Flumazenil, also known asflumazepil,[2] is a selectiveGABAAreceptor antagonist[3] administered via injection, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (particularly in cases of overdose), throughcompetitive inhibition.
It was first characterized in 1981,[4] and was first marketed in 1987 byHoffmann-La Roche under the trade nameAnexate. However, it did not receive FDA approval until December 1991. The developer lost its exclusive patent rights in 2008 and generic formulations are available.Intravenous flumazenil is primarily used to treatbenzodiazepine overdoses and to help reverse anesthesia. Administration of flumazenil bysublingual lozenge and topical cream has also been tested.[5][6]
Flumazenil has been used as anantidote in the treatment of benzodiazepine overdoses.[7] It reverses the effects of benzodiazepines bycompetitive inhibition at the benzodiazepine (BZ) recognition site on theGABA/benzodiazepine receptor complex.[7]
Flumazenil has been effectively used to treat overdoses of non-benzodiazepine hypnotics, such aszolpidem,zaleplon andzopiclone (also known as the "Z-drugs").[8]
Flumazenil has also been used inhepatic encephalopathy. It may have beneficial short‐term effects in people withcirrhosis, but there is no evidence for long-term benefits.[9]
The onset of action is rapid, and effects are usually seen within one to two minutes. The peak effect is seen at six to ten minutes. The recommended dose for adults is 200 μg every 1–2 minutes until the effect is seen, up to a maximum of 3 mg per hour. It is available as a clear, colourless solution forintravenous injection, containing 500 μg in 5 mL.[citation needed] Additional doses may be needed within 20 to 30 minutes if evidence of oversedation reappears.[10]
In terms of drug enforcement initiatives, diversion control programs and required post-marketing surveillance of adverse events, orders for flumazenil may trigger a prescription audit to the search for benzodiazepine misuse and for clinically significant adverse reactions related to their use.[12]
Epileptic patients who have become tolerant to the anti-seizure effects of the benzodiazepine clonazepam became seizure-free for several days after treatment with 1.5 mg of flumazenil.[14] Similarly, patients who were dependent on high doses of benzodiazepines (median dosage 333 mg diazepam-equivalent) were able to be stabilised on a low dose of clonazepam after 7–8 days of treatment with flumazenil.[15]
Flumazenil has been tested against placebo in benzodiazepine-dependent subjects. Results showed that typical benzodiazepine withdrawal effects were reversed with few to no symptoms.[16] Flumazenil was also shown to produce significantly fewer withdrawal symptoms than saline in a randomized, placebo-controlled study with benzodiazepine-dependent subjects. Additionally, relapse rates were much lower during subsequent follow-up.[17]
In vitro studies of tissue cultured cell lines have shown that chronic treatment with flumazenil enhanced the benzodiazepine binding site where such receptors have become more numerous and uncoupling/down-regulation of GABAA has been reversed.[18][19][20] After long-term exposure to benzodiazepines, GABAA receptors become down-regulated and uncoupled. Growth of new receptors and recoupling after prolonged flumazenil exposure has also been observed. It is thought this may be due to increased synthesis of receptor proteins.[21]
Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks.[22] This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.
Low-dose, slowsubcutaneous flumazenil administration is a safe procedure for patients withdrawing from long-term, high-dose benzodiazepine dependency.[23] It has a low risk of seizures even amongst those who have experienced convulsions when previously attempting benzodiazepine withdrawal.[24]
In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8–10 days of low-dose, slowly infused flumazenil.[25] One addiction treatment centre in Italy has used flumazenil to treat over 300 patients who were dependent on high doses of benzodiazepines (up to 70 times higher than conventionally prescribed) with physicians being among the clinic's most common patients.[26]
Flumazenil bound at the alpha-gamma interface of an α1β2γ2 GABAA receptor. H-atoms hidden.
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 theGABA/benzodiazepine receptor complex.[27] It also exhibits weak partial agonism of GABAA receptor complexes that containα6-type monomers; the clinical relevance of this is unknown.[28]
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-benzodiazepinez-drugs, such aszolpidem andzopiclone, because they act via thebenzodiazepine site of the GABA receptor[29] - it has been used to successfully treat z-drug overdose.[29][30][31]
Intravenous flumazenil has been shown to antagonizesedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers.
