Antiepileptic Drugs

ISBN-13: 9783642695209 / Angielski / Miękka / 2011 / 867 str.

Hans-Hasso Frey;D. Janz

Opis

Epileptic disorders need treatment for many years or even for life, and this makes a thorough understanding of the pharmacokinetics and possible hazards and side effects of the drugs used in treatment mandatory. During recent decades our knowledge in this field has considerably increased, not least as a result of the development of specific and sensitive methods for the determination of anti- epileptic agents in biological material. The clinical pharmacology of this group of drugs has been studied extensively and can today be regarded as well established. This does not necessarily mean that drug treatment of epilepsy is without problems. For example, it has recently been shown that one of the newer anti- epileptic drugs, greeted with great enthusiasm by clinicians, may in rare instances induce serious damage to the liver and the pancreas, and seems even to have a certain teratogenic potential. Clinical problems should be understood as a challenge to the experimental pharmacologist, who should try to find explanations for the clinical hazards, and, if possible, show new ways in which better drugs might be developed. In recent years interest has focused on the importance of the inhibitory transmitter 'l'-aminobutyric acid (GABA) in the pathophysiology of epilepsy, and there have been a series of attempts to find useful antiepileptic drugs among substances interfering with GABA metabolism in the CNS.

Spis treści

Clinical Aspects of Epileptic Diseases.- 1 Epilepsy: Seizures and Syndromes.- A. Definition.- B. Epidemiology.- C. Classification.- D. Epileptic Seizures.- E. Syndromes of Epilepsy.- F. Age-Related Syndromes.- I. Neonatal Convulsions (Neonatal Seizures).- II. Febrile Convulsions.- III. Epilepsy with Infantile Spasms (West Syndrome, Infantile Spasms, Epilepsy with Propulsive Petit Mai).- IV. Epilepsy with Myoclonic-Astatic Seizures (Lennox-Gastaut Syndrome.- V. Epilepsy with Frequent Absences (Friedmann Syndrome, Pyknolepsy).- VI. Epilepsy with Juvenile Myoclonic Jerks (Herpin-Janz Syndrome, Epilepsy with Impulsive Petit Mai, Juvenile Myoclonic Epilepsy).- VII. Awakening Epilepsy (Epilepsy with Nonfocal Grand Mai).- VIII. Benign Focal Epilepsy of Childhood [Benign Epilepsy of Children with Rolandic (Centrotemporal) Foci].- G. Age-Unrelated Epilepsy Syndromes.- I. Epilepsies with Complex Focal (Psychomotor) Seizures (Temporal, Rhinencephalic, Limbic Epilepsy).- II. Epilepsies with Simple Focal Seizures (Neocortical Epilepsy, Epilepsy with Jacksonian Seizures, Adversive Seizures, Sensory Auras, Sensory Seizures).- III. Status Epilepticus.- IV. Syndromes of Seizures Elicited by Sensory Stimuli (So-called Reflex Epilepsies).- References.- 2 Electroencephalography.- A. Introduction.- B. Main Forms of Epileptiform Patterns.- C. Focal Epileptiform Activity.- D. Bilateral Epileptiform Patterns.- E. Activation Procedures.- F. Electrocorticography and Depth-recording.- References.- 3 Epilepsy in Animals.- A. Introduction.- B. Acquired Epilepsies in Animals.- C. Inherited Epilepsies in Animals.- I. Photomyoclonic Seizures in the Baboon (Papio papio).- II. Inherited Epilepsy in Dogs.- III. Inherited Epilepsy in Mongolian Gerbils (Meriones unguiculatus).- IV. Inherited Epilepsy in Domestic Fowl.- D. Concluding Remarks.- References.- Pathophysiology of Seizure Disorders.- 4 Intermediary Metabolism.- A. Introduction.- B. Brain Energy Reserves and the Cell Redox Potential.