Flumazenil

Flumazenil
Systematic (IUPAC) name
ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate
Clinical data
Trade names Anexate, Lanexat, Mazicon, Romazicon
AHFS/Drugs.com monograph
  • AU: B3
  • US: C (Risk not ruled out)
IV
Pharmacokinetic data
Metabolism Hepatic
Half-life 7-15 min (initial)
20-30 min (brain)
40-80 min (terminal)
Excretion Urine 90-95%
Feces 5-10%
Identifiers
78755-81-4 Yes
V03AB25
PubChem CID 3373
DrugBank DB01205 Yes
ChemSpider 3256 Yes
UNII 40P7XK9392 Yes
KEGG D00697 Yes
ChEBI CHEBI:5103 Yes
ChEMBL CHEMBL407 Yes
Synonyms ethyl 8-fluoro- 5,6-dihydro- 5-methyl- 6-oxo- 4H- imidazo [1,5-a] [1,4] benzodiazepine- 3-carboxylate
Chemical data
Formula C15H14FN3O3
303.288 g/mol
 Yes (what is this?)  (verify)
A vial of flumazenil solution for injection

Flumazenil (also known as flumazepil, code name Ro 15-1788) is a GABAA receptor antagonist primarily available by injection only, and the only GABAA receptor antagonist on the market today.

It 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. 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.[1][2]

Medical uses

Flumazenil is of benefit in patients who become excessively drowsy after benzodiazepines are used for either diagnostic or therapeutic procedures.[3]

It has been used as an antidote in the treatment of benzodiazepine overdoses.[3] It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine binding site on the GABAA receptor. There are many complications that must be taken into consideration when used in the acute care setting.[3] Flumazenil's short half-life requires multiple doses and careful patient monitoring to prevent recurrence of overdose symptoms.

It is also sometimes used to reverse the effects of benzodiazepines after surgery in a manner similar to naloxone's application to reverse the effect of opiates and opioids following surgery. This requires careful monitoring by an anesthesiologist due to potential side effects and serious risks associated with both over-administering flumazenil and the removal of patient life-support and monitoring equipment before the benzodiazepines have worn off (due to flumazenil masking their continued effect).

Flumazenil has been effectively used to treat overdoses of non-benzodiazepine hypnotics, such as zolpidem, zaleplon and zopiclone.[4]

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

It has also been used in hepatic encephalopathy, though results have been mixed.[6][7]

The onset of action is rapid and usually effects are 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, 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.

Many benzodiazepines (including midazolam) have longer half-lives than flumazenil. Therefore, repeat doses of flumazenil may be required to prevent recurrent symptoms of overdosage once the initial dose of flumazenil wears off. It is hepatically metabolised to inactive compounds which are excreted in the urine. Subjects who are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure, upon rapid administration of flumazenil.

It is not recommended for routine use in those with a decreased level of consciousness.[8]

Considering its use as an antidote in benzodiazepine overdoses, orders for flumazenil may serve as a clue or trigger to initiate a more detailed prescription audit in the search for adverse drug events and clinically significant drug interactions related to the use of benzodiazepines.[9]

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.[10]

Treatment for benzodiazepine dependence & tolerance

In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8–10 days of low dose, slow infusion of flumazenil.[11] 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 doctors being one of their most common patients.[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 flumazenil.[13] 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.[14]

Flumazenil has been tested against placebo in dependent subjects, whereby typical benzodiazepine effects were reversed with little to no withdrawal symptoms.[15] Flumazenil was shown to produce significantly less withdrawal symptoms than saline in a randomized, placebo-controlled study with benzodiazepine dependent subjects. Additionally, relapse rates were much less during subsequent follow-up.[16]

Several studies have shown enhancement of the benzodiazepine binding site after chronic treatment with flumazenil where sites have become more numerous and uncoupling/down-regulation of GABAA has been reversed.[17][18][19] 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.[20]

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.[21] This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.

Clinical 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. Because the body does not produce endogenous benzodiazepines, flumazenil only creates behavioral effects when administered concurrently with a benzodiazepine receptor agonist or inverse agonist. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in humans.

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, or general anesthetics) and does not reverse the effects of opioids.

In animals pretreated with high doses of benzodiazepines over several weeks, rapid administration of flumazenil elicited symptoms of benzodiazepine withdrawal, including seizures. A similar effect was seen in adult human subjects.

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.

Synthesis

Flumazenil synthesis: Gerecke, M.; Hunkeler, W.; Kyburz, E.; Mohler, H.; Pieri, L.; Pole, P.; 1982, U.S. Patent 4,316,839.

The benzodiazepinedione nucleus is obtained from the condensation of the fluorinated isatoic anhydride with sarcosine. The first step probably involves the acylation of the amino acid nitrogen by the activated anhydride carbonyl group. The loss of carbon dioxide from the resulting carbamic acid will lead to the amide. This then cyclizes to the benzodiazepinedione. Reaction of this last intermediate with ethyl isocyanoacetate then leads to the addition of the only free amide nitrogen to the isocyanide function to afford an intermediate such as the amidine. The doubly activated acetate methylene group then condenses with the ring carbonyl group to form an imidazole, affording flumazenil.

