Chemistry:Meclizine

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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 2023, it was the 137th 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.[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] 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]

Pharmacology

Pharmacodynamics

Meclizine is an antagonist at H1 receptors (Ki = 250 nM).[16] 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] The drug has been shown to reduce the magnitude of the vestibulo-ocular reflex in healthy volunteers.[17] At the same time the drug was found to have only a small (and statistically insignificant) effect on the motion sensitivity of the utricles.[17] 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 while leaving the core vestibular response intact.[18]

Meclizine also has been reported to be a weak dopamine antagonist at D1-like and D2-like receptors but it does not cause catalepsy in mice, perhaps because of its anticholinergic activity.[19] The drug does not effect dopamine or serotonin reuptake.[20]

Pharmacokinetics

Meclizine reaches peak plasma concentration in about 1.5 hours and has an elimination half-life of 5–6 hours.[21] Despite its relatively short half-life, the drug is reported to remain effective for motion sickness for 12 – 24 hours.[22] Meclizine has low bioavailability (22–32%) and a delayed onset to action in part due to its poor solubility in water (0.1 mg/ml) and gastrointestinal fluid.[23] In children it has been found that taking meclizine with food increases its bioavailability slightly.[24] It is metabolized in the liver by the CYP2D6 enzyme.[21] Ten metabolites have been identified.[25] In rats, the main metabolite is norchlorcyclizine, which distributes extensively through body tissue.[26]

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.

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.[27]

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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.[28][29]

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Society and culture

Brand names

Meclizine is an international nonproprietary name.[30]

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 was a combination of meclizine and nicotinic acid.[31]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "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 978-3-527-60749-5. 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 978-3-318-05637-2. https://books.google.com/books?id=myNRCwAAQBAJ&pg=PA101. 
  5. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  6. ↑ "Meclizine Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Meclizine. 
  7. ↑ 7.0 7.1 "Meclizine". StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. 18 July 2022. https://pubmed.ncbi.nlm.nih.gov/32809480/. 
  8. ↑ "Drugs & Medications". 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. 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. ↑ "Histamine H1 receptors identified in mammalian brain membranes with [3Hmepyramine"]. Proceedings of the National Academy of Sciences of the United States of America 75 (12): 6290–6294. December 1978. doi:10.1073/pnas.75.12.6290. PMID 282646. 
  17. ↑ 17.0 17.1 "Pharmaceutical countermeasures have opposite effects on the utricles and semicircular canals in man". Audiology & Neuro-Otology 17 (4): 235–242. 2012. doi:10.1159/000337273. PMID 22517315. 
  18. ↑ "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. 
  19. ↑ "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.  "Catalepsy 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."
  20. ↑ "Comparison of the effects of eleven histamine H1-receptor antagonists on monoamine turnover in the mouse brain". Naunyn-Schmiedeberg's Archives of Pharmacology 349 (2): 140–144. February 1994. doi:10.1007/BF00169830. PMID 7513381. 
  21. ↑ 21.0 21.1 Cite error: Invalid <ref> tag; no text was provided for refs named pharmacokinetics
  22. ↑ "ANTIVERT FDA Drug Facts". FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/010721s058lbl.pdf. 
  23. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named bioavail
  24. ↑ "Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia". PLOS ONE 15 (4). 13 April 2020. doi:10.1371/journal.pone.0229639. PMID 32282831. Bibcode: 2020PLoSO..1529639K. 
  25. ↑ "[Biotransformation of meclozine in the human body]". Journal of Clinical Chemistry and Clinical Biochemistry 26 (2): 105–115. February 1988. PMID 3367105. 
  26. ↑ "Metabolism of Meclizine in the Rat". The Journal of Pharmacology and Experimental Therapeutics 147 (3): 380–384. March 1965. doi:10.1016/S0022-3565(25)26997-X. PMID 14269614. 
  27. ↑ Organic Synthesis. Concepts and Methods. Wiley. 2003. p. 237. ISBN 978-3-527-30272-7. 
  28. ↑ Morren H, US patent 2709169, issued 24 May 1955, assigned to Union Chimique Belge Société Anonyme
  29. ↑ Pharmaceutical Substances. Synthesis, Patents, Applications (4th ed.). Thieme. 2001. ISBN 3-13-115134-X. 
  30. ↑ "Guidelines on the Use of INNs for Pharmaceutical Substances". WHO. 1997. http://whqlibdoc.who.int/hq/1997/WHO_PHARM_S_NOM_1570.pdf. 
  31. ↑ "Drug card for Meclizine". DrugBank. Canada: University of Alberta. http://www.drugbank.ca/drugs/DB00737. 



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