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Toxicity, Benzodiazepine
Updated: Jan 28, 2010
Introduction
Background
Benzodiazepines (BZDs) are sedative-hypnotic agents that were first introduced in 1960. BZDs commonly are used for a variety of situations that include seizure control, anxiety, alcohol withdrawal, insomnia, control of drug-associated agitation, as muscle relaxants, and as preanesthetic agents. They also are combined frequently with other medications for procedural sedation.
Because of their widespread use, these drugs have propensity for abuse. In addition, benzodiazepines frequently are used in overdose, either alone or in association with other substances.
Pathophysiology
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. Benzodiazepines (BZD) exert their action by potentiating the activity of GABA. They bind to a specific receptor on the GABA A receptor complex, which facilitates the binding of GABA to its specific receptor site. BZD binding causes increased frequency of opening of the chloride channel complexed with the GABA A receptor. Chloride channel opening results in membrane hyperpolarization, which inhibits cellular excitation.
Enhanced GABA neurotransmission results in sedation, striated muscle relaxation, anxiolysis, and anticonvulsant effects. Stimulation of peripheral nervous system (PNS) GABA receptors may cause decreased cardiac contractility and vasodilation. These changes could have the potential to alter tissue perfusion.
The rate of BZD onset of action is determined by its ability to cross the blood-brain barrier. The relatively lipophilic BZDs usually produce a faster onset of effect than the relatively water-soluble BZDs. BZD effects can be potentiated when ethanol is present as coingestant. Peak blood concentrations of most agents occur within 1-3 hours. After a single dose, the lipophilic agents can have a shorter duration of action (shorter CNS effect) than water-soluble agents because rapid redistribution from the CNS to peripheral sites (eg, adipose tissue); thus, lorazepam (water soluble) has a longer CNS duration of action than diazepam (lipophilic). However, diazepam metabolizes to active intermediates with prolonged half-life extending its therapeutic effects.
BZDs are metabolized predominantly in the liver by oxidation and/or conjugation. Most BZDs are broken down into pharmacologically active metabolites, which may have longer half-lives than the parent compounds.
Frequency
United States
In 2008, a total of 78,443 benzodiazepine single-substance exposures were reported to US poison control centers, of which 332 (0.004%) resulted in major toxicity and 8 (0.0001%) resulted in death.1
International
In the 1980s, an overall rate of 5.9 fatalities per million prescriptions for BZDs occurred in Great Britain, while exposure to temazepam and flurazepam was associated with the most toxic effects.2
Mortality/Morbidity
Benzodiazepines (BZDs) generally are thought to be safe and death is rare.
- Mortality and morbidity from a pure oral BZD overdose is rare; it usually occurs in conjunction with concomitant alcohol ingestion or use of other sedative-hypnotics.
- Intravenous administration or overdose of ultrashort-acting BZDs (eg, triazolam [Halcion]) is more likely to result in apnea and death. Elderly individuals and very young persons are more susceptible to the CNS depressant effects of BZDs than people in other age groups.
- Intravenous administration is associated with greater degrees of hypotension than other routes of administration and occasional cardiac and respiratory arrest.
Age
The most reported BZD use is in persons older than 19 years.
Clinical
History
History should include the time, dose, and intent of the overdose. Determine if co-ingestants are present and the duration of benzodiazepine (BZD) use.
- Dizziness
- Confusion
- Drowsiness
- Blurred vision
- Unresponsiveness
- Anxiety
- Agitation
Physical
Focus the physical examination on the patient's vital signs, cardiorespiratory and neurologic function. "Classic" isolated BZD overdose presents as coma with normal vital signs.
- Nystagmus
- Hallucinations
- Slurred speech
- Ataxia
- Coma
- Hypotonia
- Weakness
- Altered mental status, impairment of cognition
- Amnesia
- Paradoxical agitation
- Respiratory depression
- Hypotension
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References
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Serfaty M, Masterton G. Fatal poisonings attributed to benzodiazepines in Britain during the 1980s. Br J Psychiatry. Sep 1993;163:386-93. [Medline].
[Guideline] Kleber HD, Weiss RD, Anton RF, et al. Treatment of patients with substance use disorders, second edition. American Psychiatric Association. Am J Psychiatry. Aug 2006;163(8 Suppl):5-82. [Medline]. [Full Text].
[Guideline] National Collaborating Centre for Mental Health. Self-harm: the short-term physical and psychological management and secondary prevention of self-harm in primary and secondary care. London (UK): National Institute for Clinical Excellence (NICE). 2004;199. [Full Text].
Bosse GM. Benzodiazepines. In: Emergency Medicine: A Comprehensive Study Guide. 4th ed. McGraw-Hill; 1996:759-61.
Buckley NA, Dawson AH, Whyte IM, O'Connell DL. Relative toxicity of benzodiazepines in overdose. BMJ. Jan 28 1995;310(6974):219-21. [Medline].
Cairns C. Benzodiazepine overdose and withdrawal. In: Emergency Medicine: Concepts and Clinical Practice. 3rd ed. Mosby-Year Book; 1992:2684-9.
Drummer OH, Syrjanen ML, Cordner SM. Deaths involving the benzodiazepine flunitrazepam. Am J Forensic Med Pathol. Sep 1993;14(3):238-43. [Medline].
Hoffman RS, Wipfler MG, Maddaloni MA, Weisman RS. Has the New York State triplicate benzodiazepine prescription regulation influenced sedative-hypnotic overdoses?. N Y State J Med. Oct 1991;91(10):436-9. [Medline].
Longmire AW, Seger DL. Topics in clinical pharmacology: flumazenil, a benzodiazepine antagonist. Am J Med Sci. Jul 1993;306(1):49-52. [Medline].
Mullins ME. First-degree atrioventricular block in alprazolam overdose reversed by flumazenil. J Pharm Pharmacol. Mar 1999;51(3):367-70. [Medline].
Verghese J, Merino J. Temazepam overdose associated with bullous eruptions. Acad Emerg Med. Oct 1999;6(10):1071. [Medline].
Further Reading
Keywords
BZD toxicity, sedative-hypnotic toxicity, benzodiazepine toxicity, benzodiazepine treatment, flumazenil, benzodiazepine exposure, BZD exposure, seizure control, anxiety, alcohol withdrawal, alprazolam, flunitrazepam, chlordiazepoxide, diazepam, triazolam, temazepam, flurazepam, bromazepam, clorazepate, oxazepam, nitrazepam, alprazolam, lormetazepam, lorazepam, benzodiazepine overdose
