Question

By what mechanism do benzodiazepines reduce neuronal excitability?

Why is the combination of Valium and alcohol (or barbiturates) worse than taking Valium alone?

Answer 1

1. Benzodiazepines act on γ-aminobutyric acid or GABA receptors in the brain, GABA is the major inhibitory neuron in the central nervous system. When GABA binds to its receptor, it triggers an opening of the chloride ion channel which allows inward movement of chloride ions through it. Influx of chloride ions causes hyperpolarization of the neuron and decrease neurotransmission by inhibiting the formation of action potential. Benzodiazepines potentiate the effect of GABA by binding themselves to a high affinity site on the GABA receptor (two such receptors are BZ1 and BZ2 receptors) and increasing the affinity of GABA for its binding sites. Benzodiazepines increase the frequency of channel opening caused by GABA. This results in reduced excitability and sedative and hypnotic effect of benzodiazepines. Alcohol and other CNS depressants enhance sedative effect of benzodiazepines (resulting in severe drowsiness) by increasing their plasma half-life. Benzodiazepines are metabolized by hepatic microsomal enzymes (CYP3A4) to compounds that are metabolically active. The half-life of drug represents the combined action of parent drug and metabolites. Patient with impaired liver function also experience more than usual sedative effect at normal dosage 2.