Chemistry:Etizolam

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Short description: Chemical compound
Etizolam
Etizolam.svg
File:Etizolam-from-xtal-3D-bs-17.png
Clinical data
Trade namesEtizest, Etilaam, Etizex, Depas, Sedekopan, Pasaden
Dependence
liability		Moderate
Routes of
administration		Oral, sublingual, rectal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability93%
MetabolismHepatic
Elimination half-life3.4 hours[1][2] (main metabolite is 8.2 hours)[3]
Duration of action5-7 hours
ExcretionKidney
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC17H15ClN4S
Molar mass342.85 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)
~98% pure Etizolam powder. This pictured amount is roughly 150mg, a standard dose is around 1mg.
Four blister packs of Etizex brand etizolam tablets
Etizex brand etizolam tablets

Etizolam (marketed under many brand names) is a thienodiazepine derivative[4] which is a benzodiazepine analog.[5] The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.[6][7]

Although a thienodiazepine, etizolam is clinically regarded as a benzodiazepine because of its mode of action via the benzodiazepine receptor and directly targeting GABAA allosteric modulator receptors.[4]

It possesses anxiolytic, amnesic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.[8]

It was patented in 1972[9] and approved for medical use in 1983.[10]

As of April 2021, the export of Etizolam has been banned in India.[11]


Medical uses

  • Short-term treatment of insomnia.
  • Anxiety disorders such as OCD and general anxiety disorder, mostly as a short-term medication to be used purely on an at-need basis[12]

Side effects

Long term use may result in blepharospasms,[13] especially in women.[13] Doses of 4 mg or more may cause anterograde amnesia.[citation needed]

In rare cases, erythema annulare centrifugum skin lesions have resulted.[14]

Tolerance, dependence and withdrawal

Abrupt or rapid discontinuation from etizolam, as with benzodiazepines, may result in the appearance of the benzodiazepine withdrawal syndrome, including rebound insomnia.[15] Neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam.[16] This is particularly relevant given etizolam's short half life relative to benzodiazepines such as diazepam resulting in a more rapid drug level decrease in blood plasma levels.[17]

In a study that compared the effectiveness of etizolam, alprazolam, and bromazepam for the treatment of generalized anxiety disorder, all three drugs retained their effectiveness over 2 weeks, but etizolam became more effective from 2 weeks to 4 weeks.[18] Administering .5 mg etizolam twice daily did not induce cognitive deficits over 3 weeks when compared to placebo.[19]

When multiple doses of etizolam, or lorazepam, were administered to rat neurons, lorazepam caused downregulation of alpha-1 benzodiazepine binding sites (tolerance/dependence), while etizolam caused an increase in alpha-2 benzodiazepine binding sites (reverse tolerance to anti-anxiety effects).[20] Tolerance to the anticonvulsant effects of lorazepam was observed, but no significant tolerance to the anticonvulsant effects of etizolam was observed.[20] Etizolam therefore has a reduced liability to induce tolerance, and dependence, compared with classic benzodiazepines.[20]

Etizolam may represent a possible anxiolytic of choice with reduced liability to produce tolerance and dependence after long-term treatment of anxiety and stress syndromes.[21]

Pharmacology

Etizolam pills

Etizolam, a thienodiazepine derivative, is absorbed fairly rapidly, with peak plasma levels achieved between 30 minutes and 2 hours. It has a mean elimination half life of about 3.4 hours.[3][1][2] Etizolam possesses potent hypnotic properties,[22] and is comparable with other short-acting benzodiazepines.[3] Etizolam acts as a positive allosteric modulator of the GABAA receptor by agonizing the receptor's benzodiazepine site.[23]

According to the Italian prescribing information sheet,[citation needed] etizolam belongs to a new class of diazepines, thienotriazolodiazepines. This new class is easily oxidized, rapidly metabolized, and has a lower risk of accumulation, even after prolonged treatment. Etizolam has an anxiolytic action about 6-8 times greater than that of diazepam. Etizolam produces, especially at higher dosages, a reduction in time taken to fall asleep, an increase in total sleep time, and a reduction in the number of awakenings. During tests, there were no substantial changes in deep sleep; however, it may reduce REM sleep. In EEG tests of healthy volunteers, etizolam showed some similar characteristics to tricyclic antidepressants.[24][25]

