Chemistry:Meclizine

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Short description: Chemical compound
Meclizine
Meclizine.svg
Clinical data
Trade namesBonine, Antivert, others
Other namesMeclozine
AHFS/Drugs.comMonograph
MedlinePlusa682548
License data
Routes of
administration		By mouth, under the tongue, in the cheek
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: OTC
  • US: OTC
Pharmacokinetic data
MetabolismLiver
Elimination half-life6 hours
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC25H27ClN2
Molar mass390.96 g·mol−1
3D model (JSmol)
Boiling point230 °C (446 °F)
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Meclizine, sold under the brand name Bonine, among others, is an antihistamine used to treat motion sickness and dizziness (vertigo).[1] It is taken by mouth.[1] Effects generally begin in an hour and last for up to a day.[1]

Common side effects include sleepiness and dry mouth.[1] Serious side effects may include allergic reactions.[1] Use in pregnancy appears safe, but has not been well studied; use in breastfeeding is of unclear safety.[2] It is believed to work in part by anticholinergic and antihistamine mechanisms.[1]

Meclizine was patented in 1951 and came into medical use in 1953.[3] It is available as a generic medication and often over the counter.[1][4] In 2020, it was the 142nd most commonly prescribed medication in the United States, with more than 4 million prescriptions.[5][6]

Medical uses

Meclizine is used to treat symptoms of motion sickness. Safety and efficacy in children younger than twelve years of age has not been established; therefore, use in this population is not recommended.[citation needed] Meclizine should be taken with caution in the elderly due to increased risk of confusion and amnesia.[7]

Motion sickness

Meclizine is effective in inhibiting nausea, vomiting, and dizziness caused by motion sickness.[8]

The drug is safe for treating nausea in pregnancy and is a first-line therapy for this use.[9][10] Doxylamine is similarly safe. Meclizine may not be strong enough for especially sickening motion stimuli, and second-line defenses should be tried in those cases.[11]

Vertigo

Meclizine may be used to treat vertigo, such as in those with Ménière's disease.[12][13]

Side effects

Some common side effects such as drowsiness, dry mouth, and tiredness may occur. Meclizine has been shown to have fewer dry mouth side effects than the traditional treatment for motion sickness, transdermal scopolamine.[14] A very serious allergic reaction to this drug is unlikely, but immediate medical attention should be sought if it occurs. Symptoms of a serious allergic reaction may include rash, itching, swelling, severe dizziness, and trouble breathing.[15]

Drowsiness

Drowsiness may result as a side effect of taking meclizine. Users are advised not to operate heavy machinery while under the influence. The consumption of alcohol while under the influence of meclizine may result in additional drowsiness.[1]

Elderly

As with any anticholinergic agent, meclizine may cause confusion or aggravate symptoms in those with dementia in the geriatric population (older than 65 years). Therefore, caution should be used when administering meclizine to the elderly.[16]

Mechanism of action

Meclizine is an antagonist at H1 receptors. It possesses anticholinergic, central nervous system depressant, and local anesthetic effects. Its antiemetic and antivertigo effects are not fully understood, but its central anticholinergic properties are partially responsible. The drug depresses labyrinth excitability and vestibular stimulation, and it may affect the medullary chemoreceptor trigger zone.[7] It has, however, been suggested that meclizine only has an inhibitory effect under normal viewing-circumstances, as the drug has been shown to enhance an isolated vestibular response. Much as motion sickness arises from a discrepancy between multiple senses, meclizine most likely affects a wide array of sensory mechanisms related to self-motion.[17] Meclizine also is a dopamine antagonist at D1-like and D2-like receptors[citation needed] but does not cause catalepsy[note 1] in mice, perhaps because of its anticholinergic activity.[18]

Chemistry

Meclizine is a first-generation antihistamine (nonselective H1 antagonist) of the piperazine class. It is structurally and pharmacologically similar to buclizine, cyclizine, and hydroxyzine, but has a shorter half-life of six hours compared to cyclizine and hydroxyzine with about 20 hours (though half-life should not be confused with duration).[citation needed] It is used as an antivertigo/antiemetic agent, specifically in the prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness.[7] Meclizine is sometimes combined with opioids, especially ones of the open-chain class like methadone, dextropropoxyphene, and dipipanone. Similarly, Diconal is a combination drug containing dipipanone and cyclizine.[citation needed]

Synthesis

(4-Chlorophenyl)-phenylmethanol is halogenated with thionyl chloride before adding acetylpiperazine. The acetyl group is cleaved with diluted sulfuric acid. An N-alkylation of the piperazine ring with 3-methylbenzylchloride completes the synthesis.[19]

Meclozine synthesis 01.svg

Alternatively, the last step can be replaced by a reductive N-alkylation with 3-methylbenzaldehyde. The reductive agent is hydrogen, and Raney nickel is used as a catalyst.[20][21]

