|Systematic (IUPAC) name|
|Trade names||Anexate, Lanexat, Mazicon, Romazicon|
|Biological half-life||7-15 min (initial)
20-30 min (brain)
40-80 min (terminal)
|ATC code||V03AB25 (WHO)|
|Synonyms||ethyl 8-fluoro- 5,6-dihydro- 5-methyl- 6-oxo- 4H- imidazo [1,5-a] [1,4] benzodiazepine- 3-carboxylate|
|Molar mass||303.288 g/mol|
Flumazenil (also known as flumazepil, code name Ro 15-1788) is a selective benzodiazepine receptor antagonist primarily available by injection only, and the only GABAA negative allosteric modulator on the market today. It has antagonistic and antidote properties to therapeutically used benzodiazapenes, through competitive inhibition.
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.
It has been used as an antidote in the treatment of benzodiazepine overdoses. 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. These include lowered seizure threshold, agitation, and anxiousness. 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).
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.
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.
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.
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. 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.
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. 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.
Flumazenil has been tested against placebo in dependent subjects, whereby typical benzodiazepine effects were reversed with little to no withdrawal symptoms. 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.
Laboratory research studies using tissue cultured cell lines 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. 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.
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. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.
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.
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.
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- Romazicon product information, Roche USA