Etizolam's main metabolites in humans are alpha-hydroxyetizolam and 8-hydroxyetizolam. alpha-Hydroxyetizolam is pharmacologically active and has a half-life of approximately 8.2 hours.[26]

Interactions

Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects.[27][28] Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.[29]

Overdose

Cases of intentional suicide by overdose using etizolam in combination with GABA agonists have been reported.[26][30] Although etizolam has a lower LD50 than certain benzodiazepines, the LD50 is still far beyond the prescribed or recommended dose. Flumazenil, a GABA antagonist agent used to reverse benzodiazepine overdoses, inhibits the effect of etizolam as well as classical benzodiazepines such as diazepam and chlordiazepoxide.[31]

Etizolam overdose deaths are rising - for instance, the National Records of Scotland report on drug-related deaths, 'street' Etizolam was a factor in ("implicated in, or potentially contributed to") 752, or 59%, of drug-related deaths in Scotland in 2019. It is important to highlight that more than one drug contributed to the vast majority of the deaths (by way of comparison, opiates and opioids were a factor in 1092, or 86%, of drug-related deaths).[32]

Society and culture

Brand names

Etilaam, Sedekopan, Etizest, Etizex, Pasaden or Depas

Legal status

International drug control conventions

In 1990, it was recommended that Etizolam not be placed under international control.[33] However, this attitude has changed due to increased abuse. On December 13, 2019, the World Health Organization recommended Etizolam be placed in Schedule 4 of the 1971 Convention on Psychotropic Substances.[34] This recommendation was followed by the placement of Etizolam into Schedule IV in March 2020.[35]

Australia

Etizolam is not used medically in Australia but has been found in counterfeit Xanax pills.[36]

Denmark

Etizolam is controlled in Denmark under the Danish Misuse of Drugs Act.[37]

Germany

Etizolam was controlled in Germany in July 2013[38][39] but is not used medically.

Italy

Etizolam is licensed for the treatment of anxiety, insomnia and neurosis as a prescription-only medication.[40]

[41]

India

In India, it is a prescription-only medication used for anxiety disorders, sometimes in combination with other drugs like propranolol.

United Kingdom

In the UK, etizolam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.[42]

United States

Etizolam is not authorized by the FDA for medical use in the U.S. As of March 2016, etizolam is a controlled substance in the following states: Alabama,[43] Arkansas,[44] Florida,[45] Georgia (as Schedule IV, whereas all other states listed here prohibit it as a Schedule I substance), Louisiana, Mississippi,[46] Texas,[47] South Carolina,[48] and Virginia.[49] It is controlled in Indiana as of July 1, 2017.[50] It is controlled in Ohio as of February 2018.

On December 23, 2022, the DEA announced it had begun consideration on the matter of placing Etizolam under temporary Schedule I status.[51]

Later on July 25, 2023, the DEA published a pre-print notice that Etizolam would become temporarily scheduled as a Schedule I controlled substance from 07/26/2023 to 07/26/2025.[52]

Misuse

Etizolam is a drug of potential misuse. Cases of etizolam dependence have been documented in the medical literature.[53] Since 1991, cases of etizolam misuse and addiction have substantially increased,[54] due to varying levels of accessibility and cultural popularity.[55] Pills being sold as Xanax or other benzodiazepines that are illicitly manufactured may often contain etizolam rather than their listed ingredient [56][36]

