Antiepileptic Drug Mechanisms of Action

Summary: 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, γ‐ami‐nobutyric 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 underlie the clinical efficacy of VGB.

[1]  B. Wilder.  How About the New Antiepileptic Drugs? , 1994, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[2]  D. Welty,et al.  Gabapentin anticonvulsant action in rats: disequilibrium with peak drug concentrations in plasma and brain microdialysate , 1993, Epilepsy Research.

[3]  R. Macdonald,et al.  Gabapentin actions on ligand- and voltage-gated responses in cultured rodent neurons , 1993, Epilepsy Research.

[4]  M. Leach,et al.  Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neuroglial cultures from rat cortex , 1993, Brain Research.

[5]  S. Vincent,et al.  Structure and functional expression of a member of the low voltage-activated calcium channel family. , 1993, Science.

[6]  J. Nakai,et al.  Primary structure and functional expression of the ω-conotoxin-sensitive N-type calcium channel from rabbit brain , 1993, Neuron.

[7]  G. Woodruff,et al.  Localization of [3H]gabapentin to a novel site in rat brain: autoradiographic studies. , 1993, European journal of pharmacology.

[8]  G. Woodruff,et al.  Characterisation of [3H]gabapentin binding to a novel site in rat brain: homogenate binding studies. , 1993, European journal of pharmacology.

[9]  C. Bigge,et al.  Potent and stereospecific anticonvulsant activity of 3-isobutyl GABA relates to in vitro binding at a novel site labeled by tritiated gabapentin , 1993, Epilepsy Research.

[10]  H. Kubová,et al.  Anticonvulsant Action of Oxcarbazepine, Hydroxycarbamazepine, and Carbamazepine Against Metrazol‐Induced Motor Seizures in Developing Rats , 1993, Epilepsia.

[11]  E. Harris,et al.  An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels , 1992, Epilepsy Research.

[12]  R. Olsen,et al.  Gamma-aminobutyric acidA receptor structure and function. , 1992, The Journal of biological chemistry.

[13]  Michael E. Adams,et al.  P-type calcium channels in rat central and peripheral neurons , 1992, Neuron.

[14]  W Wisden,et al.  The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[15]  D. Laurie,et al.  The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[16]  Mark E. Williams,et al.  Structure and functional expression of α 1, α 2, and β subunits of a novel human neuronal calcium channel subtype , 1992, Neuron.

[17]  I. Martin,et al.  Multiple benzodiazepine receptors: no reason for anxiety. , 1992, Trends in pharmacological sciences.

[18]  F. Pisani.  New Antiepileptic Drugs , 1991 .

[19]  P. Seeburg,et al.  Cloning, pharmacological characteristics and expression pattern of the rat GABAA receptor α4 subunit , 1991, FEBS letters.

[20]  R. Sofia,et al.  Interaction of felbamate and diazepam against maximal electroshock seizures and chemoconvulsants in mice , 1991, Pharmacology Biochemistry and Behavior.

[21]  W. Löscher,et al.  Gabapentin increases aminooxyacetic acid-induced GABA accumulation in several regions of rat brain , 1991, Neuroscience Letters.

[22]  T. Snutch,et al.  Distinct calcium channels are generated by alternative splicing and are differentially expressed in the mammalian CNS , 1991, Neuron.

[23]  P. Ellinor,et al.  Molecular cloning of multiple subtypes of a novel rat brain isoform of the α 1 subunit of the voltage-dependent calcium channel , 1991, Neuron.

[24]  T. Snutch,et al.  Primary structure of a calcium channel that is highly expressed in the rat cerebellum. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[25]  R. Sofia,et al.  Effect of Anticonvulsant Felbamate on GABAA Receptor System , 1991, Epilepsia.

[26]  J. Nakai,et al.  Primary structure and functional expression from complementary DNA of a brain calcium channel , 1991, Nature.

[27]  G. Fromm,et al.  Comparison of gabapentin with other antiepileptic and GABAergic drugs , 1991, Epilepsy Research.

[28]  S. Antonarakis,et al.  Cloning of the gamma-aminobutyric acid (GABA) rho 1 cDNA: a GABA receptor subunit highly expressed in the retina. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[29]  A. Richens.  New antiepileptic drugs. , 1990, British journal of hospital medicine.

[30]  M A Rogawski,et al.  Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. , 1990, Pharmacological reviews.

[31]  R. Gross,et al.  Valproic acid selectively reduces the low-threshold (T) calcium current in rat nodose neurons , 1990, Neuroscience Letters.

[32]  D. Prince,et al.  Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction , 1990, British journal of pharmacology.

[33]  N. Porter,et al.  Cloned GABA receptors are maintained in a stable cell line: allosteric and channel properties. , 1990, European journal of pharmacology.

[34]  B. Sakmann,et al.  Functional properties of recombinant rat GABAA receptors depend upon subunit composition , 1990, Neuron.

