Brotizolam: Difference between revisions

{{Short description|Benzodiazepine}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 459984727

| IUPAC_name = 2-Bromo-4-(2-chlorophenyl)-9-methyl-6''H''-thieno[3,2-''f''][1,2,4]triazolo[4,3-''a''][1,4]diazepine

| width = 155

| image2 = Brotizolam ball-and-stick model.png

| tradename = Lendormin

| pregnancy_category =

| legal_BR = B1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Schedule IV

| legal_US = Unscheduled

| legal_US_comment = <ref>{{Cite web | url=http://www.deadiversion.usdoj.gov/schedules/orangebook/e_cs_sched.pdf | title=DEA Diversion Control Division | access-date=2015-12-10 | archive-date=2019-10-17 | archive-url=https://web.archive.org/web/20191017084240/https://www.deadiversion.usdoj.gov/schedules/orangebook/e_cs_sched.pdf | url-status=dead }}</ref>

| legal_UK = Class C

| legal_DE = Rx-only/Anlage III

| legal_UN = Schedule IV

| bioavailability = 48–95%

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 57801-81-7

| DrugBank_Ref = {{drugbankcite|changed|drugbank}}

| DrugBank = DB09017

| smiles = ClC1=CC=CC=C1C2=NCC3=NN=C(C)N3C4=C2C=C(Br)S4

'''Brotizolam'''<ref>US 4094984 6-Phenyl-8-bromo-4H-s-triazolo-[3,4C]-thieno-[2,3E]-1,4-diazepines and salts thereof</ref> (marketed under brand name '''Lendormin''') is a [[sedative]]-[[hypnotic]]<ref>{{cite journal | vauthors = Fink M, Irwin P | title = Pharmacoelectroencephalographic study of brotizolam, a novel hypnotic | journal = Clinical Pharmacology and Therapeutics | volume = 30 | issue = 3 | pages = 336–42 | date = September 1981 | pmid = 7273596 | doi = 10.1038/clpt.1981.169 | s2cid = 30788171 }}</ref> [[thienotriazolodiazepine]]<ref>{{cite journal| vauthors = Catabay A, Taniguchi M, Jinno K, Pesek JJ, Williamsen E |title=Separation of 1,4-Benzodiazepines and Analogues Using Cholesteryl-10-Undecenoate Bonded Phase in Microcolumn Liquid Chromatography|journal=Journal of Chromatographic Science|date=1 March 1998|volume=36|issue=3|page=113|doi=10.1093/chromsci/36.3.111|doi-access=free}}<!--|access-date=3 December 2015--></ref> drug which is a [[benzodiazepine]] analog.<ref name=pmid6140948>{{cite journal | vauthors = Jochemsen R, Wesselman JG, van Boxtel CJ, Hermans J, Breimer DD | title = Comparative pharmacokinetics of brotizolam and triazolam in healthy subjects | journal = British Journal of Clinical Pharmacology | volume = 16 | issue = Suppl 2 | pages = 291S–297S | year = 1983 | pmid = 6140948 | pmc = 1428224 | doi = 10.1111/j.1365-2125.1983.tb02303.x }}</ref> It possesses [[anxiolytic]], [[anticonvulsant]], [[hypnotic]], [[sedative]] and [[skeletal muscle relaxant]] properties, and is considered to be similar in effect to other short-acting hypnotic benzodiazepines such as [[triazolam]] or [[midazolam]].<ref>{{cite journal | vauthors = Mandrioli R, Mercolini L, Raggi MA | title = Benzodiazepine metabolism: an analytical perspective | journal = Current Drug Metabolism | volume = 9 | issue = 8 | pages = 827–44 | date = October 2008 | pmid = 18855614 | doi = 10.2174/138920008786049258 | url = https://zenodo.org/record/1067769 }}</ref> It is used in the short-term treatment of [[Insomnia#Benzodiazepines|severe insomnia]]. Brotizolam is a highly potent and short-acting hypnotic, with a typical dose ranging from 0.125 to 0.25&nbsp;milligrams, which is rapidly eliminated with an average half-life of 4.4 hours (range 3.6–7.9&nbsp;hours).<ref name=pmid3281819>{{cite journal | vauthors = Langley MS, Clissold SP | title = Brotizolam. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an hypnotic | journal = Drugs | volume = 35 | issue = 2 | pages = 104–22 | date = February 1988 | pmid = 3281819 | doi = 10.2165/00003495-198835020-00002 | s2cid = 243228878 }}</ref>

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It was patented in 1974<ref>US4094984 6-Phenyl-8-bromo-4H-s-triazolo-[3,4C]-thieno-[2,3E]-1,4-diazepines and salts thereof</ref> and came into medical use in 1984.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=539 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA539 |language=en}}</ref> Brotizolam is not approved for sale in the UK, United States or Canada. It is approved for sale in the Netherlands, Germany, Spain, Belgium, Luxembourg, Austria, Portugal, Israel, Italy, Taiwan and Japan.

