Etizolam

Last updated

Etizolam
Etizolam.svg
Etizolam-from-xtal-3D-bs-17.png
Clinical data
Trade names Etizest, Etilaam, Etizex, Depas, Sedekopan, Pasaden
Dependence
liability 		Moderate
Routes of
administration 		Oral, sublingual, rectal
ATC code
Legal status
Legal status
Pharmacokinetic data
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
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 InfoCard 100.188.773 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H15ClN4S
Molar mass 342.85 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 Yes check.svgY
  • Key:VMZUTJCNQWMAGF-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)
Etizolam powder. Pictured is roughly 150 mg; a standard dose is around 1 mg PureEtizolam.jpg
Etizolam powder. Pictured is roughly 150 mg; a standard dose is around 1 mg
Etizex brand etizolam tablets Etizex brand etizolam tablets.jpg
Etizex brand etizolam tablets

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 [6] The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.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]

Contents

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

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

Etizolam pills Etizolam.jpg
Etizolam pills

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 - for instance, the National Records of Scotland report on drug-related deaths, 'street' Etizolam was a factor in ("implicated in, or potentially contributed to") 752, or 59%, of drug-related deaths in Scotland in 2019. It is important to highlight that more than one drug contributed to the vast majority of the deaths (by way of comparison, opiates and opioids were a factor in 1092, or 86%, of drug-related deaths). [33]

Society and culture

Brand names

Etilaam, Sedekopan, Etizest, Etizex, Pasaden or Depas

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

Related Research Articles

<span class="mw-page-title-main">Benzodiazepine</span> Class of depressant drugs

Benzodiazepines, colloquially known as "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and was made available in 1960 by Hoffmann–La Roche, which followed with the development of diazepam (Valium) three years later, in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.

<span class="mw-page-title-main">Diazepam</span> Benzodiazepine sedative

Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken orally, as a suppository inserted into the rectum, intramuscularly, intravenously or used as a nasal spray. When injected intravenously, effects begin in one to five minutes and last up to an hour. When taken by mouth, effects begin after 15 to 60 minutes.

<span class="mw-page-title-main">Alprazolam</span> Benzodiazepine medication

Alprazolam, sold under the brand name Xanax among others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the management of anxiety disorders, especially panic disorder and generalized anxiety disorder (GAD). Other uses include the treatment of chemotherapy-induced nausea, together with other treatments. GAD improvement occurs generally within a week. Alprazolam is generally taken orally.

<span class="mw-page-title-main">Clonazepam</span> Benzodiazepine medication

Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, obsessive–compulsive disorder (OCD), and akathisia. It is a long-acting tranquilizer of the benzodiazepine class. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. It is typically taken orally but is also used intravenously. Effects begin within one hour and last between eight and twelve hours in adults.

<span class="mw-page-title-main">Zopiclone</span> Hypnotic medication

Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine, specifically a cyclopyrrolone, used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system, via modulating GABAA receptors similarly to the way benzodiazepine drugs do inducing sedation but not with the anti-anxiety properties of the benzodiazepines.

<span class="mw-page-title-main">Bromazepam</span> Benzodiazepine drug

Bromazepam, sold under many brand names, is a benzodiazepine. It is mainly an anti-anxiety agent with similar side effects to diazepam. In addition to being used to treat anxiety or panic states, bromazepam may be used as a premedicant prior to minor surgery. Bromazepam typically comes in doses of 3 mg and 6 mg tablets.

<span class="mw-page-title-main">Flurazepam</span> Hypnotic medication

Flurazepam is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It produces a metabolite with a long half-life, which may stay in the bloodstream for days. Flurazepam was patented in 1968 and came into medical use the same year. Flurazepam, developed by Roche Pharmaceuticals, was one of the first benzodiazepine hypnotic medications to be marketed.

