Mechanisms of Antiepileptic Drugs.
- Author:
Jae Moon KIM
1
Author Information
1. Department of Neurology, College of Medicine, Chungnam National University, Chungnam, Korea. jmoonkim@hanbat.chungnam.ac.kr
- Publication Type:Review
- Keywords:
Antiepileptic drugs;
Mechanism;
Ion channel;
Neurotransmitters
- MeSH:
4-Aminobutyrate Transaminase;
Action Potentials;
Amino Acids;
Anticonvulsants*;
Barbiturates;
Benzodiazepines;
Binding Sites;
Biological Transport, Active;
Butyric Acid;
Calcium Channels;
Calcium Channels, T-Type;
Carbamazepine;
Chloride Channels;
Ethosuximide;
Excitatory Amino Acids;
Fires;
gamma-Aminobutyric Acid;
Glutamic Acid;
Ion Channels;
Membranes;
Neuroglia;
Neurons;
Neurotransmitter Agents;
Norepinephrine;
Phenytoin;
Receptors, GABA;
Receptors, GABA-A;
Receptors, Neurotransmitter;
Receptors, Purinergic P1;
Sodium;
Sodium Channels;
Synapses;
Valproic Acid;
Vigabatrin
- From:Journal of Korean Epilepsy Society
2000;4(2):108-118
- CountryRepublic of Korea
- Language:Korean
-
Abstract:
Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed prior to 1980 appear to act on sodium channels, gamma-amino butyric acid type A (GABA(A)) receptors or calcium channels. Benzodiazepines and barbiturates enhance GABA(A) receptormediated inhibition. Barbiturates increase the duration of chloride channel opening and at higher doses, they block voltage-dependent calcium channels presynaptically, decreasing excitatory amino acid (EAAs) transmission. Benzodiazepines also interact with the GABA(A) receptor complex and increase the frequency of chloride channel opening. Phenytoin, carbamazepine and possibly sodium valproate decrease high frequency repetitive firing of action potentials by enhancing sodium channel inactivation. At higher doses, PHT may block sodium channels presynaptically and decrease EAAs release. In addition to the action on sodium channel, CBZ interacts with adenosine receptor and decrease C-AMP, and block reuptake of norepinephrine. VPA shows diverse mechanisms including sodium channel blocking. It increases synaptosomal GABA by increasing production and decreasing break-down and interacts with T-type calcium channels preventing thalamocortical interaction necessary for absence. Ethosuximide and sodium valproate reduce a low threshold (T-type) calcium channel current. The mechanisms of action of newly developed AEDs are not fully established. Felbamate is broad-spectrum, and probably has multiple actions on sodium channels, interaction with GABA(A) receptors, and interaction with NM.D.A receptors. Gabapentin binds to a high affinity site on neuronal membranes in a restricted regional distribution of the CNS. This binding site may be related to a possible active transport process of gabapentin into neurons. However this has not proven and the mechanism of action of gabapentin remains uncertain. It is structurally related to GABA and its action of antiepileptic activity is suspected due to change of neuronal amino acids (interfere glutamate synthesis, block GABA uptake, and enhance GABA release). Lamotrigine, initially developed as an antifolate drug, decreases sustained high frequency repetitive firing of voltage-dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. It may also interact with GABA receptors but its primary antiepileptic action is on the sodium channel similar to the PHT and CBZ. Because of such a diverse mechanism of action, LTG is one of the wide spectrum AEDs. Oxcarbazepine's mechanism of action is not known ; however, its similarity in structure and clinical efficacy to that of carbamazepine suggests that its mechanism of action may involve inhibition of sustained high frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin is a "designer" drug as is developed rationally, and it reversibly 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 underlie the clinical efficacy of VGB. Tiagabine is a potent blocker of GABA re-uptake by glia and neuron.
