Etiology
Benzodiazepines are the most commonly prescribed medications for anxiety, sedation, and sleep. Overdose can be intentional in suicidal patients; accidental in combination with other central nervous system depressants, such as alcohol and opioids, and in older people; and occasionally by medication error (patient administered or iatrogenic).
Pathophysiology
When ingested, benzodiazepines (BZDs) are well absorbed from the gastrointestinal tract and enter the bloodstream rapidly. Co-administration of alcohol increases the rate and extent of absorption while antacid preparations containing magnesium or aluminum 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 BZDs such as diazepam and more stable in less-lipophilic BZDs such as lorazepam. Counterintuitively, BZD half-life is not consistent with duration of action: diazepam has a long half-life but short duration of action, in contrast to lorazepam, which has a short half-life yet relatively longer peak duration of action.
In the serum, >70% of BZD is protein bound and is unavailable to produce a clinical effect. The unbound fraction crosses the blood-brain barrier and interacts with neuronal BZD receptors in the central nervous system (CNS). Patients who are elderly or debilitated, children, and patients with liver disease or low serum albumin are therefore at higher risk of overdose.
BZDs 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 BZD 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 generalized CNS depression.
BZDs may be directly active or have active metabolites, or both. BZDs are metabolized 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.
BZD overdose occurs when the drug effect is beyond that which is clinically desired; overdose is therefore not a quantitative amount or degree of effect, but rather a subjectively determined effect that is excessive. Mild sedation as a result of a suicide attempt is considered overdose, whereas a more profound sedation in a preoperative patient may be considered satisfactory. Overdose is determined as excess CNS sedation.
Because of the variability of effects, excess sedation as a result of BZDs 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. Other patients may have excess sedation because of individual factors, drug interaction, or comorbidity.
The cellular mechanisms underlying BZD 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 nonselective mGluR ligands on adenylate cyclase activity was diminished in mice that showed signs of BZD withdrawal. The mRNA expression levels of mGluR2 and mGluR3 were lowered in the cerebral cortex of mice pretreated with diazepam or alprazolam. Therefore, a reduction in the expression of group II mGluRs subunits may be involved in the development of BZD dependence.[15]
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