <ref name=pmid23357028/>
|-
| [[Histamine H4 receptor|H<sub>4</sub>]] || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]] || 490 || Human || <ref name=pmid23357028/>
|-
| [[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]] || 2100 || Human || <ref name=pmid23357028/>
|-
| [[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]] || 650 || Human || <ref name=pmid23357028/>
|-
| [[Muscarinic acetylcholine receptor M4|M<sub>4</sub>]] || 380 || Human || <ref name=pmid23357028/>
|-
| [[Muscarinic acetylcholine receptor M5|M<sub>5</sub>]] || 180 || Human || <ref name=pmid23357028/>
|- class="sortbottom"
| colspan="4" style="width: 1px;" |Values are K<sub>i</sub> (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.
|}

Doxylamine acts primarily as an [[receptor antagonist|antagonist]] or [[inverse agonist]] of the [[histamine]] [[H1 receptor|H<sub>1</sub> receptor]].<ref name="pmid23229983">{{cite journal | vauthors = Vande Griend JP, Anderson SL | title = Histamine-1 receptor antagonism for treatment of insomnia | journal = Journal of the American Pharmacists Association | volume = 52 | issue = 6 | pages = e210–e219 | year = 2012 | pmid = 23229983 | doi = 10.1331/JAPhA.2012.12051 }}</ref><ref name="pmid23357028" /> This action is responsible for its [[antihistamine]] and [[sedative]] properties.<ref name="pmid23229983" /><ref name="pmid23357028" /> To a lesser extent, doxylamine acts as an [[receptor antagonist|antagonist]] of the [[muscarinic acetylcholine receptor]]s,<ref name=pmid23229983/><ref name=pmid23357028/> an action responsible for its [[anticholinergic]] and (at high doses) [[deliriant]] effects.<ref name=pmid23229983/><ref name=pmid23357028/>

===Pharmacokinetics===
The [[bioavailability]] of doxylamine is 24.7% for [[oral administration]] and 70.8% for [[intranasal administration]].<ref name=pmid12214324>{{cite journal | vauthors = Pelser A, Müller DG, du Plessis J, du Preez JL, Goosen C | title = Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats | journal = Biopharmaceutics & Drug Disposition | volume = 23 | issue = 6 | pages = 239–244 | date = September 2002 | pmid = 12214324 | doi = 10.1002/bdd.314 | s2cid = 32126626 }}</ref> The [[Tmax (pharmacology)|T<sub>max</sub>]] of doxylamine is 1.5 to 2.5 hours.<ref name=KrygerRoth2010>{{cite book| vauthors = Kryger MH, Roth T, Dement WC |title=Principles and Practice of Sleep Medicine E-Book|url=https://books.google.com/books?id=3B52V4PnrVkC&pg=PA925|date=1 November 2010|publisher=Elsevier Health Sciences|isbn=978-1-4377-2773-9|page=925}}</ref> Its [[elimination half-life]] is 10 to 12{{nbsp}}hours (range 7 to 15{{nbsp}}hours).<ref name=KrygerRoth2010/><ref name="pmid29671128" /><ref name="pmid27057416">{{cite journal | vauthors = Culpepper L, Wingertzahn MA | title = Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia: A Systematic Review of Efficacy and Safety | journal = The Primary Care Companion for CNS Disorders | volume = 17 | issue = 6 | date = 2015 | pmid = 27057416 | pmc = 4805417 | doi = 10.4088/PCC.15r01798 }}</ref> Doxylamine is [[metabolism|metabolized]] in the [[liver]] primarily by the [[cytochrome P450]] [[enzyme]]s [[CYP2D6]], [[CYP1A2]], and [[CYP2C9]].<ref name=KrygerRoth2010/><ref name="pmid19153052">{{cite journal | vauthors = Krystal AD | title = A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: the empirical basis for U.S. clinical practice | journal = Sleep Medicine Reviews | volume = 13 | issue = 4 | pages = 265–274 | date = August 2009 | pmid = 19153052 | doi = 10.1016/j.smrv.2008.08.001 }}</ref> The main [[metabolite]]s are ''N''-desmethyldoxylamine, ''N'',''N''-didesmethyldoxylamine, and doxylamine ''N''-oxide.<ref>{{cite journal | vauthors = Holder CL, Korfmacher WA, Slikker W, Thompson HC, Gosnell AB | title = Mass spectral characterization of doxylamine and its rhesus monkey urinary metabolites | journal = Biomedical Mass Spectrometry | volume = 12 | issue = 4 | pages = 151–158 | date = April 1985 | pmid = 2861861 | doi = 10.1002/bms.1200120403 | s2cid = 6020605 | url = https://zenodo.org/record/1229133 }}</ref> Doxylamine is [[elimination (pharmacology)|eliminated]] 60% in the [[urine]] and 40% in [[feces]].<ref name=NZlabel/>

