Doxylamine is a first-generation antihistamine used as a short-term sedative and hypnotic (sleep aid) or in combination formulations to provide night-time allergy and cold relief. It provides a calmative effect in preparations containing the analgesics paracetamol (acetaminophen) and codeine. It is prescribed in combination with vitamin B6 (pyridoxine) to prevent morning sickness in pregnant women. Its fetal safety rating is "A" (no evidence of risk) in Briggs' Reference Guide to Fetal and Neonatal Risk.
|Trade names||Unisom, Vicks Formula 44 (in combination with Dextromethorphan), others|
|Metabolism||Hepatic (CYP2D6, CYP1A2, CYP2C9)|
|Elimination half-life||10–12 hours|
|Excretion||Urine (60%), feces (40%)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||270.369 g·mol−1|
|3D model (JSmol)|
It was first described in 1948.
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 sleep problems (insomnia).
As of 2004, doxylamine and diphenhydramine were the agents most commonly used to treat short-term insomnia. As of 2008, 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".
Doxylamine succinate is a potent anticholinergic and has a side-effect profile common to such drugs, including dry mouth, ataxia, urinary retention, drowsiness, memory problems, inability to concentrate, hallucinations, psychosis, and a marked increased sensitivity to external stimuli. Like many hypnotics, it should not be combined with other antihistamines, such as cetirizine (Zyrtec) or diphenhydramine (Benadryl), as this combination can increase the risk of serious side effects. Some people can have a different reaction: instead of sedating, it stimulates. Using doxylamine over a long period of time is not recommended. However, the drug is not addictive. It can be mildly psychologically addictive to some people. If used for longer periods of time, withdrawal effects are unlikely to be experienced with prolonged use, but mild withdrawal symptoms are likely if taken long-term.
Because of its relatively long elimination half-life (10–12 hours), doxylamine is associated with daytime/next-day drowsiness, grogginess, dry mouth, and tiredness when used as a hypnotic. The shorter elimination half-life of diphenhydramine (4–8 hours) may give it an advantage over doxylamine in this regard.
Doxylamine succinate is generally safe for administration to healthy adults. The median lethal dose (LD50) is estimated to be 50–500 mg/kg in humans. Symptoms of overdose may include dry mouth, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death. Fatalities have been reported from doxylamine overdose. These have been characterized by coma, tonic-clonic (or grand mal) seizures and cardiorespiratory arrest. Children appear to be at a high risk for cardiorespiratory 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 1000 mg doxylamine succinate. Rarely, an overdose results in rhabdomyolysis and acute kidney injury.
Studies of doxylamine's carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse. The carcinogenicity of the drug in humans is not well studied, and the IARC lists the drug as "not classifiable as to its carcinogenicity to humans".
|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 minor hypnotic, anticholinergic, and (at high doses) deliriant effects.
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 12 hours. Doxylamine is metabolized in the liver primarily by the cytochrome P450 enzymes CYP2D6, CYP1A2, and CYP2C9. The main metabolites are N-desmethyldoxylamine, N,N-didesmethyldoxylamine, and doxylamine N-oxide. Doxylamine is eliminated 60% in the urine and 40% in feces.
Society and cultureEdit
- It is the sedating ingredient of NyQuil (generally in combination with dextromethorphan and 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), and Sleep Aid (generic, Australia).
- 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 with a class A safety rating for pregnancy (no evidence of risk).
- In Canada:
- 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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