Antiepileptic drugs: combination therapy and interactions

Half-title......Page 3
Title......Page 5
Copyright......Page 6
Contents......Page 7
List of contributors......Page 10
Foreword......Page 15
Foreword......Page 17
Acknowledgements......Page 19
Part I Introduction......Page 21
Historical aspects......Page 23
Polypharmacy......Page 25
Epidemiology of combination therapy......Page 26
Efficacy can be enhanced by combination therapy......Page 27
The evidence for the benefits of combined therapy is often poor......Page 28
Toxicity may be greater with combination therapy than monotherapy......Page 29
Combination therapy may be associated with an increased risk of medication error......Page 31
REFERENCES......Page 32
Rationale for combination therapy......Page 36
Potential advantages of combination therapy......Page 37
Additive efficacy/infra-additive adverse effects......Page 38
Evidence of benefits of combination therapy versus monotherapy......Page 39
Potential problems with combined AEDs......Page 40
Pharmacokinetic interactions......Page 41
Selection of AED combinations......Page 42
Summary......Page 43
REFERENCES......Page 44
Introduction......Page 46
Metabolism......Page 47
Central pharmacokinetics......Page 48
Pharmacodynamics......Page 49
Adverse events......Page 54
Misconceptions about the use of genetic tests......Page 55
REFERENCES......Page 59
Part II Pharmacokinetic interactions......Page 65
Mechanisms of drug interactions......Page 67
Absorption......Page 68
Distribution......Page 69
Metabolism......Page 71
Elimination......Page 73
REFERENCES......Page 74
Principles of drug metabolism......Page 77
The cytochrome P450 system......Page 78
CYP2C9 and CYP2C19......Page 79
CYP2D6......Page 82
CYP3A4......Page 83
Uridine diphosphate-glucuronosyltransferases......Page 85
Enzyme induction......Page 86
The constitutive androstane receptor and phenobarbital-type induction......Page 87
Induction caused by peroxisome proliferators......Page 88
Enzyme induction as a cause of drug interactions......Page 89
Enzyme inhibition......Page 90
Slowly reversible inhibition......Page 91
Enzyme inhibition as a cause of drug interactions......Page 92
Enzyme-based techniques......Page 94
Prediction of metabolic drug interactions based on in vitro data......Page 95
Identification of the enzymes responsible for the metabolism of the test drug......Page 96
Predicting interactions affecting the metabolism of the test drug......Page 97
Assessment of the influence of the test drug on the activity of drug-metabolizing isoenzymes......Page 99
Predicting effects of the test drug on the metabolism of other drugs......Page 100
Crucial factors in predicting in vitro–in vivo correlations......Page 102
Extent of metabolism of the substrate through the affected enzyme......Page 103
Role of metabolites......Page 104
Complex or biphasic interactions......Page 105
Other sources of variability......Page 106
Conclusions......Page 107
REFERENCES......Page 108
General principles......Page 113
Phenytoin......Page 116
Activated charcoal......Page 117
Antineoplastic therapy......Page 118
Phenytoin actions affecting the pharmacokinetics and/or pharmacodynamics of other drugs......Page 119
Carbamazepine......Page 120
Phenobarbital......Page 121
Vigabatrin......Page 122
Gabapentin......Page 123
Oxcarbazepine......Page 124
REFERENCES......Page 125
Introduction......Page 131
Effect of phenobarbital on other drugs......Page 132
Effect of other drugs on phenobarbital......Page 133
Effect of phenytoin on other drugs......Page 134
Effect of other drugs on phenytoin......Page 135
Carbamazepine......Page 136
Effect of other drugs on carbamazepine......Page 137
Effect of valproate on other drugs......Page 138
Effect of methsuximide on other drugs......Page 139
Effect of felbamate on other drugs......Page 140
Effect of gabapentin on other drugs......Page 141
Effect of lamotrigine on other drugs......Page 142
Effect of other drugs on lamotrigine......Page 143
Effect of oxcarbazepine on other drugs......Page 144
Effect of other drugs on oxcarbazepine......Page 145
Effect of vigabatrin on other drugs......Page 146
Effect of other drugs on topiramate......Page 147
Effect of zonisamide on other drugs......Page 148
REFERENCES......Page 150
Introduction......Page 159
