ISBN: 3540653740
TITLE: Antiepileptic Drugs
AUTHOR: Eadie, M.J.; Vajda, F. (Eds.)
TOC:

CHAPTER 1
Classification of Epileptic Seizures and the Epilepsies and Drugs of Choice for Their Treatment
F.E. Dreifuss and N.B. Fountain 1
A. Introduction 1
B. The International Classification of Epileptic Seizures 3
I. Partial Seizures 3
II. Generalized Seizures 3
C. Classification of the Epilepsies and Epileptic Syndromes 5
I. Idiopathic Epilepsies 5
1. Idiopathic Epilepsies with Partial Seizures 5
2. Idiopathic Epilepsies with Generalized Seizures 7
II. Symptomatic Epilepsies 7
1. Symptomatic Epilepsies with Partial Seizures 7
2. Symptomatic Epilepsies with Generalized Seizures 8
III. Epilepsies That Are Difficult to Categorize 8
1. West's Syndrome 8
2. Lennox-Gastaut Syndrome 9
3. Acquired Epileptic Aphasia (the Landau-Kleffner Syndrome) 9
4. Epilepsy with Continuous Spike-Wave during Slow Wave Sleep 9
D. Influence of Technological Advances on the Understanding of Semiology 9
I. Singular Nuclear Gene Disorders 9
II. Complex Inheritance Disorders 10
E. Drugs of Choice for Epileptic Seizures and the Epilepsies 10
I. Drugs for Epileptic Seizures 11
1. Partial Seizures 11
2. Generalized Seizures 12
II. Drugs for the Epilepsies 13
1. Idiopathic Epilepsies with Partial Seizures 13
2. Idiopathic Epilepsies with Generalized Seizures 14.3. Symptomatic Epilepsies with Localization-Related Seizures 14
4. Symptomatic Epilepsies with Generalized Seizures 14
5. Febrile Convulsions 15
F. Conclusion 15
References 15
CHAPTER 2
Animal Models of Epilepsy and Epileptic Seizures
W. Lscher. With 1 Figure 19
A. Introduction 19
B. Animal Models of Epilepsy 21
I. Localization-Related (Focal, Local, Partial) Epilepsies 24
1. Idiopathic (Primary) Focal Epilepsies 24
a) Dogs with Idiopathic Localization-Related Epilepsy 25
2. Symptomatic (Secondary) Focal Epilepsies 26
a) The Kindling Model of Temporal Lobe Epilepsy 27
b) The Kainate Model 31
c) The Pilocarpine Model 31
d) Chronic Epilepsy Following Status Epilepticus 32
e) Spontaneous Focal Seizures Following Local Application of Metals, Chemical Convulsants or Toxins 33
II. Generalized Epilepsies 33
1. Animal Models of Idiopathic Primary Generalized Epilepsies 34
a) Epileptic Dogs 34
b) Rats with Generalized Absence Epilepsy 34
c) The Lethargic (lh/lh) Mouse 35
d) The Spontaneously Epileptic Double Mutant Rat 36
e) Transgenic or Knockout Mice 36
III. Undetermined Epilepsies 37
1. Tottering Mice 37
IV. Special Syndromes 38
a) Epileptic Gerbils 38

b) Audiogenic Seizure Susceptible Mice 39
c) Audiogenic Seizure Susceptible Rats 40
d) Epileptic Baboons with Photomyoclonic Seizures 41
e) El Mice 43
C. Animal Models of Epileptic Seizures 43
I. Animal Models of Partial (Focal, Local) Seizures 44
1. Epileptic Animals with Focal Seizures 44
2. Focal Seizures Induced in Normal, Non-epileptic Animals 48
II. Animal Models of Generalized Seizures 50
1. Epileptic Animals with Primary Generalized Seizures 50
a) Genetic Animal Models of Epilepsy with Generalized Convulsive Seizures 50
b) Genetic Animal Models of Epilepsy with Generalized Non-convulsive Seizures) 50
2. Primary Generalized Seizures Induced in Normal, Non-epileptic Animals 51
a) Models of Convulsive Seizures 51
b) Models of Absence or Myoclonic Seizures 53
D. Conclusions 55
References 56
CHAPTER 3
Epileptogenesis: Electrophysiology
J. O. Willoughby. With 7 Figures 63
A. Introduction 63
B. Partial (Focal, or Lesional) Epilepsy 64
I. Overview 64
II. The Single Neuron: Normal Population 64
III. The Single Neuron: Epileptic Population 67
IV. Connectivity 68
V. Other Processes 70
C. Generalized Epilepsy: Absence Seizures 71
I. Overview 71
II. Cortical Processes 73
III. Thalamic Processes 73
IV. Human Studies 74
D. Generalized Epilepsy: Convulsive Seizures 75
I. Overview 75
II. Excessive Excitation or Impaired Inhibition 76
III. Anatomical Distribution of Convulsions: Cortex and Hippocampus 76
IV. Electrophysiological Distribution of Convulsions: Cortex and Brain Stem 77
V. Human Studies: Predisposing Brain Processes and a Synthesis 79
References 81
CHAPTER 4
Epileptogenesis: Biochemical Aspects
B. Jarrott 87
A. Introduction 87
B. Methods for Studying Epileptogenesis 87