<span class="mw-page-title-main">Oxazepam</span> Benzodiazepine medication

Oxazepam is a short-to-intermediate-acting benzodiazepine. Oxazepam is used for the treatment of anxiety, insomnia, and to control symptoms of alcohol withdrawal syndrome.

<span class="mw-page-title-main">Clobazam</span> Benzodiazepine class medication

Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970, and an anticonvulsant since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.

<span class="mw-page-title-main">Estazolam</span> Triazolobenzodiazepine tranquilizer drug

Estazolam, sold under the brand name Prosom among others, is a tranquilizer medication of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. Estazolam is an intermediate-acting oral benzodiazepine. It is used for short-term treatment of insomnia.

<span class="mw-page-title-main">Clorazepate</span> Benzodiazepine medication

Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

<span class="mw-page-title-main">Prazepam</span> Benzodiazepine drug

Prazepam is a benzodiazepine derivative drug developed by Warner-Lambert in the 1960s. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. Prazepam is a prodrug for desmethyldiazepam which is responsible for the therapeutic effects of prazepam.

<span class="mw-page-title-main">Ketazolam</span> Chemical compound

Ketazolam is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.

<span class="mw-page-title-main">Clotiazepam</span> Chemical compound

Clotiazepam is a thienodiazepine drug which is a benzodiazepine analog. The clotiazepam molecule differs from benzodiazepines in that the benzene ring has been replaced by a thiophene ring. It possesses anxiolytic, skeletal muscle relaxant, anticonvulsant, sedative properties. Stage 2 NREM sleep is significantly increased by clotiazepam.

<span class="mw-page-title-main">Chlordiazepoxide</span> Benzodiazepine class sedative and hypnotic medication

Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol, benzodiazepines, and other drugs.

<span class="mw-page-title-main">Benzodiazepine withdrawal syndrome</span> Signs and symptoms due to benzodiazepine discontinuation in physically dependent persons

Benzodiazepine withdrawal syndrome is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stops taking them without a safe taper schedule.

<span class="mw-page-title-main">Benzodiazepine dependence</span> Medical condition

Benzodiazepine dependence defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of substance use, according to the DSM-IV. In the case of benzodiazepine dependence, the continued use seems to be typically associated with the avoidance of unpleasant withdrawal reaction rather than with the pleasurable effects of the drug. Benzodiazepine dependence develops with long-term use, even at low therapeutic doses, often without the described drug seeking behavior and tolerance.

<span class="mw-page-title-main">Diclazepam</span> Benzodiazepine medication

Diclazepam (Ro5-3448), also known as chlorodiazepam and 2'-chloro-diazepam, is a benzodiazepine and functional analog of diazepam. It was first synthesized by Leo Sternbach and his team at Hoffman-La Roche in 1960. It is not currently approved for use as a medication, but rather sold as an unscheduled substance. Efficacy and safety have not been tested in humans.

<span class="mw-page-title-main">Clonazolam</span> Benzodiazepine

Clonazolam is a drug of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. Although little research has been done about its effects and metabolism, it is sold online as a designer drug.

<span class="mw-page-title-main">Flubromazolam</span> Triazolobenzodiazepine drug

Flubromazolam (JYI-73) is a triazolobenzodiazepine (TBZD), which are benzodiazepine (BZD) derivatives. Flubromazolam is reputed to be highly potent, and concerns have been raised that clonazolam and flubromazolam in particular may pose comparatively higher risks than other designer benzodiazepines, due to their ability to produce strong sedation and amnesia at oral doses of as little as 0.5 mg. Life-threatening adverse reactions have been observed at doses of only 3 mg of flubromazolam.

