Etizolam
Benzodiazepine analog drug From Wikipedia, the free encyclopedia
Etizolam (marketed under numerous brand names) is a thienodiazepine derivative[5] which is a benzodiazepine analog.[6] The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.[7][8]
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| Trade names | Etizest, Etilaam, Etizex, Depas, Sedekopan, Pasaden |
| Dependence liability | Moderate |
| Routes of administration | Oral, sublingual, rectal |
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| Bioavailability | 93% |
| Metabolism | Hepatic |
| Elimination half-life | 3.4 hours[2][3] (main metabolite is 8.2 hours)[4] |
| Duration of action | 5-7 hours |
| Excretion | Kidney |
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| ECHA InfoCard | 100.188.773 |
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| Formula | C17H15ClN4S |
| Molar mass | 342.85 g·mol−1 |
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Although a thienodiazepine, etizolam is clinically regarded as a benzodiazepine because of its mode of action via the benzodiazepine receptor and directly targeting GABAA allosteric modulator receptors.[5]
It possesses anxiolytic, amnesic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.[9]
It was patented in 1972[10] and first approved for medical use in Japan in 1984.[11]
As of April 2021, the export of etizolam has been banned in India.[12]
Medical uses
Side effects
Summarize
Perspective
Long term use may result in blepharospasms,[14] especially in women.[14] Doses of 4 mg or more may cause anterograde amnesia.[citation needed]
In rare cases, erythema annulare centrifugum skin lesions have resulted.[15]
Tolerance, dependence and withdrawal
Abrupt or rapid discontinuation from etizolam, as with benzodiazepines, may result in the appearance of the benzodiazepine withdrawal syndrome, including rebound insomnia.[16] Neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam.[17] 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.[18]
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.[19] Administering .5 mg etizolam twice daily did not induce cognitive deficits over 3 weeks when compared to placebo.[20]
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).[21] Tolerance to the anticonvulsant effects of lorazepam was observed, but no significant tolerance to the anticonvulsant effects of etizolam was observed.[21] Etizolam therefore has a reduced liability to induce tolerance, and dependence, compared with classic benzodiazepines.[21]
Etizolam may represent a possible anxiolytic of choice with reduced liability to produce tolerance and dependence after long-term treatment of anxiety and stress syndromes.[22]
Pharmacology
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Perspective
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 3.4 hours.[4][2][3] Etizolam possesses potent hypnotic properties,[23] and is comparable with other short-acting benzodiazepines.[4] Etizolam acts as a positive allosteric modulator of the GABAA receptor by agonizing the receptor's benzodiazepine site.[24]
According to the Italian prescribing information 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 6-8 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.[25][26]
Etizolam's main metabolites in humans are alpha-hydroxyetizolam and 8-hydroxyetizolam. alpha-Hydroxyetizolam is pharmacologically active and has a half-life of approximately 8.2 hours.[27]
Interactions
Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects.[28][29] Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.[30]
Overdose
Cases of intentional suicide by overdose using etizolam in combination with GABA agonists have been reported.[27][31] 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.[32]
Etizolam overdose deaths are rising in Scotland, especially among women - for instance, the National Records of Scotland report on drug-related deaths have, "have increased significantly in Scotland in recent years, with a much greater percentage increase in deaths among women than among men". By 2018 1,187 overdoses were officially recorded, a 107% increase from 2008, this means that this has been the highest peak to date. Although, men still outnumber women in drug-related deaths.[33]
Society and culture
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Perspective
Brand names
Etilaam, Sedekopan, Etizest, Etizex, Pasaden or Depas
Legal status
International drug control conventions
In 1990, it was recommended that Etizolam not be placed under international control.[34] However, this attitude has changed due to increased abuse. On December 13, 2019, the World Health Organization recommended Etizolam be placed in Schedule 4 of the 1971 Convention on Psychotropic Substances.[35] This recommendation was followed by the placement of Etizolam into Schedule IV in March 2020.[36]
Australia
Etizolam is not used medically in Australia but has been found in counterfeit Xanax pills.[37]
Denmark
Etizolam is controlled in Denmark under the Danish Misuse of Drugs Act.[38]
Germany
Etizolam was controlled in Germany in July 2013[39][40] but is not used medically.
Italy
Etizolam is licensed for the treatment of anxiety, insomnia and neurosis as a prescription-only medication.[41][42]
India
In India, it is a Narcotics prescription-only (NRx) medication used for anxiety disorders, sometimes in combination with other drugs, i.e. the beta blocker propranolol.
United Kingdom
In the UK, etizolam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.[43]
United States
Etizolam is not authorized by the FDA for medical use in the U.S. As of March 2016, etizolam is a controlled substance in the following states: Alabama,[44] Arkansas,[45] Florida,[46] Georgia (as Schedule IV, whereas all other states listed here prohibit it as a Schedule I substance), Louisiana, Mississippi,[47] Texas,[48] South Carolina,[49] and Virginia.[50] It is controlled in Indiana as of July 1, 2017.[51] It is controlled in Ohio as of February 2018.
On December 23, 2022, the DEA announced it had begun consideration on the matter of placing Etizolam under temporary Schedule I status.[52]
Later on July 25, 2023, the DEA published a pre-print notice that Etizolam would become temporarily scheduled as a Schedule I controlled substance from 26 July 2023 to 26 July 2025.[53]
Misuse
Etizolam is a drug of potential misuse. Cases of etizolam dependence have been documented in the medical literature.[54] Since 1991, cases of etizolam misuse and addiction have substantially increased,[55] due to varying levels of accessibility and cultural popularity.[56] Pills being sold as Xanax or other benzodiazepines that are illicitly manufactured may often contain etizolam rather than their listed ingredient[57][37]
See also
References
External links
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