Doxylamine Explained

Watchedfields:changed
Verifiedrevid:456483386
Iupac Name:(RS)-N,N-dimethyl-2-[1-phenyl-1-(pyridin-2-yl)ethoxy]ethan-1-amine
Width:200px
Width2:200px
Alt2:Ball-and-stick model of the doxylamine molecule
Tradename:Unisom, Vicks Formula 44 (in combination with Dextromethorphan), others
Pregnancy Us:B
Pregnancy Au:A
Pregnancy Category:A (Briggs)
Legal Au:S3
Legal Us:OTC
Routes Of Administration:By mouth
Bioavailability:Oral

24.7%
Intranasal: 70.8%

Metabolism:Hepatic (CYP2D6, CYP1A2, CYP2C9)
Elimination Half-Life:10–12 hours (range 7–15 hours)
Excretion:Urine (60%), feces (40%)[1]
Iuphar Ligand:7171
Cas Number:469-21-6
Atc Prefix:R06
Atc Suffix:AA09
Pubchem:3162
Drugbank:DB00366
Chemspiderid:3050
Unii:95QB77JKPL
Kegg:D07878
Chebi:51380
Chembl:1004
C:17
H:22
N:2
O:1
Smiles:n1ccccc1C(c1ccccc1)(C)OCCN(C)C
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:HCFDWZZGGLSKEP-UHFFFAOYSA-N

Doxylamine is an antihistamine medication used to treat insomnia and allergies, and—in combination with pyridoxine (vitamin B6)—to treat morning sickness in pregnant women. It is available over-the-counter and is typically sold under such brand names as Equate, Unisom, or ZzzQuil, among others; and it is used in nighttime cold medicines (e.g., NyQuil) and pain medications containing acetaminophen and/or codeine to help with sleep. The medication is delivered chemically by the salt doxylamine succinate and is taken by mouth. Doxylamine and other first-generation antihistamines are the most widely used sleep medications in the world.Typical side effects of doxylamine (at recommended doses) include dizziness, drowsiness, grogginess, and dry mouth, among others.[2]

As an antihistamine, doxylamine is an inverse agonist of the histamine H1 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. (N.b.: An agonist is 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 an inverse agonist targets the same receptors as those of a given agonist, but causes a response opposite to that caused by the agonist. An antagonist blocks the action of a given agonist.)

Doxylamine is also a potent anticholinergic, meaning that it causes delium at high doses—i.e., at much higher doses than recommended.[3] (Specifically it is an antagonist of the muscarinic acetylcholine receptors M1 through M5.) These sedative and deliriant effects have in some cases led to using the drug recreationally. Doxylamine was first described in 1948 or 1949.[4]

Medical uses

Doxylamine is an antihistamine used to treat sneezing, runny nose, watery eyes, hives, skin rash, itching, and other cold or allergy symptoms. It is also used as a short-term treatment for insomnia.[5]

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. As of 2004, doxylamine and diphenhydramine, which are both over-the-counter medications, were the agents most commonly used to treat short-term insomnia.[6] 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".[7] [8] Neither version of their guidelines explicitly included or mentioned doxylamine, although diphenhydramine was discussed. 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.

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 4weeks of 0.47 (95% 0.06 to 0.89).[9] The certainty of evidence was rated as moderate. No data were available for doxylamine in terms of longer-term treatment (3months). For comparison, the other sedating medicines assessed, doxepin and trimipramine (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.

Doses of doxylamine that have been used for sleep range from 5 to 50mg, with 25mg being the typical dose.[10] [11] [12]

Morning sickness

Doxylamine is used in the combination drug pyridoxine/doxylamine to treat morning sickness (nausea and vomiting of pregnancy).[13] It is the only medication approved by the United States Food and Drug Administration for the treatment of morning sickness.

Available forms

See also: Pyridoxine/doxylamine.

