Chemistry:Mexazolam

From HandWiki

Mexazolam[1] (marketed under the trade names Melex and Sedoxil)[2] is a drug which is a benzodiazepine derivative.[3] Mexazolam has been trialed for anxiety and was found to be effective in alleviating anxiety at one week follow-up. Mexazolam is metabolised via the CYP3A4 pathway. HMG-CoA reductase inhibitors including simvastatin, simvastatin acid, lovastatin, fluvastatin, atorvastatin and cerivastatin inhibit the metabolism of mexazolam,[4] but not the HMG-CoA reductase inhibitor pravastatin.[5][6] Its principal active metabolites are chlorodesmethyldiazepam (also known as chloronordiazepam or delorazepam, trade name Dadumir) and chloroxazepam (also known as lorazepam, trade name Ativan).[7] Researchers have found a dose of 1.67 mg mexazolam equals 5 mg diazepam. [8] Clinical studies suggest that 3 mg of mexazolam has a comparable effect to 1.5 mg of alprazolam.[9]

Pharmacokinetics

Mexazolam is a long-acting benzodiazepine that undergoes extensive hepatic metabolism. In humans, the parent drug is primarily oxidized by cytochrome P450 3A isoforms, yielding two active benzodiazepine metabolites: chloronordiazepam and chloroxazepam. Mexazolam follows biphasic elimination profile: the initial distribution phase has a half-life of approximately 1.4 hours, reflecting rapid tissue uptake and first-pass metabolism, following by a terminal phase with a half-life of about 76 hours. The long duration of the terminal phase driven by high plasma protein binding (over 90 percent) and gradual release from peripheral compartments.[10] The active metabolites further extend duration of action of the drug.[10][11] The elimination half-lives of the active metabolites is 130–200 h, which supports once-daily dosing but also calls for caution regarding accumulation and residual sedative effects during prolonged therapy.[10]

Mechanism of action

Mexazolam's primary target is GABAA receptor, benzodiazepine site, via the active metabolite chloronordiazepam.[11] Mexazolam potentiates GABA currents at α2/α3 (anxiolytic) subunit‑containing receptors. The drug has minimal effect on α1 (sedative) amplitude;[12][11] as such, mexazolam has lower sedative load compared to classical benzodiazepines[11] such as chlordiazepoxide.[13]

See also

References

  1. ↑ DE Patent 1954065
  2. ↑ "Benzodiazepine Names". non-benzodiazepines.org.uk. http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html. 
  3. ↑ "Kinetics and mechanism of the acid-base equilibrium of mexazolam and comparison with those of other commercial benzodiazepinooxazole drugs". Chemical & Pharmaceutical Bulletin 35 (9): 3831–3837. September 1987. doi:10.1248/cpb.35.3831. PMID 2893667. 
  4. ↑ "The effects of concurrent atorvastatin therapy on the pharmacokinetics of intravenous midazolam". Anaesthesia 58 (9): 899–904. September 2003. doi:10.1046/j.1365-2044.2003.03339.x. PMID 12911366. 
  5. ↑ "Sex difference in inhibition of in vitro mexazolam metabolism by various 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors in rat liver microsomes". Drug Metabolism and Disposition 30 (8): 904–910. August 2002. doi:10.1124/dmd.30.8.904. PMID 12124308. 
  6. ↑ "A comparison of the effects of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) reductase inhibitors on the CYP3A4-dependent oxidation of mexazolam in vitro". Drug Metabolism and Disposition 29 (3): 282–288. March 2001. PMID 11181496. http://dmd.aspetjournals.org/cgi/content/full/29/3/282. 
  7. ↑ "Mexazolam: clinical efficacy and tolerability in the treatment of anxiety". Neurology and Therapy 3 (1): 1–14. June 2014. doi:10.1007/s40120-014-0016-7. PMID 26000220. 
  8. ↑ "Psychotropic dose equivalence in Japan". Psychiatry and Clinical Neurosciences 69 (8): 440–447. August 2015. doi:10.1111/pcn.12275. PMID 25601291. 
  9. ↑ "Mexazolam and Alprazolam in the Treatment of Generalised Anxiety Disorder: A Double-Blind, Randomised Clinical Trial". Clin Drug Invest. 4 (21). https://www.medscape.com/viewarticle/406221?form=fpf. 
  10. ↑ 10.0 10.1 10.2 "Mexazolam: clinical efficacy and tolerability in the treatment of anxiety". Neurology and Therapy 3 (1): 1–14. June 2014. doi:10.1007/s40120-014-0016-7. PMID 26000220. 
  11. ↑ 11.0 11.1 11.2 11.3 "Voltage-clamp evidence of GABAA receptor subunit-specific effects: pharmacodynamic fingerprint of chlornordiazepam, the major active metabolite of mexazolam, as compared to alprazolam, bromazepam, and zolpidem". Pharmacological Reports 74 (5): 956–968. October 2022. doi:10.1007/s43440-022-00411-x. PMID 36097257. 
  12. ↑ "Tranquilizer/Anxiolytics: Mexazolam". NeuroPsychopharmacotherapy. 2022. pp. 2151–2159. doi:10.1007/978-3-030-62059-2_162. ISBN 978-3-030-62058-5. https://link.springer.com/rwe/10.1007/978-3-030-62059-2_162. 
  13. ↑ "The benzodiazepines: A brief review of pharmacology and therapeutics". Anxiolytics. 2000. pp. 1–11. doi:10.1007/978-3-0348-8470-9_1. ISBN 978-3-0348-9581-1. https://link.springer.com/chapter/10.1007/978-3-0348-8470-9_1. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Mexazolam&oldid=4031381"