I. In Humans 87
1. Imaging Techniques 87
2. Neurophysiological Studies on Cortical Slices Maintained In Vitro 88
3. Microdialysis 88

II. Animal Models 88
1. Kindling 88
2. Kainate Model 89
3. Genetic Strains 89
III. Biochemical Techniques 89
C. Role of Neurotransmitters in Epileptogenesis 90
I. Amino Acids 90
1. l-Glutamate 90
a) Glutamate Release and Reuptake 90
b) Glutamate Receptors 91
a) NMDA Receptors 92
b) AMPA/Kainate Receptors 93
g) Metabotropic Glutamate Receptors 94
2. GABA 94
a) GABA Synthesis and Storage 94
b) GABA Transporters 96
c) GABA Receptors 96
a) GABAA Receptors 96
b) GABAB Receptors 97
II. Biogenic Amines 98
1. Noradrenaline 98
2. 5-Hydroxytryptamine 100
3. Acetylcholine 100
III. Neuropeptides 101
1. Neuropeptide Y 102
2. Somatostatin 102
3. Cholecystokinin 103
4. Dynorphin 103
IV. Purines 103
V. Nitric Oxide 105
D. Postsynaptic Effects 106
I. Role of Ca 2+ Channels and Ca 2+ Binding Proteins 106
II. Immediate Early Genes 107
E. Neurotrophins and Neurogenesis 110
I. Mossy Fibre Sprouting in the Hippocampus 111
II. Neuronal Migration Disorders in the Cortex 114
F. Conclusions 114
References 114
CHAPTER 5
Cellular Actions of Antiepileptic Drugs
R.L. Macdonald 123
A. Introduction 123
B. Established Antiepileptic Drug Mechanisms of Action 123
I. Phenytoin and Carbamazepine 123
II. Benzodiazepines and Barbiturates 125
III. Ethosuximide and Trimethadione 127
IV. Valproic Acid 129
C. Newly Developed Antiepileptic Drug Mechanisms of Action 129
I. Gabapentin 129
II. Lamotrigine 132
III. Oxcarbazepine 134
IV. Vigabatrin 135
V. Tiagabine 137
VI. Topiramate 138
VII. Felbamate 139
References 141
CHAPTER 6
The Search for New Anticonvulsants
D. Schmidt 151
A. Introduction 151
B. Pharmacological Strategies in the Search for New Anticonvulsants 152
I. Rational Drug Design 157
1. Selective Enhancement of GABAergic Neurotransmission 157
2. Selective Attenuation or Blockade of Excitatory Aminoacidergic Neurotransmission 159
3. Selective Modulation of Ion Channels 159
4. Other Strategies for Rational Drug Design 160
II. Random Screening or Molecular Structural Variation of
Known Compounds 160
1. Retigabine 161
2. TV 1901 161
3. Dezinamide 161

4. MDL 27,192 161
C. Clinical Evaluation of Preclinical Development Strategies 161
D. Strategies for Future Drug Development 163
I. Chemical Systems for Delivery of Antiepileptic Drugs to Regions of the Brain 164
II. Rational Polytherapy 164
III. Predictive Identification of Responders 165
IV. Strategies for the Development of Drugs for Unresponsive
Epilepsies 165
V. Identification of Genetic Defects in Epilepsy 165
E. Conclusions 165
References 168
CHAPTER 7
Measurement of Anticonvulsants and Their Metabolites in Biological Fluids
W.D. Hooper and L.P. Johnson 173
A. Introduction 173
B. Chromatographic Methods 173
I. Gas Chromatography and High Performance Liquid
Chromatography 174
C. Capillary Electrophoresis and Micellar Electrokinetic Capillary Electrophoresis 175
I. Antiepileptic Drug Analysis by Capillary Electrophoresis and Micellar Electrokinetic Capillary Electrophoresis 176
D. Stereoselective Drug Analysis 177
E. Immunoassay Methods 178
I. Immunoassay Instrumentation 179
II. Analytical Performance 180
III. Non-laboratory Immunoassay Antiepileptic Drug
Monitoring 181
F. Free Drug Monitoring 181
I. Saliva 182
G. Quality Assurance 183
References 183
CHAPTER 8
Older Anticonvulsants Continuing in Use but with Limited Advance in Knowledge
M.J. Eadie and F.J.E. Vajda. With 2 Figures 189
A. Introduction 189
B. Phenobarbitone and Congeners 189
I. Chemistry and Use 189
1. Chemistry 189
2. Use 190
II. Pharmacodynamics 190
1. Animal Models of Epilepsy 190
2. Electrophysiological Actions 191
3. Biochemical Actions 191
III. Pharmacokinetics 191
1. Absorption 191
a) Phenobarbitone 191
b) Methylphenobarbitone 192
c) Primidone 192
2. Distribution 192
a) Phenobarbitone 192
b) Methylphenobarbitone 192
c) Primidone 193
3. Elimination 193
a) Metabolism 193
a) Phenobarbitone 193
b) Methylphenobarbitone 195
g) Primidone 195
b) Elimination Parameters 196
a) Phenobarbitone 196
b) Methylphenobarbitone 196
g) Primidone 196
4. Applied Pharmacokinetics 197
a) Phenobarbitone 197
b) Methylphenobarbitone 197
