Diazepam (Valium)

Diazepam is a classical 1,4-benzodiazepine and a positive allosteric modulator of the GABA-A receptor, the brain's main inhibitory ion channel. It binds the benzodiazepine site at the interface between an α (α1/α2/α3/α5) and the γ2 subunit: a site distinct from where GABA itself binds. It has essentially no effect on its own. It only amplifies the receptor's response to GABA that is already present. By increasing the affinity of the receptor for GABA it raises the frequency of chloride-channel opening (benzodiazepines increase opening frequency, whereas barbiturates prolong opening duration). The greater Cl⁻ influx hyperpolarises the neuron and lowers its excitability, producing dose-dependent anxiolysis, sedation, anterograde amnesia, muscle relaxation and anticonvulsant activity. These actions map onto specific α subunits: α1-containing receptors mediate sedation and much of the amnestic and anticonvulsant effect, while α2/α3 mediate anxiolysis and muscle relaxation. Diazepam is non-selective across α1/α2/α3/α5, which is why it is simultaneously sedating, anxiolytic, myorelaxant and anticonvulsant. Its clinical action is prolonged by long-lived active metabolites, chiefly desmethyldiazepam (nordazepam), with temazepam and oxazepam, which are themselves GABA-A modulators. Repeated use causes tolerance and physical dependence through receptor down-regulation and uncoupling, so abrupt discontinuation can precipitate a withdrawal syndrome including rebound anxiety and seizures.