- I. Cerebral Energy Use During Seizures.- II. Brain Redox Potential and Lactic Acidosis.- C. Seizures and Glycolytic Flux.- I. Regulation of Glycolysis: Phosphofructokinase.- II. Hexokinase.- III. Pyruvate Kinase.- D. The Citric Acid Cycle and Epileptic Seizures.- I. Energy Metabolism.- II. Amino Acid Metabolism.- III. Ammonia Metabolism.- E. Free Fatty Acid Metabolism.- F. Metabolic Mechanisms of Neuronal-Cell Damage During Status Epilepticus.- I. Role of Extracerebral Factors.- II. Role of Sustained Cell Firing.- III. Role of Energy Failure.- IV. Lactic Acidosis.- V. Calcium “Cytotoxicity”.- G. Epileptic Seizures in the Neonate.- I. Mobilization of Glycogen Reserves.- II. Limited Transport Capacity of the Blood-brain Barrier.- References.- 5 Monoamines and the Pathophysiology of Seizure Disorders.- A. Introduction.- B. Catecholamines.- I. Electrically Induced Seizures.- II. Seizures Induced by Chemical Agents.- III. Reflex Epilepsy Models.- IV. Other Models of Epilepsy.- C. Serotonin.- I. Electrically Induced Seizures.- II. Seizures Induced by Pentylenetetrazol.- III. Reflex Epilepsy Models.- D. Histamine.- E. Conclusions.- References.- 6 Acetylcholine.- A. Introduction.- B. Effect of Cholinergic Drugs on Susceptibility to Seizures.- C. Effect of Experimental and Spontaneous Seizures on the Cholinergic System.- I. Electroshock and Convulsant Drugs.- II. Spontaneous and Audiogenic Convulsions.- III. Focal Epilepsy.- D. Kindling and the Cholinergic System.- E. Conclusions.- References.- 7 GABA and Other Amino Acids.- A. Introduction: Amino Acids as Neurotransmitters.- B. Amino Acids Producing Inhibition.- I. Introduction.- II. GABA.- III. Glycine.- IV. Taurine.- C. Amino Acids Producing Excitation.- I. Dicarboxylic Amino Acids.- II. Sulphinic and Sulphonic Acids.- D. Concluding Remarks.- I. Inherited Abnormalities of Amino Acid Metabolism and Epilepsy.- II. Amino Acids and Antiepileptic Drugs.- References.- 8 Prostaglandins.- A. Introduction.- B. Effects of Prostaglandins on Experimentally Induced Convulsions.- C. Convulsant Effect of Prostaglandins.- D. Release of Prostaglandins During Convulsions.- E. Conclusions.- References.- General Pharmacology of Antiepileptic Drugs.- 9 Chemical Constitution and Pharmacological Effect.- A. Introduction.- B. Five-Membered Heterocyclic Compounds.- I. Hydantoins.- II. Oxazolidinediones.- III. Succinimides.- C. Six-Membered Heterocyclic Compounds.- I. Barbiturates and Other Compounds.- II. Phenobarbital and Primidone.- D. Acyl Ureas.- E. Tricyclic Compounds: Carbamazepine.- F. Benzodiazepines.- G. Valproic Acid.- H. Miscellaneous Compounds.- References.- 10 Biochemistry.- A. Introduction.- B. Ionic Permeability.- I. Effects on Sodium Conductance.- II. Effects on Calcium Conductance.- III. Effects on Potassium Conductance.- IV. Effects on Chloride Conductance.- C. Neurotransmitter Metabolism, Disposition, and Dynamics.- I. Effects on Intracellular Processes Related to Transmitter Release.- II. Effects on Neurotransmitter Metabolism and Disposition.- III. Effects on Receptor-Ionophore Dynamics.- D. Perspective.- References.- 11 Tolerance and Dependence.- A. Introduction.- B. Tolerance.- I. Metabolic Tolerance.- II. Functional Tolerance.- III. Acute Tolerance.- IV. Conclusions.- C. Physical Dependence.- I. Experimental Evidence.- II. Clinical Evidence.- III. Conclusions.- References.- 12 Animal Experimental Methods in the Study of Antiepileptic Drugs.- A. Introduction.- B. Models of Epileptiform Phenomena in Animals.