c) Primidone 198
IV. Interactions 198
1. Pharmacodynamic Interactions 198
2. Pharmacokinetic Interactions 199
a) Phenobarbitone Affecting Other Substances 199
b) Other Substances Affecting Phenobarbitone 199
a) Methylphenobarbitone 200
b) Primidone 200
V. Adverse Effects 200
1. Idiosyncratic Effects 200
2. Dose-Determined Effects 201
3. Effects on the Foetus and Neonate 202
C. Succinimides 202
I. Chemistry and Use 202
1. Chemistry 202
2. Use 203
II. Pharmacodynamics 203
1. Animal Models of Epilepsy 203
2. Electrophysiological Studies 204
3. Biochemical Effects 204
III. Pharmacokinetics 204
1. Absorption 204
2. Distribution 205
3. Elimination 205
a) Metabolism 205
b) Elimination Parameters 206
4. Applied Pharmacokinetics 207
IV. Interactions 207
1. Pharmacodynamic Interactions 207
2. Pharmacokinetic Interactions 208
V. Adverse Effects 208
D. Sulthiame 208
I. Chemistry and Use 208
II. Pharmacodynamics 209
III. Pharmacokinetics 209
IV. Interactions 210
V. Adverse Effects 210
E. Acetazolamide 210
I. Chemistry and Use 210
II. Pharmacodynamics 211
III. Pharmacokinetics 211
IV. Interactions 212
V. Adverse Effects 212
F. Bromides 212
I. Chemistry and Use 212
II. Pharmacodynamics 213
III. Pharmacokinetics 213
IV. Interactions 213
V. Adverse Effects 213
References 213
CHAPTER 9
Phenytoin and Congeners
H. Kutt and C.L. Harden. With 1 Figure 229
A. Phenytoin 229
I. Introduction 229
II. Chemistry and Use 229
1. Chemistry 229
2. Indications and Use 230
III. Pharmacodynamics 230
IV. Pharmacokinetics 232
1. Absorption 232
2. Distribution 232
3. Elimination 233
a) Metabolism 233
a) Pharmacogenetics 235
b) Elimination Parameters 236
4. Clinical Pharmacokinetics 236
a) Dose-Plasma Level Relationships 236
b) Plasma Level-Effects Relationships 236
a) Beneficial Effects 236
b) Acute Toxic Effects 237
g) Initial Target Range Concentration 237
V. Interactions 237
VI. Adverse Effects 238
1. Acute Toxicity 238
2. Idiosyncratic Adverse Effects 240
3. Teratogenicity 240
a) Folate, Anaemia, Teratogenesis 241
b) Mechanisms of Idiosyncratic Toxicity and Teratogenicity 241
4. Chronic Toxicity 242
a) Enzyme Induction 243
B. Fosphenytoin 243
I. Introduction 243
II. Chemistry and Use 243
1. Chemistry 243
2. Indications and Use 244
III. Pharmacodynamics 245
IV. Pharmacokinetics 245
1. Absorption and Disposition 245
2. Metabolism 245
3. Clinical Pharmacokinetics 246
V. Adverse Effects 246
C. Mephenytoin 246
I. Introduction 246
II. Chemistry and Use 247
1. Chemistry 247
2. Indications and Use 248
III. Pharmacodynamics 248
IV. Pharmacokinetics 248
1. Absorption and Disposition 248
2. Metabolism 249
a) Pharmacogenetics 249
3. Clinical Pharmacokinetics 250
a) Dose-Plasma Level Relationships 250
b) Plasma Level-Effect Relationships 251
a) Beneficial Effects 251
b) Acute Toxic Effects 251
V. Interactions 251
VI. Adverse Effects 251
D. Ethotoin 252
I. Introduction 252
II. Chemistry and Use 253
1. Chemistry 253
2. Indications and Use 253
III. Pharmacodynamics 253
IV. Pharmacokinetics 253
1. Absorption and Disposition 253
2. Metabolism 254
3. Clinical Pharmacokinetics 254
a) Dose-Plasma Level Relationships 254
b) Plasma Level-Effects Relationships 255
a) Beneficial Effects 255
b) Acute Toxic Effects 255
V. Interactions 255
VI. Adverse Effects 255
E. Phenacetamide 255
I. Introduction 255
II. Chemistry and Use 256
1. Chemistry 256
2. Indications and Use 256
III. Pharmacodynamics 256
IV. Pharmacokinetics 257
1. Absorption and Disposition 257
2. Metabolism 257
3. Clinical Pharmacokinetics 257
a) Dose, Plasma Level and Effect Relationships 257
V. Interactions 257
VI. Adverse Effects 258
F. Albutoin 258
I. Introduction 258
II. Chemistry and Use 258
III. Pharmacology 258
1. Animal Pharmacology 258
2. Human Use 259
References 259
CHAPTER 10
Carbamazepine
R.G. Dickinson, M.J. Eadie and F.J.E. Vajda. With 1 Figure 267
A. Introduction 267
B. Chemistry and Use 267
I. Chemistry 267
II. Use 268
C. Pharmacodynamics 268
I. Biochemical Effects 269
1. Ion Channels and Receptors 269
a) Na^+ Channels 269
b) Benzodiazepine Receptors 269
c) Ca 2+ Channels 269
d) Adenosine Receptors 270
2. Effects on Neurotransmitters 270
a) GABA 270
b) Catecholamines 270

c) Serotonin 270
d) Acetylcholine 271
