Doxylamine

Doxylamine
Skeletal formula of the doxylamine molecule
Ball-and-stick model of the doxylamine molecule
Systematic (IUPAC) name
(RS)-N,N-dimethyl-2-(1-phenyl-1-pyridin-2-yl-ethoxy)-ethanamine
Clinical data
Trade names Unisom
AHFS/Drugs.com monograph
MedlinePlus a682537
Pregnancy
category
  • AU: A
  • US: B (No risk in non-human studies)
  • A (Briggs)
Routes of
administration		 Oral
Legal status
Legal status
  • AU: S3 (Pharmacist only)
  • US: OTC
Pharmacokinetic data
Bioavailability Oral: 24.7%, Intranasal: 70.8%[1]
Metabolism Hepatic (CYP3A4-meditated)
Biological half-life 6–12 hours
Excretion Urine (60%), feces (40%)[2]
Identifiers
CAS Number 469-21-6 YesY
ATC code R06AA09 (WHO)
PubChem CID 3162
IUPHAR/BPS 7171
DrugBank DB00366 YesY
ChemSpider 3050 YesY
UNII 95QB77JKPL YesY
KEGG D07878 YesY
ChEBI CHEBI:51380 YesY
ChEMBL CHEMBL1004 YesY
Chemical data
Formula C17H22N2O
Molar mass 270.369 g/mol
  (verify)

Doxylamine[3] is a first-generation antihistamine, first reported in 1949.[4] 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.[5]

Indications

Doxylamine is a member of the ethanolamine class of antihistamines and has anti-allergy power superior to almost every other antihistamine on the market, with the exception of diphenhydramine (Benadryl); it is also the most effective over-the-counter sedative available in the United States and is more sedating than some prescription hypnotics.[6] One study found that doxylamine succinate was more effective than the barbiturate phenobarbital for use as a sedative.[6] The dosage required to induce sleep can be as low as 6.25 mg, but is usually effective in dosages of up to 25 mg. Higher doses are not recommended by the United States Food and Drug Administration, although single dosage recommendations of up to 50 mg are common in some countries, including Australia (where it is marketed under the names Restavit and Dozile), Russia (Valocordin-Doxylamine) and India (Vomentin).

A 2010 placebo-controlled, double-blind randomized controlled trial found the formulation of doxylamine and pyridoxine marketed as Diclegis to be effective in controlling nausea and vomiting due to pregnancy.[7]

Metabolites

The main metabolites are N-desmethyldoxylamine, N,N-didesmethyldoxylamine, and doxylamine N-oxide.[8][9]

Side effects

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 Zyrtec (cetirizine) or Benadryl (diphenhydramine), 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.

Toxicity

Doxylamine succinate is generally safe for administration to healthy adults. Typical preparations that contain doxylamine range from 6.25 mg to 50 mg. The median lethal dose (LD50) is estimated to be 50–500 mg/kg in humans.[10] Symptoms of overdose may include dry mouth, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death.[11] 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.[2] Rarely, an overdose results in rhabdomyolysis and acute renal failure.[12]

Studies of doxylamine's carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse.[13] 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".[14]

Formulations

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

See also

References

  1. ↑ Pelser, Andries; Müller, Douw G.; du Plessis, Jeanetta; du Preez, Jan L.; Goosen, Colleen (2002). "Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats". Biopharmaceutics & Drug Disposition 23 (6): 239–244. doi:10.1002/bdd.314. PMID 12214324.
  2. 1 2 Dozile. medsafe.govt.nz
  3. ↑ Cada, DJ; Demaris, K; Levien, TL; Baker, DE (October 2013). "Doxylamine succinate/pyridoxine hydrochloride.". Hospital pharmacy 48 (9): 762–6. doi:10.1310/hpj4809-762. PMC 3857125. PMID 24421551.
  4. ↑ Sperber, Nathan.; Papa, Domenick.; Schwenk, Erwin.; Sherlock, Margaret. (1949). "Pyridyl-Substituted Alkamine Ethers as Antihistaminic Agents". Journal of the American Chemical Society 71 (3): 887–890. doi:10.1021/ja01171a034. PMID 18113525.
  5. ↑ Briggs, Gerald G.; Freeman, Roger K.; Yaffe, Sumner J. (2008). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams & Wilkins. doi:10.1258/om.2009.090002. ISBN 978-0-7817-7876-3.
  6. 1 2 Doxylamine. drugbank.ca
  7. ↑ Koren, Gideon; Clark, Shannon; Hankins, Gary D.V.; Caritis, Steve N.; Miodovnik, Menachem; Umans, Jason G.; Mattison, Donald R. (2010). "Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial". American Journal of Obstetrics and Gynecology 203 (6): 571.e1–571.e7. doi:10.1016/j.ajog.2010.07.030. PMID 20843504.
  8. ↑ Holder, C. L.; Korfmacher, W. A.; Slikker Jr, W.; Thompson Jr, H. C.; Gosnell, A. B. (1985). "Mass spectral characterization of doxylamine and its rhesus monkey urinary metabolites". Biomedical mass spectrometry 12 (4): 151–158. doi:10.1002/bms.1200120403. PMID 2861861.
  9. ↑ rxlist.com, Khedezla.
  10. ↑ DOXYLAMINE SUCCINATE. hazard.com
  11. ↑ Syed, Husnain; Sumit Som; Nazia Khan; Wael Faltas (17 March 2009). "Doxylamine toxicity: seizure, rhabdomyolysis and false positive urine drug screen for methadone". BMJ Case Reports (BMJ Group) 2003 (90): 845. doi:10.1136/bcr.09.2008.0879. PMID 21686586.
  12. ↑ Leybishkis B, B; Fasseas P; Ryan KF. (2001). "Doxylamine overdose as a potential cause of rhabdomyolysis". American Journal of the Medical Sciences (Lippincott Williams & Wilkins) 322 (1): 48–9. doi:10.1097/00000441-200107000-00009. PMID 11465247.
  13. ↑ Doxylamine succinate (CAS 562-10-7). berkeley.edu
  14. ↑ DOXYLAMINE SUCCINATE. International Agency for Research on Cancer (IARC) - Summaries & Evaluations
  15. ↑ chattem.com, UNISOM Drug facts
  16. ↑ Slaughter, Shelley R.; Hearns-Stokes, Rhonda; van der Vlugt, Theresa; Joffe, Hylton V. (2014). "FDA Approval of Doxylamine–Pyridoxine Therapy for Use in Pregnancy". New England Journal of Medicine 370 (12): 1081–1083. doi:10.1056/NEJMp1316042. PMID 24645939.
  17. ↑ unisom.ca product page
This article is issued from Wikipedia - version of the Wednesday, April 13, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.