Aetiology
Benzodiazepines are most commonly prescribed for anxiety, sedation, and sleep. Overdose can be intentional as an act of self-harm, through recreational misuse, or accidental (such as a medication error). The effects of benzodiazepine overdose may be potentiated if ingested in combination with other central nervous system depressants, such as alcohol and opioids.
Pathophysiology
When ingested, benzodiazepines are well absorbed from the gastrointestinal tract and enter the bloodstream rapidly. Co-administration of alcohol increases absorption while antacid preparations containing magnesium or aluminium will reduce and delay absorption. Lorazepam is often given by sublingual administration, reaching peak levels within 60 minutes. Intramuscular injection (IM) is more variable in the onset of clinical effects. IM absorption is more erratic with highly lipophilic benzodiazepines such as diazepam and more stable in less-lipophilic benzodiazepines such as lorazepam. Peak plasma concentration of diazepam is reached in approximately 1 hour with a half-life of around 24 to 48 hours. By contrast, the half-life of lorazepam is around 12 to 16 hours.[18]
In the serum, >70% of benzodiazepine is protein bound and is unavailable to produce a clinical effect. The unbound fraction crosses the blood-brain barrier and interacts with neuronal benzodiazepine receptors in the central nervous system (CNS). Elderly patients and those with liver disease or hypoalbuminaemia are therefore potentially at higher risk of toxicity.
Benzodiazepines enhance the activity of the inhibitory neurotransmitter gamma-aminobenzoic acid (GABA) in the CNS. GABA receptors are located on postsynaptic neurons. The binding of a benzodiazepine molecule to a site on the GABA receptor complex potentiates the inhibitory effect of GABA. The clinical effects depend on the location of GABA neurons in the CNS and include sleep induction, excitement inhibition, anxiolysis, other sedative/hypnotic and antiseizure action, and generalised CNS depression.
Benzodiazepines may be directly active or have active metabolites, or both. Benzodiazepines are metabolised by demethylation or conjugation with glucuronide, or are hydroxylated in the liver. Some of the active metabolites have a longer half-life than the parent compound. In general, those with active metabolites have a longer duration of clinical effects.
Benzodiazepine overdose occurs when the drug effect is beyond that which is clinically desired; the clinical effect of overdose is therefore not a quantitative amount or degree of effect, but rather a subjectively determined effect that is excessive.
Because of the variability of effects, excess sedation as a result of benzodiazepines can manifest in various ways, including respiratory depression, coma, and death. Overdose, even with excess sedation, is not determined by quantitative assay in blood or urine; tolerant patients may have unusually high assays, yet show little effect.
The cellular mechanisms underlying benzodiazepine dependence have not been fully elucidated. Metabotropic glutamate receptors (mGluRs) have been shown to be involved in the pathophysiology of dependence and withdrawal. The inhibitory effect of non-selective mGluR ligands on adenylate cyclase activity was diminished in mice that showed signs of benzodiazepine withdrawal. The mRNA expression levels of mGluR2 and mGluR3 were lowered in the cerebral cortex of mice pre-treated with diazepam or alprazolam. Therefore, a reduction in the expression of group II mGluRs sub-units may be involved in the development of benzodiazepine dependence.[19]
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