Wikipedia

Doxylamine

Doxylamineis anantihistaminemedication used to treatinsomniaandallergies,and—in combination withpyridoxine(vitamin B6)—to treatmorning sicknessinpregnantwomen. It is availableover-the-counterand is typically sold under such brand names asEquateorUnisom,among others; and it is used in nighttimecold medicines(e.g.,NyQuil) andpain medicationscontainingacetaminophenand/orcodeineto help withsleep.The medication is delivered chemically by the saltdoxylamine succinateand is taken bymouth.Doxylamine and otherfirst-generation antihistaminesare the most widely used sleep medications in the world.[6]Typicalside effectsof doxylamine (at recommended doses) includedizziness,drowsiness,grogginess,anddry mouth,among others.[7][4]

Doxylamine
Skeletal formula of the doxylamine molecule
Ball-and-stick model of the doxylamine molecule
Clinical data
Trade namesUnisom,VicksFormula 44 (in combination withDextromethorphan), others
AHFS/Drugs.comMonograph
MedlinePlusa682537
Pregnancy
category
  • AU:A
  • A (Briggs)
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU:S3(Pharmacist only)
  • US:OTC
Pharmacokineticdata
BioavailabilityOral:24.7%[1]
Intranasal:70.8%[1]
MetabolismHepatic(CYP2D6,CYP1A2,CYP2C9)[2]
Eliminationhalf-life10–12 hours (range 7–15 hours)[2][3][4]
ExcretionUrine(60%),feces(40%)[5]
Identifiers
  • (RS)-N,N-dimethyl-2-[1-phenyl-1-(pyridin-2-yl)ethoxy]ethan-1-amine
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.006.742Edit this at Wikidata
Chemical and physical data
FormulaC17H22N2O
Molar mass270.376g·mol−1
3D model (JSmol)
  • n1ccccc1C(c1ccccc1)(C)OCCN(C)C
  • InChI=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,13-14H2,1-3H3checkY
  • Key:HCFDWZZGGLSKEP-UHFFFAOYSA-NcheckY
(verify)

As an antihistamine, doxylamine is aninverse agonistof thehistamineH1receptor.As a first-generation antihistamine, it typically crosses theblood–brain barrierinto thebrain,thereby producing a suite ofsedativeandhypnoticeffects that are mediated by thecentral nervous system.(N.b.: Anagonistis a molecule that activates certain receptors (i.e., specific cellular proteins) in a cell to produce a specific pharmacological response, causing the cell to modify its activity—while aninverse agonisttargets the same receptors as those of a given agonist, but causes a response opposite to that caused by the agonist. Anantagonistblocks the action of a given agonist.)

Doxylamine is also a potent anticholinergic, meaning that itcauses delirumathighdoses—i.e., atmuch higherdoses than recommended.[8](Specifically it is anantagonistof themuscarinic acetylcholine receptorsM1throughM5.) These sedative and deliriant effects have in some cases led to using the drug recreationally. Doxylamine was first described in 1948 or 1949.[9]

Medical uses

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Doxylamine is an antihistamine used to treatsneezing,runny nose,watery eyes,hives,skin rash,itching,and othercoldorallergysymptoms. It is also used as a short-term treatment for insomnia.[10]

Insomnia

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The first-generation sedating antihistaminesdiphenhydramine,doxepin,doxylamine, andpyrilamineare the most widely used medications in the world for preventing and treating insomnia.[6]As of 2004, doxylamine and diphenhydramine, which are both over-the-counter medications, were the agents most commonly used to treat short-term insomnia.[11]As of 2008 and 2017, over-the-counter antihistamines were not recommended by theAmerican Academy of Sleep Medicinefor treatment of chronic insomnia "due to the relative lack of efficacy and safety data".[12][13]Neither version of their guidelines explicitly included or mentioned doxylamine, although diphenhydramine was discussed.[12][13]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.[4]

A majorsystematic reviewandnetwork meta-analysisof medications for the treatment of insomnia published in 2022 found that doxylamine had aneffect size(standardized mean difference(SMD)) againstplacebofor treatment of insomnia at 4weeks of 0.47 (95%CITooltip confidence interval0.06 to 0.89).[14]Thecertainty of evidencewas rated as moderate.[14]No data were available for doxylamine in terms of longer-term treatment (3months).[14]For comparison, the other sedating medicines assessed,doxepinandtrimipramine(both of which are tricyclic antidepressants) had effect sizes (SMD) at 4weeks 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.[14]

