Doxylamine

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Doxylamine
Skeletal formula of the doxylamine molecule
Ball-and-stick model of the doxylamine molecule
Clinical data
Trade namesUnisom, Vicks Formula 44 (in combination with Dextromethorphan), 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
Intranasal: 70.8%[1]
MetabolismHepatic (CYP2D6, CYP1A2, CYP2C9)[2]
Elimination half-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
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,13-14H2,1-3H3 checkY
  • Key:HCFDWZZGGLSKEP-UHFFFAOYSA-N checkY
  (verify)

Doxylamine, sold under the brand name Unisom among others, is an

acetaminophen and codeine, to help with sleep. The medication is taken by mouth
.

first-generation antihistamine and crosses the blood–brain barrier into the brain, thereby producing centrally mediated sedative and hypnotic
effects.

Doxylamine was first described in 1948 or 1949.[7] Several of the first-generation antihistamines, including doxylamine, are the most widely used sleep medications in the world.[8] Doxylamine is also a potent anticholinergic, which means it also works as a deliriant at much higher than recommended doses as a result.[9] Its sedative and deliriant effects have led to some cases of recreational use.

Medical uses

Doxylamine is an antihistamine used to treat

itching, and other cold or allergy symptoms. It is also used as a short-term treatment for insomnia.[10]

Insomnia

The first-generation sedating antihistamines

pyrilamine are the most widely used medications in the world for preventing and treating insomnia.[8] 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 the American Academy of Sleep Medicine for 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 major

certainty of evidence was rated as moderate.[14] No data were available for doxylamine in terms of longer-term treatment (3 months).[14] For comparison, the other sedating medicines assessed, doxepin and trimipramine (both of which are tricyclic antidepressants) had effect sizes (SMD) at 4 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.[14]

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

Morning sickness

Doxylamine is used in the combination drug pyridoxine/doxylamine to treat morning sickness (nausea and vomiting of pregnancy).[19][20][21] It is the only medication approved by the United States Food and Drug Administration for the treatment of morning sickness.[19][20]

Available forms

See also: Pyridoxine/doxylamine

Doxylamine is used medically as doxylamine succinate, the

dextromethorphan hydrobromide), where it serves as the sedating component.[23][24]

Contraindications

The

fetal safety rating of doxylamine is "A" (no evidence of risk).[25]

Side effects

mental confusion, and delirium.[18][6]

Because of its relatively long

hangover effect".[18] The shorter elimination half-life of diphenhydramine (4–8 hours) compared to doxylamine may give it an advantage over doxylamine as a sleep aid in this regard.[27]

Antihistamines like doxylamine are sedating initially but

discontinuation.[6][28]

Occasional case reports of coma and rhabdomyolysis have been reported with doxylamine.[2] This is in contrast to diphenhydramine.[2]

Studies of doxylamine's

carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse.[29] 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".[30]

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.[31][32]

Overdose

Doxylamine is generally safe for administration to healthy adults. Doses of doxylamine of up to 1,600 mg/day for 6 months have been given to adults with

cardiopulmonary arrest. Children appear to be at a high risk for cardiopulmonary arrest. A toxic dose for children of more than 1.8 mg/kg has been reported. A 3-year-old child died 18 hours after ingesting 1,000 mg doxylamine succinate.[5] Rarely, an overdose results in rhabdomyolysis and acute kidney injury.[36]

Pharmacology

Pharmacodynamics

Doxylamine[37]
Site Ki (nM) Species Ref
SERTTooltip Serotonin transporter >10,000 Human [38]
NETTooltip Norepinephrine transporter >10,000 Human [38]
DATTooltip Dopamine transporter >10,000 Human [38]
5-HT2A >10,000 Human [38]
5-HT2C >10,000 Human [38]
α1B >10,000 Human [38]
α2A >10,000 Human [38]
α2B >10,000 Human [38]
α2C >10,000 Human [38]
H1 42 Human [38]
H2 ND ND ND
H3 >10,000 Human [38]
H4 ND ND ND
M1 490 Human [38]
M2 2,100 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 an

H1 receptor.[39][38] This action is responsible for its antihistamine and sedative properties.[39][38] To a lesser extent, doxylamine acts as an antagonist of the muscarinic acetylcholine receptors,[39][38] an action responsible for its anticholinergic and (at high doses) deliriant effects.[39][38]

Pharmacokinetics

The

elimination half-life is 10 to 12 hours (range 7 to 15 hours).[2][3][4] Doxylamine is metabolized in the liver primarily by the cytochrome P450 enzymes CYP2D6, CYP1A2, and CYP2C9.[2][40] The main metabolites are N-desmethyldoxylamine, N,N-didesmethyldoxylamine, and doxylamine N-oxide.[41] Doxylamine is eliminated 60% in the urine and 40% in feces.[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

Doxylamine is a member of the

bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, orphenadrine, and phenyltoloxamine.[8][42]

History

Doxylamine is a first-generation antihistamine and was discovered by Nathan Sperber and colleagues and was first reported in 1948 or 1949.[43][7][44] It has been the antihistamine component of NyQuil since 1966.[43]

Bendectin, a combination of doxylamine, pyridoxine (vitamin B6), and

congenital 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

Formulations

Doxylamine is primarily used as the succinic acid salt, doxylamine succinate.

  • It is the sedating ingredient of
    acetaminophen
    ).
  • In 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 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[46] with a class A safety rating for pregnancy (no evidence of risk).
  • In Canada:
    • Doxylamine succinate and pyridoxine (vitamin B6) are the ingredients of Diclectin, which is used to prevent morning sickness.
    • It is also available in combination with vitamin B6 and
      folic acid
      under the brand name Evanorm (marketed by Ion Healthcare).
  • In India
    • Doxylamine preparations are available typically in combination with pyridoxine that may also contain folic acid. Doxylamine usage is thus restricted for pregnant women.

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