Availability

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

See also

References

  1. ↑ D.B. Rye, D.L. Bliwise, K. Parker, L.M. Trotti, P. Saini, J. Fairley, A. Freeman, P.S. Garcia, M.J. Owens, J.C. Ritchie and A. Jenkins (21 November 2012). "Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABAA Receptors". Sci. Transl. Med. 4 (161): 161ra151. doi:10.1126/scitranslmed.3004685. PMID 23175709.
  2. ↑ http://clinicaltrials.gov/show/NCT01183312
  3. ↑ 3.0 3.1 3.2 Goldfrank, Lewis R. (2002). Goldfrank's toxicologic emergencies. New York: McGraw-Hill Medical Publ. Division. ISBN 0-07-136001-8.
  4. ↑ Nelson, Lewis H.; Flomenbaum, Neal; Goldfrank, Lewis R.; Hoffman, Robert Louis; Howland, Mary Deems; Neal A. Lewin (2006). Goldfrank's toxicologic emergencies. New York: McGraw-Hill, Medical Pub. Division. ISBN 0-07-147914-7.
  5. ↑ D.B. Rye, D.L. Bliwise, K. Parker, L.M. Trotti, P. Saini, J. Fairley, A. Freeman, P.S. Garcia, M.J. Owens, J.C. Ritchie and A. Jenkins (2012). "Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABAA Receptors". Sci. Transl. Med. 4 (161): 161ra151. doi:10.1126/scitranslmed.3004685. PMID 23175709.
  6. ↑ Goulenok C, Bernard B, Cadranel JF et al. (March 2002). "Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis". Aliment. Pharmacol. Ther. 16 (3): 361–72. doi:10.1046/j.1365-2036.2002.01191.x. PMID 11876688.
  7. ↑ Als-Nielsen B, Gluud LL, Gluud C (2004). Als-Nielsen, Bodil, ed. "Benzodiazepine receptor antagonists for hepatic encephalopathy". Cochrane Database Syst Rev (2): CD002798. doi:10.1002/14651858.CD002798.pub2. PMID 15106178.
  8. ↑ Wood, Lawrence D. H.; Hall, Jesse B.; Schmidt, Gregory D. 1952 (2005). Principles of critical care. McGraw-Hill Professional. ISBN 0-07-141640-4.
  9. ↑ Kawano DF, Ueta J, Sankarankutty AK, Pereira LR, de Freitas O (2009). "Midazolam-related drug interactions: detection of risk situations to the patient safety in a brazilian teaching hospital". J Patient Saf 5 (2): 69–74. doi:10.1097/PTS.0b013e3181a5dafa. PMID 19920444.
  10. ↑ Alexander Hammers, Matthias J. Koepp, Mark P. Richardson, Rene Hurlemann, David J. Brooks & John S. Duncan (June 2003). "Grey and white matter flumazenil binding in neocortical epilepsy with normal MRI. A PET study of 44 patients". Brain 126 (Pt 6): 1300–1308. doi:10.1093/brain/awg138. PMID 12764053.
  11. ↑ Lugoboni, Fabio; Faccini, Marco; Quaglio, Gianluca; Casari, Rebecca; Albiero, Anna; Pajusco, Benedetta (2011). "Agonist substitution for high-dose benzodiazepine-dependent patients: let us not forget the importance of flumazenil". Addiction 106 (4): 853–853. doi:10.1111/j.1360-0443.2010.03327.x. ISSN 0965-2140.
  12. ↑ Lugoboni, Fabio; Leone, Roberto (2012). "WHAT IS STOPPING US FROM USING FLUMAZENIL?". Addiction 107 (7): 1359–1359. doi:10.1111/j.1360-0443.2012.03851.x. ISSN 0965-2140.
  13. ↑ Savic, I (1991). "Feasibility of reversing benzodiazepine tolerance with flumazenil". The Lancet 337 (8734): 133–137. doi:10.1016/0140-6736(91)90799-U. ISSN 0140-6736.
  14. ↑ Quaglio, Gianluca; Pattaro, Cristian; Gerra, Gilberto; Mathewson, Sophie; Verbanck, Paul; Des Jarlais, Don C.; Lugoboni, Fabio (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. ISSN 0165-1781. PMID 22424905.
  15. ↑ G. Gerra, G. Giucasto, A. Zaimovic, G. Fertonani, B. Chittolini, P. Avanzini, R. Caccavari & R. Delsignore (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.
  16. ↑ Gerra, G.; Zaimovic, A.; Giusti, F.; Moi, G.; Brewer, C. (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. ISSN 1355-6215. PMID 14578014.
  17. ↑ Danka Pericic, Josipa Lazic & Dubravka Svob Strac (August 2005). "Chronic treatment with flumazenil enhances binding sites for convulsants at recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors". Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 59 (7): 408–414. doi:10.1016/j.biopha.2005.02.003. PMID 16084060.
  18. ↑ Danka Pericic, Maja Jazvinscak Jembrek, Dubravka Svob Strac, Josipa Lazic & Ivana Rajcan Spoljaric (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.
  19. ↑ Danka Pericic, Josipa Lazic, Maja Jazvinscak Jembrek, Dubravka Svob Strac & Ivana Rajcan (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.
  20. ↑ Maja Jazvinscak Jembrek, Dubravka Svob Strac, Josipa Vlainic & Danka Pericic (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.
  21. ↑ L. Saxon, S. Borg & A. J. Hiltunen (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.

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