Cardenal - Mechanism of Action

Mechanism of Action

GABA_A receptors are the primary target for barbiturates in the central nervous system. As is the case for other clinically important barbiturates, phenobarbital prolongs and potentiates the action of GABA on GABA_A receptors and at higher concentrations directly activates the receptors. In contrast to anesthetic barbitruates such as pentobarbital, phenobarbital is minimally sedating at effective anticonvulsant doses. Possible explanations for the reduced sedative effect of phenobarbital include more regionally restricted action; partial agonist activity; reduced propensity to directly activate GABA_A receptors (possibly including extrasynaptic receptors containing δ subunits); and reduced activity at other ion channel targets, including voltage-gated calcium channels. Although the precise sites where barbiturates interact with GABA_A receptors has not been defined, the second and third transmembrane domains of the β subunit appear to be critical; binding may involve a pocket formed by β-subunit methionine 286 as well as α-subunit methionine 236. In addition to effects on GABA_A receptors, barbiturates block AMPA receptors, and they inhibit glutamate release through an effect on P/Q-type high-voltage activated calcium channels. The combination of these various actions likely accounts for their diverse clinical activities.