e) Substance P 271
f) Glutamate 271
g) Somatostatin 271
3. Other Biochemical Changes 271
II. Electrophysiological Effects 271
1. Effects at the Cellular Level 271
2. Effects on Neuronal Pools 272
III. Effects in Animal Models of Epilepsy 273
1. Models of Generalized Epilepsy 273
2. Models of Partial Epilepsy 273
IV. Human Studies 274
D. Pharmacokinetics 274
I. Absorption 275
II. Distribution 276
1. Apparent Volume of Distribution 276
2. Plasma Protein Binding 276
3. Body Fluid and Tissue Distribution 277
a) Blood 277
b) Cerebrospinal Fluid 277
c) Saliva 277
d) Milk 277
e) Foetal Blood and Amniotic Fluid 277
f) Body Tissues 277
III. Elimination 278
1. Metabolism 278
2. Elimination Parameters 280
a) Half-life 280
b) Clearance 281
c) Carbamazepine-10,11-epoxide 281
IV. Clinical Pharmacokinetics 281
a) Pregnancy 283
b) Disease States 283
E. Interactions 284
I. Pharmacodynamic Interactions 284
II. Pharmacokinetic Interactions 284
1. Interactions Which Lower Plasma Carbamazepine
Concentrations 284
2. Interactions Which Raise Plasma Carbamazepine
Concentrations 285
3. Interactions in Which Carbamazepine Lowers the Plasma
Concentrations, or Increases the Clearances, of
Other Drugs 286
4. Interactions Leading to Raised Concentrations of Other Drugs 286
F. Adverse Effects 287
I. Biochemical Abnormalities 287
II. Dose-Determined Adverse Effects 287
1. Hyponatraemia 288
III. Idiosyncratic Adverse Effects 288
1. Aromatic Anticonvulsant Hypersensitivity Syndrome 289
2. Skin 289
3. Nervous System 289
4. Haematological 290
5. Cardiovascular 290
6. Respiratory 290
7. Alimentary Tract 290
8. Liver 291
9. Pancreas 291
10. Kidneys 291
11. Bone 291
12. Porphyria 291
13. Thyroid 291
IV. Foetal Toxicity 291
References 292
CHAPTER 11
Oxcarbazepine
S.C. Schachter. With 1 Figure 319
A. Introduction 319
B. Chemistry and Use 319
C. Pharmacodynamics 319
I. Biochemical Pharmacology 319
II. Animal Models of Epilepsy 320
III. Human Epilepsies 321
1. Monotherapy Trials 321
a) Controlled Monotherapy Trials in Newly Diagnosed
or Previously Untreated Patients 321
a) Study Designs 321
b) Enrolment Information 321
g) Results 322
d) Conclusions 323
b) Pre-surgery Trials 323
2. Add-on and Open-label, Long-term Trials 323
D. Pharmacokinetics 324
I. Absorption, Bioavailability, and Distribution 324
II. Elimination 324
1. Metabolism 324
2. Elimination Parameters 324
III. Clinical Pharmacokinetics 324
1. Special Patient Groups 325
a) Hepatic and Renal Impairment 325
b) The Elderly and Children 325
E. Interactions 325
I. Effects on Other Drugs 325
II. Effects of Other Drugs on Oxcarbazepine 325
F. Adverse Effects 326
I. Animal Studies 326
1. Acute Exposure 326
2. Teratogenicity/Carcinogenicity/Mutagenicity 326
II. Human Studies 326
1. Add-on, Open-label Trials 326
2. Monotherapy Trials in Newly Diagnosed or Previously
Untreated Patients 326
III. Particular Adverse Effects in Humans 327
1. Rashes 327
2. Overdosage 328
IV. Laboratory Abnormalities 328
V. Pregnancy 328
References 328
CHAPTER 12
Lamotrigine
M.C. Walker and J.W.A.S. Sander 331
A. Introduction 331
B. Chemistry and Use 331
I. Chemistry 331
1. Analytical Methods 331
II. Use 332
C. Pharmacodynamics 333
I. Anticonvulsant Effects 333
1. Animal Models of Epilepsy 333
a) Maximal Electroshock Seizures 333
b) Chemoconvulsant Tests 333
c) Afterdischarge Tests 334
d) Electrically Induced Kindling 334
e) Genetic Seizure Models 335
f) Models of Status Epilepticus 335
2. Mechanism of Action 336
a) Neurochemical Actions 336
b) Ionic Conductances 337
a)Na^+ Channels 337
b)Ca^2+ Channels 339
g)K^+ Channels 339
c) Ligand Binding to Receptors 339
II. Other Central Nervous System Effects 340
1. Effects on the EEG and Sleep 340
2. Memory and Long-Term Potentiation 340
3. Excitotoxic and Ischaemic Neuronal Injury 341
4. Effects on Involuntary Movement Disorders 342
5. Morphine Withdrawal 343
6. Increased Atmospheric Pressure 344
7. Anxiolytic Effects 344
III. Effects Outside the Central Nervous System 344
1. Effects on Peripheral Nerves and Analgesic Effects 344
2. Other Effects 345
D. Pharmacokinetics 345
I. Absorption 345
II. Distribution 346
III. Elimination 347
1. Elimination Parameters 347
2. Metabolism 348
IV. Clinical Pharmacokinetics 348