[[File:Doxylamine levels after a single 25 mg oral dose of doxylamine.png|class=skin-invert-image|thumb|left|450px|Doxylamine concentrations after a single 25 mg oral dose of doxylamine in healthy volunteers. X-axis represents the time in hours after initial dose.<ref name="pmid29671128">{{cite journal | vauthors = Allison M, Hale C | title = A Phase I Study of the Pharmacokinetics and Pharmacodynamics of Intranasal Doxylamine in Subjects with Chronic Intermittent Sleep Impairment | journal = Drugs in R&D | volume = 18 | issue = 2 | pages = 129–136 | date = June 2018 | pmid = 29671128 | pmc = 5995792 | doi = 10.1007/s40268-018-0232-1 }}</ref>]]

{{Clear}}

==Chemistry==
Doxylamine is a member of the [[ethanolamine]] class of antihistamines.<ref name="SimonsSimons2011">{{cite journal | vauthors = Simons FE, Simons KJ | title = Histamine and H1-antihistamines: celebrating a century of progress | journal = The Journal of Allergy and Clinical Immunology | volume = 128 | issue = 6 | pages = 1139–1150.e4 | date = December 2011 | pmid = 22035879 | doi = 10.1016/j.jaci.2011.09.005 | doi-access = free }}</ref> Other antihistamines from this group include [[bromodiphenhydramine]], [[carbinoxamine]], [[clemastine]], [[dimenhydrinate]], [[diphenhydramine]], [[orphenadrine]], and [[phenyltoloxamine]].<ref name="SimonsSimons2011" /><ref name="pmid23173575">{{cite journal | vauthors = Kalpaklioglu F, Baccioglu A | title = Efficacy and safety of H1-antihistamines: an update | journal = Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry | volume = 11 | issue = 3 | pages = 230–237 | date = 2012 | pmid = 23173575 | doi = 10.2174/1871523011202030230 }}</ref>

==History==
Doxylamine is a first-generation [[antihistamine]] and was discovered by Nathan Sperber and colleagues and was first reported in 1948 or 1949.<ref name="Atta-ur-Rahman2018">{{cite book | veditors = Atta-ur-Rahman | date = 11 July 2018 | title = Frontiers in Clinical Drug Research - Anti-Allergy Agents, Volume 3 | publisher = Bentham Science Publishers |page=30 | isbn = 978-1-68108-337-7 | oclc = 1048922805 | url = https://books.google.com/books?id=EIJoDwAAQBAJ&pg=PA30}}</ref><ref name="Fis2006" /><ref name="pmid18113525">{{cite journal | vauthors = Sperber N, Papa D | title = Pyridyl-substituted alkamine ethers as antihistaminic agents | journal = Journal of the American Chemical Society | volume = 71 | issue = 3 | pages = 887–890 | date = March 1949 | pmid = 18113525 | doi = 10.1021/ja01171a034 | bibcode = 1949JAChS..71..887S }}</ref> It has been the antihistamine component of [[NyQuil]] since 1966.<ref name="Atta-ur-Rahman2018" />