[35]  P. Seeburg,et al.  γ‐Aminobutyric AcidA Receptor α5‐Subunit Creates Novel Type II Benzodiazepine Receptor Pharmacology , 1990 .

[36]  H. Lester,et al.  Rat brain expresses a heterogeneous family of calcium channels. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[37]  R. Twyman,et al.  Intraburst kinetic properties of the GABAA receptor main conductance state of mouse spinal cord neurones in culture. , 1990, The Journal of physiology.

[38]  R. Twyman,et al.  Barbiturate regulation of kinetic properties of the GABAA receptor channel of mouse spinal neurones in culture. , 1989, The Journal of physiology.

[39]  P. Seeburg,et al.  Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. , 1989, Science.

[40]  E. Ben-Menachem.  Pharmacokinetic Effects of Vigabatrin on Cerebrospinal Fluid Amino Acids in Humans , 1989, Epilepsia.

[41]  P. Seeburg,et al.  Two novel GABAA receptor subunits exist in distinct neuronal subpopulations , 1989, Neuron.

[42]  T. Halonen,et al.  Specificity of Vigabatrin for the GABAergic System in Human Epilepsy , 1989, Epilepsia.

[43]  N. Akaike,et al.  Effects of chlordiazepoxide, chlorpromazine, diazepam, diphenylhydantoin, flunitrazepam and haloperidol on the voltage-dependent sodium current of isolated mammalian brain neurons , 1989, Brain Research.

[44]  D. Prince,et al.  Printed in Great Britain , 2005 .

[45]  J. Schwarz,et al.  Phenytoin and Carbamazepine: Potential‐ and Frequency‐Dependent Block of Na Currents in Mammalian Myelinated Nerve Fibers , 1989, Epilepsia.

[46]  D. Prince,et al.  Characterization of ethosuximide reduction of low‐threshold calcium current in thalamic neurons , 1989, Annals of neurology.

[47]  G. Tomaselli,et al.  Sodium channels from human brain RNA expressed in Xenopus oocytes. Basic electrophysiologic characteristics and their modification by diphenylhydantoin. , 1989, The Journal of clinical investigation.

[48]  P. Seeburg,et al.  Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology , 1989, Nature.

[49]  K. Magleby,et al.  Gating scheme for single GABA-activated Cl- channels determined from stability plots, dwell-time distributions, and adjacent-interval durations , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[50]  D. Prince,et al.  Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons , 1989, Neuroscience Letters.

[51]  R. Macdonald,et al.  Differential regulation of γ‐aminobutyric acid receptor channels by diazepam and phenobarbital , 1989 .

[52]  R. Twyman,et al.  Kinetic properties of the GABAA receptor main conductance state of mouse spinal cord neurones in culture. , 1989, The Journal of physiology.

[53]  R L Macdonald,et al.  Antiepileptic Drug Actions , 1989, Epilepsia.

[54]  E. Ben-Menachem,et al.  Effect of γ‐Vinyl GABA on Interictal Spikes and Sharp Waves in Patients with Intractable Complex Partial Seizures , 1989 .

[55]  K. Campbell,et al.  The biochemistry and molecular biology of the dihydropyridine-sensitive calcium channel , 1988, Trends in Neurosciences.

[56]  W. Catterall,et al.  Structure and function of voltage-sensitive ion channels. , 1988, Science.

[57]  R. Macdonald,et al.  Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. , 1988, The Journal of pharmacology and experimental therapeutics.

[58]  E. Costa,et al.  Actions of benzodiazepine and beta-carboline derivatives on gamma-aminobutyric acid-activated Cl- channels recorded from membrane patches of neonatal rat cortical neurons in culture. , 1987, The Journal of pharmacology and experimental therapeutics.

[59]  P. Seeburg,et al.  Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor super-family , 1987, Nature.

[60]  W. Löscher,et al.  Effect of microinjections of γ-vinyl GABA or isoniazid into substantia nigra on the development of amygdala kindling in rats , 1987, Experimental Neurology.

[61]  J. McNamara,et al.  Anti-seizure and anti-epileptogenic effect of γ-vinyl γ-aminobutyric acid in amygdaloid kindling , 1986, Brain Research.

[62]  M. Leach,et al.  Pharmacological Studies on Lamotrigine, A Novel Potential Antiepileptic Drug , 1986, Epilepsia.

[63]  R. Macdonald,et al.  Carbamazepine and 10,11-epoxycarbamazepine produce use- and voltage-dependent limitation of rapidly firing action potentials of mouse central neurons in cell culture. , 1986, The Journal of pharmacology and experimental therapeutics.

[64]  A. Schousboe,et al.  Differential effect of gamma-vinyl GABA and valproate on GABA-transaminase from cultured neurones and astrocytes , 1986, Neuropharmacology.

[65]  R. Macdonald,et al.  Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. , 1986, The Journal of pharmacology and experimental therapeutics.