Doxylamine is used medically as doxylamine succinate, the succinate 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) (brand names Bendectin, Bonjesta, Diclegis).[14] Doxylamine is available alone as immediate-release oral tablets containing 25mg doxylamine succinate. Oral tablets containing 12.5mg doxylamine succinate as well as oral capsules containing 25mg doxylamine succinate were also previously available but were discontinued. The combination of doxylamine and pyridoxine is available in the form of extended- and delayed-release oral tablets containing 10 to 20mg doxylamine succinate and 10 to 20mg pyridoxine hydrochloride. Doxylamine alone is available over-the-counter, whereas doxylamine in combination with pyridoxine is a prescription-only medication. Doxylamine is also available in over-the-counter nighttime cold medicine products such as NyQuil Cold & Flu (contains acetaminophen, doxylamine succinate 6.25 to 12.5mg, and dextromethorphan hydrobromide), where it serves as the sedating component.[15] [16]

Contraindications

The fetal safety rating of doxylamine is "A" (no evidence of risk).[17]

Side effects

Side effects of doxylamine include dizziness, drowsiness, and dry mouth, among others. Doxylamine is a potent anticholinergic and has a side-effect profile common to such drugs, including blurred vision, dry mouth, constipation, muscle incoordination, urinary retention, mental confusion, and delirium.[18]

Because of its relatively long elimination half-life (10–12hours), doxylamine is associated with next-day effects including sedation, drowsiness, grogginess, dry mouth, and tiredness when used as a hypnotic.[19] This may be described as a "hangover effect". 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.[20]

Antihistamines like doxylamine are sedating initially but tolerance occurs with repeated use and can result in rebound insomnia upon discontinuation.[21]

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

Studies of doxylamine's carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse.[22] 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".[23]

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.[24] [25]

Overdose

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 with schizophrenia, with little toxicity encountered.[26] The median lethal dose is estimated to be 50–500mg/kg in humans.[27] Symptoms of overdose may include dry mouth, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death.[28] Fatalities have been reported from doxylamine overdose. These have been characterized by coma, 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 1.8mg/kg has been reported. A 3-year-old child died 18 hours after ingesting 1,000mg doxylamine succinate.[1] Rarely, an overdose results in rhabdomyolysis and acute kidney injury.[29]

Pharmacology

Pharmacodynamics

Doxylamine[30]
Site Ki (nM) Species Ref
>10,000 Human [31]
>10,000 Human
>10,000 Human
>10,000 Human
>10,000 Human
>10,000 Human
>10,000 Human
>10,000 Human
>10,000 Human
42 Human
>10,000 Human
490 Human
2,100 Human
650 Human
380 Human
180 Human
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 antagonist or inverse agonist of the histamine H1 receptor.[32] This action is responsible for its antihistamine and sedative properties. To a lesser extent, doxylamine acts as an antagonist of the muscarinic acetylcholine receptors,[32] [31] an action responsible for its anticholinergic and (at high doses) deliriant effects.[32] [31]

Pharmacokinetics

The bioavailability of doxylamine is 24.7% for oral administration and 70.8% for intranasal administration.[33] The Tmax of doxylamine is 1.5 to 2.5 hours.[34] Its elimination half-life is 10 to 12hours (range 7 to 15hours).[34] [35] Doxylamine is metabolized in the liver primarily by the cytochrome P450 enzymes CYP2D6, CYP1A2, and CYP2C9.[34] [36] The main metabolites are N-desmethyldoxylamine, N,N-didesmethyldoxylamine, and doxylamine N-oxide.[37] Doxylamine is eliminated 60% in the urine and 40% in feces.[1]

Chemistry

Doxylamine is a member of the ethanolamine class of antihistamines.[38] Other antihistamines from this group include bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, orphenadrine, and phenyltoloxamine.[39]

History

Doxylamine is a first-generation antihistamine and was discovered by Nathan Sperber and colleagues and was first reported in 1948 or 1949.[40] [41] It has been the antihistamine component of NyQuil since 1966.

Bendectin, a combination of doxylamine, pyridoxine (vitamin B6), and dicyclomine (an anticholinergic antispasmodic agent), was marketed for treatment of morning sickness in 1956.[42] This product was reformulated in 1976 to remove dicyclomine. 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 defects. However, these concerns have not been supported by studies.[43] [44] In 2013, doxylamine/pyridoxine was reintroduced in the United States under the brand name Diclegis. The combination was not removed from the market in Canada, where it had been marketed since 1979.