See also


References

  1. ↑ 1.0 1.1 "Etizolam". https://www.drugbank.ca/drugs/DB09166#half-life. 
  2. ↑ 2.0 2.1 "Drug & Chemical Evaluation - Etizolam". U.S. Drug Enforcement Administration. U.S. Department of Justice. March 2020. https://www.deadiversion.usdoj.gov/drug_chem_info/etizolam.pdf. 
  3. ↑ 3.0 3.1 3.2 "Single and multiple dose pharmacokinetics of etizolam in healthy subjects". European Journal of Clinical Pharmacology 40 (2): 181–185. 1991-02-01. doi:10.1007/BF00280074. PMID 2065698. 
  4. ↑ 4.0 4.1 "Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions". Arzneimittel-Forschung 49 (2): 88–95. February 1999. doi:10.1055/s-0031-1300366. PMID 10083975. 
  5. ↑ "Experimental versus theoretical log D7.4, pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances". Drug Testing and Analysis 10 (8): 1258–1269. March 2018. doi:10.1002/dta.2387. PMID 29582576. https://pure.hud.ac.uk/ws/files/13273614/logDpKaPPB_13thMar2018.pdf. 
  6. ↑ "Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs". Biological & Pharmaceutical Bulletin 28 (9): 1711–6. September 2005. doi:10.1248/bpb.28.1711. PMID 16141545. 
  7. ↑ "Separation of 1,4-Benzodiazepines and Analogues Using Cholesteryl-10-Undecenoate Bonded Phase in Microcolumn Liquid Chromatography". Journal of Chromatographic Science 36 (3): 111–118. 1 March 1998. doi:10.1093/chromsci/36.3.111. 
  8. ↑ "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism 9 (8): 827–844. October 2008. doi:10.2174/138920008786049258. PMID 18855614. https://zenodo.org/record/1067769. 
  9. ↑ "Triazolothienodiazepine compounds" US patent 3904641
  10. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 536. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA536. 
  11. ↑ "EGazette Home". https://egazette.nic.in/(S(mvrpcylnllixbwz4hcsumack))/default.aspx. 
  12. ↑ "Effects of different cyclodextrins on the morphology, loading and release properties of poly (DL-lactide-co-glycolide)-microparticles containing the hypnotic agent etizolam". Journal of Microencapsulation 24 (3): 214–24. May 2007. doi:10.1080/02652040601058152. PMID 17454433. 
  13. ↑ 13.0 13.1 "Etizolam and benzodiazepine induced blepharospasm". Journal of Neurology, Neurosurgery, and Psychiatry 75 (3): 506–507. March 2004. doi:10.1136/jnnp.2003.019869. PMID 14966178. 
  14. ↑ "Etizolam-induced superficial erythema annulare centrifugum". Clinical and Experimental Dermatology 27 (1): 34–6. January 2002. doi:10.1046/j.0307-6938.2001.00943.x. PMID 11952667. 
  15. ↑ "Rebound insomnia induced by abrupt withdrawal of hypnotics in sleep-disturbed rats". European Journal of Pharmacology 597 (1–3): 46–50. November 2008. doi:10.1016/j.ejphar.2008.08.024. PMID 18789918. 
  16. ↑ "[A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam"] (in ja). Rinsho Shinkeigaku = Clinical Neurology 42 (2): 136–9. February 2002. PMID 12424963. https://www.neurology-jp.org/Journal/cgi-bin/journal.cgi?lg=jp&pg=smry&vl=42&no=2&tp=136. 
  17. ↑ "Elimination half-life of drugs: value and limitations". Annual Review of Medicine 36 (1): 421–7. February 1985. doi:10.1146/annurev.me.36.020185.002225. PMID 3994325. 
  18. ↑ "Etizolam in the treatment of generalized anxiety disorder: a controlled clinical trial". The Journal of International Medical Research 17 (5): 455–60. 25 June 2016. doi:10.1177/030006058901700507. PMID 2572494. 