E. Interactions 349
I. Pharmacodynamic Interactions 349
II. Pharmacokinetic Interactions 349
F. Adverse Effects 350
I. Animal Toxicity 350
II. Human Toxicity 351
References 352
CHAPTER 13
Valproate
D.D. Shen and R.H. Levy 359
A. Introduction 359
B. Chemistry and Use 359
I. Chemistry 359
II. Use 359
C. Pharmacodynamics 360
I. Experimental Animal Studies 360
II. Biochemical Pharmacology 360
D. Pharmacokinetics 362
I. Absorption 362
II. Distribution 363
III. Elimination 364
1. Clearence Parameters 364
2. Metabolism 366
E. Interactions 367
I. Other Drugs Affecting Valproate 367
II. Valproate Affecting Other Drugs 368
F. Adverse Effects 369
References 369
CHAPTER 14
Vigabatrin
E. Ben-Menachem. With 1 Figure 375
A. Chemistry and Use 375
I. Chemical Characteristics 375
1. Enantiomers 375
II. Use 375
B. Pharmacodynamics 375
I. Biochemical Pharmacology 375
1. Effects on GABA and Other Amino Acids 375
II. Animal Models 376
1. Anticonvulsive Effects 376
2. Prevention of Epileptogenesis 377
3. Neuroprotective Effects 377
III. Humans 377
1. CSF and Brain Concentrations of GABA and Other
Amino Acids 377
2. Magnetic Resonance Spectroscopy 378
3. Effects on Platelets 379
4. Human Epilepsy 379
a) Adults with Partial Seizures 379
a) Major Single-Blind Studies 379
b) Major Double-Blind Studies 379
g) Monotherapy Studies 382
d) Long-term Studies 382
b) Children with Partial Seizures 382
c) Children with Infantile Spasms 383
d) Children with the Lennox-Gastaut Syndrome 383
C. Pharmacokinetics 384
I. Absorption and Bioavailability 384
II. Distribution 384
1. Body Tissues and Fluids 384
2. Placental Transfer 384
III. Elimination 385
1. Metabolism 385
2. Elimination Parameters 385
IV. Clinical Pharmacokinetics 385
D. Interactions 385
E. Adverse Effects 386
I. General Effects 386
II. Psychosis 386
III. Visual Field Defects 388
IV. Teratogenicity 388
F. Use in Clinical Practice 389
I. Dosage 389
II. Dose Titration 389
III. Laboratory Monitoring 389
References 390
CHAPTER 15
Benzodiazepines
C. Kilpatrick. With 1 Figure 395
A. Introduction 395
B. Pharmacodynamics of Benzodiazepines in General 395
I. Animal Models of Epilepsy 395
II. Biochemical Pharmacology 396
C. Benzodiazepine Adverse Effects and Their Mechanisms 397
D. Diazepam 399
I. Chemistry 399
II. Pharmacodynamics 399
1. Humans 399
III. Pharmacokinetics 400
1. Absorption 400
2. Distribution 400
a) Cerebrospinal Fluid 400
b) Brain 401
c) Plasma Protein Binding 401
3. Elimination 401
a) Metabolism 401
b) Elimination Parameters 402
c) Excretion 403
4. Clinical Pharmacokinetics 403
a) Plasma Concentration: Clinical Effect Relationships 405
b) Treatment of Status Epilepticus 405
IV. Interactions 406
V. Adverse Effects 406
E. Clobazam 407
I. Chemistry 407
II. Pharmacodynamics 407
1. Mechanism of Action 407
2. Animal Models 408
3. Human Studies 408
III. Pharmacokinetics 409
1. Absorption 409
2. Distribution 409
a) Protein Binding 409
3. Elimination 409
a) Metabolism 409
b) Elimination Parameters 410
4. Clinical Pharmacokinetics 410
IV. Interactions 411
V. Adverse Effects 411
F. Clonazepam 411
I. Chemistry and Use 411
1. Chemistry 411
2. Use 412
II. Pharmacodynamics 412
1. Tolerance 412
III. Pharmacokinetics 413
1. Absorption 413
2. Distribution 413
3. Elimination 413
a) Metabolism 413
b) Elimination Parameters 413
IV. Interactions 414
V. Adverse Effects 414
G. Lorazepam 414
H. Nitrazepam 415
I. Midazolam 415
References 416
CHAPTER 16
Gabapentin
F.J.E. Vajda 425
A. Introduction 425
B. Chemistry and Use 425
I. Chemical Structure and Properties 425
II. Analytical Methods for Measuring Gabapentin 426
III. Use 426
C. Pharmacodynamics 426
I. Biochemical Pharmacology 426
1. Effects on GABAergic Mechanisms 426
a) Effects on GABA Accumulation 427
b) Effects on GABA and Glutamate Metabolic
Pathways 427
c) Effects on Receptors and Ion Channels 427
2. Effects on Membrane Amino Acid Transport 428
3. Studies on the Gabapentin Binding Site in Animal Brains 429
a) Distribution of Gabapentin Specific Binding Sites 430
4. Overview of Biochemical Pharmacology 430
II. Studies at a Cell or Tissue Level 430
1. Hippocampal Slices 431
2. Cultured Neurons 431
III. Animal Models of Epilepsy 431
1. Spectrum of Activity 431
