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 popularity, these drugs commonly are abused. In addition, BZDs 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. BZDs 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, vasodilation, and enhanced perfusion.
The rate of BZD onset of action is determined by rate of BZD absorption from the GI tract. The relatively lipophilic BZDs usually are absorbed more rapidly and produce a faster onset of effect than the relatively water-soluble BZDs. BZD absorption is especially rapid when ethanol is present and the stomach is empty. Peak blood concentrations of most agents occur within 1-3 hours. After a single dose, the lipophilic agents 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).
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 2005, a total of 67,593 BZD exposures were reported to US poison control centers, of which 3018 (0.04%) resulted in major toxicity and 243 (0.003%) resulted in death. From 1995-2002, the frequency of ED visits involving BZD increased by 41%.
International
In the 1980s, an overall rate of 5.9 fatalities per million prescriptions for BZDs occurred in Great Britain; temazepam and flurazepam appeared to be the most toxic.
Mortality/Morbidity
BZDs generally are thought to be safe and death is rare.
- Mortality from a pure 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 BZD use.
- Dizziness
- Confusion
- Drowsiness
- Blurred vision
- Unresponsiveness
- Anxiety
- Agitation
Physical
Focus the physical examination on the patient's vital signs and cardiorespiratory and neurologic function.
- 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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References
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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].
Lai MW, Klein-Schwartz W, Rodgers GC, Abrams JY, Haber DA, Bronstein AC. 2005 Annual Report of the American Association of Poison Control Centers' national poisoning and exposure database. Clin Toxicol (Phila). 2006;44(6-7):803-932. [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].
Watson WA, Litovitz TL, Rodgers GC Jr, Klein-Schwartz W, Reid N, Youniss J. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 2005;23(5):589-666. [Medline].
Further Reading
Keywords
BZD toxicity, sedative-hypnotic toxicity, benzodiazepine toxicity, benzodiazepine exposure, BZD exposure, seizure control, anxiety, alcohol withdrawal, insomnia, control of drug-associated agitation, muscle relaxants, preanesthetic agents, BZD overdose, nystagmus,hallucinations, slurred speech, ataxia, coma, hypotonia, altered mental status, impairment of cognition, amnesia, paradoxical agitation, respiratory depression, hypotension, alprazolam, flunitrazepam, chlordiazepoxide, diazepam, triazolam, temazepam, flurazepam, bromazepam, clorazepate, oxazepam, nitrazepam, loprazolam, lormetazepam, lorazepam, benzodiazepine overdose
