Etizolam

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Etizolam
Etizolam.svg
EtizXtal3.png
Systematic (IUPAC) name
4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
Clinical data
Trade names Etilaam, Etizest
Dependence
liability
Moderate
Routes of
administration
Oral, sublingual, rectal
Legal status
Legal status
  • DE: Anlage III (Prescription only)
  • UK: Controlled as psychoactive substance
  • US: Schedule I in Alabama, Arkansas, Florida, Mississippi, and Virginia, Schedule IV in Georgia; not FDA approved. Unscheduled in the remaining states.
Pharmacokinetic data
Bioavailability 93%
Metabolism Hepatic
Biological half-life

6.2 hours[1]

(main metabolite is 8.2 hours)
Excretion Renal
Identifiers
CAS Number 40054-69-1 YesY
ATC code N05BA19 (WHO)
PubChem CID 3307
ChemSpider 3191 YesY
UNII A76XI0HL37 YesY
KEGG D01514 YesY
ChEMBL CHEMBL1289779 N
Chemical data
Formula C17H15ClN4S
Molar mass 342.07 g/mol
 NYesY (what is this?)  (verify)

Etizolam (marketed under the brand name Etilaam, Etizola, Sedekopan, Etizest, Pasaden or Depas) is a benzodiazepine analog. The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.[2][3] It possesses amnesic, anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.[4]

Indications[edit]

Side effects[edit]

Very Rare

Tolerance, dependence and withdrawal[edit]

Abrupt or rapid withdrawal from etizolam, as with benzodiazepines, may result in the appearance of the benzodiazepine withdrawal syndrome, including rebound insomnia.[8] Neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam.[9] 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.[10]

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, a type of reverse tolerance.[11] Administering .5 mg etizolam twice daily did not induce cognitive deficits over 3 weeks when compared to placebo.[12]

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).[13] Tolerance to the anticonvulsant effects of lorazepam was observed, but no significant tolerance to the anticonvulsant effects of etizolam was observed.[13] Etizolam therefore has a reduced liability to induce tolerance, and dependence, compared with classic benzodiazepines.[13]

Pharmacology[edit]

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 3.5 hours.[14] Etizolam possesses potent hypnotic properties,[15] and is comparable with other short-acting benzodiazepines.[14] Etizolam acts as a full agonist at the benzodiazepine receptor to produce its range of therapeutic and adverse effects.[16]

In addition, etizolam, unlike most benzodiazepines (some of which can increase levels of estradiol), has prolactogenic effects, leading to an increase in blood levels of prolactin.[17]

According to the Italian P.I. 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 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.[1]

Legal status[edit]

United States[edit]

Etizolam is not authorized by the FDA for medical use in the U.S. However, it currently remains unscheduled and is legal for research purposes. As of March 2016, etizolam is a controlled substance in the following states: Alabama, Arkansas,[18] Florida,[19] Mississippi,[20] Virginia,[21] and Georgia.[22]

United Kingdom[edit]

Unlike other thienodiazepines such as brotizolam and clotiazepam, etizolam is not controlled under the Misuse of Drugs Act 1971 or licensed as a medicine in the United Kingdom.[23] Etizolam is, however, in scope of the Psychoactive Substances Act 2016, thus making its importation and sale illegal across the United Kingdom.[24]

Germany[edit]

Etizolam was controlled in Germany in July 2013.[25]

Japan[edit]

Etizolam also called Depas, is restricted as a benzodiazepine analogs in Japan from October 2016 onwards.