2. Standard Seizure Models in Mice and Rats 432
a) Maximal Electroshock Testing 432
b) Seizures Induced by Glutamate, Aspartate and Kainic Acid 432
c) Hippocampal Kindled Seizures 432
d) Audiogenic Seizures in Mice 433
e) Seizures in the Photosensitive Baboon 433
f) Reflex Epilepsy 433
g) Classical Absences 433
IV. Antinociceptive Effects 433
V. Antispasticity Effects 433
VI. Human Studies 434
D. Pharmacokinetics 434
I. Pharmacokinetics in Animals 434
II. Pharmacokinetics in Humans 435
1. Absorption and Bioavailability 435
2. Distribution 435
a) Brain, CSF and Plasma Gabapentin Concentration Relationships 435
3. Elimination 436
a) Metabolism 436
b) Elimination Parameters 436
4. Clinical Pharmacokinetics 436
a) Plasma Concentration-Dose Relationships 436
b) Effects of Food, Multiple Dosing, Age and
Disease 437
c) Gabapentin and Renal Function 437
d) Plasma Gabapentin Concentrations and Therapeutic Effects 437
E. Interactions 437
I. Effect of Gabapentin on Other Drugs 437
1. Other Antiepileptic Drugs 438
a) Multiple Drug Interactions 438
2. Oral Contraceptives 438
II. Effects of Other Drugs on Gabapentin 438
F. Adverse Effects 439
I. Animal Studies 439
1. Acute Exposure 439
2. Subacute Exposure 439
3. Chronic Exposure 439
4. Mutagenicity 439
5. Carcinogenicity 439
6. Teratogenicity 440
II. Human Studies 440
1. Add-on Pivotal Placebo-Controlled Studies in Refractory Patients 440
2. Monotherapy Trials in Previously Untreated Patients 440
3. Particular Adverse Effects in Humans 440
a) Quality of Life 440
4. Overdosage 441
5. Laboratory Abnormalities 441
6. Pregnancy 441
References 441
CHAPTER 17
Tiagabine
S.C. Schachter. With 3 Figures 447
A. Introduction 447
B. Chemistry and Use 447
C. Pharmocodynamics 448
I. Biochemical Pharmacology 448
II. Electrophysiology 448
III. Animal Seizure Models 449
1. Electrically and Chemically Induced Epilepsy Models 449
2. Genetic Epilepsy Models 450
3. Anxiolytic Effects 450
4. Analgesic Effects 450
5. Effect on Cerebral Ischaemia 450
IV. Human Studies 450
1. Adult Add-on, Parallel-Design Trials 451
a) Study Designs 451
b) Enrolment Information 451
c) Results 451
2. Open-label, Long-term Treatment 452
3. Monotherapy Studies 453
a) Dose-Ranging, Tiagabine-Substitution Study 453
b) Multicentre High-Versus Low-Dose Study 454
4. Paediatric Trials 454
D. Pharmacokinetics 454
I. Animal Pharmacokinetics 454
II. Human Pharmacokinetics 455
1. Absorption and Bioavailability 455
2. Distribution 455
3. Elimination 455
a) Metabolism 455
b) Elimination Parameters 456
4. Applied Pharmacokinetics 456
5. Special Patient Groups 456
a) Hepatic and Renal Impairment 456
b) The Elderly and Children 456
E. Interactions 456
I. Pharmacodynamic Interactions 456
II. Pharmacokinetic Interactions 457
1. Effect of Tiagabine on the Pharmacokinetics of Other Drugs 457
2. Effects of Other Drugs on the Pharmacokinetics of Tiagabine 457
F. Adverse Effects 457
I. Animal Animal Toxicology 457
1. Acute Toxicity 457
2. Chronic Toxicity 457
3. Teratogenicity, Carcinogenicity, Mutagenicity 458
II. Human Studies 458
1. Add-on, Parallel-Group Studies 458
2. Monotherapy Trials 459
3. Long-term Studies 459
4. Special Safety Issues in Humans 459
a) Death 459
b) Rash, Psychosis, Status Epilepticus 459
c) Overdosage 460
d) Laboratory Values 460
e) Neuropsychological Function and Cognitive Effects 460
f) Pregnancy 460
References 461
CHAPTER 18
Topiramate
D. Heaney and S. Shorvon. With 1 Figure 465
A. Introduction 465
B. Chemistry 465
C. Pharmacodynamics 466
I. Animal Models of Epilepsy 466
II. Biochemical Pharmacology 466
1. Na^+ Channels 466
2. GABA-Mediated Cl - Influx 467
3. Glutamate Receptors 467
4. Carbonic Anhydrase 468
5. Other Actions 468
III. Toxicology 468
1. Systemic Toxicity 468
2. Carcinogenicity 469
3. Reproductive and Teratology Studies 469
IV. Human Studies 469
1. Placebo-Controlled Double-blind Add-on Trials 469

2. Non-Controlled Add-on Trials 472
3. Monotherapy Studies 472
4. Add-on Therapy for Generalized Seizures 473
5. The Lennox-Gastaut Syndrome 473
D. Pharmacokinetics 474
I. Absorption 474
II. Distribution 474
III. Elimination 475
1. No Interacting Drug Present 475
2. Interacting Drugs Present 475
IV. Special Situations 476
