The principal mechanism of action of barbiturates is believed to be their affinity for the GABAA receptor (Acts on GABA : BDZ receptor Cl- channel complex). GABA is the principal inhibitory neurotransmitter in the mammalian central nervous system (CNS). Barbiturates bind to the GABAA receptor at the alpha subunit, which are binding sites distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABA-ergic effect, barbiturates also block the AMPA receptor, a subtype of glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABAA receptors and inhibit excitatory AMPA receptors can explain the CNS-depressant effects of these agents. At higher concentration they inhibit the Ca2+-dependent release of neurotransmitters.
Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABAA receptor (pharmacodynamics: this increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABAA receptor (pharmacodynamics: this increases the potency of GABA). The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in overdose.
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