Update on the mechanism of action of antiepileptic drugs.
Novel antiepileptic drugs (AEDs) are thought to act on voltage-sensitive ion channels, on inhibitory neurotransmission or on excitatory neurotransmission. Two successful examples of rational AED design that potentiate GABA-mediated inhibition are vigabatrin (VGB) by irreversible inhibition of GABA-transaminase, and tiagabine (TGB) by blocking GABA uptake. Lamotrigine (LTG) prolongs inactivation of voltage-dependent sodium channels. The anticonvulsant action of remacemide (RCM) is probably largely due to blockade of NMDA receptors and prolonged inactivation of sodium channels induced by its desglycinated metabolite. Felbamate (FBM) apparently blocks NMDA receptors, potentiates GABA-mediated responses, blocks L-type calcium channels, and possibly also prolongs sodium channel inactivation. Similarly, topiramate (TPM) has multiple probable sites of action, including sodium channels, GABA receptors, and glutamate (AMPA) receptors. Gabapentin (GBP) apparently has a completely novel type of action, probably involving potentiation of GABA-mediated inhibition and possibly also inactivation of sodium channels. The therapeutic advantages of the novel AEDs are as yet only partially explained by our present understanding of their mechanisms of action.
Meldrum
B S
BS
Department of Neurology, University of London, England.
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use; D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use; D000588:Amines; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D003509:Cyclohexanecarboxylic Acids; D004827:Epilepsy / Q000188:drug therapy*; D000078328:Felbamate; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000077206:Gabapentin; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D000077213:Lamotrigine; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018377:Neurotransmitter Agents / Q000502:physiology; D009557:Nipecotic Acids / Q000494:pharmacology / Q000627:therapeutic use; D010627:Phenethylamines / Q000494:pharmacology / Q000627:therapeutic use; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D000078308:Tiagabine; D000077236:Topiramate; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D000081:Acetamides; D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D007473:Ion Channels; D018377:Neurotransmitter Agents; D009557:Nipecotic Acids; D010627:Phenethylamines; D048448:Phenylcarbamates; D011409:Propylene Glycols; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D000077236:Topiramate; C089135:FPL 12495; D005632:Fructose; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000612:4-Aminobutyrate Transaminase; C067553:remacemide; D020888:Vigabatrin; D000077213:Lamotrigine; D000078328:Felbamate; D000078308:Tiagabine