Etizolam
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| 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) |
| 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  |
| ATC code | N05BA19 |
| PubChem | CID 3307 |
| ChemSpider | 3191 |
| UNII | A76XI0HL37 |
| KEGG | D01514 |
| ChEMBL | CHEMBL1289779  |
| Chemical data | |
| Formula | C17H15ClN4S |
| Mol. mass | 342.07 |
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Etizolam[1] (marketed under the brand name Etilaam, Etizola, Sedekopan, Pasaden or Depas) is a thienodiazepine drug which is a benzodiazepine analog. The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring.[2] It possesses amnesic, anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.[3]
Contents |
[edit] Indications
- Short-term treatment of insomnia[4]
- Short-term treatment of anxiety or panic attacks, if a benzodiazepine is required[5]
[edit] Dosage
- For anxiety: 1–2 mg two times per day (maximum 4 mg per day)
- For insomnia: 2–4 mg before bedtime
A 1 mg dose of etizolam is approximately equivalent to that of 10 mg of diazepam, see List of benzodiazepines.
[edit] Side effects
- Blepharospasms with long term use[6]
Very Rare
- Erythema annulare centrifugum skin lesions[7]
[edit] Tolerance, dependence and withdrawal
Abrupt or over rapid withdrawal from etizolam as with benzodiazepines may result in the appearance of the benzodiazepine withdrawal syndrome, including rebound insomnia.[8] A neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal has been documented in a case of abrupt withdrawal from etizolam.[9]
1. Patients with generalized anxiety disorder were either treated with Etizolam (0.5 mg), Alprazolam (0.5 mg), or Bromazepam (3 mg) twice a day. While all three drugs retained their effectiveness over two weeks, etizolam actually started to become more effective than the other benzos from to 2 weeks to 4 weeks (reverse tolerance in a way). The researchers also note antidepressant activity in etizolam not seen in the other two drugs tested. [10] PubMed Etizolam in the treatment of generalized anxiety disorder
2. No cognitive deficits over 3 weeks compared to placebo were noticed with etizolam 0.5 mg BID, a curious finding for a BZD agonist [11] PubMed 0. Effects of treatment with etizolam 0.5 mg BID on cognitive performance
3. When multiple doses of etizolam or lorazepam were administered to rat neurons, lorazepam caused downregulation of alpha-1 BZD sites (aka tolerance/dependence), while etizolam caused an increase in alpha-2 BZD sites (aka reverse tolerance to anti-anxiety effect).
Also, the researchers noted a marked tolerance over time to the anticonvulsant effects of lorazepam, but no significant tolerance to anticonvulsant effects of etizolam.
Quote from abstract: "These data suggest that etizolam is endowed with a reduced liability to induce tolerance and dependence compared with classical benzodiazepines." [12] Low tolerance and dependence liabilities of etizolam
[edit] Contraindications and special caution
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.[13]
[edit] Pharmacology
Etizolam, a thienodiazepine derivative, is absorbed fairly rapidly, with peak plasma levels achieved between 30 minutes and 2 hours, and has a mean elimination half life of about 3 and a half hours.[14] However, its pharmacologically active metabolite alpha-hydroxyetizolam, which has the same potency as etizolam, is eliminated more slowly, with a mean half life of just over 8 hours. 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 as well as adverse effects.[16] Similar to other benzodiazepines, etizolam binds unselectively to benzodiazepine receptor subtypes.[17]
In addition, etizolam, unlike most other benzodiazepines (some of which can increase levels of estradiol), has prolactogenic effects, leading to an increase in prolactin blood levels.[18]
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. There is a reduction of REM sleep. In EEG tests of healthy volunteers, etizolam showed some characteristics of tricyclic antidepressants.[5]
[edit] Interactions
Itraconazole and fluvoxamine slow down the rate of elimination of etizolam leading to accumulation of etizolam and thus increased pharmacological effects.[19][20] Carbamazepine speeds up the metabolism of etizolam resulting in reduced pharmacological effects of etizolam.[21]
[edit] Overdose
Etizolam has been used in cases of suicidal benzodiazepine overdose. An overdose of etizolam can prove fatal.[22] 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.
[edit] Abuse
Etizolam is a drug of potential abuse. Etizolam has been shown to be able to substitute for the behavioural effects of barbiturates in primate studies.[23] Etizolam is marketed on the designer drug market in Europe.[citation needed] However, conflicting reports from the World Health Organization, made public in 1991, dispute the abuse claims.[24]
[edit] See also
- Brotizolam
- Clotiazepam
- Benzodiazepine
- Benzodiazepine dependence
- Benzodiazepine withdrawal syndrome
- Long-term effects of benzodiazepines
[edit] References
- ^ DE Patent 2229845
- ^ 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.
- ^ 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.
- ^ 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.
- ^ a b "Depas". Retrieved February 3, 2009.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Etizolam in the Treatment of GAD (PubMed Abstract)
- ^ Effects of 0.5 mg BID Etizolam on cognitive performance (PubMed Abstract)
- ^ Low tolerance and dependence liabilities of etizolam
- ^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM. et al. (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.
- ^ 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.
- ^ 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. PMID 1363923.
- ^ 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. PMC 1854765. PMID 2574062.
- ^ 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.
- ^ Kaneda Y (2000). "Short Communication: Prolactogenic effects of etizolam". Neuro Endocrinol. Lett. 21 (6): 475–476. PMID 11335869.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Woolverton WL, Nader MA (December 1995). "Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline". Psychopharmacology (Berl.) 122 (3): 230–6. doi:10.1007/BF02246544. PMID 8748392.
- ^ WHO Expert Committee on Drug Dependence
[edit] External links
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