Doses of doxylamine that have been used for sleep range from 5 to 50mg, with 25mg being the typical dose.[15][16][17][18]

Morning sickness

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Doxylamine is used in thecombination drugpyridoxine/doxylamineto treatmorning sickness(nausea and vomiting of pregnancy).[19][20][21]It is the only medication approved by the United StatesFood and Drug Administrationfor the treatment of morning sickness.[19][20]

Available forms

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See also:Pyridoxine/doxylamine

Doxylamine is used medically as doxylamine succinate, thesuccinatesaltof doxylamine, and is available both alone (brand names Decapryn, Doxy-Sleep-Aid, Unisom) and in combination withpyridoxine(a form ofvitamin B6) (brand names Bendectin, Bonjesta, Diclegis).[22]Doxylamine is available alone asimmediate-releaseoraltabletscontaining 25mg doxylamine succinate.[22]Oral tablets containing 12.5mg doxylamine succinate as well as oralcapsulescontaining 25mg doxylamine succinate were also previously available but were discontinued.[22]Thecombination of doxylamine and pyridoxineis available in the form ofextended-anddelayed-releaseoral tablets containing 10 to 20mg doxylamine succinate and 10 to 20mg pyridoxine hydrochloride.[22]Doxylamine alone is availableover-the-counter,whereas doxylamine in combination with pyridoxine is aprescription-only medication.[22]Doxylamine is also available in over-the-counter nighttimecold medicineproducts such as NyQuil Cold & Flu (containsacetaminophen,doxylamine succinate 6.25 to 12.5mg, anddextromethorphan hydrobromide), where it serves as the sedating component.[23][24]

Contraindications

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Thefetalsafety ratingof doxylamine is "A" (no evidence of risk).[25]

Side effects

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Side effectsof doxylamine includedizziness,drowsiness,anddry mouth,among others.[4]Doxylamine is a potentanticholinergicand has aside-effectprofile common to such drugs, includingblurred vision,dry mouth,constipation,muscle incoordination,urinary retention,mental confusion,anddelirium.[18][7]

Because of its relatively longelimination half-life(10–12hours), doxylamine is associated with next-day effects includingsedation,drowsiness,grogginess,dry mouth,andtirednesswhen used as ahypnotic.[26][18]This may be described as a "hangover effect".[18]The shorter elimination half-life of diphenhydramine (4–8hours) compared to doxylamine may give it an advantage over doxylamine as a sleep aid in this regard.[27]

Antihistamines like doxylamine are sedating initially buttoleranceoccurs with repeated use and can result inrebound insomniaupondiscontinuation.[7][28]

Occasionalcase reportsofcomaandrhabdomyolysishave been reported with doxylamine.[2]This is in contrast to diphenhydramine.[2]

Studies of doxylamine'scarcinogenicityin mice and rats have produced positive results for bothliverandthyroid cancer,especially in the mouse.[29]The carcinogenicity of the drug in humans is not well-studied, and theInternational Agency for Research on Cancerlists the drug as "not classifiable as to its carcinogenicity to humans".[30]

Continuous and/or cumulative use ofanticholinergicmedications, including first-generation antihistamines, is associated with a higher risk of cognitive decline and dementia in older people.[31][32]

Overdose

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Doxylamine is generally safe for administration to healthy adults. Doses of doxylamine of up to 1,600mg/day for 6months have been given to adults withschizophrenia,with littletoxicityencountered.[33]Themedian lethal dose(LD50) is estimated to be 50–500mg/kg in humans.[34]Symptoms ofoverdosemay includedry mouth,dilated pupils,insomnia,night terrors,euphoria,hallucinations,seizures,rhabdomyolysis,and death.[35]Fatalities have been reported from doxylamine overdose. These have been characterized bycoma,tonic-clonic (or grand mal) seizuresandcardiopulmonary arrest.Children appear to be at a high risk for cardiopulmonary arrest. A toxic dose for children of more than 1.8mg/kg has been reported. A 3-year-old child died 18 hours after ingesting 1,000mg doxylamine succinate.[5]Rarely, an overdose results inrhabdomyolysisandacute kidney injury.[36]

