The high affinity binding site for flumazenil is found on the extracellular surface of the GABA A receptor at an interface between the α and γ 2 subunits, in close proximity to the benzodiazepine binding site 7. This specificity is not surprising given these latter agents have different binding sites on the receptor. On the other hand, it does not reverse the effects of other GABAergic sedative/hypnotics such as barbiturates, inhalational anaesthetics, propofol or ethanol, nor does it reverse the effects of opioids. It can also reverse the effects of structurally dissimilar sedatives which also bind to the benzodiazepine binding site, namely the cyclopyrrolone zopiclone, the pyrazolopyrimidine zaleplon and the imidazopyridine zolpidem. Flumazenil has a very rapid onset of action after parenteral administration, and competitively antagonizes the sedating effects of a wide range of benzodiazepines such as midazolam, diazepam and lorazepam at the GABA A receptor. A structurally similar investigational agent (Ro 15–4513) developed at the same time held promise as an antidote to ethanol, but only flumazenil has been approved for human use. To understand this discordant practice requires understanding how these antidotes differ, and the modern approach to the unconscious overdose patient.įlumazenil (Ro 15–1788) is an imidazobenzodiazepine, developed by Hoffmann‐La Roche in the 1980s. Experts recommend against widespread use, restricted to very narrow indications or only on the recommendation of a medical toxicologist 3, 4, 5 while discouraging empirical administration as part of a ‘coma cocktail’ 1, 2, 6. Flumazenil, on the other hand, carries a ‘black box’ warning in the United States. Recently, as one element of the public health response to an epidemic of opioid overdose, programmes have appeared to allow bystanders to carry and administer naloxone before the arrival of paramedics, circumventing the usual barriers to access a prescription medicine like naloxone. Only naloxone is on the World Health Organization core list of essential medicines. Yet only naloxone has retained its place on the so‐called ‘coma cocktail’, the short list of empirical treatments to be considered when treating altered mental status of unknown cause 1, 2. Their effects are rapidly titratable, specific and relatively short in duration, allowing both diagnostic and therapeutic use. Both enjoy very rapid onset after parenteral administration, and are able to reverse coma caused by either opioids or benzodiazepines quickly. It is therefore surprising to many that these two antidotes have experienced widely different uptake into clinical practice. As such, these antidotes are generally regarded as exemplars of the ideal antidote. These highly specific antagonists inhibit the noxious effects of two important drug classes (the opioids and the benzodiazepines) by competitive binding at their respective target receptors, and are essentially devoid of agonist effects. Perhaps the two best examples of pharmacologically pure antidotes are naloxone and flumazenil. Indeed, the science of antidotal therapy has advanced in step with an improved understanding of the mechanism of action and toxicity of various natural and synthetic drugs. The quest for the ideal antidote has its origins in antiquity, and helped define the discipline of pharmacology.
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