Benzodiazepines

PathophysiologyTop

Benzodiazepines are central nervous system (CNS) depressants. They are rapidly absorbed from the gastrointestinal tract, metabolized in the liver, and undergo minimal renal elimination in an unchanged form. The half-life of diazepam is between 40 and 70 hours. The therapeutic index of benzodiazepines is high. Moderate poisoning occurs after the administration of >10 times the therapeutic dose. Short-acting benzodiazepines (eg, midazolam, alprazolam) have a high potential for dependency. One of the undesirable effects of benzodiazepines—amnesia—is used for criminal purposes (mainly flunitrazepam; the so-called date rape drugs). Zaleplon (not currently sold in Canada), zopiclone, and zolpidem are the most commonly prescribed hypnotic drugs. Their mechanism of action and adverse effects are similar to those of benzodiazepines and overdose treatment is the same.

Clinical Features and DiagnosisTop

1. Signs and symptoms of poisoning: Psychomotor retardation, slurred speech, unsteady gait, dizziness, ataxia, dyskinesia, diplopia, somnolence, coma, hyporeflexia, pinpoint pupils, hypotension, hypothermia.

2. Diagnostic tests: Urine qualitative tests for benzodiazepines, serum electrolyte levels, and arterial blood gas analysis. In patients with profound coma, check for other toxic substances in blood and urine (benzodiazepine poisoning may often be combined with ingestion of other substances, particularly alcohol). Computed tomography (CT) of the brain and blood glucose may be helpful, as the differential diagnosis of benzodiazepine overdose includes intracranial disorders and hypoglycemia.

TreatmentTop

1. Decontamination: If <1 hour has elapsed from the ingestion of a very high dose of benzodiazepines, gastric lavage or activated charcoal (25-100 g) may be considered, but they carry the risk of aspiration in patients with decreased level of consciousness and the benefits are unclear, if any.Evidence 1Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and indirectness. Chyka PA, Seger D, Krenzelok EP, Vale JA; American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Position paper: Single-dose activated charcoal. Clin Toxicol (Phila). 2005;43(2):61-87. Review. PubMed PMID: 15822758. Benson BE, Hoppu K, Troutman WG, et al; American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Position paper update: gastric lavage for gastrointestinal decontamination. Clin Toxicol (Phila). 2013 Mar;51(3):140-6. doi: 10.3109/15563650.2013.770154. Epub 2013 Feb 18. Review. PubMed PMID: 23418938.

2. Antidote: IV flumazenil 0.5 to 2 mg. In unconscious patients with benzodiazepine poisoning administration of flumazenil usually results in full recovery of consciousness for a relatively short period of time (measured in minutes). Do not use flumazenil in patients treated with benzodiazepines for life-threatening indications (eg, epilepsy), patients receiving long-term benzodiazepine treatment (risk of withdrawal seizures), or in patients with suspected mixed poisoning with benzodiazepines and tricyclic or tetracyclic antidepressants. Flumazenil can precipitate arrhythmia and seizures and should not be used routinely.Evidence 2Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and indirectness. An H, Godwin J. Flumazenil in benzodiazepine overdose. CMAJ. 2016 Dec 6;188(17-18):E537. doi: 10.1503/cmaj.160357. Epub 2016 Nov 14. PubMed PMID: 27920113; PubMed Central PMCID: PMC5135539. Penninga EI, Graudal N, Ladekarl MB, Jürgens G. Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication--A Systematic Review with Meta-Analyses of Randomised Trials. Basic Clin Pharmacol Toxicol. 2016 Jan;118(1):37-44. doi: 10.1111/bcpt.12434. Epub 2015 Jul 28. Review. PubMed PMID: 26096314.

3. Methods of enhanced elimination: None available.

4. Symptomatic treatment: Maintain vital functions and correct abnormalities. Invasive ventilation may be required. Manage hypothermia.