Flumazenil (also known as flumazepil, code name Ro 15-1788[3]) is a selective GABAAreceptor antagonist[4] 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.
It was first characterized in 1981,[5] and was first marketed in 1987 by Hoffmann-La Roche under the trade name Anexate. However, it did not receive FDA approval until December 20, 1991. The developer lost its exclusive patent rights 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.[6][7]
The drug has been used as an antidote in the treatment of benzodiazepine overdoses.[8] It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine (BZ) recognition site on the GABA/benzodiazepine receptor complex. There are many complications that must be taken into consideration when used in the acute care setting.[8] These include lowered seizure threshold, agitation, and anxiousness. Flumazenil's short half-life requires multiple doses. Because of the potential risks of withdrawal symptoms and the drug's short half-life, patients must be carefully monitored to prevent recurrence of overdose symptoms or adverse side effects.
Flumazenil is also sometimes used after surgery to reverse the sedative effects of benzodiazepines. This is similar to naloxone's application to reverse the effect of opiates and opioids following surgery. Administration of the drug requires careful monitoring by an anesthesiologist due to potential side effects and serious risks associated with over-administeration. Likewise, post-surgical monitoring is also necessary because flumazenil can mask the apparent metabolization ("wearing off") of the drug after removal of patient life-support and monitoring equipment.
Flumazenil has been effectively used to treat overdoses of non-benzodiazepine hypnotics, such as zolpidem, zaleplon and zopiclone (also known as "Z-drugs").[9]
The drug 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.[10]
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 min if evidence of oversedation reappears.[11]
Many benzodiazepines (including midazolam) have longer half-lives than flumazenil. Therefore, in cases of overdose, repeated doses of flumazenil may be required to prevent recurrent symptoms once the initial dose of flumazenil wears off.[citation needed]
It is hepatically metabolised to inactive compounds which are excreted in the urine. Individuals who are physically dependent on benzodiazepines may experience benzodiazepine withdrawal symptoms, including seizures, upon rapid administration of flumazenil.
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.[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.[15] 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.[16]
Flumazenil has been tested against placebo in benzo-dependent subjects. Results showed that typical benzodiazepine withdrawal effects were reversed with few to no symptoms.[17] 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.[18]
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.[19][20][21] 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.[22]
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.[23] 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.[24] It has a low risk of seizures even amongst those who have experienced convulsions when previously attempting benzodiazepine withdrawal.[25]
In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8–10 days of low-dose, slowly infused flumazenil.[26] 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.[27]
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.[28] It also exhibits weak partial agonism of GABAA receptor complexes that contain α6-type monomers; the clinical relevance of this is unknown.[29]
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[30] - it has been used to successfully treat z-drug overdose.[30][31][32]
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. In India it is manufactured by Roche Bangladesh Pharmaceuticals and USAN Pharmaceuticals.
^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, Lugoboni F (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.
^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, 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. PMID16084060.
^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.
^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.
^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.
^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.
^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.
^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.
^Hadingham KL, Garrett EM, Wafford KA, Bain C, Heavens RP, Sirinathsinghji DJ, Whiting PJ (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. PMID8632757.
