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Etizolam

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Etizolam
Clinical data
Trade namesEtilaam, Etizest
Dependence
liability		Moderate
Routes of
administration		Oral, sublingual, rectal
ATC code
Legal status
Legal status
  • DE: Anlage III (Special prescription form required)
  • 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
Bioavailability93%
MetabolismHepatic
Elimination half-life6.2 hours[1] (main metabolite is 8.2 hours)
ExcretionRenal
Identifiers
  • 4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.188.773 Edit this at Wikidata
Chemical and physical data
FormulaC17H15ClN4S
Molar mass342.07 g/mol g·mol−1
3D model (JSmol)
  • ClC1=CC=CC=C1C2=NCC3=NN=C(C)N3C4=C2C=C(CC)S4
  • InChI=1S/C17H15ClN4S/c1-3-11-8-13-16(12-6-4-5-7-14(12)18)19-9-15-21-20-10(2)22(15)17(13)23-11/h4-8H,3,9H2,1-2H3 checkY
  • Key:VMZUTJCNQWMAGF-UHFFFAOYSA-N checkY
 ☒NcheckY (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 The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.[2][3] It possesses amnesic, anxiolytic, anticonvulsant, hypnotic,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

Side effects

Very Rare

Tolerance, dependence and withdrawal

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

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]

Denmark

Etizolam is controlled in Denmark under the Danish Misuse of Drugs Act.[18]

Germany

Etizolam was controlled in Germany in July 2013.[19]

Japan

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

United Kingdom

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.[20] Etizolam may, however, fall under the scope of the Psychoactive Substances Act 2016, thus potentially making its importation and sale illegal across the United Kingdom in some cases.[21]

The Psychoactive Substances Act 2016 exempts "medicinal products" as defined in the Human Medicines Regulations 2012,[22] and in turn those regulations define a medicinal product as "any substance or combination of substances presented as having properties of preventing or treating disease in human beings"[23] and further defines a prescription only medication as:

"In these Regulations references to a prescription only medicine are to any of the following—

(a)a medicinal product that is covered by an authorisation of which it is a term that the product is to be available only on prescription;

(b)a medicinal product that—

(i)is covered by an EU marketing authorisation, and

(ii)is classified in the authorisation as a prescription only medicine"

Etizolam does have an EU Marketing authorization as it is legally sold in Italy as a prescription only medicine there, and certainly it could be argued that, in its pharmaceutical form, Etizolam tablets is a substance that is being presented as having properties of treating disease in human beings. It could therefore be argued that Etizolam—at least, in its medicinal product form—would not fall under the scope of the Psychoactive Substances Act.

United States

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,[24] Florida,[25] Mississippi,[26] Virginia,[27] and Georgia.[28]

Interactions

Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects.[29][30] Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.[31]

Overdose

See also: Benzodiazepine overdose

Cases of intentional suicide by overdose using etizolam in combination with GABA agonists have been reported.[32][33] 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.[34]

Abuse

See also: Benzodiazepine misuse

Etizolam is a drug of potential abuse. Cases of etizolam dependence have been documented in the medical literature.[35] However, conflicting reports from the World Health Organization, made public in 1991, dispute the abuse claims.[36]

See also

References

  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 1738986. 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 1854765. PMID 2574062.
  17. ^ Kaneda Y (2000). "Short Communication: Prolactogenic effects of etizolam". Neuro Endocrinol. Lett. 21 (6): 475–476. PMID 11335869.
  18. ^ "Bekendtgørelse om euforiserende stoffer". retsinformation.dk (in Danish). Retrieved 2016-11-21.
  19. ^ http://www.bundesgesundheitsministerium.de/fileadmin/dateien/Downloads/B/Betaeubungsmittelgesetz/27_BtMAEndV.pdf and http://www.gesetze-im-internet.de/btmg_1981/index.html.
  20. ^ http://www.legislation.gov.uk/ukpga/1971/38/contents.
  21. ^ http://www.legislation.gov.uk/ukpga/2016/2/contents/enacted/data.htm
  22. ^ http://www.legislation.gov.uk/ukpga/2016/2/schedule/1/enacted
  23. ^ http://www.legislation.gov.uk/uksi/2012/1916/regulation/2/made
  24. ^ http://www.healthy.arkansas.gov/aboutadh/rulesregs/controlled_substances_list.pdf
  25. ^ http://www.leg.state.fl.us/Statutes/index.cfm?App_mode=Display_Statute&URL=0800-0899/0893/Sections/0893.03.html
  26. ^ http://billstatus.ls.state.ms.us/documents/2014/html/HB/1200-1299/HB1231SG.htm
  27. ^ "18VAC110-20-322. Placement of Chemicals in Schedule I." Commonwealth of Virginia. 2 December 2015. Retrieved 11 March 2016.
  28. ^ http://www.namsdl.org/library/946E60B2-ABB3-24A6-F087859B3EA48EC1/
  29. ^ 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.
  30. ^ 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.
  31. ^ 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.
  32. ^ 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.
  33. ^ 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.
  34. ^ 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.
  35. ^ Gupta S, Garg B (2014). "A case of etizolam dependence". Indian J Pharmacol. 46 (6): 655–656. doi:10.4103/0253-7613.144943. PMC 4264086. PMID 25538342.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  36. ^ WHO Expert Committee on Drug Dependence
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