Flumazenil

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Flumazenil
Flumazenil.svg
Flumazenil ball-and-stick model.png
Clinical data
Trade names Anexate, others
Other namesethyl 8-fluoro- 5,6-dihydro- 5-methyl- 6-oxo- 4H- imidazo [1,5-a] [1,4] benzodiazepine- 3-carboxylate, RO 15-1788
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category
  • AU:B3
Routes of
administration 		Intranasal, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver
Elimination half-life 7–15 min (initial)
20–30 min (brain)
40–80 min (terminal)
Excretion Urine 90–95%
Feces 5–10%
Identifiers
  • Ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate
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PubChem CID
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ECHA InfoCard 100.128.069 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H14FN3O3
Molar mass 303.293 g·mol−1
3D model (JSmol)
  • Fc(c1)ccc-2c1C(=O)N(C)Cc3n2cnc3C(=O)OCC
  • InChI=1S/C15H14FN3O3/c1-3-22-15(21)13-12-7-18(2)14(20)10-6-9(16)4-5-11(10)19(12)8-17-13/h4-6,8H,3,7H2,1-2H3 Yes check.svgY
  • Key:OFBIFZUFASYYRE-UHFFFAOYSA-N Yes check.svgY
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A vial of flumazenil solution for injection Flumazenil1.JPG
A vial of flumazenil solution for injection

Flumazenil, also known as flumazepil, [2] is a selective GABAA receptor antagonist [3] administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (particularly in cases of overdose), through competitive inhibition.

Contents

It was first characterized in 1981, [4] and was first marketed in 1987 by Hoffmann-La Roche under the trade name Anexate. 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 treat benzodiazepine overdoses and to help reverse anesthesia. Administration of flumazenil by sublingual lozenge and topical cream has also been tested. [5] [6]

Medical uses

Flumazenil benefits people who become excessively drowsy after use of benzodiazepines for either diagnostic or therapeutic procedures. [7]

Flumazenil has been used as an antidote in the treatment of benzodiazepine overdoses. [7] It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine (BZ) recognition site on the GABA/benzodiazepine receptor complex. [7]

Flumazenil has been effectively used to treat overdoses of non-benzodiazepine hypnotics, such as zolpidem, zaleplon and zopiclone (also known as the "Z-drugs"). [8]

It may also be effective in reducing excessive daytime sleepiness while improving vigilance in primary hypersomnias, such as idiopathic hypersomnia. [5]

Flumazenil has also been used in hepatic encephalopathy. It may have beneficial short‐term effects in people with cirrhosis, 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 for intravenous 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]

It is not recommended for routine use in those with a decreased level of consciousness. [11]

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]

PET radioligand

Radiolabeled with the radioactive isotope carbon-11, flumazenil may be used as a radioligand in neuroimaging with positron emission tomography to visualize the distribution of GABAA receptors in the human brain. [13]

Treatment for benzodiazepine dependence & tolerance

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, slow subcutaneous 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]

Pharmacology

Flumazenil bound at the alpha-gamma interface of an a1b2g2 GABAA receptor. H-atoms hidden. 6X3U GABAAR Flumazenil.png
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 the GABA/benzodiazepine receptor complex. [27] It also exhibits weak partial agonism of GABAA receptor complexes that contain α6-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-benzodiazepine z-drugs, such as zolpidem and zopiclone, because they act via the benzodiazepine site of the GABA receptor [29] - it has been used to successfully treat z-drug overdose. [29] [30] [31]

Pharmacodynamics

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.

Availability

Flumazenil is sold under a wide variety of brand names worldwide like Anexate, Lanexat, Mazicon, Romazicon.