Antibiotics......Page 160
Cisplatin......Page 161
Metronidazole......Page 162
Antihypertensive drugs......Page 163
Itraconazole......Page 164
Warfarin......Page 165
Interactions affected by felbamate......Page 166
Acetaminophen (paracetamol)......Page 167
Probenecid......Page 168
Dextropropoxyphene......Page 169
Activated charcoal......Page 170
Felodipine......Page 171
Nimodipine......Page 172
Warfarin......Page 173
Antineoplastic agents......Page 174
Fluconazole......Page 175
Rifampin......Page 176
Cyclophosphamide......Page 177
Fluconazole......Page 178
Mexiletine......Page 179
Theophylline......Page 180
Isoniazid......Page 181
Other drugs......Page 182
Interactions affecting topiramate......Page 183
Ibuprofen......Page 184
Salicylic acid......Page 185
Interactions affected by vigabatrin......Page 186
REFERENCES......Page 187
Part III Pharmacodynamic interactions......Page 199
Distinction between pharmacodynamic and pharmacokinetic drug interactions......Page 201
Types of pharmacodynamic interaction......Page 202
Clinical significance of pharmacodynamic interactions......Page 204
Desirable interactions......Page 206
Undesirable interactions......Page 207
Clinical relevance of pharmacodynamic interactions: monotherapy versus combination therapy......Page 210
REFERENCES......Page 211
Basic principles......Page 213
Isobolographic analysis......Page 214
Other methods......Page 219
Methodological pitfalls......Page 222
Basic principles......Page 223
Optimal design......Page 224
Questionably valid design......Page 225
REFERENCES......Page 226
Interactions between conventional antiepileptic drugs......Page 228
Interactions between conventional and newer antiepileptic drugs......Page 231
Interactions between newer antiepileptic drugs......Page 232
N-methyl-D-aspartate receptor antagonists......Page 233
AMPA/KA receptor antagonists......Page 236
Ligands of metabotropic glutamate receptors......Page 238
Interaction of antiepileptic drugs with voltage-dependent calcium channel inhibitors......Page 239
Concluding remarks......Page 240
REFERENCES......Page 242
Introduction......Page 248
What is the impact of drug load on PD interactions?......Page 249
Add-on placebo-controlled trials......Page 250
Other studies......Page 251
Negative-PD interactions: efficacy......Page 255
PD interactions: side effects......Page 256
Trial designs......Page 257
REFERENCES......Page 258
Introduction......Page 261
Combination of AEDs and AD in the treatment of affective disorders......Page 262
ADs effects on seizure threshold......Page 263
Adverse effects......Page 265
APs effects on seizure threshold......Page 266
Convulsant effect of atypical APs (clozapine, olanzapine, quetiapine and risperidone)......Page 267
PD interactions with stimulants of the CNS......Page 268
Adverse effects......Page 269
AEDs in the treatment of pain......Page 270
Conclusions......Page 271
REFERENCES......Page 272
Part IV Drug interactions in specific patient populations and special conditions......Page 275
Introduction......Page 277
Phenobarbital, phenytoin and carbamazepine......Page 279
Valproate......Page 280
Lamotrigine......Page 281
Epilepsy resistant to a first-line monotherapy......Page 282
Cryptogenic or symptomatic partial epilepsy......Page 283
Infantile spasms......Page 284
Myoclonic–astatic epilepsy......Page 285
Combining AEDs with non-AED drugs......Page 286
REFERENCES......Page 288
Pharmacoepidemiology......Page 293
Age-related alterations in pharmacodynamics......Page 294
Age-related alterations in pharmacokinetics......Page 295
Other......Page 298
Felbamate......Page 299
Valproate......Page 300
Phenytoin......Page 301
Phenytoin......Page 302
Oxcarbazepine......Page 303
Other......Page 304
Carbamazepine......Page 305
Phenytoin......Page 306
REFERENCES......Page 307
Scope of the problem......Page 314
Antiepileptic drugs and hormonal contraceptives......Page 315
Maternal complications associated with AED......Page 316
Polycystic ovaries......Page 317
Fetal complications associated with AED......Page 318
Epoxides......Page 320
Phenytoin birth defects and epoxide hydrolase activity......Page 321
Free radical intermediates of AEDs and teratogenicity......Page 322
Neural tube defects and AEDs......Page 323