  19. ↑ "Effects of treatment with etizolam 0.5 mg BID on cognitive performance: a 3-week, multicenter, randomized, double-blind, placebo-controlled, two-treatment, three-period, noninferiority crossover study in patients with anxiety disorder". Clinical Therapeutics 31 (12): 2851–9. December 2009. doi:10.1016/j.clinthera.2009.12.010. PMID 20110024. 
  20. ↑ 20.0 20.1 20.2 "Low tolerance and dependence liabilities of etizolam: molecular, functional, and pharmacological correlates". European Journal of Pharmacology 519 (1–2): 31–42. September 2005. doi:10.1016/j.ejphar.2005.06.047. PMID 16107249. 
  21. ↑ "Low tolerance and dependence liabilities of etizolam: molecular, functional, and pharmacological correlates". European Journal of Pharmacology 519 (1–2): 31–42. September 2005. doi:10.1016/j.ejphar.2005.06.047. PMID 16107249. 
  22. ↑ "Effects of thienodiazepine derivatives, etizolam and clotiazepam on the appearance of Fm theta". The Japanese Journal of Psychiatry and Neurology 46 (4): 927–31. December 1992. doi:10.1111/j.1440-1819.1992.tb02862.x. PMID 1363923. 
  23. ↑ "Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones". British Journal of Pharmacology 98 (3): 735–40. November 1989. doi:10.1111/j.1476-5381.1989.tb14600.x. PMID 2574062. 
  24. ↑ "Depas". http://www.carloanibaldi.com/terapia/schede/DEPAS.htm. 
  25. ↑ "Etizolam" (in en). PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/3307. 
  26. ↑ 26.0 26.1 "Case report: Etizolam and its major metabolites in two unnatural death cases". Forensic Science International 182 (1–3): e1-6. November 2008. doi:10.1016/j.forsciint.2008.08.012. PMID 18976871. 
  27. ↑ "Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism". European Journal of Clinical Pharmacology 60 (6): 427–30. August 2004. doi:10.1007/s00228-004-0789-1. PMID 15232663. 
  28. ↑ "Effects of concomitant fluvoxamine on the plasma concentration of etizolam in Japanese psychiatric patients: wide interindividual variation in the drug interaction". Therapeutic Drug Monitoring 26 (6): 638–42. December 2004. doi:10.1097/00007691-200412000-00009. PMID 15570188. 
  29. ↑ "Induction of the metabolism of etizolam by carbamazepine in humans". European Journal of Clinical Pharmacology 61 (3): 185–8. May 2005. doi:10.1007/s00228-005-0904-y. PMID 15776275. 
  30. ↑ "Blood concentrations of new designer benzodiazepines in forensic cases". Forensic Science International 268: 35–38. November 2016. doi:10.1016/j.forsciint.2016.09.006. PMID 27685473. 
  31. ↑ "Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline". Psychopharmacology 122 (3): 230–6. December 1995. doi:10.1007/bf02246544. PMID 8748392. 
  32. ↑ "Drug-related deaths in Scotland 2018". National Records of Scotland. https://www.nrscotland.gov.uk/files//statistics/drug-related-deaths/2019/drug-related-deaths-19-pub.pdf. 
  33. ↑ "Expert Committee on Drug Dependence's Twenty Seventh Report". September 28, 1990. https://apps.who.int/iris/bitstream/handle/10665/40616/WHO_TRS_808.pdf?sequence=1&isAllowed=y. 
  34. ↑ "Letter of WHO Director-General to UN Secretary-General dated November 15th 2019". https://www.who.int/medicines/access/controlled-substances/UNSG_letter_42ECDD_recommendations_15Nov19.pdf. 
  35. ↑ "News: Recently scheduled benzodiazepines Flualprazolam and Etizolam associated with multiple post-mortem and DUID cases in UNODC EWA". United Nations Office on Drugs and Crime. March 2020. https://www.unodc.org/LSS/Announcement/Details/ad0c279b-b4d4-49f3-b638-cd87755d2d42. 
  36. ↑ 36.0 36.1 "Warnings over counterfeit benzodiazepines". https://www.health.nsw.gov.au/news/Pages/20191212_02.aspx. 