References

  1. ↑ Anvisa (31 March 2023). "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 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  2. ↑ Hunkeler W, Möhler H, Pieri L, Polc P, Bonetti EP, Cumin R, et al. (April 1981). "Selective antagonists of benzodiazepines". Nature. 290 (5806): 514–516. Bibcode:1981Natur.290..514H. doi:10.1038/290514a0. PMID   6261143. S2CID   4340263.{{cite journal}}: CS1 maint: overridden setting (link)
  3. ↑ Whitwam JG, Amrein R (1 January 1995). "Pharmacology of flumazenil". Acta Anaesthesiologica Scandinavica. Supplementum. 108: 3–14. doi:10.1111/j.1399-6576.1995.tb04374.x. PMID   8693922. S2CID   24494744.
  4. ↑ Whitwam JG (October 1988). "Flumazenil: a benzodiazepine antagonist". BMJ. 297 (6655): 999–1000. doi:10.1136/bmj.297.6655.999. PMC   1834756 . PMID   2903780.
  5. 1 2 Rye DB, Bliwise DL, Parker K, Trotti LM, Saini P, Fairley J, et al. (November 2012). "Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors". Science Translational Medicine. 4 (161): 161ra151. doi:10.1126/scitranslmed.3004685. PMID   23175709. S2CID   44236050.{{cite journal}}: CS1 maint: overridden setting (link)
  6. ↑ Clinical trial number NCT01183312 for "Flumazenil for the Treatment of Primary Hypersomnia" at ClinicalTrials.gov
  7. 1 2 3 Goldfrank LR (2002). Goldfrank's toxicologic emergencies. New York: McGraw-Hill Medical Publ. Division. ISBN   978-0-07-136001-2.
  8. ↑ Nelson LH, Flomenbaum N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA (2006). Goldfrank's toxicologic emergencies. New York: McGraw-Hill, Medical Pub. Division. ISBN   978-0-07-147914-1.
  9. ↑ Goh ET, Andersen ML, Morgan MY, Gluud LL (August 2017). "Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy". The Cochrane Database of Systematic Reviews. 2017 (8): CD002798. doi:10.1002/14651858.CD002798.pub4. PMC   6483298 . PMID   28796283.{{cite journal}}: CS1 maint: article number as page number (link)
  10. ↑ 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. ISBN   978-1-264-25807-9.
  11. ↑ Wood LD, Hall JB, Schmidt GD (2005). Principles of critical care. McGraw-Hill Professional. ISBN   978-0-07-141640-5.
  12. ↑ 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. PMID   19920444. S2CID   12973546.
  13. ↑ Hammers A, Koepp MJ, Richardson MP, Hurlemann R, Brooks DJ, Duncan JS (June 2003). "Grey and white matter flumazenil binding in neocortical epilepsy with normal MRI. A PET study of 44 patients". Brain. 126 (Pt 6): 1300–1318. doi: 10.1093/brain/awg138 . PMID   12764053.{{cite journal}}: CS1 maint: overridden setting (link)
  14. ↑ Savic I, Widén L, Stone-Elander S (January 1991). "Feasibility of reversing benzodiazepine tolerance with flumazenil". Lancet. 337 (8734): 133–137. doi:10.1016/0140-6736(91)90799-U. PMID   1670787. S2CID   41180892.
  15. ↑ 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. PMID   22424905. S2CID   28979824.
  16. ↑ 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. PMID   8803645.{{cite journal}}: CS1 maint: overridden setting (link)
  17. ↑ 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. PMID   14578014. S2CID   21255719.
  18. ↑ Pericić D, Lazić J, Strac DS (August 2005). "Chronic treatment with flumazenil enhances binding sites for convulsants at recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors". Biomedicine & Pharmacotherapy. 59 (7): 408–414. doi:10.1016/j.biopha.2005.02.003. PMID   16084060.{{cite journal}}: CS1 maint: overridden setting (link)
  19. ↑ 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. PMID   15659288.{{cite journal}}: CS1 maint: overridden setting (link)
  20. ↑ 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. PMID   15531382.{{cite journal}}: CS1 maint: overridden setting (link)
  21. ↑ 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. PMID   18453026. S2CID   9033302.{{cite journal}}: CS1 maint: overridden setting (link)
  22. ↑ 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. PMID   20451546. S2CID   41351863.{{cite journal}}: CS1 maint: overridden setting (link)
  23. ↑ 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. PMID   27166362. S2CID   27167585.{{cite journal}}: CS1 maint: overridden setting (link)
  24. ↑ 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. PMID   28613124. S2CID   42432213.{{cite journal}}: CS1 maint: overridden setting (link)
  25. ↑ Lugoboni F, Faccini M, Quaglio G, Casari R, Albiero A, Pajusco B (April 2011). "Agonist substitution for high-dose benzodiazepine-dependent patients: let us not forget the importance of flumazenil". Addiction. 106 (4): 853. doi: 10.1111/j.1360-0443.2010.03327.x . PMID   21320225.
  26. ↑ Lugoboni F, Leone R (July 2012). "What is stopping us from using flumazenil?". Addiction. 107 (7): 1359. doi: 10.1111/j.1360-0443.2012.03851.x . PMID   22509854.
  27. ↑ Hood SD, Norman A, Hince DA, Melichar JK, Hulse GK (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. PMC   4014019 . PMID   23126253.
  28. ↑ 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. PMID   8632757.
  29. 1 2 Gunja N (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. PMC   3657020 . PMID   23404347.
  30. ↑ Thornton SL, Negus E, Carstairs SD (November 2013). "Pediatric zolpidem ingestion demonstrating zero-order kinetics treated with flumazenil". Pediatric Emergency Care. 29 (11): 1204–1206. doi:10.1097/PEC.0b013e3182aa139c. PMID   24196090. S2CID   34655918.
  31. ↑ Lheureux P, Debailleul G, De Witte O, Askenasi R (March 1990). "Zolpidem intoxication mimicking narcotic overdose: response to flumazenil". Human & Experimental Toxicology. 9 (2): 105–107. Bibcode:1990HETox...9..105L. doi:10.1177/096032719000900209. PMID   2111156. S2CID   34525063.
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