Interactions[edit]

Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects.[26][27] Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.[28]

Overdose[edit]

Cases of intentional suicide by overdose using etizolam in combination with GABA agonists have been reported.[29][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]

Abuse[edit]

Etizolam is a drug of potential abuse. Cases of etizolam dependence have been documented in the medical literature.[32] However, conflicting reports from the World Health Organization, made public in 1991, dispute the abuse claims.[33]

See also[edit]

References[edit]

  1. ^ a b c "Depas". Retrieved October 31, 2015. 
  2. ^ Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A (September 2005). "Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs" (PDF). Biol. Pharm. Bull. 28 (9): 1711–6. doi:10.1248/bpb.28.1711. PMID 16141545. 
  3. ^ Catabay, A.; Taniguchi, M.; Jinno, K.; Pesek, J. J.; Williamsen, E. (1 March 1998). "Separation of 1,4-Benzodiazepines and Analogues Using Cholesteryl-10-Undecenoate Bonded Phase in Microcolumn Liquid Chromatography". Journal of Chromatographic Science. 36 (3): 113. doi:10.1093/chromsci/36.3.111. 
  4. ^ Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Curr. Drug Metab. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614. 
  5. ^ Lopedota A, Cutrignelli A, Trapani A, et al. (May 2007). "Effects of different cyclodextrins on the morphology, loading and release properties of poly (DL-lactide-co-glycolide)-microparticles containing the hypnotic agent etizolam". J Microencapsul. 24 (3): 214–24. doi:10.1080/02652040601058152. PMID 17454433. 
  6. ^ Wakakura M, Tsubouchi T, Inouye J (March 2004). "Etizolam and benzodiazepine induced blepharospasm". J. Neurol. Neurosurg. Psychiatr. 75 (3): 506–7. doi:10.1136/jnnp.2003.019869. PMC 1738986free to read. PMID 14966178. 
  7. ^ Kuroda K, Yabunami H, Hisanaga Y (January 2002). "Etizolam-induced superficial erythema annulare centrifugum". Clin. Exp. Dermatol. 27 (1): 34–6. doi:10.1046/j.0307-6938.2001.00943.x. PMID 11952667. 
  8. ^ Hirase M, Ishida T, Kamei C (November 2008). "Rebound insomnia induced by abrupt withdrawal of hypnotics in sleep-disturbed rats". Eur. J. Pharmacol. 597 (1–3): 46–50. doi:10.1016/j.ejphar.2008.08.024. PMID 18789918. 
  9. ^ Kawajiri M, Ohyagi Y, Furuya H, et al. (February 2002). "[A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam]". Rinsho Shinkeigaku (in Japanese). 42 (2): 136–9. PMID 12424963. 
  10. ^ http://www.annualreviews.org/doi/abs/10.1146/annurev.me.36.020185.002225?journalCode=med
  11. ^ Bertolino, A; Mastucci, E; Porro, V; Corfiati, L; Palermo, M; Ecari, U; Ceccarelli, G (1989). "Etizolam in the treatment of generalized anxiety disorder: A controlled clinical trial". The Journal of international medical research. 17 (5): 455–60. PMID 2572494. 
  12. ^ De Candia, MP; Di Sciascio, G; Durbano, F; Mencacci, C; Rubiera, M; Aguglia, E; Garavini, A; Bersani, G; Di Sotto, A; Placidi, G; Cesana, BM (2009). "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. doi:10.1016/j.clinthera.2009.12.010. PMID 20110024. 
  13. ^ a b c Sanna, E; Busonero, F; Talani, G; Mostallino, MC; Mura, ML; Pisu, MG; MacIocco, E; Serra, M; Biggio, G (2005). "Low tolerance and dependence liabilities of etizolam: Molecular, functional, and pharmacological correlates". European Journal of Pharmacology. 519 (1–2): 31–42. doi:10.1016/j.ejphar.2005.06.047. PMID 16107249. 
