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Doxylamine is an antihistamine medication used to treat insomnia and allergy, and—in combination with pyridoxine (vitamin B6)—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 (e.g., NyQuil) and containing paracetamol (acetaminophen) 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 of doxylamine include dizziness, drowsiness, grogginess, and dry mouth, among others.
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.
Doxylamine is also a potent anticholinergic, meaning that it deliriant at high doses (i.e., at much higher doses than recommended). Specifically, it is an antagonist of the muscarinic acetylcholine receptors M1 through M5. These sedative and deliriant effects have in some cases led to the drug being used recreationally. Doxylamine was first described in 1948 or 1949.
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). 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.
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. 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.
Antihistamines like doxylamine are sedating initially but drug tolerance occurs with repeated use and can result in rebound insomnia upon discontinuation.
Occasional of coma and rhabdomyolysis have been reported with doxylamine overdose. This is in contrast to diphenhydramine.
Studies of doxylamine's carcinogenicity in mice and rats have produced positive results for both liver cancer and thyroid cancer, especially in the mouse. Doxylamine succinate (CAS 562-10-7) . berkeley.edu. 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". DOXYLAMINE SUCCINATE. International Agency for Research on Cancer (IARC) – Summaries & Evaluations.
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.
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| 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. This action is responsible for its antihistamine and sedative properties. To a lesser extent, doxylamine acts as an antagonist of the muscarinic acetylcholine receptors, an action responsible for its anticholinergic and (at high doses) deliriant effects.
Bendectin, a combination of doxylamine, pyridoxine (vitamin B6), and dicyclomine (an anticholinergic antispasmodic agent), was marketed for treatment of morning sickness in 1956. 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. 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.
Pharmacokinetics
The bioavailability of doxylamine is 24.7% for oral administration and 70.8% for intranasal administration. The Tmax of doxylamine is 1.5 to 2.5 hours. Its elimination half-life is 10 to 12hours (range 7 to 15hours). Doxylamine is metabolism in the liver primarily by the cytochrome P450 CYP2D6, CYP1A2, and CYP2C9. The main are N-desmethyldoxylamine, N, N-didesmethyldoxylamine, and doxylamine N-oxide. Doxylamine is eliminated 60% in the urine and 40% in feces.
Chemistry
Doxylamine is a member of the ethanolamine class of antihistamines. Other antihistamines from this group include bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, orphenadrine, and phenyltoloxamine.
History
Doxylamine is a first-generation antihistamine and was discovered by Nathan Sperber and colleagues and was first reported in 1948 or 1949. It has been the antihistamine component of NyQuil since 1966.
Society and culture
Formulations
Doxylamine is primarily used as the succinic acid salt, doxylamine succinate.
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