Brotizolam

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Brotizolam
Brotizolam.svg
Brotizolam ball-and-stick model.png
Clinical data
Trade names Lendormin
AHFS/Drugs.com International Drug Names
Routes of
administration 		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 48–95%
Metabolism Hepatic
Elimination half-life 4.4 hours (range, 2.6–6.9 h)
Excretion Renal
Identifiers
  • 2-Bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.055.404 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H10BrClN4S
Molar mass 393.69 g·mol−1
3D model (JSmol)
  • ClC1=CC=CC=C1C2=NCC3=NN=C(C)N3C4=C2C=C(Br)S4
  • InChI=1S/C15H10BrClN4S/c1-8-19-20-13-7-18-14(9-4-2-3-5-11(9)17)10-6-12(16)22-15(10)21(8)13/h2-6H,7H2,1H3 Yes check.svgY
  • Key:UMSGKTJDUHERQW-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Brotizolam [3] (marketed under brand name Lendormin) is a sedative-hypnotic [4] thienotriazolodiazepine [5] drug which is a benzodiazepine analog. [6] 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. [7] It is used in the short-term treatment of severe insomnia. Brotizolam is a highly potent and short-acting hypnotic, with a typical dose ranging from 0.125 to 0.25 milligrams, which is rapidly eliminated with an average half-life of 4.4 hours (range 3.6–7.9 hours). [8]

Contents

It was patented in 1974 [9] and came into medical use in 1984. [10] 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 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. [11]

Brotizolam, in a dose of 0.25 mg can be used as a premedication prior to surgery, this dose was found to be comparable in efficacy to 2 mg flunitrazepam as a premedicant prior to surgery. [12]

Side effects

Common side effects of brotizolam are typical of hypnotic benzodiazepines and are related to CNS depression, and include somnolence, ataxia, headache, anterograde amnesia, dizziness, fatigue, impairment of motor functions, slurred speech, confusion, and clumsiness.

Less common side effects include hypotension, respiratory depression, hallucinations, nausea and vomiting, palpitations, and paradoxical reactions (i.e. aggression, anxiety, violent behavior, etc.).

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 mg). [13]

In clinical trials brotizolam 0.125 to 0.5 mg improved sleep in insomniacs similarly to nitrazepam 2.5 and 5 mg, flunitrazepam 2 mg and triazolam 0.25 mg, whilst brotizolam 0.5 mg was shown to be superior to flurazepam 30 mg, but inferior to temazepam 30 mg in some studies. Brotizolam at dosages below 0.5 mg at night usually produced minimal morning drowsiness; no residual impairment of psychomotor performance occurs following dosages within the recommended range of 0.125 to 0.25 mg. No serious side effects have been reported to date and the most frequently observed adverse experiences are drowsiness, headache and dizziness. Mild rebound insomnia may occur in some patients when treatment is stopped. [8]

Contraindications and special caution

Thienodiazepines and benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders. [14]

Pharmacology

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. [6] Brotizolam induces impairment of motor function and has hypnotic properties. [15]

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. [16]

Abuse

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. [17]

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. [18] 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.

Commercial names

NameCountries
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

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">Flunitrazepam</span> Benzodiazepine sedative

Flunitrazepam, sold under the brand name Rohypnol among others, is a benzodiazepine used to treat severe insomnia and assist with anesthesia. As with other hypnotics, flunitrazepam has been advised to be prescribed only for short-term use or by those with chronic insomnia on an occasional basis.

<span class="mw-page-title-main">Hypnotic</span> Drug whose use induces sleep

Hypnotic, or soporific drugs, commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to induce sleep and to treat insomnia (sleeplessness).

