How does phenobarbital enhance GABAergic transmission at the GABA-A receptor, and how does this differ mechanistically from diazepam?

• A Phenobarbital increases the frequency of chloride channel opening; diazepam increases its duration
• B Phenobarbital acts as a direct GABA mimetic at the receptor site; diazepam blocks GABA reuptake
• C Both act solely by increasing the frequency of channel opening
• D Phenobarbital increases the duration of chloride channel opening; diazepam increases its frequency ✓

Explanation

Barbiturates bind at a distinct site on the GABA-A chloride channel complex and prolong the duration of each opening burst, whereas benzodiazepines bind to a gamma-subunit interface site and increase the frequency of channel opening. At high concentrations barbiturates can open the channel directly even without GABA, explaining their capacity to cause anaesthesia and respiratory depression, unlike benzodiazepines.

Reference: Katzung Basic and Clinical Pharmacology, 15th ed.

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