title: Antiepileptic drug mechanisms of action.
abstract: Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium channels, gamma-aminobutyric acid type A (GABAA) receptors, or calcium channels. Benzodiazepines and barbiturates enhance GABAA receptor-mediated inhibition. Phenytoin (PHT), carbamazepine (CBZ), and possibly valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing sodium-channel inactivation. Ethosuximide (ESM) and VPA reduce a low threshold (T-type) calcium-channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin (GBP) binds to a high-affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of GBP into neurons; however, this has not been proven, and the mechanism of action of GBP remains uncertain. Lamotrigine (LTG) decreases sustained high-frequency repetitive firing of voltage-dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. The mechanism of action of oxcarbazepine (OCBZ) is not known; however, its similarity in structure and clinical efficacy to CBZ suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin (VGB) irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underline the clinical efficacy of VGB.
authors.affiliation: Department of Neurology, University of Michigan Medical Center, Ann Arbor, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Macdonald
authors.forename: K M
authors.initials: KM
authors.lastname: Kelly
mesh_terms: D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use; D000200:Action Potentials / Q000187:drug effects; D000588:Amines; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001463:Barbiturates / Q000494:pharmacology / Q000627:therapeutic use; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D015220:Calcium Channels / Q000187:drug effects; D002220:Carbamazepine / Q000494:pharmacology / Q000627:therapeutic use; D002490:Central Nervous System / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids; D004827:Epilepsy / Q000188:drug therapy; D000077206:Gabapentin; D006801:Humans; D007473:Ion Channels / Q000187:drug effects*; D000077213:Lamotrigine; D010672:Phenytoin / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D015222:Sodium Channels / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use; D014293:Trimethadione / Q000494:pharmacology / Q000627:therapeutic use; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D001463:Barbiturates; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D007473:Ion Channels; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D015222:Sodium Channels; D014227:Triazines; D001569:Benzodiazepines; D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D010672:Phenytoin; D000077206:Gabapentin; D020888:Vigabatrin; D014293:Trimethadione; D000077213:Lamotrigine