Society and culture

Formulations

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

Notes and References

  1. Web site: New Zealand Datasheet: Doxylamine Succinate. Medsafe, New Zealand Medicines and Medical Devices Safety Authority. https://web.archive.org/web/20160322211016/http://www.medsafe.govt.nz/profs/datasheet/d/Dozilecap.pdf. 22 March 2016. 16 July 2008. dead.
  2. Neubauer DN . The evolution and development of insomnia pharmacotherapies . Journal of Clinical Sleep Medicine . 3 . 5 Suppl . S11–S15 . August 2007 . 17824496 . 1978321 . 10.5664/jcsm.26930 .
  3. Web site: Doxylamine - PsychonautWiki .
  4. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery . 2006 . John Wiley & Sons . 9783527607495 . 546 .
  5. Web site: Doxylamine: MedlinePlus Drug Information.
  6. Ringdahl EN, Pereira SL, Delzell JE . Treatment of primary insomnia . The Journal of the American Board of Family Practice . 17 . 3 . 212–219 . 2004 . 15226287 . 10.3122/jabfm.17.3.212 . free .
  7. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M . Clinical guideline for the evaluation and management of chronic insomnia in adults . Journal of Clinical Sleep Medicine . 4 . 5 . 487–504 . October 2008 . 18853708 . 2576317 . 10.5664/jcsm.27286 .
  8. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL . Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline . Journal of Clinical Sleep Medicine . 13 . 2 . 307–349 . February 2017 . 27998379 . 5263087 . 10.5664/jcsm.6470 .
  9. 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 . 6 . Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis . Lancet . 400 . 10347 . 170–184 . July 2022 . 35843245 . 10.1016/S0140-6736(22)00878-9 . 250536370 . free . 11380/1288245 . free .
  10. Book: Psychotropic Drug Handbook. 9780781762731. Perry PJ . 2007. Lippincott Williams & Wilkins.
  11. Dupuis G, Vaugeois JM . [The interesting anti-H1 effects in maintenance insomnia: A reflection on the comparative advantages of doxylamine and doxepin] . French . L'Encephale . 46 . 1 . 80–82 . February 2020 . 30879783 . 10.1016/j.encep.2019.01.006 . The interesting anti-H1 effects in maintenance insomnia: A reflection on the comparative advantages of doxylamine and doxepin . 151085176 . free .
  12. Lie JD, Tu KN, Shen DD, Wong BM . Pharmacological Treatment of Insomnia . P & T . 40 . 11 . 759–771 . November 2015 . 26609210 . 4634348 .
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  14. Web site: Drugs@FDA: FDA-Approved Drugs . accessdata.fda.gov . 23 August 2022.
  15. Web site: VICKS NYQUIL COLD AND FLU - acetaminophen, dextromethorphan hydrobromide, and doxylamine succinate capsule, liquid filled . DailyMed . U.S. National Library of Medicine .
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  20. Book: Rutter P, Newby D . Community Pharmacy ANZ – eBook: Symptoms, Diagnosis and Treatment . 11 September 2015 . Elsevier Health Sciences . 978-0-7295-8345-9 . 99.
  21. Stahl SM . Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines . CNS Spectrums . 13 . 12 . 1027–1038 . December 2008 . 19179941 . 10.1017/s1092852900017089 . 6849261 .
  22. http://potency.berkeley.edu/chempages/DOXYLAMINE%20SUCCINATE.html Doxylamine succinate (CAS 562-10-7)
  23. http://www.inchem.org/documents/iarc/vol79/79-05.html DOXYLAMINE SUCCINATE
  24. Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB . 6 . Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study . JAMA Internal Medicine . 175 . 3 . 401–407 . March 2015 . 25621434 . 4358759 . 10.1001/jamainternmed.2014.7663 . Rebecca Hubbard .
  25. Carrière I, Fourrier-Reglat A, Dartigues JF, Rouaud O, Pasquier F, Ritchie K, Ancelin ML . Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study . Archives of Internal Medicine . 169 . 14 . 1317–1324 . July 2009 . 19636034 . 2933398 . 10.1001/archinternmed.2009.229 .
  26. Book: 1978 . Federal Register, Volume 43, Issues 114-121 . Office of the Federal Register, National Archives and Records Service, General Services Administration . 25584 . 1768512 .
  27. Web site: DOXYLAMINE SUCCINATE . hazard.com . usurped . https://web.archive.org/web/20220117012245/http://hazard.com/msds/mf/baker/baker/files/d8882.htm . 2022-01-17 .
