Etizolam

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Etizolam
Etizolam.svg
Etizolam3d.png
Systematic (IUPAC) name
7-(2-Chlorophenyl)-4-ethyl-13-methyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaene
Clinical data
Trade names Etilaam
Pregnancy cat. N
Legal status Unscheduled (UK) Unscheduled (US)
Dependence liability High
Routes Oral, Sublingual
Pharmacokinetic data
Bioavailability 93%
Metabolism Hepatic
Half-life

3.4 hours

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

Etizolam (marketed under the brand name Etilaam, Etizest, Etizola, Sedekopan, Pasaden or Depas) is a benzodiazepine analog.[1] The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring, making the drug a thienodiazepine.[2] It possesses amnesic, anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.[3]

Indications[edit]

Dosage[edit]

  • 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[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.[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 classical benzodiazepines.[13]

Contraindications and special caution[edit]

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.[14]

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.[15] Etizolam possesses potent hypnotic properties,[16] and is comparable with other short-acting benzodiazepines.[15] Etizolam acts as a full agonist at the benzodiazepine receptor to produce its range of therapeutic and adverse effects.[17] Similar to other benzodiazepines, etizolam binds non-selectively to benzodiazepine receptor subtypes.[dubious ][18]

In addition, etizolam, unlike most other benzodiazepines (some of which can increase levels of estradiol), has prolactogenic effects, leading to an increase in blood levels of prolactin.[19]

According to the Italian P.I. sheet, 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 not substantial changes in deep sleep; however, it may reduce REM sleep. In EEG tests of healthy volunteers, etizolam showed some characteristics of tricyclic antidepressants.[5]

Interactions[edit]

Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects.[20][21] Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.[22]

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[edit]

Cases of intentional suicide by overdose using etizolam have been reported.[23] Although etizolam has a lower LD50 than certain benzodiazepines, the LD50 is still far beyond the prescribed or recommended dose. Many lethal etizolam overdoses were due to drug interactions.[citation needed]

Abuse[edit]

Etizolam is a drug of potential abuse. However, conflicting reports from the World Health Organization, made public in 1991, dispute the abuse claims.[24]

However the drug has seen a large amount of popularity as a research chemical since 2012 which suggests it is being abused for recreational use.[25]

See also[edit]

References[edit]

  1. ^ DE 2229845 
  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. ^ 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. 
  4. ^ 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. 
  5. ^ a b "Depas". Retrieved February 3, 2009. 
  6. ^ 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. 
  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. 
  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. 
  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. 
  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. ^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (Nov 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Ann Pharm Fr 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604. 
  15. ^ 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. PMID 2065698. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ 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. 
  19. ^ Kaneda Y (2000). "Short Communication: Prolactogenic effects of etizolam". Neuro Endocrinol. Lett. 21 (6): 475–476. PMID 11335869. 
  20. ^ 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. 
  21. ^ 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. 
  22. ^ 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. 
  23. ^ 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. 
  24. ^ WHO Expert Committee on Drug Dependence
  25. ^ "Etizolam". UK Chemical Research. Retrieved 26 July 2014. 

External links[edit]