E. Interactions 476
I. Pharmacodynamic Interactions 476
II. Pharmacokinetic Interactions 476
1. Effects of Other Drugs on Topiramate 476
2. Effects of Topiramate on Various Drugs 476
a) Antiepileptic Drugs 476
b) Other Drugs 477
F. Adverse Effects 478
G. Clinical Use 479
I. Indications 479
II. Dosage and Administration 479
1. Dosage Titration 479
2. Patient Monitoring 480
3. Overdosage 480
4. Discontinuation of Topiramate 480
H. Conclusions 480
References 481
CHAPTER 19
Zonisamide

I.E. Leppik 485
A. Chemistry and Use 485
B. Pharmacodynamics 485
I. Studies in Animals 485
II. Studies in Humans 486
1. Efficacy in Localization-Related Epilepsies 486
2. Efficacy in Generalized Epilepsies 488
III. Measurement in Biological Fluids 489
C. Pharmacokinetics 489
I. Absorption 490
II. Distribution 490
III. Elimination 490
1. Elimination Parameters 490
2. Metabolism and Excretion 491
D. Interactions 491
I. Pharmacokinetic Interactions 491
E. Adverse Effects 493
I. Clinical Trials 493
II. Overdosage 494
III. Teratogenicity 495
F. Dose and Administration 495
References 495
CHAPTER 20
Felbamate
W.H. Theodore 499
A. Introduction 499
B. Chemistry and Use 499
C. Pharmacodynamic Studies 499
I. Animal Models of Epilepsy 499
II. Biochemical Actions 500
III. Human Studies 501
1. Partial Epilepsy 501
2. Generalized Epilepsy 501
D. Pharmacokinetics 503
I. Absorption 503
II. Distribution 503
III. Elimination 503
E. Interactions 504
F. Adverse Effects 505
I. Dose-Related Adverse Effects 505
II. Idiosyncratic Adverse Effects 506
G. Use of Felbamate in Practice 507
I. Role of Felbamate Blood Levels 507
II. Managing Drug Interactions 508
III. Stopping Felbamate 508
H. Conclusions 509
References 509
CHAPTER 21
Drugs Under Clinical Trial
E. Perucca.With 4 Figures 515
A. Introduction 515
B. Levetiracetam 516
I. Chemistry 516
II. Pharmacodynamics 516
1. Anticonvulsant Activity in Animal Models 516
2. Mechanism of Action 517
3. Other Pharmacological Effects and Toxicology Data 518
III. Pharmacokinetics 518
IV. Drug Interactions 519
V. Antiepileptic Efficacy and Adverse Effects 519
C. Losigamone 520
I. Chemistry 520
II. Pharmacodynamics 520
1. Anticonvulsant Activity in Animal Models 520
2. Mechanism of Action 521
3. Other Pharmacological Effects and Toxicology Data 523
III. Pharmacokinetics 523
IV. Drug Interactions 524
V. Antiepileptic Efficacy and Adverse Effects 525
D. Remacemide 525
I. Chemistry 526
II. Pharmacodynamics 526
1. Anticonvulsant Activity in Animal Models 526
2. Mechanism of Action 527
3. Other Pharmacological Effects and Toxicology Data 528
III. Pharmacokinetics 529
IV. Drug Interactions 530
V. Antiepileptic Efficacy and Adverse Effects 531
E. Rufinamide 531
I. Pharmacodynamics 532
II. Pharmacokinetics and Drug Interactions 532
III. Antiepileptic Efficacy and Adverse Effects 533
F. Stiripentol 533
I. Chemistry 533
II. Pharmacodynamics 533
1. Anticonvulsant Activity in Animal Models 533
2. Mechanism of Action 534
3. Other Pharmacological Effects and Toxicology Data 534
III. Pharmacokinetics 535
IV. Drug Interactions 536
V. Efficacy and Adverse Effects 536
G. Drugs in Early Clinical Development 537
I. 534U87 537
II. Abecarnil 537
III. Anti-epilepsirine 538
IV. AWD-140-190 538
V. D-2916 (Soretolide) 538
VI. D-23129 (Retigabine) 538
VII. Dezinamide 539
VIII. Ganaxolone 540
IX. Isobutyl-GABA (Pregabalin) 540
X. LY300164 541
XI. Monohydroxycarbazepine 541
XII. PNU-151774 542
XIII. N-Valproyl-glycinamide 542
XIV. SB-204269 543
H. Conclusion 543
References 543
CHAPTER 22
Anticonvulsant Combinations and Interactions
P. N. Patsalos 553
A. Introduction 553
B. Extent of the Problem 553
C. Pharmacokinetic Interactions 554
I. Cytochrome P450 555
D. Pharmacodynamic Interactions 558
E. Interactions of the Generally Available Anticonvulsant Drugs 558
I. Pharmacokinetic Interactions 558
1. Phenobarbitone 558
a) Interactions Affecting Phenobarbitone 558
a) Valproic Acid 558
b) Phenytoin 559
g) Miscellaneous Interactions 559
b) Interactions Where Phenobarbitone Affects Other
Drugs 561
a) Anticoagulants 561
b) Calcium Antagonists 562
g) Oral Contraceptives 562
d) Paracetamol 562
e) Valproic Acid 562
z) Miscellaneous Interactions 562
2. Phenytoin 563
a) Interactions Affecting Phenytoin 563