Folate deficiency as a potential mechanism of AED teratogenicity......Page 324
Lamotrigine......Page 326
Zonisamide......Page 327
FHS......Page 328
Fetal valproate syndrome......Page 330
Newer AED and anomalies......Page 331
Neonatal complications associated with AED......Page 332
Developmental delay......Page 333
Conclusion......Page 334
REFERENCES......Page 335
Introduction......Page 345
Epidemiology of epilepsy in the mentally retarded......Page 346
Intractability of seizures......Page 347
Drug interactions and adverse effects......Page 348
Phenobarbital......Page 349
Valproate......Page 350
Oxcarbazepine......Page 351
Lamotrigine......Page 352
Topiramate......Page 353
Levetiracetam......Page 354
Conclusion......Page 355
REFERENCES......Page 356
Frequency and importance of interactions......Page 361
Awareness of the issues......Page 362
Mechanism of interactions and contraceptive failure......Page 363
Specific AED interactions with OCs......Page 364
Specific AED interactions with parenteral sex steroid administration......Page 365
OC effect on LTG......Page 366
Summary......Page 367
REFERENCES......Page 368
Antidepressant drugs......Page 370
Others......Page 372
The role of CYP450 system on metabolism of psychotropic drugs......Page 373
SSRI–NSRI......Page 375
Others......Page 377
Benzisoxazoles and benzisothiazoles......Page 378
Interactions between anticonvulsants and anxiolytics......Page 379
Anticonvulsants and antipsychotic drugs......Page 380
Conclusions......Page 383
REFERENCES......Page 384
Introduction: AEDs in non-epileptic conditions......Page 389
Rationale for using AEDs in disorders other than epilepsy......Page 390
Drug interactions in various health conditions......Page 391
Unpredicted interactions when more than two drugs are used......Page 393
Interactions with folk medicine......Page 394
Gabapentin......Page 395
Levetiracetam......Page 397
Phenobarbital......Page 398
Phenytoin......Page 399
Tiagabine......Page 400
Topiramate......Page 401
Summary......Page 402
REFERENCES......Page 403
Introduction......Page 412
Indications for drug monitoring in antiepileptic combination therapy......Page 413
Avoidance of underdosage......Page 414
Avoidance of intoxication and identification of suspected side effects......Page 415
Measurement of the free (non-protein bound) concentration of AEDs......Page 417
Limits and dangers of the determination of serum concentrations of AEDs......Page 418
Future of monitoring......Page 419
REFERENCES......Page 420
Introduction......Page 423
Review of psychometric studies......Page 424
Methodological considerations......Page 428
Serum concentration-effect relationships......Page 429
Discussion of cognitive effects......Page 430
Clinical effects......Page 431
Subjective patient complaints......Page 432
Conclusion......Page 434
REFERENCES......Page 436
Part V Conclusions and future perspectives......Page 439
Introduction......Page 441
Pharmacotherapy-resistant seizures......Page 442
Scale of the problem......Page 443
Rational polytherapy......Page 444
Combination therapy with old AEDs......Page 445
Lamotrigine plus......Page 447
Topiramate plus......Page 448
Combination therapy of three or more AEDs......Page 449
New perspectives on resistance to pharmacotherapy......Page 451
REFERENCES......Page 455
Introduction......Page 461
Experimental animal models......Page 462
Disease progression......Page 464
Pharmacokinetic factors and interactions......Page 465
Development of drug combinations: a modeling approach......Page 466
Assessment of efficacy of drug combinations: experimental aspects......Page 469
Controlled seizure activity and pharmacologic endpoints......Page 470
Design of experiments......Page 471
Integrated PK/PD modeling......Page 472
Summary and conclusions......Page 473
REFERENCES......Page 474
Introduction......Page 478
Improved definition of epileptic syndromes: recent and promising tools to study combinations of AEDs......Page 479
Designing RP in a single drug (with multiple mechanisms)......Page 481
Designing 'curative' antiepileptogenic drugs......Page 482
Clinical studies to test combinations of AEDs......Page 483
Safety aspects......Page 487
Pharmacovigilance......Page 488
Pharmacogenomics and choice of the personal AED......Page 491
REFERENCES......Page 492
Index......Page 495