==Medical uses==

Brotizolam is prescribed for the short-term treatment, 2–4 weeks only of [[Insomnia#Benzodiazepines|severe or debilitating insomnia]]. Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Brotizolam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or getting to sleep. Hypnotics should only be used on a short-term basis or in those with chronic insomnia on an occasional basis.<ref>{{cite journal | vauthors = Rickels K | title = The clinical use of hypnotics: indications for use and the need for a variety of hypnotics | journal = Acta Psychiatrica Scandinavica. Supplementum | volume = 332 | pages = 132–41 | year = 1986 | pmid = 2883820 | doi = 10.1111/j.1600-0447.1986.tb08990.x | s2cid = 46560074 }}</ref>

Brotizolam, in a dose of 0.25&nbsp;mg can be used as a premedication prior to surgery, this dose was found to be comparable in efficacy to 2&nbsp;mg [[flunitrazepam]] as a premedicant prior to surgery.<ref>{{cite journal | vauthors = Nishiyama T, Yamashita K, Yokoyama T, Imoto A, Manabe M | title = Effects of quazepam as a preoperative night hypnotic: comparison with brotizolam | journal = Journal of Anesthesia | volume = 21 | issue = 1 | pages = 7–12 | year = 2007 | pmid = 17285406 | doi = 10.1007/s00540-006-0445-2 | s2cid = 24584685 }}</ref>

Common side effects of brotizolam are typical of hypnotic benzodiazepines and are related to [[Central nervous system|CNS depression]], and include [[somnolence]], [[ataxia]], [[headache]], [[anterograde amnesia]], [[dizziness]], [[Fatigue (medical)|fatigue]], impairment of motor functions, slurred speech, [[confusion]], and [[Accident-proneness|clumsiness]].

Brotizolam can cause residual side effects the next day such as impaired cognitive and motor functions as well as drowsiness. Disruption of sleep patterns may also occur such as suppression of [[REM sleep]]. These side effects are more likely at higher doses (above 0.5–1&nbsp;mg).<ref>{{cite journal | vauthors = Nicholson AN, Stone BM, Pascoe PA | title = Studies on sleep and performance with a triazolo-1, 4-thienodiazepine (brotizolam) | journal = British Journal of Clinical Pharmacology | volume = 10 | issue = 1 | pages = 75–81 | date = July 1980 | pmid = 7397057 | pmc = 1430017 | doi = 10.1111/j.1365-2125.1980.tb00504.x }}</ref>

Thienodiazepines and benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, [[alcoholism|alcohol]] or drug-dependent individuals and individuals with [[comorbid]] [[psychiatric disorders]].<ref>{{cite journal | vauthors = Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A | display-authors = 6 | title = Benzodiazepine dependence: focus on withdrawal syndrome | language = French | journal = Annales Pharmaceutiques Françaises | volume = 67 | issue = 6 | pages = 408–13 | date = November 2009 | pmid = 19900604 | doi = 10.1016/j.pharma.2009.07.001 | url = http://www.masson.fr/masson/S0003-4509(09)00138-2 | trans-title = Benzodiazepine dependence: Focus on withdrawal syndrome }}</ref>

Brotizolam has been shown in animal studies to be a very high potency thienodiazepine. The [[elimination half-life]] of brotizolam is 3–6 hours. It is absorbed rapidly after administration; after administration, it is metabolized into active metabolites, one of which is far less potent than brotizolam and the other is only present in very small amounts in the blood and thus the [[metabolites]] of brotizolam do not have significant pharmacological effect in humans.<ref name=pmid6140948/> Brotizolam induces impairment of motor function and has hypnotic properties.<ref>{{cite journal | vauthors = Yasui M, Kato A, Kanemasa T, Murata S, Nishitomi K, Koike K, Tai N, Shinohara S, Tokomura M, Horiuchi M, Abe K | display-authors = 6 | title = [Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes] | journal = Nihon Shinkei Seishin Yakurigaku Zasshi = Japanese Journal of Psychopharmacology | volume = 25 | issue = 3 | pages = 143–51 | date = June 2005 | pmid = 16045197 }}</ref>

Brotizolam increases the slow wave light sleep (SWLS) in a dose-dependent manner whilst suppressing deep sleep stages. Less time is spent in stages 3 and 4, which are the deep sleep stages, when GABAergics such as brotizolam are used. Benzodiazepines and thienodiazepines are therefore not ideal hypnotics in the treatment of insomnia. The suppression of deep sleep stages by either may be especially problematic to the elderly as they naturally spend less time in the deep sleep stage.<ref>{{cite journal | vauthors = Noguchi H, Kitazumi K, Mori M, Shiba T | title = Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats | journal = Journal of Pharmacological Sciences | volume = 94 | issue = 3 | pages = 246–51 | date = March 2004 | pmid = 15037809 | doi = 10.1254/jphs.94.246 | doi-access = free }}</ref>