a) Alcohol 563
b) Amiodarone 563
g) Antiulcer Agents 564
d) Carbamazepine 565
e) Isoniazid 565
z) Phenobarbitone 565
h) Valproic Acid 566
q) Miscellaneous Interactions 566
b) Interactions Where Phenytoin Affects Other Drugs 567
a) Anticoagulant Drugs 567
b) Dexamethasone 567
g) Theophylline 567
d) Miscellaneous Interactions 567
3. Primidone 569
a) Interactions Affecting Primidone 569
b) Interactions Where Primidone Affects Other Drugs 569
4. Ethosuximide 569
a) Interactions Affecting Ethosuximide 569
b) Interactions Where Ethosuximide Affects Other Drugs 570
5. Carbamazepine 570
a) Interactions Affecting Carbamazepine 570
a) Antibiotics 570
b) Antidepressants 570
g) Anticonvulsant Drugs (Enzyme-Inducing) 571
d) Calcium Channel Blockers 571
e) Cimetidine 571
z) Imidazole Drugs 571
h) Valproic Acid 571
q) Miscellaneous Interactions 572
b) Interactions Where Carbamazepine Affects Other Drugs 572
6. Diazepam 573
a) Interactions Affecting Diazepam 573
b) Interactions Where Diazepam Affects Other
Drugs 573
7. Clonazepam 573
a) Interactions Affecting Clonazepam 573
b) Interactions Where Clonazepam Affects Other Drugs 574
8. Valproic Acid 574
a) Interactions Affecting Valproic Acid 574
b) Interactions Where Valproic Acid Affects Other Drugs 574
9. Clobazam 575
a) Interactions Affecting Clobazam 575
b) Interactions Where Clobazam Affects Other Drugs 575
II. Pharmacodynamic Interactions 575
1. Interactions Between Anticonvulsant Drugs 575
2. Interactions Between Anticonvulsant Drugs and Other Drugs 576
F. Interactions of the Recently Licensed Anticonvulsant Drugs 576
I. Pharmacokinetic Interactions 576
1. Vigabatrin 576
a) Interactions Affecting Vigabatrin 576
b) Interactions Where Vigabatrin Affects Other Drugs 577
2. Lamotrigine 577
a) Interactions Affecting Lamotrigine 577
b) Interactions Where Lamotrigine Affects Other
Drugs 577
3. Gabapentin 579
a) Interactions Affecting Gabapentin 579
b) Interactions Where Gabapentin Affects Other Drugs 579
4. Topiramate 579
a) Interactions Affecting Topiramate 579
b) Interactions Where Topiramate Affects Other Drugs 579
5. Felbamate 580
a) Interactions Affecting Febamate 580
b) Interactions Where Felbamate Affects Other Drugs 580
6. Oxcarbazepine 580
a) Interactions Affecting Oxcarbazepine 581
b) Interactions Where Oxcarbazepine Affects Other Drugs 581
7. Tiagabine 581
a) Interactions Affecting Tiagabine 581
b) Interactions Where Tiagabine Affects Other Drugs 582
8. Zonisamide 582
a) Interactions Affecting Zonisamide 582
b) Interactions Where Zonisamide Affects Other Drugs 582
II. Pharmacodynamic Interactions 582
1. Interactions Between Anticonvulsant Drugs 582
2. Interactions Between Anticonvulsant Drugs and
Other Drugs 582
G. Conclusions 582
References 583
CHAPTER 23
The Use of Antiepileptic Drugs in Clinical Practice
M.J. Eadie 589
A. Introduction 589
B. Changes in Antiepileptic Drug Use for Epilepsy 589
I. Increased Knowledge of the Natural History of
Epilepsy 589
II. A More Critical Application of Pharmacokinetic Concepts 590
III. The Availability of New Antiepileptic Drugs 591
IV. A Better Understanding of the Mechanisms of Action of Antiepileptic Drugs 591
V. The Maturing of the Surgical Therapy of Epilepsy 592
C. The Decision to Prescribe Antiepileptic Drug Therapy 592
I. Prevention of Anticipated (Usually Situation-Related)
Seizures 592
II. After a Solitary Seizure 593
III. Definite Epilepsy 594
D. The Choice of an Antiepileptic Drug 594
E. Initiating Drug Therapy 596
F. Continuing Drug Therapy 600
I. No Further Seizures and No Adverse Effects Occur 600
II. Adverse Effects Occur 600
III. Seizures Continue Despite Therapy 600
IV. Antiepileptic Drug Monotherapy Fails 601
1. Antiepileptic Drug Combinations 601
2. Pharmacokinetic Interactions Between
Anticonvulsants 602
V. The Patient's Physiological Status Alters 603
1. Age 603
2. Menstrual Cycle 604
3. Pregnancy 604
4. Intercurrent Illness 606
VI. Status Epilepticus Occurs 606
1. Generalized Convulsive Status Epilepticus 607
2. Non-convulsive Status Epilepticus 607
G. Duration of Therapy 608
H. Withdrawal of Therapy 609
I. Use of Antiepileptic Drugs for Indications Other than Epilepsy 609
References 610
Subject Index 615
END