  28. Syed H, Som S, Khan N, Faltas W . Doxylamine toxicity: seizure, rhabdomyolysis and false positive urine drug screen for methadone . BMJ Case Reports . 2009 . 90 . 845 . 17 March 2009 . 21686586 . 3028279 . 10.1136/bcr.09.2008.0879 .
  29. Leybishkis B, Fasseas P, Ryan KF . Doxylamine overdose as a potential cause of rhabdomyolysis . The American Journal of the Medical Sciences . 322 . 1 . 48–49 . July 2001 . 11465247 . 10.1097/00000441-200107000-00009 .
  30. Web site: PDSP Ki Database . Psychoactive Drug Screening Program (PDSP). Bryan Roth . Roth BL, Driscol J . University of North Carolina at Chapel Hill and the United States National Institute of Mental Health . 14 August 2017 .
  31. Krystal AD, Richelson E, Roth T . Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications . Sleep Medicine Reviews . 17 . 4 . 263–272 . August 2013 . 23357028 . 10.1016/j.smrv.2012.08.001 .
  32. Vande Griend JP, Anderson SL . Histamine-1 receptor antagonism for treatment of insomnia . Journal of the American Pharmacists Association . 52 . 6 . e210–e219 . 2012 . 23229983 . 10.1331/JAPhA.2012.12051 .
  33. Pelser A, Müller DG, du Plessis J, du Preez JL, Goosen C . Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats . Biopharmaceutics & Drug Disposition . 23 . 6 . 239–244 . September 2002 . 12214324 . 10.1002/bdd.314 . 32126626 .
  34. Book: Kryger MH, Roth T, Dement WC . Principles and Practice of Sleep Medicine E-Book. 1 November 2010. Elsevier Health Sciences. 978-1-4377-2773-9. 925.
  35. Culpepper L, Wingertzahn MA . Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia: A Systematic Review of Efficacy and Safety . The Primary Care Companion for CNS Disorders . 17 . 6 . 2015 . 27057416 . 4805417 . 10.4088/PCC.15r01798 .
  36. Krystal AD . A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: the empirical basis for U.S. clinical practice . Sleep Medicine Reviews . 13 . 4 . 265–274 . August 2009 . 19153052 . 10.1016/j.smrv.2008.08.001 .
  37. Holder CL, Korfmacher WA, Slikker W, Thompson HC, Gosnell AB . Mass spectral characterization of doxylamine and its rhesus monkey urinary metabolites . Biomedical Mass Spectrometry . 12 . 4 . 151–158 . April 1985 . 2861861 . 10.1002/bms.1200120403 . 6020605 .
  38. Simons FE, Simons KJ . Histamine and H1-antihistamines: celebrating a century of progress . The Journal of Allergy and Clinical Immunology . 128 . 6 . 1139–1150.e4 . December 2011 . 22035879 . 10.1016/j.jaci.2011.09.005 . free .
  39. Kalpaklioglu F, Baccioglu A . Efficacy and safety of H1-antihistamines: an update . Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry . 11 . 3 . 230–237 . 2012 . 23173575 . 10.2174/1871523011202030230 .
  40. Book: Atta-ur-Rahman . 11 July 2018 . Frontiers in Clinical Drug Research - Anti-Allergy Agents, Volume 3 . Bentham Science Publishers . 30 . 978-1-68108-337-7 . 1048922805 .
  41. Sperber N, Papa D . Pyridyl-substituted alkamine ethers as antihistaminic agents . Journal of the American Chemical Society . 71 . 3 . 887–890 . March 1949 . 18113525 . 10.1021/ja01171a034 .
  42. Book: Briggs GG, Freeman RK, Yaffe SJ . 28 March 2012 . Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk . 9 . Lippincott Williams & Wilkins . 453 . 978-1-4511-5359-0 . 1232803849 .
  43. Nuangchamnong N, Niebyl J . Doxylamine succinate-pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview . International Journal of Women's Health . 6 . 401–409 . 2014 . 24748822 . 3990370 . 10.2147/IJWH.S46653 . free .
  44. Madjunkova S, Maltepe C, Koren G . The delayed-release combination of doxylamine and pyridoxine (Diclegis®/Diclectin ®) for the treatment of nausea and vomiting of pregnancy . Paediatric Drugs . 16 . 3 . 199–211 . June 2014 . 24574047 . 4030125 . 10.1007/s40272-014-0065-5 .
  45. Slaughter SR, Hearns-Stokes R, van der Vlugt T, Joffe HV . FDA approval of doxylamine-pyridoxine therapy for use in pregnancy . The New England Journal of Medicine . 370 . 12 . 1081–1083 . March 2014 . 24645939 . 10.1056/NEJMp1316042 . free .

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