View source for Talk:Flumazenil

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'''Flumazenil''' (sold as '''Anexate''', '''Romazicon''', and known by its developmental code '''Ro 15-1788''') is an [[psychoactive class::antisedative]] substance of the [[chemical class::imidazobenzodiazepine]] chemical class that produces antisedative effects when [[administered]], especially when reversing [[benzodiazepines]].

It is a highly selective benzodiazepine receptor antagonist<ref>Whitwam, J. G., & Amrein, R. (1995). Pharmacology of flumazenil. Acta Anaesthesiologica Scandinavica, 39(s108), 3-14.</ref> that is primarily used in the treatment of benzodiazepine overdoses via competitive inhibition at the benzodiazepine binding site on the [[GABA|GABA<sub>A</sub>]] receptor,<ref>Whyte, IM (2004). "Benzodiazepines". Medical toxicology. Philadelphia: Williams & Wilkins. pp. 811–22. ISBN 0-7817-2845-2.</ref> although it has also been used to treat overdoses of non-benzodiazepine hypnotics such as [[zolpidem]] and [[zopiclone]] (see [[Z-drug]]). However, it is ineffective for reversing overdoses of [[barbiturates]], [[opioids]], or [[alcohol]]. Due to its short half-life, multiple doses and careful patient monitoring are required to prevent recurrence of overdose symptoms.(<-- is this sentence necessary here?) {{citation needed}} (1. I think it should be elsewhere? 2. The cite flag isn't really ''too'' needed. Although it's definitely preferred, it's obvious that if flumazenil lasts short, some benzodiazepines last longer.)

It is also used medically to reverse the effects of benzodiazepines following surgery, in a way similar to naloxone being used for surgeries involving [[opioids]].{{citation needed}} <--(Is a cite flag needed much here? That's kind of a "common sense"/inferrable thing) Outside of an acute care setting, flumanezil may also be effective in reducing excessive daytime sleepiness while improving vigilance in primary hypersomnias, such as idiopathic hypersomnia.{{citation needed}} (this def needs a cite flag)

Flumazenil was first introduced in 1987 by Hoffmann-La Roche under the trade name"Anexate, but only ''approved'' by the FDA on December 20, 1991. Flumazenil went off patent in 2008, so, at present, generic formulations of this drug are available.{{citation needed}}(this def needs a cite flag)


Whether flumazenil produces any psychoactive effects on its own is currently subject to debate. Although the body produces no known benzodiazepine receptor agonists, some studies suggest that flumazenil does produce effects on its own.<ref>Neave, N., Reid, C., Scholey, A., Thompson, J., Moss, M., Ayre, G., ... & Girdler, N. (2000). Dose-dependent effects of flumazenil on cognition, mood, and cardio-respiratory physiology in healthy volunteers. British dental journal, 189(12), 668.</ref>

==History and culture==
{{historyStub}}

==Chemistry==
{{chemistry}}
Flumazenil is an organic heterocyclic compound that is 5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine which is substituted at positions 3, 5, 6, and 8 by ethoxycarbonyl, methyl, oxo, and fluoro groups, respectively. It is used as an antidote to benzodiazepine overdose. It has a role as a GABA antagonist and an antidote to benzodiazepine poisoning. It is an ethyl ester, an organofluorine compound and an imidazobenzodiazepine.<ref>Sivilotti ML (2016) Flumazenil, naloxone and the 'coma cocktail'. British journal of clinical pharmacology 81, 428-436 [PubMed:26469689]</ref>

==Pharmacology==
Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex.<ref>Hood, Sean David; Norman, Amanda; Hince, Dana Adelle; Melichar, Jan Krzysztof; Hulse, Gary Kenneth (February 2014). "Benzodiazepine dependence and its treatment with low dose flumazenil". British Journal of Clinical Pharmacology. 77 (2): 285–294. doi:10.1111/bcp.12023. ISSN 1365-2125. PMC 4014019. PMID 23126253.</ref> It also exhibits weak partial agonism of GABAA receptor complexes that contain α6-type monomers; the clinical relevance of this is unknown.<ref>Hadingham, K. L.; Garrett, E. M.; Wafford, K. A.; Bain, C.; Heavens, R. P.; Sirinathsinghji, D. J.; Whiting, P. J. (February 1996). "Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors". Molecular Pharmacology. 49 (2): 253–259. ISSN 0026-895X. PMID 8632757.</ref>

Flumazenil does not antagonize all of the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, and most anesthetics) and does not reverse the effects of opioids. It will however antagonize the action of non-benzodiazepine z-drugs, such as zolpidem and zopiclone, because they act via the benzodiazepine site of the GABA receptor<ref>Gunja, Naren (June 2013). "The clinical and forensic toxicology of Z-drugs". Journal of Medical Toxicology. 9 (2): 155–162. doi:10.1007/s13181-013-0292-0. ISSN 1937-6995. PMC 3657020. PMID 23404347.</ref> - it has been used to successfully treat z-drug overdose.<ref>Gunja, Naren (June 2013). "The clinical and forensic toxicology of Z-drugs". Journal of Medical Toxicology. 9 (2): 155–162. doi:10.1007/s13181-013-0292-0. ISSN 1937-6995. PMC 3657020. PMID 23404347.</ref>

Intravenous flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers. The duration and degree of reversal of sedative benzodiazepine effects are related to the dose and plasma concentrations of flumazenil.