Bendectin, a combination of doxylamine, pyridoxine (vitamin B<sub>6</sub>), and [[dicyclomine]] (an [[anticholinergic]] [[antispasmodic]] agent), was marketed for treatment of morning sickness in 1956.<ref name="BriggsFreemanYaffe2012">{{cite book | vauthors = Briggs GG, Freeman RK, Yaffe SJ | date = 28 March 2012 | title = Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk | edition = 9 | publisher = Lippincott Williams & Wilkins |page=453 | isbn = 978-1-4511-5359-0 | oclc = 1232803849 | url = https://books.google.com/books?id=ScPvM03B3lUC&pg=PA453}}</ref> This product was reformulated in 1976 to remove dicyclomine.<ref name="BriggsFreemanYaffe2012" /> The reformulated product was voluntarily discontinued by the manufacturer in the United States in 1983 due to concerns about an alleged association with [[congenital limb defect]]s.<ref name="BriggsFreemanYaffe2012" /> However, these concerns have not been supported by studies.<ref name="pmid24748822">{{cite journal | vauthors = Nuangchamnong N, Niebyl J | title = Doxylamine succinate-pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview | journal = International Journal of Women's Health | volume = 6 | pages = 401–409 | date = 2014 | pmid = 24748822 | pmc = 3990370 | doi = 10.2147/IJWH.S46653 | doi-access = free }}</ref><ref name="pmid24574047">{{cite journal | vauthors = Madjunkova S, Maltepe C, Koren G | title = The delayed-release combination of doxylamine and pyridoxine (Diclegis®/Diclectin ®) for the treatment of nausea and vomiting of pregnancy | journal = Paediatric Drugs | volume = 16 | issue = 3 | pages = 199–211 | date = June 2014 | pmid = 24574047 | pmc = 4030125 | doi = 10.1007/s40272-014-0065-5 }}</ref> In 2013, doxylamine/pyridoxine was reintroduced in the United States under the brand name Diclegis.<ref name="pmid24748822" /><ref name="pmid24574047" /> The combination was not removed from the market in Canada, where it had been marketed since 1979.<ref name="pmid24748822" /><ref name="pmid24574047" />

==Society and culture==

===Formulations===
Doxylamine is primarily used as the [[succinic acid]] [[salt (chemistry)|salt]], doxylamine succinate.

* It is the sedating ingredient of [[NyQuil]] (generally in combination with [[dextromethorphan]] and [[acetaminophen]]).
* In [[Commonwealth of Nations|Commonwealth]] countries, such as Australia, Canada, South Africa, and the United Kingdom, doxylamine is available prepared with [[paracetamol]] (acetaminophen) and [[codeine]] under the brand name Dolased, Propain Plus, Syndol, or Mersyndol, as treatment for [[tension headache]] and other types of [[pain]].
* Doxylamine succinate is used in general [[over-the-counter drug|over-the-counter]] sleep-aids branded as Somnil (South Africa), Dozile, Donormyl, Lidène (France, Russian Federation), Dormidina (Spain, Portugal), Restavit, Unisom-2, Sominar (Thailand), Sleep Aid (generic, Australia) and Dorminox (Poland).
* In the United States:
** Doxylamine succinate is the active ingredient in many over-the-counter sleep aids branded under various names.
** Doxylamine succinate and pyridoxine (Vitamin B6) are the ingredients of Diclegis, approved by the FDA in April 2013 becoming the only drug approved for morning sickness<ref name=SlaughterHearns-Stokes2014>{{cite journal | vauthors = Slaughter SR, Hearns-Stokes R, van der Vlugt T, Joffe HV | title = FDA approval of doxylamine-pyridoxine therapy for use in pregnancy | journal = The New England Journal of Medicine | volume = 370 | issue = 12 | pages = 1081–1083 | date = March 2014 | pmid = 24645939 | doi = 10.1056/NEJMp1316042 | doi-access = free }}</ref> with a class A [[Pregnancy category|safety rating for pregnancy]] (no evidence of risk).
* In [[Canada]]:
** Doxylamine succinate and [[pyridoxine]] ([[vitamin B6|vitamin B<sub>6</sub>]]) are the ingredients of Diclectin, which is used to prevent [[morning sickness]].
** It is also available in combination with vitamin B<sub>6</sub> and [[folic acid]] under the brand name Evanorm (marketed by Ion Healthcare).
* In [[India]]
** Doxylamine preparations are available typically in combination with pyridoxine which may also contain folic acid. Doxylamine usage is thus restricted for pregnant women.

== References ==
{{Reflist}}

{{Navboxes
| title = [[Medicine|Medical use]]s
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[[Category:2-Pyridyl compounds]]
[[Category:Antiemetics]]
[[Category:Antihistamines]]
[[Category:Dimethylamino compounds]]
[[Category:Ethers]]
[[Category:H1 receptor antagonists]]
[[Category:Hypnotics]]
[[Category:M1 receptor antagonists]]
[[Category:M3 receptor antagonists]]
[[Category:M4 receptor antagonists]]
[[Category:M5 receptor antagonists]]
[[Category:Sedatives]]
[[Category:Ethanolamines]]