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 | |
| Pregnancy cat. | ? |
| Legal status | ? (US) |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | 93% |
| Metabolism | Hepatic |
| Half-life | about 6 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 |
| SMILES | eMolecules & PubChem |
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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 The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring.[2] It possesses amnesic, anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.[3]
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[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: 0.50-1 mg two or three times per day (maximum 2 mg per day)
- For insomnia: 1-2 mg before bedtime
A 2mg dose of etizolam is approximately equivalent to that of 10mg 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 other 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]
[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.[10]
[edit] Pharmacology
Etizolam a thienodiazepine benzodiazepine 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. 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. So it can be classified as a short-medium action benzodiazepine.[11] Etizolam possesses potent hypnotic properties.[12] Etizolam acts as a full agonist at the benzodiazepine receptor to produce its range of therapeutic as well as adverse effects.[13] Similar to other benzodiazepines etizolam binds unselectively to benzodiazepine receptor subtypes.[14]
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.[15]
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.[16][17] Carbamazepine speeds up the metabolism of etizolam resulting in reduced pharmacological effects of etizolam.[18]
[edit] Overdose
Etizolam has been used in cases of suicidal benzodiazepine overdose. An overdose of etizolam can prove fatal.[19] 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.[20]
[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. http://www.jstage.jst.go.jp/article/bpb/28/9/1711/_pdf.
- ^ 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. http://www.benthamdirect.org/pages/content.php?CDM/2008/00000009/00000008/0009F.SGM.
- ^ 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". http://www.carloanibaldi.com/terapia/schede/DEPAS.htm. 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1738986.
- ^ 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]" (in Japanese). Rinsho Shinkeigaku 42 (2): 136–9. PMID 12424963.
- ^ 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.
- ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1854765.
- ^ 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. http://www.journalarchive.jst.go.jp/jnlpdf.php?cdjournal=jphs1951&cdvol=64&noissue=3&startpage=179&lang=en&from=jnlabstract.
- ^ Kaneda Y (2000). "Short Communication: Prolactogenic effects of etizolam". Neuro Endocrinol. Lett. 21 (6): 475–476. PMID 11335869. http://www.nel.edu/21_6/NEL21062000B001_Kaneda.htm.
- ^ 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.
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