Doxylamine

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. Insomnia The first-generation sedating antihistamines diphenhydramine, doxylamine, and pyrilamine are the most widely used medications in the world for preventing and treating insomnia. 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". Neither version of their guidelines explicitly included or mentioned doxylamine, although diphenhydramine was discussed. The certainty of evidence was rated as moderate. It is the only medication approved by the United States Food and Drug Administration for the treatment of morning sickness. Doxylamine is available alone as immediate-release oral tablets containing 25mg doxylamine succinate. ==Contraindications==

The fetal safety rating of doxylamine is "A" (no evidence of risk). ==Side effects==

Side effects of doxylamine include dizziness, drowsiness, and dry mouth, among others. Antihistamines like doxylamine are sedating initially but tolerance occurs with repeated use and can result in rebound insomnia upon discontinuation. Occasional case reports of coma and rhabdomyolysis have been reported with doxylamine overdose. 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". 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. ==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. However, modern toxicology data and medical case reports do not back this finding up. The median lethal dose () is estimated to be 50–500mg/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 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 three-year-old child died 18 hours after ingesting 1,000mg doxylamine succinate. ==Pharmacology==

Pharmacodynamics Doxylamine acts primarily as an antagonist or inverse agonist of the histamine H1 receptor. 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 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. ==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. This product was reformulated in 1976 to remove dicyclomine. 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. • 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), 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 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 and may also contain folic acid. Doxylamine usage is thus restricted for pregnant women. == References ==