<span class="mw-page-title-main">Temazepam</span> Insomnia medication

Temazepam, sold under the brand name Restoril among others, is a medication of the benzodiazepine class which is generally used to treat severe or debilitating insomnia. It is taken by mouth. Temazepam is rapidly absorbed, and significant hypnotic and anxiolytic effects begin in less than 30 minutes and can last for up to eight hours. Prescriptions for hypnotics such as temazepam have seen a dramatic decrease since 2010, while anxiolytics such as alprazolam, clonazepam, and lorazepam have increased or remained stable. Temazepam and similar hypnotics, such as triazolam (Halcion) are generally reserved for severe and debilitating insomnia. They have largely been replaced by z-drugs and atypical antidepressants as first line treatment for insomnia.

<span class="mw-page-title-main">Sedative</span> Drug that reduces excitement without inducing sleep

A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but the majority of them affect the neurotransmitter gamma-aminobutyric acid (GABA). In spite of the fact that each sedative acts in its own way, most produce relaxing effects by increasing GABA activity.

<span class="mw-page-title-main">Triazolam</span> Triazolobenzodiazepine class medication

Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties, triazolam's amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced as well.

<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">Nitrazepam</span> Benzodiazepine sedative

Nitrazepam, sold under the brand name Mogadon among others, is a hypnotic drug of the benzodiazepine class used for short-term relief from severe, disabling anxiety and insomnia. It also has sedative (calming) properties, as well as amnestic, anticonvulsant, and skeletal muscle relaxant effects.

<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">Zaleplon</span> Medication used to treat insomnia

Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved for medical use in the United States in 1999.

<span class="mw-page-title-main">Quazepam</span> Benzodiazipine

Quazepam, sold under the brand name Doral among others, is a relatively long-acting benzodiazepine derivative drug developed by the Schering Corporation in the 1970s. Quazepam is used for the treatment of insomnia, including sleep induction and sleep maintenance. Quazepam induces impairment of motor function and has relatively selective hypnotic and anticonvulsant properties with considerably less overdose potential than other benzodiazepines. Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture.

<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">Loprazolam</span> Benzodiazepine

Loprazolam (triazulenone) marketed under many brand names is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It is licensed and marketed for the short-term treatment of moderately-severe insomnia.

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

Camazepam is a benzodiazepine psychoactive drug, marketed under the brand names Albego, Limpidon and Paxor. It is the dimethyl carbamate ester of temazepam, a metabolite of diazepam. While it possesses anxiolytic, anticonvulsant, skeletal muscle relaxant and hypnotic properties it differs from other benzodiazepines in that its anxiolytic properties are particularly prominent but has comparatively limited anticonvulsant, hypnotic and skeletal muscle relaxant properties.

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

Etizolam is a thienodiazepine derivative which is a benzodiazepine analog. 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.

<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">Lormetazepam</span> Benzodiazepine medication

Lormetazepam, sold under the brand name Noctamid among others, is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative and temazepam analogue. It possesses hypnotic, anxiolytic, anticonvulsant, sedative, and skeletal muscle relaxant properties.

<span class="mw-page-title-main">Fosazepam</span> Benzodiazepam

Fosazepam is a drug belonging to the benzodiazepine class, which are primarily anti-anxiety and sedative-hypnotic agents. It is a water soluble derivative of diazepam which has been substituted with a dimethylphosphoryl group to improve solubility in water. At equipotent doses, it possesses sedative and anxiolytic properties that are qualitatively and quantitatively similar to the effects of diazepam, with equal sedative-hypnotic, anti-convulsive, and muscle relaxant effects. In comparison to an equipotent dose of nitrazepam, its effects tended to be of noticeably milder magnitude.

<span class="mw-page-title-main">Benzodiazepine use disorder</span> Illicit use of benzodiazepine drugs

Benzodiazepine use disorder (BUD), also called misuse or abuse, is the use of benzodiazepines without a prescription and/or for recreational purposes, which poses risks of dependence, withdrawal and other long-term effects. Benzodiazepines are one of the more common prescription drugs used recreationally. When used recreationally benzodiazepines are usually administered orally but sometimes they are taken intranasally or intravenously. Recreational use produces effects similar to alcohol intoxication.