[66]  R. Sofia,et al.  Comparative Anticonvulsant Activity and Neurotoxicity of Felbamate and Four Prototype Antiepileptic Drugs in Mice and Rats , 1986, Epilepsia.

[67]  W. Sieghart,et al.  Postnatal Development of Proteins Associated with Different Benzodiazepine Receptors , 1986, Journal of neurochemistry.

[68]  J. McNamara,et al.  Anti-seizure and anti-epileptogenic effect of gamma-vinyl gamma-aminobutyric acid in amygdaloid kindling. , 1986, Brain research.

[69]  R. Tsien,et al.  Three types of neuronal calcium channel with different calcium agonist sensitivity , 1985, Nature.

[70]  B. Tabakoff,et al.  The development of Type I and Type II benzodiazepine receptors in the mouse cortex and cerebellum , 1985, Pharmacology Biochemistry and Behavior.

[71]  E. Schlicker,et al.  Gabapentin decreases monoamine release without affecting acetylcholine release in the brain. , 1985, Arzneimittel-Forschung.

[72]  T. Pedley,et al.  Recent Advances in Epilepsy , 1984 .

[73]  A. Sjoerdsma,et al.  Biochemical and clinical effects of γ‐vinyl GABA in patients with epilepsy , 1984, Neurology.

[74]  A. Sjoerdsma,et al.  Biochemical and clinical effects of gamma-vinyl GABA in patients with epilepsy. , 1984, Neurology.

[75]  R. Macdonald,et al.  Multiple actions of phenytoin on mouse spinal cord neurons in cell culture. , 1983, The Journal of pharmacology and experimental therapeutics.

[76]  W. Reimann.  Inhibition by GABA, baclofen and gabapentin of dopamine release from rabbit caudate nucleus: are there common or different sites of action? , 1983, European journal of pharmacology.

[77]  B. Meldrum,et al.  Anticonvulsant action in mice with sound-induced seizures of the optical isomers of γ-vinyl GABA , 1983 .

[78]  B. Meldrum,et al.  Anticonvulsant action in mice with sound-induced seizures of the optical isomers of gamma-vinyl GABA. , 1983, European journal of pharmacology.

[79]  W. Burnham,et al.  Pharmacological investigation of gamma-aminobutyric acid (gaba) and fully-developed generalized seizures in the amygdala-kindled rat , 1982, Neuropharmacology.

[80]  J. Barker,et al.  Diazepam and (--)-pentobarbital: fluctuation analysis reveals different mechanisms for potentiation of gamma-aminobutyric acid responses in cultured central neurons. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[81]  C. Braestrup,et al.  [3H]Propyl β‐Carboline‐3‐Carboxylate as a Selective Radioligand for the BZ1 Benzodiazepine Receptor Subclass , 1981, Journal of neurochemistry.

[82]  C. Marescaux,et al.  Increased gamma-aminobutyric acid (GABA), homocarnosine and β-alanine in cerebrospinal fluid of patients treated with γ-vinyl GABA (4-amino-hex-5-enoic acid) , 1981 .

[83]  B. Beer,et al.  Differential ontogeny of type 1 and type 2 benzodiazepine receptors. , 1981, Life sciences.

[84]  C. Marescaux,et al.  Increased gamma-aminobutyric acid (GABA), homocarnosine and beta-alanine in cerebrospinal fluid of patients treated with gamma-vinyl GABA (4-amino-hex-5-enoic acid). , 1981, Life sciences.

[85]  J. Wada,et al.  The Xth epilepsy international symposium , 1980 .

[86]  B. Beer,et al.  Resolution of two biochemically and pharmacologically distinct benzodiazepine receptors , 1979, Pharmacology Biochemistry and Behavior.

[87]  P. Schechter,et al.  Attempts to correlate alterations in brain GABA metabolism by GABA-T inhibitors with their anticonvulsant effects. , 1979, Advances in experimental medicine and biology.

[88]  N. Seiler,et al.  Metabolic inhibitors and subcellular distribution of GABA , 1979, Journal of neuroscience research.

[89]  P. Schechter,et al.  γ‐VINYL GABA (4‐amino‐hex‐5‐enoic acid), A NEW SELECTIVE IRREVERSIBLE INHIBITOR OF GABA‐T: EFFECTS ON BRAIN GABA METABOLISM IN MICE 1 , 1977, Journal of neurochemistry.

[90]  P. Schechter,et al.  Audiogenic seizure protection by elevated brain GABA concentration in mice: Effects of γ-acetylenic GABA and γ-vinyl GABA, two irreversible GABA-T inhibitors , 1977 .

[91]  B. Metcalf,et al.  4-amino-hex-5-enoic acid, a selective catalytic inhibitor of 4-aminobutyric-acid aminotransferase in mammalian brain. , 1977, European journal of biochemistry.

[92]  I. Chanarin,et al.  ANTICONVULSANT THERAPY, MEGALOBLASTIC HAEMOPOIESIS AND FOLIC ACID METABOLISM , 1966 .