Benzodiazepines - Function



Benzodiazepines are drugs used to treat a variety of conditions, such as generalized seizures, alcohol withdrawal, eclampsia, and anxiety. They work by increasing GABA activity, specifically by increasing the frequency of chloride channel opening in response to binding of GABA to GABA-A channels in the brain. Benzodiazepines are first-line treatments for generalized seizures, status epilepticus, and all types of alcohol withdrawal.  Benzodiazepines are used second-line for treating eclampsia in pregnant women, and may also be used to treat anxiety disorders. Due to their sedative effects, benzodiazepines are also used to treat insomnia and to induce anesthesia. Notably, this sedating effect comes from CNS  nervous depression, which can cause respiratory depression that can be fatal  without ventilatory support. Another side effect to look out for is tolerance or dependence over time. Importantly, an overdose of benzodiazepines can be reversed with the drug, flumazenil.

Key Points

  • Benzodiazepines
    • Mechanism
      • Facilitate GABAA action by increasing frequency of Cl- channel opening
        • Thus ↓ neuron firing
        • Increased influx of negatively charged chloride ions in response to GABA binding →  leads to hyperpolarization of the postsynaptic neuron and suppression of action potential firing (anticonvulsant effect).
        • As opposed to increasing the duration of Cl- channel opening which is the mechanism of benzodiazepines
    • Indications
      • Status epilepticus (acute seizures)
        • IV lorazepam is 1st line
        • High efficacy and rapid onset of action for acute seizures
      • Alcohol/benzo withdrawal (delirium tremens)
        • Lorazepam and diazepam are both 1st line agents
        • Lorazepam preferred in severe liver disease (no active metabolites)
          • Diazepam has active liver metabolites, which can accumulate and cause toxicity
      • Eclampsia
        • IV diazepam is 2nd line after MgSO4
      • Hypnotic
        • May be used for treatment of insomnia
          • Note: decreases REM sleep
        • Midazolam used to induce general anesthesia
      • Generalized Anxiety (with diazepam use)
      • Night terrors, sleepwalking (with diazepam use)
    • Adverse Effects
      • CNS depression (sedation)
        • Should be avoided in elderly (fall risk), or patients taking other sedative drugs (barbiturates, alcohol, neuroleptics, 1st-generation antihistamines) due to additive effects
      • Respiratory depression
        • Less risk than barbiturates
        • Via suppression of medullary breathing centers
      • Tolerance/dependence
        • May induce withdrawal syndrome similar to alcohol withdrawal (e.g. seizures)
        • Especially with rapid-acting benzos; quick onset but short duration increases withdrawal symptoms and increases abuse potential
    • Reversal
      • Reverse overdose with flumazenil