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ↑ "DEA Diversion Control Division" (PDF). Archived from the original (PDF) on 2019-10-17. Retrieved 2015-12-10.
  3. ↑ US 4094984 6-Phenyl-8-bromo-4H-s-triazolo-[3,4C]-thieno-[2,3E]-1,4-diazepines and salts thereof
  4. ↑ Fink M, Irwin P (September 1981). "Pharmacoelectroencephalographic study of brotizolam, a novel hypnotic". Clinical Pharmacology and Therapeutics. 30 (3): 336–42. doi:10.1038/clpt.1981.169. PMID   7273596. S2CID   30788171.
  5. ↑ Catabay A, Taniguchi M, Jinno K, Pesek JJ, Williamsen E (1 March 1998). "Separation of 1,4-Benzodiazepines and Analogues Using Cholesteryl-10-Undecenoate Bonded Phase in Microcolumn Liquid Chromatography". Journal of Chromatographic Science. 36 (3): 113. doi: 10.1093/chromsci/36.3.111 .
  6. 1 2 Jochemsen R, Wesselman JG, van Boxtel CJ, Hermans J, Breimer DD (1983). "Comparative pharmacokinetics of brotizolam and triazolam in healthy subjects". British Journal of Clinical Pharmacology. 16 (Suppl 2): 291S –297S. doi:10.1111/j.1365-2125.1983.tb02303.x. PMC   1428224 . PMID   6140948.
  7. ↑ Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID   18855614.
  8. 1 2 Langley MS, Clissold SP (February 1988). "Brotizolam. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an hypnotic". Drugs. 35 (2): 104–22. doi:10.2165/00003495-198835020-00002. PMID   3281819. S2CID   243228878.
  9. ↑ US4094984 6-Phenyl-8-bromo-4H-s-triazolo-[3,4C]-thieno-[2,3E]-1,4-diazepines and salts thereof
  10. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 539. ISBN   9783527607495.
  11. ↑ Rickels K (1986). "The clinical use of hypnotics: indications for use and the need for a variety of hypnotics". Acta Psychiatrica Scandinavica. Supplementum. 332: 132–41. doi:10.1111/j.1600-0447.1986.tb08990.x. PMID   2883820. S2CID   46560074.
  12. ↑ Nishiyama T, Yamashita K, Yokoyama T, Imoto A, Manabe M (2007). "Effects of quazepam as a preoperative night hypnotic: comparison with brotizolam". Journal of Anesthesia. 21 (1): 7–12. doi:10.1007/s00540-006-0445-2. PMID   17285406. S2CID   24584685.
  13. ↑ Nicholson AN, Stone BM, Pascoe PA (July 1980). "Studies on sleep and performance with a triazolo-1, 4-thienodiazepine (brotizolam)". British Journal of Clinical Pharmacology. 10 (1): 75–81. doi:10.1111/j.1365-2125.1980.tb00504.x. PMC   1430017 . PMID   7397057.
  14. ↑ Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome" [Benzodiazepine dependence: Focus on withdrawal syndrome]. Annales Pharmaceutiques Françaises (in French). 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID   19900604.
  15. ↑ Yasui M, Kato A, Kanemasa T, Murata S, Nishitomi K, Koike K, et al. (June 2005). "[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes]". Nihon Shinkei Seishin Yakurigaku Zasshi = Japanese Journal of Psychopharmacology. 25 (3): 143–51. PMID   16045197.
  16. ↑ Noguchi H, Kitazumi K, Mori M, Shiba T (March 2004). "Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats". Journal of Pharmacological Sciences. 94 (3): 246–51. doi: 10.1254/jphs.94.246 . PMID   15037809.
  17. ↑ Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". The Journal of Clinical Psychiatry. 66 (Suppl 9): 31–41. PMID   16336040.
  18. ↑ Lee KK, Chan TY, Chan AW, Lau GS, Critchley JA (1995). "Use and abuse of benzodiazepines in Hong Kong 1990-1993--the impact of regulatory changes". Journal of Toxicology. Clinical Toxicology. 33 (6): 597–602. doi:10.3109/15563659509010615. PMID   8523479.

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