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Benzodiazepines
SPECIFIC SUBSTANCES
Benzodiazepines
antagonist, can be given in carefully selected patients, usually to avoid the need for mechanical ventilation. Its efficacy is determined clinically from the improvement in consciousness level and respiration. Flumazenil is used more often than is justified by the severity of the poisoning and should be reserved for patients with coma, hypotension or respiratory depression who are known not to have epilepsy, and not to have ingested pro-convulsants concurrently.3,4 It should be used cautiously if patients are habituated to benzodiazepines, to avoid acute withdrawal. It has been reported to precipitate convulsions and cardiac arrhythmias when tricyclic antidepressants have been taken and a normal electrocardiogram is mandatory (i.e. no QRS or QT abnormality) before its use.5 Other pro-convulsants (e.g. cocaine, amfetamines) also present a risk since the use of flumazenil will make controlling convulsions due to another toxic agent more difficult. The usual use for flumazenil is in patients with obstructive airways disease, or possibly to avoid ventilation in a child (unlicensed use). UK experience indicates that flumazenil is generally safe if used cautiously in poisoning.6 Flumazenil has a short half-life (about 1 hour). Therefore, patients with severe poisoning in whom it is indicated may need repeated doses (0.5 milligrams intravenously over 1 minute), the same dose repeated if there is no response or only a partial response or an intravenous infusion of 0.5e2.0 mg/hour. Most patients poisoned with benzodiazepines will respond to flumazenil 1 milligram. Many benzodiazepines have long half-lives (e.g. diazepam, 36 hours) and can also have active metabolites with long half-lives (e.g. nordiazepam, about 100 hours), and although major functions return rapidly it can be several days before patients recover the ability to perform skilled tasks safely. Flumazenil can also be used in children, where it has proved beneficial in severe intoxication, although such cases are rare.7 A
James W Dear D Nicholas Bateman
Abstract Benzodiazepine compounds are rarely fatal if ingested alone but will potentiate central nervous system depression caused by coingested medication. Although an antagonist, flumazenil, is available, its use in overdose is associated with potential hazard, particularly the risk of precipitating convulsions or withdrawal if given in excess to those who have co-ingested a pro-convulsant, who take benzodiazepines regularly or who are known epileptic patients. Routine use in all cases is therefore not advised, and indications are restricted to patients who develop reduced ventilation and coma and who otherwise would require mechanical ventilation and have not ingested tricyclic antidepressants or other pro-convulsants, including cocaine.
Keywords Benzodiazepines; diazepam; flumazenil; zolpidem; zopiclone
Introduction Many benzodiazepine compounds are marketed; the main differences relate to their duration of action. Benzodiazepines and the related non-benzodiazepine hypnotic agents (zaleplon, zopiclone, zolpidem) are often taken in overdose with other central nervous system (CNS) depressants or ethanol, and potentiate the respiratory depressant effects of the co-ingestants. Combination with opioids appears to be particularly hazardous. However, co-ingestion of benzodiazepines can prevent convulsions induced by other agents taken in a mixed overdose. For this reason, routine use of benzodiazepine antagonists in poisoning as a ‘diagnostic test’ is not recommended.
Clinical features
REFERENCES 1 Gaudreault P, Guay J, Thivierge RL, Verdy I. Benzodiazepine poisoning. Clinical and pharmacological considerations and treatment. Drug Saf 1991; 6: 247e65. 2 Hojer J, Baechrendtz S, Gustafsson L. Benzodiazepines poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med 1989; 226: 117e22. 3 Kulka PJ, Lauven PM. Benzodiazepine antagonists e an update of their role in the emergency care of overdose patients. Drug Saf 1992; 7: 381e6. 4 Weinbroum A, Rudick V, Sorkine P, et al. Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. Crit Care Med 1996; 24: 199e206. 5 Mordel A, Winkler E, Almog S, Tirosh M, Ezra D. Seizures after flumazenil administration in a case of combined benzodiazepine and tricyclic anti-depressant overdose. Crit Care Med 1992; 20: 1733e4. 6 Veiraiah A, Dyas J, Cooper G, Routledge PA, Thompson JP. Flumazenil use in benzodiazepine overdose in the UK: a retrospective survey of NPIS data. Emerg Med J 2012; 29: 565e9. 7 Wiley CC, Wiley 2nd JF. Pediatric benzodiazepine ingestion resulting in hospitalization. J Toxicol Clin Toxicol 1998; 36: 227e31.
When taken alone in overdose, all benzodiazepines produce similar clinical features (drowsiness, dizziness, ataxia, dysarthria, nystagmus); less commonly, coma and hypotension develop.1,2 Respiratory depression is a potential complication, particularly when opioids, ethanol and other CNS depressants have also been ingested, and may require special attention when the patient has pre-existing chronic obstructive pulmonary disease.
Management Generally, the only management required is careful nursing and supportive care. Flumazenil, a specific benzodiazepine James W Dear PhD FRCPE is a Senior Clinical Lecturer and Consultant in Clinical Pharmacology at the University of Edinburgh, UK. Competing interests: none declared. D Nicholas Bateman MD FRCP FRCPE FBPhS FAACT FEAPCCT is Honorary Professor in Clinical Toxicology at the University of Edinburgh. Formerly he was Consultant Physician and Director of the National Poisons Information Service (Edinburgh Unit) at the Royal Infirmary, Edinburgh, UK. Competing interests: none declared.