Flumazenil is sold under a wide variety of brand names worldwide like Anexate, Lanexat, Mazicon, Romazicon. In India it is manufactured by Roche Bangladesh Pharmaceuticals and USAN Pharmaceuticals.

Low-dose, slow subcutaneous flumazenil administration is a safe procedure for patients withdrawing from long-term, high-dose benzodiazepine dependence.<ref>Faccini, Marco; Leone, Roberto; Opri, Sibilla; Casari, Rebecca; Resentera, Chiara; Morbioli, Laura; Conforti, Anita; Lugoboni, Fabio (October 2016). "Slow subcutaneous infusion of flumazenil for the treatment of long-term, high-dose benzodiazepine users: a review of 214 cases". Journal of Psychopharmacology (Oxford, England). 30 (10): 1047–1053. doi:10.1177/0269881116647505. ISSN 1461-7285. PMID 27166362. S2CID 27167585.</ref> It has a low risk of seizures even amongst those who have experienced convulsions when previously attempting benzodiazepine withdrawal.<ref>Tamburin, Stefano; Faccini, Marco; Casari, Rebecca; Federico, Angela; Morbioli, Laura; Franchini, Enrica; Bongiovanni, Luigi Giuseppe; Lugoboni, Fabio (October 2017). "Low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high-dose benzodiazepine dependence". Journal of Psychopharmacology (Oxford, England). 31 (10): 1369–1373. doi:10.1177/0269881117714050. ISSN 1461-7285. PMID 28613124. S2CID 42432213.</ref>

==Subjective effects==
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Flumazenil producing any effects in the body on its own is questionable. A study has ''suggested'' that it produces performance-declining effects that appear to be dose-dependent.<ref>Neave, N., Reid, C., Scholey, A., Thompson, J., Moss, M., Ayre, G., ... & Girdler, N. (2000). Dose-dependent effects of flumazenil on cognition, mood, and cardio-respiratory physiology in healthy volunteers. British dental journal, 189(12), 668.</ref> Flumazenil often produces effects by means of immediate withdrawal, similar to [[naloxone]]. As such, a patient may wake up agitated, extremely wakeful, or could experience seizures.


{{effects/physical|
*'''[[Dizziness]]
*'''[[Nausea]]
*'''[[Headaches]]
*'''[[Seizures]]'''
}}
{{effects/cognitive|
*'''[[Anxiety]]'''
*'''[[Depersonalization]]'''{{citation needed}}
*'''[[Depression]]'''
*'''[[Cognitive dysphoria|Dysphoria]] or [[Euphoria]]'''{{citation needed}}
*'''[[Irritability]]'''
*'''[[Paranoia]]'''

 
}}
{{effects/visual|
*'''[[Visual acuity suppression]] {{citation needed}} 

}}
==Toxicity and harm potential==
{{toxicity}}
It is strongly recommended that one use [[responsible use|harm reduction practices]] when using this substance.
===Lethal dosage===
===Tolerance and addiction potential===
===Dangerous interactions===
{{DangerousInteractions}}
{{DangerousInteractions/Intro}}

==Legal status==
{{LegalStub}}
* <b>Sweden</b>: Flumazenil is a prescription only medication.<ref>http://rkrattsbaser.gov.se/sfst?fritext=1992%3A1554&upph=false&post_id=3</ref>

==See also==
*[[Responsible use]]
*[[Benzodiazepine]]
*[[Naloxone]]
*[[Receptor]]
==External links==
*[https://en.wikipedia.org/wiki/Flumazenil Flumazenil (Wikipedia)]
*[https://isomerdesign.com/PiHKAL/explore.php?id=3739 Flumazenil (TiHKAL / Isomer Design)]
*[https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cf39cdaf-8cb7-4dbb-8672-9cf8e91ac86c DailyMed, Flumazenil Injection information (Last updated 2012) (Sandoz)]

==Literature==
==References==
<references />

[[Category:Psychoactive substance]][[Category:Proofread]][[Category:Approval]]

[[Category:Psychoactive substance]]
[[Category:Benzodiazepine]]