Meclozine synthesis 02.svg

Meclizine is obtained and used as a racemate, a 1:1 mixture of the two stereoisomers. Drug forms contain the racemic dihydrochloride.[citation needed]

Names

Meclizine is an international nonproprietary name.[22]

It is sold under the brand names Bonine, Bonamine, Antivert, Postafen, Sea Legs, and Dramamine II (Less Drowsy Formulation). Emesafene is a combination of meclizine (1/3) and pyridoxine (2/3). In Canada, Antivert Tab (which is no longer available) was a combination of meclizine and nicotinic acid.[23]

Notes

  1. ↑ "[C]atalepsy was assessed by the bar method[:] the front paws were gently placed on a horizontal metal bar with 2 mm diameter suspended 4 cm above, and the length of time the mouse maintains this abnormal posture was measured."[18]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Meclizine Hydrochloride Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/meclizine-hydrochloride.html. 
  2. ↑ "Meclizine Use During Pregnancy". https://www.drugs.com/pregnancy/meclizine.html. 
  3. ↑ Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 547. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA547. 
  4. ↑ Advanced Therapies in Pediatric Endocrinology and Diabetology: Workshop, Rome, October 2014. Karger Medical and Scientific Publishers. 2015. p. 101. ISBN 9783318056372. https://books.google.com/books?id=myNRCwAAQBAJ&pg=PA101. 
  5. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  6. ↑ "Meclizine - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Meclizine. 
  7. ↑ 7.0 7.1 7.2 "Meclizine". StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. 18 July 2022. https://pubmed.ncbi.nlm.nih.gov/32809480/. 
  8. ↑ "Drugs & Medications" (in en). https://www.webmd.com/drugs/2/drug-144800/motion-sickness-meclizine-oral/details. 
  9. ↑ "Antiemetische Therapie bei Schwangerschaftserbrechen" (in de). Arznei-Telegramm 40: 87–89. 2009. http://www.arznei-telegramm.de/html/2009_10/0910087_01.html. 
  10. ↑ "Meclozin" (in de). Embryotox. Bundesministerium für Gesundheit. http://www.embryotox.de/meclozin.html. 
  11. ↑ "Evaluation of several common antimotion sickness medications and recommendations concerning their potential usefulness during special operations.". Pensacola, Florida: Naval Aerospace Research Lab. 2 December 2009. http://oai.dtic.mil/oai/oai?verb=getRecord&metadataPrefix=html&identifier=ADA511823. 
  12. ↑ "Meniere's disease". Nature Reviews. Disease Primers 2: 16028. May 2016. doi:10.1038/nrdp.2016.28. PMID 27170253. 
  13. ↑ "Meclizine". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. January 2017. https://www.ncbi.nlm.nih.gov/books/NBK547895/. 
  14. ↑ "Transdermal scopolamine, oral meclizine, and placebo in motion sickness". Clinical Pharmacology and Therapeutics 36 (1): 116–120. July 1984. doi:10.1038/clpt.1984.148. PMID 6734040. 
  15. ↑ "Meclizine - oral, Antivert, D-vert, Dramamine II". MedicineNet. http://www.medicinenet.com/meclizine_cyclizine-oral/article.htm. 
  16. ↑ "Meclizine". Drug Information Provided by Lexi-Comp. January 2010. http://www.merck.com/mmpe/print/lexicomp/meclizine.html. 
  17. ↑ "The effects of meclizine on motion sickness revisited". British Journal of Clinical Pharmacology 86 (8): 1510–1518. August 2020. doi:10.1111/bcp.14257. PMID 32077140. 
  18. ↑ 18.0 18.1 "Prediction of drug-induced catalepsy based on dopamine D1, D2, and muscarinic acetylcholine receptor occupancies". Drug Metabolism and Disposition 25 (6): 675–684. June 1997. PMID 9193868. http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9193868. Retrieved 12 June 2014. 
  19. ↑ Organic Synthesis. Concepts and Methods. Wiley. 2003. p. 237. ISBN 978-3-527-30272-7. 
  20. ↑ Morren H, US patent 2709169, issued 24 May 1955, assigned to Union Chimique Belge Société Anonyme
  21. ↑ Pharmaceutical Substances. Synthesis, Patents, Applications (4th ed.). Thieme. 2001. ISBN 3-13-115134-X. 
  22. ↑ "Guidelines on the Use of INNs for Pharmaceutical Substances". WHO. 1997. http://whqlibdoc.who.int/hq/1997/WHO_PHARM_S_NOM_1570.pdf. 
  23. ↑ "Drug card for Meclizine". DrugBank. Canada: University of Alberta. http://www.drugbank.ca/drugs/DB00737. 

External links



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