Brotizolam is a drug with a potential for abuse. Drug misuse is defined as taking the drug to achieve a 'high', or continuing to take the drug in the long term against medical advice.<ref>{{cite journal | vauthors = Griffiths RR, Johnson MW | title = Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds | journal = The Journal of Clinical Psychiatry | volume = 66 | issue = Suppl 9 | pages = 31–41 | year = 2005 | pmid = 16336040 }}</ref>

Abuse of brotizolam, although not widespread, was a problem in [[Hong Kong]] back in the late 1980s and 1990s. To control benzodiazepine abuse in Hong Kong, the Government's Pharmacy and Poisons Board reclassified benzodiazepines as Dangerous Drugs in October 1990. Apart from formal prescriptions, detailed records were then required for the supply and dispensing of these drugs. These regulations were applied initially only to brotizolam, [[triazolam]] and [[flunitrazepam]] as they were the major benzodiazepines of abuse. The impact of these regulatory changes on benzodiazepine use has been studied by analyzing the sales patterns of seven benzodiazepines between 1990 and 1993. In 1991, the sales of flunitrazepam and triazolam fell, but the sales of five unrestricted benzodiazepines increased.<ref>{{cite journal | vauthors = Lee KK, Chan TY, Chan AW, Lau GS, Critchley JA | title = Use and abuse of benzodiazepines in Hong Kong 1990-1993--the impact of regulatory changes | journal = Journal of Toxicology. Clinical Toxicology | volume = 33 | issue = 6 | pages = 597–602 | year = 1995 | pmid = 8523479 | doi = 10.3109/15563659509010615 }}</ref> Particular problems arose with the trafficking and abuse of [[nimetazepam]] and the abuse of [[temazepam]] within that same year in 1991. The regulations that were originally only applied to brotizolam, triazolam and flunitrazepam were now being extended to include all benzodiazepines by January 1992. A regulation requiring the use of proper prescriptions and detailed records for the supply and dispensing of benzodiazepines, appears to have curbed, at least partially, their abuse in Hong Kong. There are still some problems with [[temazepam]], [[nimetazepam]], [[triazolam]], and brotizolam, but they are not major.

{| class="wikitable"

! Name !! Countries

|-

| '''Bondormin''', '''Brotizolam'''

| [[Israel]]

|-

| '''Dormex'''

| [[Chile]]

|-

| '''Lendorm'''

| [[Austria]], [[Denmark]]

|-

| '''Lendormin'''

| [[South Africa]], [[Belgium]], [[Germany]], [[Hungary]], [[Italy]], [[Japan]], [[Netherlands]], [[Portugal]], [[Taiwan]]

|-

| '''Lendormine'''

| [[Switzerland]]

|-

| '''Lindormin'''

| [[Mexico]]

|-

| '''Noctilan'''

| [[Chile]]

|-

| '''Sintonal'''

| [[Spain]]

== See also ==

*[[Thienodiazepine]]s

*[[Long-term effects of benzodiazepines]]

*[[Flubrotizolam]]

*[[Fluclotizolam]]

*[[Flurazepam]]

*[[Responsible drug use]], [[recreational drug use]]

*[[GABA]]

== References ==

{{reflist|32em}}

== Further reading ==

{{refbegin|32em}}

* {{cite journal | vauthors = Greenblatt DJ, Locniskar A, Shader RI | title = Pilot pharmacokinetic study of brotizolam, a thienodiazepine hypnotic, using electron-capture gas-liquid chromatography | journal = Sleep | volume = 6 | issue = 1 | pages = 72–6 | year = 1983 | pmid = 6844800 | doi = 10.1093/sleep/6.1.72 | doi-access = free }}

* {{cite journal | vauthors = Langley MS, Clissold SP | title = Brotizolam. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an hypnotic | journal = Drugs | volume = 35 | issue = 2 | pages = 104–22 | date = February 1988 | pmid = 3281819 | doi = 10.2165/00003495-198835020-00002 | s2cid = 243228878 }}

* {{cite journal | vauthors = Bechtel WD | title = Pharmacokinetics and metabolism of brotizolam in humans | journal = British Journal of Clinical Pharmacology | volume = 16 | issue = Suppl 2 | pages = 279S–283S | year = 1983 | pmid = 6661373 | pmc = 1428235 | doi = 10.1111/j.1365-2125.1983.tb02301.x }}

* {{cite journal | vauthors = Jochemsen R, Wesselman JG, Hermans J, van Boxtel CJ, Breimer DD | title = Pharmacokinetics of brotizolam in healthy subjects following intravenous and oral administration | journal = British Journal of Clinical Pharmacology | volume = 16 | issue = Suppl 2 | pages = 285S–290S | year = 1983 | pmid = 6661374 | pmc = 1428208 | doi = 10.1111/j.1365-2125.1983.tb02302.x }}

{{refend}}

== External links ==

{{Insomnia pharmacotherapies}}

{{GABAAR PAMs}}

[[Category:2-Chlorophenyl compounds]]

[[Category:GABAA receptor positive allosteric modulators]]

[[Category:Bromoarenes]]

[[Category:Thienotriazolodiazepines]]