  14. ^ a b Fracasso C, Confalonieri S, Garattini S, Caccia S (1991). "Single and multiple dose pharmacokinetics of etizolam in healthy subjects". Eur. J. Clin. Pharmacol. 40 (2): 181–5. doi:10.1007/BF00280074. PMID 2065698. 
  15. ^ Nakamura J, Mukasa H (December 1992). "Effects of thienodiazepine derivatives, etizolam and clotiazepam on the appearance of Fm theta". Jpn. J. Psychiatry Neurol. 46 (4): 927–31. doi:10.1111/j.1440-1819.1992.tb02862.x. PMID 1363923. 
  16. ^ Yakushiji T, Fukuda T, Oyama Y, Akaike N (November 1989). "Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones". Br. J. Pharmacol. 98 (3): 735–40. doi:10.1111/j.1476-5381.1989.tb14600.x. PMC 1854765free to read. PMID 2574062. 
  17. ^ Kaneda Y (2000). "Short Communication: Prolactogenic effects of etizolam". Neuro Endocrinol. Lett. 21 (6): 475–476. PMID 11335869. 
  18. ^ http://www.healthy.arkansas.gov/aboutadh/rulesregs/controlled_substances_list.pdf
  19. ^ http://www.leg.state.fl.us/Statutes/index.cfm?App_mode=Display_Statute&URL=0800-0899/0893/Sections/0893.03.html
  20. ^ http://billstatus.ls.state.ms.us/documents/2014/html/HB/1200-1299/HB1231SG.htm
  21. ^ "18VAC110-20-322. Placement of Chemicals in Schedule I.". Commonwealth of Virginia. 2 December 2015. Retrieved 11 March 2016. 
  22. ^ http://www.namsdl.org/library/946E60B2-ABB3-24A6-F087859B3EA48EC1/
  23. ^ http://www.legislation.gov.uk/ukpga/1971/38/contents.
  24. ^ http://www.legislation.gov.uk/ukpga/2016/2/contents/enacted/data.htm
  25. ^ http://www.bundesgesundheitsministerium.de/fileadmin/dateien/Downloads/B/Betaeubungsmittelgesetz/27_BtMAEndV.pdf and http://www.gesetze-im-internet.de/btmg_1981/index.html.
  26. ^ Araki K, Yasui-Furukori N, Fukasawa T, et al. (August 2004). "Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism". Eur. J. Clin. Pharmacol. 60 (6): 427–30. doi:10.1007/s00228-004-0789-1. PMID 15232663. 
  27. ^ Suzuki Y, Kawashima Y, Shioiri T, Someya T (December 2004). "Effects of concomitant fluvoxamine on the plasma concentration of etizolam in Japanese psychiatric patients: wide interindividual variation in the drug interaction". Ther Drug Monit. 26 (6): 638–42. doi:10.1097/00007691-200412000-00009. PMID 15570188. 
  28. ^ Kondo S, Fukasawa T, Yasui-Furukori N, et al. (May 2005). "Induction of the metabolism of etizolam by carbamazepine in humans". Eur. J. Clin. Pharmacol. 61 (3): 185–8. doi:10.1007/s00228-005-0904-y. PMID 15776275. 
  29. ^ Nakamae T, Shinozuka T, Sasaki C, et al. (November 2008). "Case report: Etizolam and its major metabolites in two unnatural death cases". Forensic Sci. Int. 182 (1–3): e1–6. doi:10.1016/j.forsciint.2008.08.012. PMID 18976871. 
  30. ^ Høiseth, Gudrun; Tuv, Silja Skogstad; Karinen, Ritva (2016). "Blood concentrations of new designer benzodiazepines in forensic cases". Forensic Science International. doi:10.1016/j.forsciint.2016.09.006. 
  31. ^ Woolverton WL, Nader MA, et al. (December 1995). "Case report: Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline.". Psychopharmacology (Berl). 122 (3): 230–236. doi:10.1007/BF02246544. PMID 8748392. 
  32. ^ Gupta S, Garg B (2014). "A case of etizolam dependence". Indian J Pharmacol. 46 (6): 655–656. doi:10.4103/0253-7613.144943. PMC 4264086free to read. PMID 25538342. 
  33. ^ WHO Expert Committee on Drug Dependence

External links[edit]