Mechanism of Action of Phenobarbital
Phenobarbital works primarily by enhancing and prolonging the inhibitory effects of gamma-aminobutyric acid (GABA) at GABA-A receptors, and at higher concentrations, directly activating these receptors to produce CNS depression and anticonvulsant effects. 1, 2
Primary Mechanism: GABA-A Receptor Modulation
Phenobarbital acts as a positive allosteric modulator of GABA-A receptors through several distinct mechanisms:
Prolongs channel opening time: Phenobarbital increases the mean open time of GABA-A receptor chloride channels without altering the frequency of channel openings 3
Increases burst duration: Unlike benzodiazepines (which increase burst frequency), phenobarbital specifically increases the duration of bursting GABA receptor currents by stabilizing the open state of the chloride channel 3
Binding site: The drug binds to a modulatory site distinct from the benzodiazepine binding site, likely involving the second and third transmembrane domains of the β subunit, particularly around β-subunit methionine 286 and α-subunit methionine 236 2
Increases channel-opening equilibrium: Phenobarbital increases the channel-opening equilibrium constant (φ₋₁ = k_op/k_cl) by decreasing the channel-closing rate constant (k_cl) approximately 8-fold while changing the channel-opening rate constant (k_op) by less than 2-fold 4
Direct Receptor Activation
At higher (anesthetic) concentrations, phenobarbital can directly activate GABA-A receptors independent of GABA binding, producing deeper levels of CNS depression 1, 2
Additional Mechanisms Contributing to Anticonvulsant Activity
Beyond GABA-A receptor modulation, phenobarbital has several other important mechanisms:
Glutamate antagonism: Blocks AMPA/kainate receptors, reducing excitatory neurotransmission 2
Calcium channel inhibition: Inhibits glutamate release through effects on P/Q-type high-voltage activated calcium channels 2
Selective anticonvulsant effect: Phenobarbital has a unique selective anticonvulsant activity independent of its sedative effects, limiting seizure spread and raising the seizure threshold in generalized tonic-clonic epilepsy 1
CNS Depression Effects
The drug produces dose-dependent CNS depression through multiple pathways:
Depresses sensory cortex and decreases motor activity 1
Alters cerebellar function and produces drowsiness, sedation, and hypnosis 1
Respiratory depression: Acts directly on the medullary respiratory center, diminishing sensitivity to carbon dioxide in a dose-dependent manner 1
Pharmacokinetic Properties Affecting Mechanism
Low lipid solubility: Phenobarbital has the lowest lipid solubility among barbiturates, resulting in slower penetration across the blood-brain barrier and delayed onset (15 minutes or more for maximal CNS depression after IV administration) 1
Protein binding: Only 20-45% protein bound, allowing more free drug to be available at receptor sites 1
Hepatic metabolism: Metabolized primarily by CYP2C9 (with minor contributions from CYP2C19 and CYP2E1), and induces hepatic microsomal enzymes, affecting metabolism of other drugs 5, 6
Important Clinical Caveat
A critical limitation exists in neonatal seizures: After recurrent seizures, neuronal chloride accumulation occurs due to downregulation of the potassium-chloride cotransporter 2 (KCC2) and upregulation of sodium-potassium-chloride cotransporter 1 (NKCC1), causing GABA to become excitatory rather than inhibitory 7. In this context, phenobarbital can paradoxically aggravate seizures when applied after many ictal events have already occurred, as it enhances the now-excitatory actions of GABA 7. This underscores the importance of rapid treatment of severe neonatal seizures before secondary epileptogenesis develops 7.