MEDICINE --:-
1
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Dear JW, Bateman DN, Benzodiazepines, Medicine (2016), http://dx.doi.org/10.1016/j.mpmed.2015.12.025
Benzodiazepines
antagonist, can be given in carefully selected patients, usually to avoid the need for mechanical ventilation. Its efficacy is determined clinically from the improvement in consciousness level and respiration. Flumazenil is used more often than is justified by the severity of the poisoning and should be reserved for patients with coma, hypotension or respiratory depression who are known not to have epilepsy, and not to have ingested pro-convulsants concurrently.3,4 It should be used cautiously if patients are habituated to benzodiazepines, to avoid acute withdrawal. It has been reported to precipitate convulsions and cardiac arrhythmias when tricyclic antidepressants have been taken and a normal electrocardiogram is mandatory (i.e. no QRS or QT abnormality) before its use.5 Other pro-convulsants (e.g. cocaine, amfetamines) also present a risk since the use of flumazenil will make controlling convulsions due to another toxic agent more difficult. The usual use for flumazenil is in patients with obstructive airways disease, or possibly to avoid ventilation in a child (unlicensed use). UK experience indicates that flumazenil is generally safe if used cautiously in poisoning.6 Flumazenil has a short half-life (about 1 hour). Therefore, patients with severe poisoning in whom it is indicated may need repeated doses (0.5 milligrams intravenously over 1 minute), the same dose repeated if there is no response or only a partial response or an intravenous infusion of 0.5e2.0 mg/hour. Most patients poisoned with benzodiazepines will respond to flumazenil 1 milligram. Many benzodiazepines have long half-lives (e.g. diazepam, 36 hours) and can also have active metabolites with long half-lives (e.g. nordiazepam, about 100 hours), and although major functions return rapidly it can be several days before patients recover the ability to perform skilled tasks safely. Flumazenil can also be used in children, where it has proved beneficial in severe intoxication, although such cases are rare.7 A
James W Dear D Nicholas Bateman
Abstract Benzodiazepine compounds are rarely fatal if ingested alone but will potentiate central nervous system depression caused by coingested medication. Although an antagonist, flumazenil, is available, its use in overdose is associated with potential hazard, particularly the risk of precipitating convulsions or withdrawal if given in excess to those who have co-ingested a pro-convulsant, who take benzodiazepines regularly or who are known epileptic patients. Routine use in all cases is therefore not advised, and indications are restricted to patients who develop reduced ventilation and coma and who otherwise would require mechanical ventilation and have not ingested tricyclic antidepressants or other pro-convulsants, including cocaine.
Keywords Benzodiazepines; diazepam; flumazenil; zolpidem; zopiclone
Introduction Many benzodiazepine compounds are marketed; the main differences relate to their duration of action. Benzodiazepines and the related non-benzodiazepine hypnotic agents (zaleplon, zopiclone, zolpidem) are often taken in overdose with other central nervous system (CNS) depressants or ethanol, and potentiate the respiratory depressant effects of the co-ingestants. Combination with opioids appears to be particularly hazardous. However, co-ingestion of benzodiazepines can prevent convulsions induced by other agents taken in a mixed overdose. For this reason, routine use of benzodiazepine antagonists in poisoning as a ‘diagnostic test’ is not recommended.
Clinical features
REFERENCES 1 Gaudreault P, Guay J, Thivierge RL, Verdy I. Benzodiazepine poisoning. Clinical and pharmacological considerations and treatment. Drug Saf 1991; 6: 247e65. 2 Hojer J, Baechrendtz S, Gustafsson L. Benzodiazepines poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med 1989; 226: 117e22. 3 Kulka PJ, Lauven PM. Benzodiazepine antagonists e an update of their role in the emergency care of overdose patients. Drug Saf 1992; 7: 381e6. 4 Weinbroum A, Rudick V, Sorkine P, et al. Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. Crit Care Med 1996; 24: 199e206. 5 Mordel A, Winkler E, Almog S, Tirosh M, Ezra D. Seizures after flumazenil administration in a case of combined benzodiazepine and tricyclic anti-depressant overdose. Crit Care Med 1992; 20: 1733e4. 6 Veiraiah A, Dyas J, Cooper G, Routledge PA, Thompson JP. Flumazenil use in benzodiazepine overdose in the UK: a retrospective survey of NPIS data. Emerg Med J 2012; 29: 565e9. 7 Wiley CC, Wiley 2nd JF. Pediatric benzodiazepine ingestion resulting in hospitalization. J Toxicol Clin Toxicol 1998; 36: 227e31.
When taken alone in overdose, all benzodiazepines produce similar clinical features (drowsiness, dizziness, ataxia, dysarthria, nystagmus); less commonly, coma and hypotension develop.1,2 Respiratory depression is a potential complication, particularly when opioids, ethanol and other CNS depressants have also been ingested, and may require special attention when the patient has pre-existing chronic obstructive pulmonary disease.
Management Generally, the only management required is careful nursing and supportive care. Flumazenil, a specific benzodiazepine James W Dear PhD FRCPE is a Senior Clinical Lecturer and Consultant in Clinical Pharmacology at the University of Edinburgh, UK. Competing interests: none declared. D Nicholas Bateman MD FRCP FRCPE FBPhS FAACT FEAPCCT is Honorary Professor in Clinical Toxicology at the University of Edinburgh. Formerly he was Consultant Physician and Director of the National Poisons Information Service (Edinburgh Unit) at the Royal Infirmary, Edinburgh, UK. Competing interests: none declared.
MEDICINE --:-
1
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Dear JW, Bateman DN, Benzodiazepines, Medicine (2016), http://dx.doi.org/10.1016/j.mpmed.2015.12.025