Pharmacology

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Pharmacodynamics

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Doxylamine[37]
Site Ki(nM) Species Ref
SERTTooltip Serotonin transporter 10000+ Human [38]
NETTooltip Norepinephrine transporter 10000+ Human [38]
DATTooltip Dopamine transporter 10000+ Human [38]
5-HT2A 10000+ Human [38]
5-HT2C 10000+ Human [38]
α1B 10000+ Human [38]
α2A 10000+ Human [38]
α2B 10000+ Human [38]
α2C 10000+ Human [38]
H1 42 Human [38]
H2 ND ND ND
H3 10000+ Human [38]
H4 ND ND ND
M1 490 Human [38]
M2 2100 Human [38]
M3 650 Human [38]
M4 380 Human [38]
M5 180 Human [38]
Values are Ki(nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Doxylamine acts primarily as anantagonistorinverse agonistof thehistamineH1receptor.[39][38]This action is responsible for itsantihistamineandsedativeproperties.[39][38]To a lesser extent, doxylamine acts as anantagonistof themuscarinic acetylcholine receptors,[39][38]an action responsible for itsanticholinergicand (at high doses)delirianteffects.[39][38]

Pharmacokinetics

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Thebioavailabilityof doxylamine is 24.7% fororal administrationand 70.8% forintranasal administration.[1]TheTmaxof doxylamine is 1.5 to 2.5 hours.[2]Itselimination half-lifeis 10 to 12hours (range 7 to 15hours).[2][3][4]Doxylamine ismetabolizedin theliverprimarily by thecytochrome P450enzymesCYP2D6,CYP1A2,andCYP2C9.[2][40]The mainmetabolitesareN-desmethyldoxylamine,N,N-didesmethyldoxylamine, and doxylamineN-oxide.[41]Doxylamine iseliminated60% in theurineand 40% infeces.[5]

Doxylamine concentrations after a single 25 mg oral dose of doxylamine in healthy volunteers. X-axis represents the time in hours after initial dose.[3]

Chemistry

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Doxylamine is a member of theethanolamineclass of antihistamines.[6]Other antihistamines from this group includebromodiphenhydramine,carbinoxamine,clemastine,dimenhydrinate,diphenhydramine,orphenadrine,andphenyltoloxamine.[6][42]

History

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Doxylamine is a first-generationantihistamineand was discovered by Nathan Sperber and colleagues and was first reported in 1948 or 1949.[43][9][44]It has been the antihistamine component ofNyQuilsince 1966.[43]

Bendectin, a combination of doxylamine, pyridoxine (vitamin B6), anddicyclomine(ananticholinergicantispasmodicagent), was marketed for treatment of morning sickness in 1956.[45]This product was reformulated in 1976 to remove dicyclomine.[45]The reformulated product was voluntarily discontinued by the manufacturer in the United States in 1983 due to concerns about an alleged association withcongenital limb defects.[45]However, these concerns have not been supported by studies.[19][20]In 2013, doxylamine/pyridoxine was reintroduced in the United States under the brand name Diclegis.[19][20]The combination was not removed from the market in Canada, where it had been marketed since 1979.[19][20]

Society and culture

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Formulations

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Doxylamine is primarily used as thesuccinic acidsalt,doxylamine succinate.

  • It is the sedating ingredient ofNyQuil(generally in combination withdextromethorphanandacetaminophen).
  • InCommonwealthcountries, such as Australia, Canada, South Africa, and the United Kingdom, doxylamine is available prepared withparacetamol(acetaminophen) andcodeineunder the brand name Dolased, Propain Plus, Syndol, or Mersyndol, as treatment fortension headacheand other types ofpain.
  • Doxylamine succinate is used in generalover-the-countersleep-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[46]with a class Asafety rating for pregnancy(no evidence of risk).
  • InCanada:
    • Doxylamine succinate andpyridoxine(vitamin B6) are the ingredients of Diclectin, which is used to preventmorning sickness.
    • It is also available in combination with vitamin B6andfolic acidunder the brand name Evanorm (marketed by Ion Healthcare).
  • InIndia
    • Doxylamine preparations are available typically in combination with pyridoxine which may also contain folic acid. Doxylamine usage is thus restricted for pregnant women.

References

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