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==Abuse==
==Abuse==
{{See also|Benzodiazepine misuse}}
{{See also|Benzodiazepine misuse}}
Etizolam is a drug of potential abuse. Cases of abuse have been documented in the medical literature.<ref>[Gupta, S.; Garg, B. A case of etizolam dependence. <i>Indian J Pharmacol.</i> <b>2014</b>, <i>46</i>, 655-656. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264086/]</ref> However, conflicting reports from the World Health Organization, made public in 1991, dispute the abuse claims.<ref>[http://whqlibdoc.who.int/trs/WHO_TRS_808.pdf WHO Expert Committee on Drug Dependence]</ref>
Etizolam is a drug of potential abuse. Cases of abuse have been documented in the medical literature.<ref>Gupta, S.; Garg, B. A case of etizolam dependence. <i>Indian J Pharmacol.</i> <b>2014</b>, <i>46</i>, 655-656. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264086/</ref> However, conflicting reports from the World Health Organization, made public in 1991, dispute the abuse claims.<ref>[http://whqlibdoc.who.int/trs/WHO_TRS_808.pdf WHO Expert Committee on Drug Dependence]</ref>


==See also==
==See also==

Revision as of 07:05, 4 February 2016

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: Unscheduled
  • US: Schedule I in Alabama, Arkansas and Mississippi, 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 The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.[2][3] It possesses amnesic, anxiolytic, anticonvulsant, hypnotic,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

Dosage

  • Anxiety disorders associated with depression: 1 mg two to three times a day (maximum 3 mg per day)
  • For panic disorder (associated with agoraphobia): 0.5 mg two times per day (maximum 1 mg per day)
  • For insomnia: 1–2 mg once daily before bedtime[6]

A 1 mg dose of etizolam is approximately equivalent to a 10 mg dose of diazepam, see list of benzodiazepines.

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.[9] Neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam.[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 were observed, but no significant tolerance to the anticonvulsant effects of etizolam were observed.[13] Etizolam therefore has a reduced liability to induce tolerance, and dependence, compared with classic benzodiazepines.[13]

Contraindications and special caution

Etizolam is metabolized by the liver and is contraindicated in those with severely impaired hepatic function. It may impair the ability to drive and operate machinery so caution should be applied. Elderly patients should start on a lower dose as they are more susceptible to the sedative effects of etizolam. It is not recommended to be taken during pregnancy or breastfeeding.[6]

Etizolam can increase the sedative and antidepressant actions of other medication such as neuroleptics, analgesics, anaesthetics, antiepileptics, sedatives and first-generation antihistamines. Co-administration with these medications should be avoided unless instructed by a medical professional. Alcohol should also be avoided.[6]

Drugs inhibiting the enzymes CYP2C19 and CYP3A4, such as fluvoxamine, should not be taken concurrently as etizolam can increase the plasma levels of these enzymes.[6]

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] Similar to other benzodiazepines, etizolam binds non-selectively to benzodiazepine receptor subtypes.[dubious – discuss][17]

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.[18]

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]

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 it is a thienodiazepine, an analog of benzodiazepines, which are Schedule IV drug under Federal Scheduling Guidelines, it does not fall under the Federal Analog Act, which only applies to Schedule I and II drugs.[19]

Etizolam is a controlled substance in the following states: Alabama, Arkansas[20] and Mississippi.[21]

In the state of Georgia,[22] Etizolam has been added to schedule IV as of 2015

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.[23]

Germany

Etizolam was controlled in Germany in July 2013.[24]

Poland

Etizolam may be scheduled under the Act on Counteracting Drug Addiction and the State Sanitary Inspection -Article 27c

Interactions

Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects.[25][26] Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.[27]

Etizolam, similarly to other GABAergic agonists including the benzodiazepines has a strong synergistic effect with ethanol and the consequences of co-ingestion of the two drugs can drastically compound the side effects of either drug.[medical citation needed] This can result in (among other effects) anterograde amnesia (blackouts) and severe respiratory depression which in extreme cases can lead to death.[medical citation needed]

Overdose

See also: Benzodiazepine overdose

Cases of intentional suicide by overdose using etizolam in combination with GABA antagonists have been reported.[28] 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 benzodiazapine overdoses, inhibits the effect of etizolam as well as classical benzodiazepines such as diazepam and chlordiazepoxide.[29]

Abuse

See also: Benzodiazepine misuse

Etizolam is a drug of potential abuse. Cases of abuse have been documented in the medical literature.[30] However, conflicting reports from the World Health Organization, made public in 1991, dispute the abuse claims.[31]

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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: |access-date= requires |url= (help)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ a b c d Pharmaceuticals, Intas. "Etilaam - .25mg, .50mg,.1mg". Etilaam's prescribing info sheet for doctors in India. Intas Pharmaceuticals.
  7. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Ozawa M, Nakada Y, Sugimachi K; et al. (March 1994). "Pharmacological characterization of the novel anxiolytic beta-carboline abecarnil in rodents and primates". Jpn. J. Pharmacol. 64 (3): 179–87. doi:10.1254/jjp.64.179. PMID 7912751.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Kaneda Y (2000). "Short Communication: Prolactogenic effects of etizolam". Neuro Endocrinol. Lett. 21 (6): 475–476. PMID 11335869.
  19. ^ http://www.law.cornell.edu/uscode/text/21/802
  20. ^ http://www.healthy.arkansas.gov/aboutADH/RulesRegs/ControlledSubstanceListSummary.pdf
  21. ^ http://billstatus.ls.state.ms.us/documents/2014/html/HB/1200-1299/HB1231SG.htm
  22. ^ http://www.namsdl.org/library/946E60B2-ABB3-24A6-F087859B3EA48EC1/
  23. ^ http://www.legislation.gov.uk/ukpga/1971/38/contents.
  24. ^ http://www.bundesgesundheitsministerium.de/fileadmin/dateien/Downloads/B/Betaeubungsmittelgesetz/27_BtMAEndV.pdf and http://www.gesetze-im-internet.de/btmg_1981/index.html.
  25. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ 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.
  30. ^ Gupta, S.; Garg, B. A case of etizolam dependence. Indian J Pharmacol. 2014, 46, 655-656. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264086/
  31. ^ WHO Expert Committee on Drug Dependence
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