Doxylamine is a first-generation antihistamine. It can be used by itself as a short-term sedative and in combination with other drugs to provide night-time allergy and cold relief. Doxylamine is also used in combination with the analgesics paracetamol (acetaminophen) and codeine as an analgesic/calmative preparation, and is prescribed in combination with vitamin B6 (pyridoxine) to prevent morning sickness in pregnant women. Its fetal safety is "A" in Briggs’ Reference Guide to Foetal and Neonatal Risk.
|Trade names||Unisom, others|
|Metabolism||Hepatic (CYP2D6, CYP1A2, CYP2C9)|
|Biological half-life||10–12 hours|
|Excretion||Urine (60%), feces (40%)|
|Chemical and physical data|
|Molar mass||270.369 g/mol|
|3D model (JSmol)|
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. Using doxylamine over a long period of time is not recommended. However, the drug is not addictive, and withdrawal effects are unlikely to be experienced with prolonged use.
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 1,000 mg doxylamine succinate. Rarely, an overdose results in rhabdomyolysis and acute renal failure.
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 of the histamine H1 receptor. This action is responsible for its antihistamine and sedative effects. The drug is also acts as an antagonist of the muscarinic acetylcholine receptors to a lesser extent. This action is responsible for the anticholinergic and, at high doses, deliriant effects of doxylamine.
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 (UK version no longer contains doxylamine as of 2015), 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, 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.
- In Canada:
- In India
- Doxylamine preparations are available typically in combination with Pyridoxine that may also contain folic acid. The use of Doxylamine is thus restricted to pregnant women.
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