References

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  31. ↑ Høiseth G, Tuv SS, Karinen R (November 2016). "Blood concentrations of new designer benzodiazepines in forensic cases". Forensic Science International. 268: 35–38. doi:10.1016/j.forsciint.2016.09.006. PMID   27685473.
  32. ↑ 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. 122 (3): 230–6. doi:10.1007/bf02246544. PMID   8748392. S2CID   24836734.
  33. ↑ "Drug-related deaths in Scotland 2018" (PDF). National Records of Scotland.
  34. ↑ "Expert Committee on Drug Dependence's Twenty Seventh Report" (PDF). World Health Organization . September 28, 1990. Retrieved July 3, 2023.
  35. ↑ "Letter of WHO Director-General to UN Secretary-General dated November 15th 2019" (PDF). www.who.int.
  36. ↑ "News: Recently scheduled benzodiazepines Flualprazolam and Etizolam associated with multiple post-mortem and DUID cases in UNODC EWA". United Nations Office on Drugs and Crime. March 2020.
  37. 1 2 "Warnings over counterfeit benzodiazepines". NSW Health.
  38. ↑ "Bekendtgørelse om euforiserende stoffer". retsinformation.dk (in Danish). Retrieved 2016-11-21.
  39. ↑ "Verordnungsentwurf der Bundesregierung" [Federal draft regulation](PDF). Bundesministerium für Gesundheit (Federal Ministry of Health) (in German). Archived from the original (PDF) on 18 March 2016.
  40. ↑ "Gesetz über den Verkehr mit Betäubungsmitteln" [Law on traffic with tranquillizers]. Bundesministerium der Justiz und für Verbraucherschutz (Federal Ministry of Justice and Consumer Protection) (in German).
  41. ↑ "DEPAS - Etizolam". 2017-08-31. Retrieved 2018-05-14.
  42. ↑ PubChem. "Etizolam". pubchem.ncbi.nlm.nih.gov. Retrieved 2021-03-06.
  43. ↑ "The Misuse of Drugs Act 1971 (Amendment) Order 2017".
  44. ↑ "Alabama Code Title 20. Food, Drugs, and Cosmetics § 20-2-23". Findlaw.
  45. ↑ "List of Controlled Substances" (PDF). State of Arkansas. Archived from the original (PDF) on 2 February 2011.
  46. ↑ "Statutes & Constitution: Online Sunshine". www.leg.state.fl.us.
  47. ↑ "HB1231 (As Sent to Governor) - 2014 Regular Session". billstatus.ls.state.ms.us.
  48. ↑ "Health and Safety Code Chapter 481. Texas Controlled Substances Act". statutes.capitol.texas.gov. Retrieved 2019-07-12.
  49. ↑ "Controlled Substance Schedule | SCDHEC". www.scdhec.gov. Retrieved 2019-03-20.
  50. ↑ "18VAC110-20-322. Placement of Chemicals in Schedule I". Commonwealth of Virginia. 2 December 2015. Retrieved 11 March 2016.
  51. ↑ "Ellington's bill banning two deadly drugs could soon be law - State of Indiana House of Representatives". www.indianahouserepublicans.com.
  52. ↑ "(Proposed Rule) Schedules of Controlled Substances: Temporary Placement of Etizolam, Flualprazolam, Clonazolam, Flubromazolam, and Diclazepam in Schedule I". Federal Register . DEA. December 23, 2022.
  53. ↑ "Schedules of Controlled Substances: Temporary Placement of Etizolam, Flualprazolam, Clonazolam, Flubromazolam, and Diclazepam in Schedule I" (PDF). Federal Register . DEA. July 25, 2023. Retrieved 2023-07-25.
  54. ↑ Gupta S, Garg B (2014). "A case of etizolam dependence". Indian Journal of Pharmacology. 46 (6): 655–6. doi: 10.4103/0253-7613.144943 . PMC   4264086 . PMID   25538342.
  55. ↑ Allison D (20 April 2018). "How to tackle Dundee's fake valium epidemic". BBC News.
  56. ↑ Guirguis A. "Novel psychoactive substances: understanding the new illegal drug market". Pharmaceutical Journal. Archived from the original on 2019-04-11. Retrieved 2018-10-18.
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