The duration and degree of reversal ofsedative benzodiazepine effects are related to the dose and plasma concentrations of flumazenil.
^Mihic S, Mayfield J (2023)."Hypnotics and sedatives.". In Brunton LL, Knollmann BC (eds.).Goodman & Gilman's: The Pharmacological Basis of Therapeutics (14th ed.). McGraw Hill.ISBN978-1-264-25807-9.
^Kawano DF, Ueta J, Sankarankutty AK, Pereira LR, de Freitas O (June 2009). "Midazolam-related drug interactions: detection of risk situations to the patient safety in a brazilian teaching hospital".Journal of Patient Safety.5 (2):69–74.doi:10.1097/PTS.0b013e3181a5dafa.PMID19920444.S2CID12973546.
^Quaglio G, Pattaro C, Gerra G, Mathewson S, Verbanck P, Des Jarlais DC, et al. (August 2012). "High dose benzodiazepine dependence: description of 29 patients treated with flumazenil infusion and stabilised with clonazepam".Psychiatry Research.198 (3):457–462.doi:10.1016/j.psychres.2012.02.008.PMID22424905.S2CID28979824.
^Gerra G, Giucasto G, Zaimovic A, Fertonani G, Chittolini B, Avanzini P, et al. (June 1996). "Intravenous flumazenil following prolonged exposure to lormetazepam in humans: lack of precipitated withdrawal".International Clinical Psychopharmacology.11 (2):81–88.doi:10.1097/00004850-199611020-00002.PMID8803645.{{cite journal}}: CS1 maint: overridden setting (link)
^Gerra G, Zaimovic A, Giusti F, Moi G, Brewer C (October 2002). "Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controlled study".Addiction Biology.7 (4):385–395.doi:10.1080/1355621021000005973.PMID14578014.S2CID21255719.
^Pericić D, Jazvinsćak Jembrek M, Svob Strac D, Lazić J, Spoljarić IR (January 2005). "Enhancement of benzodiazepine binding sites following chronic treatment with flumazenil".European Journal of Pharmacology.507 (1–3):7–13.doi:10.1016/j.ejphar.2004.10.057.PMID15659288.{{cite journal}}: CS1 maint: overridden setting (link)
^Pericić D, Lazić J, Jembrek MJ, Strac DS, Rajcan I (December 2004). "Chronic exposure of cells expressing recombinant GABAA receptors to benzodiazepine antagonist flumazenil enhances the maximum number of benzodiazepine binding sites".Life Sciences.76 (3):303–317.doi:10.1016/j.lfs.2004.07.013.PMID15531382.{{cite journal}}: CS1 maint: overridden setting (link)
^Jazvinsćak Jembrek M, Svob Strac D, Vlainić J, Pericić D (July 2008). "The role of transcriptional and translational mechanisms in flumazenil-induced up-regulation of recombinant GABA(A) receptors".Neuroscience Research.61 (3):234–241.doi:10.1016/j.neures.2008.03.005.PMID18453026.S2CID9033302.{{cite journal}}: CS1 maint: overridden setting (link)
^Saxon L, Borg S, Hiltunen AJ (August 2010). "Reduction of aggression during benzodiazepine withdrawal: effects of flumazenil".Pharmacology, Biochemistry, and Behavior.96 (2):148–151.doi:10.1016/j.pbb.2010.04.023.PMID20451546.S2CID41351863.{{cite journal}}: CS1 maint: overridden setting (link)
^Faccini M, Leone R, Opri S, Casari R, Resentera C, Morbioli L, et al. (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.30 (10):1047–1053.doi:10.1177/0269881116647505.PMID27166362.S2CID27167585.{{cite journal}}: CS1 maint: overridden setting (link)
^Tamburin S, Faccini M, Casari R, Federico A, Morbioli L, Franchini E, et al. (October 2017). "Low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high-dose benzodiazepine dependence".Journal of Psychopharmacology.31 (10):1369–1373.doi:10.1177/0269881117714050.PMID28613124.S2CID42432213.{{cite journal}}: CS1 maint: overridden setting (link)
^Hadingham KL, Garrett EM, Wafford KA, Bain C, Heavens RP, Sirinathsinghji DJ, et al. (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.doi:10.1016/S0026-895X(25)08706-1.PMID8632757.
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