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Disorders of Consciousness
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Sedative/hypnotic drug use disorder (e.g. benzodiazepines, barbiturates, opiates, phenothiazines, and tricyclic antidepressants alone or in combination): Elderly and those with mild cognitive impairment (MCI), pre-MCI, and dementia are particularly sensitive.Naloxone may be given diagnostically and therapeutically in suspected opiate toxicity. However, its half-life is comparatively shorter than most opioids, and prolonged monitoring is required.Flumazenil may acutely reverse suspected benzodiazepine toxicity although it carries a risk of provoking seizures and should be avoided in most circumstances.
Interaction of the benzodiazepines with the GABAA receptor
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
The original 5-phenyl-1,4-benzodiazepines all appear to be agonists with similar efficacy: they potentiate GABAA receptor-activated currents by increasing the probability of channel opening in response to a given GABA stimulus. In vivo, these compounds are sedative, anxiolytic, anticonvulsant and myorelaxant. However, compounds also exist that bind potently to the benzodiazepine binding site without modulating GABAA receptor activity. These are the benzodiazepine antagonists, of which the first to be identified was flumazenil, or Ro 15-1788 (Hunkeler et al, 1981), the structure of which is shown in Figure 2.4. This compound has nanomolar affinity for the benzodiazepine binding site, no overt benzodiazepine-like behavioural properties, and will reverse all the biological effects of classical benzodiazepines, both in vitro and in vivo. As a pharmacological tool, flumazenil has been indispensible not only in characterising the effects of benzodiazepines but also exploring benzodiazepine receptor sensitivity changes. Flumazenil is used therapeutically to control benzodiazepine anaesthesia. Its effects and uses in animals and man will be discussed in Chapters 6 and 10.
Sedative and Hypnotic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Arup Kumar Misra, Pramod Kumar Sharma
Flumazenil is used for the treatment of benzodiazepine overdose and also indicated to reverse sedative action of benzodiazepines used during clinical procedures and general anesthesia. Flumazenil may exhibit seizures if administrated to patients who have developed benzodiazepine’s tolerance or dependence and taking the drug for long duration (Hood et al., 2014).
Common substance use disorders in older adults
Published in Hospital Practice, 2020
Lynsey Seim, Priyanka Vijapura, Sandeep Pagali, M Caroline Burton
Discontinuation of benzodiazepines might need pharmacological intervention at times. Acute overdose can be reversed using flumazenil. Chronic use of benzodiazepines will need gradual dose reduction to reduce withdrawal symptoms or relapse. A 2018 Cochrane systematic review revealed benefit with valproate, while tricyclic antidepressants were noted to have benefit at longest follow-up [57]. Benzodiazepine withdrawal symptoms are also reduced by use of pregabalin, captodiame, paroxetine, tricyclic antidepressants, and flumazenil. Valproate and cyamemazine have demonstrated reduction of the relapse rate of benzodiazepine use [57]. These pharmacological interventions need to be used with careful consideration of risks and benefits in older adults given their cholinergic property and central nervous system side effects. Melatonin and Ramelteon have also demonstrated help in decreasing benzodiazepine use as a hypnotic [58].
Recent developments on triazole nucleus in anticonvulsant compounds: a review
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Amongst all pharmacodynamic models suggested for binding to the benzodiazepine receptor at least two features are common: an aromatic ring and a coplanar proton accepting group in suitable distance. Also, the presence of a second out-of-plane, aromatic ring could potentiate binding to the receptor. Abbas Shafiee and his team launched a project to design simple non-rigid structures with benzodiazepine activity based on the proposed SAR. A series of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole derivatives (29, Figure 6), with a simple non-rigid structure, were designed, which had all the suggested requirements for binding to the benzodiazepine receptors. Their benzodiazepine effects and anticonvulsant activity were evaluated. Among the tested compounds, compound 29a with dichloro-substituent showed the best anticonvulsant activity with an ED50 of 12.0 mg/kg in the PTZ models. To clarify whether the designed compounds could mimic the structure of a benzodiazepine agonist, conformational analysis on designed molecules as well as a known benzodiazepine agonist estazolam was performed followed by superimposition of energy minima conformers. The results showed that the main proposed pharmacofores were well matched. In addition, the activity of the compounds is significantly reduced by flumazenil, a benzodiazepine antagonist, which further confirms that this effect is mediated through benzodiazepine receptors.
Designer benzodiazepines: a report of exposures recorded in the National Poison Data System, 2014–2017
Published in Clinical Toxicology, 2019
Joseph E. Carpenter, Brian Patrick Murray, Camille Dunkley, Ziad N. Kazzi, Melissa H. Gittinger
The majority of exposures (224, 95%) were through ingestion. Inhalational/nasal (5, 2%) and parenteral (5, 2.1%) exposures were also reported. The most common clinical effects observed (Table 3) were drowsiness/lethargy (65%), slurred speech (17%), confusion (14%), and agitation/irritability (14%). Less common, but serious effects observed included hypotension (8%), coma (8%), bradycardia (4%), respiratory depression (3%), respiratory arrest (0.4%), and cardiac arrest (0.4%). Treatments performed included intravenous fluids (31.6%), naloxone (7%), oxygen (7%), and benzodiazepines (6%). Flumazenil was administered in 4% of cases; intubation was performed in 3%.