  37. ↑ "Bekendtgørelse om euforiserende stoffer" (in da). https://www.retsinformation.dk/Forms/R0710.aspx?id=137169. 
  38. ↑ "Verordnungsentwurf der Bundesregierung" (in de). Bundesministerium für Gesundheit (Federal Ministry of Health). http://www.bundesgesundheitsministerium.de/fileadmin/dateien/Downloads/B/Betaeubungsmittelgesetz/27_BtMAEndV.pdf. 
  39. ↑ "Gesetz über den Verkehr mit Betäubungsmitteln" (in de). Bundesministerium der Justiz und für Verbraucherschutz (Federal Ministry of Justice and Consumer Protection). http://www.gesetze-im-internet.de/btmg_1981/index.html. 
  40. ↑ "DEPAS - Etizolam". 2017-08-31. https://www.codifa.it/farmaci/d/depas-etizolam-ansiolitici-benzodiazepinici. 
  41. ↑ PubChem. "Etizolam" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/3307. 
  42. ↑ "The Misuse of Drugs Act 1971 (Amendment) Order 2017". http://www.legislation.gov.uk/uksi/2017/634/contents/made. 
  43. ↑ "Alabama Code Title 20. Food, Drugs, and Cosmetics § 20-2-23". https://codes.findlaw.com/al/title-20-food-drugs-and-cosmetics/al-code-sect-20-2-23.html. 
  44. ↑ "List of Controlled Substances". State of Arkansas. http://www.healthy.arkansas.gov/aboutadh/rulesregs/controlled_substances_list.pdf. 
  45. ↑ "Statutes & Constitution: Online Sunshine". http://www.leg.state.fl.us/Statutes/index.cfm?App_mode=Display_Statute&URL=0800-0899/0893/Sections/0893.03.html. 
  46. ↑ "HB1231 (As Sent to Governor) - 2014 Regular Session". http://billstatus.ls.state.ms.us/documents/2014/html/HB/1200-1299/HB1231SG.htm. 
  47. ↑ "Health and Safety Code Chapter 481. Texas Controlled Substances Act". https://statutes.capitol.texas.gov/Docs/HS/htm/HS.481.htm. 
  48. ↑ "Controlled Substance Schedule | SCDHEC". https://www.scdhec.gov/health-regulation/drug-control-register-verify/controlled-substance-schedule. 
  49. ↑ "18VAC110-20-322. Placement of Chemicals in Schedule I" (in en). Commonwealth of Virginia. 2 December 2015. http://law.lis.virginia.gov/admincode/title18/agency110/chapter20/section322/. 
  50. ↑ "Ellington's bill banning two deadly drugs could soon be law - State of Indiana House of Representatives". http://www.indianahouserepublicans.com/news/press-releases/ellington-s-bill-banning-two-deadly-drugs-could-soon-be-law/. 
  51. ↑ "(Proposed Rule) Schedules of Controlled Substances: Temporary Placement of Etizolam, Flualprazolam, Clonazolam, Flubromazolam, and Diclazepam in Schedule I". DEA. December 23, 2022. https://www.federalregister.gov/documents/2022/12/23/2022-27278/schedules-of-controlled-substances-temporary-placement-of-etizolam-flualprazolam-clonazolam. 
  52. ↑ "Schedules of Controlled Substances: Temporary Placement of Etizolam, Flualprazolam, Clonazolam, Flubromazolam, and Diclazepam in Schedule I". DEA. July 25, 2023. https://public-inspection.federalregister.gov/2023-15748.pdf. 
  53. ↑ "A case of etizolam dependence". Indian Journal of Pharmacology 46 (6): 655–6. 2014. doi:10.4103/0253-7613.144943. PMID 25538342. 
  54. ↑ "How to tackle Dundee's fake valium epidemic". BBC News. 20 April 2018. https://www.bbc.com/news/uk-scotland-43822454. 
  55. ↑ "Novel psychoactive substances: understanding the new illegal drug market". https://www.pharmaceutical-journal.com/opinion/insight/novel-psychoactive-substances-understanding-the-new-illegal-drug-market/20205503.article. 
  56. ↑ "Drug Data Xanax". https://www.ecstasydata.org/results.php?start=0&search_field=all&s=xanax. 

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