- I. Electrically Induced Seizures.- II. Chemically Induced Ictal and Interictal States (Exclusive of Metals).- III. Focal Epileptogenesis Through Local Application of Metals or Metal Salts.- IV. Local Freezing as Epileptogenic Factor.- V. Models for Secondary and Progressive Epileptogenic Lesions.- VI. Animals with “Inborn” Epilepsy: Genetic Models.- VII. Circadian Aspects.- C. Some Nonsymptomatic Models.- I. Biophysical Approach.- II. Biochemical Approach.- D. Discussion.- I. Models for Screening.- II. Testing for “Special Indications”.- References.- Appendix to Chapter 12 Antiepileptic Drug Development Program.- A. Antiepileptic Drug Development Programm.- B. Anticonvulsant Screening Project.- I. Phase I.- II. Phase II.- III. Phase III.- IV. Phase IV.- V. Phase V.- VI. Phase VI.- VII. Phase VII.- C. Toxicity/Selected Pharmacology Project.- D. Primate Model of Epilepsy.- E. Controlled Clinical Trials.- References.- Specific Pharmacology of Antiepileptic Drugs.- 13 Hydantoins.- A. Introduction.- B. Chemistry.- I. Physicochemical Properties.- II. Structure-Activity Relationships.- III. Analytical Methods.- C. Anticonvulsant Activity.- I. Anticonvulsant Potency in Laboratory Animals.- II. Anticonvulsant Potency in Man.- III. Mechanism of Anticonvulsant Action.- D. Other Central Nervous System Effects.- E. Actions Outside the CNS.- I. Cardiac Muscle.- II. Smooth Muscle.- III. Skeletal Muscle.- IV. Other Actions.- F. Pharmacokinetics.- I. Absorption and Bioavailability.- II. Distribution.- III. Biotransformation.- IV. Excretion.- G. Drug Interactions.- H. Toxicology.- I. Acute Toxicity.- II. Chronic Toxicity Studies.- III. Teratogenic Effects.- IV. Mutagenic Effects.- V. Other Toxic Effects.- References.- 14 Barbituric Acid Derivatives.- A. Introduction.- B. Chemistry and Physicochemical Properties.- I. Relationship of Molecular Structure to Anticonvulsant Activity.- II. Relationship of Acidic and Lipophilic Properties of Barbituric Acid Derivatives to CNS Activity.- C. Analytical Methods for Determination of Barbituric Acid Derivatives in Biological Fluids and Tissues.- D. Anticonvulsant Activity.- E. Other CNS Effects.- F. Pharmacodynamic Effects Outside the CNS.- G. Pharmacokinetics.- I. Absorption.- II. Distribution.- III. Metabolism.- IV. Excretion.- H. Drug Interactions.- J. Toxicology.- References.- 15 Primidone.- A. Chemistry and Physicochemical Properties.- I. Physicochemical Properties.- II. Analytical Methods for Determination from Biological Material.- B. Anticonvulsant Activity.- I. Anticonvulsant Efficacy in Laboratory Animals.- II. Anticonvulsant Potency in Man.- III. Mechanism of Anticonvulsant Action.- C. Other Central Nervous System Effects.- D. Pharmacodynamic Actions Outside the Central Nervous System.- E. Pharmacokinetics.- I. Absorption.- II. Distribution.- III. Metabolism.- IV. Elimination.- F. Drug Interactions.- G. Toxicology.- I. Acute Toxicology.- II. Chronic Toxicity Studies.- III. Teratogenic Effect.- IV. Mutagenic Effect.- V. Other Toxic Effects.- VI. Clinical Intoxications.- References.- 16 Carbamazepine.- A. Introduction.- B. Chemistry and Physicochemical Properties.- C. Anticonvulsant Activity.- I. Anticonvulsant Activity in Rodent-Screening Tests.- II. Anticonvulsant Activity in Further Animal Models.- III. Pharmacological Effects Possibly Related to Anticonvulsant Activity.- IV. Neurobiochemical Effects Possibly Related to Anticonvulsant Activity.- V. Mechanisms of Action.- D. Behavioral, Neurological, and Autonomic Effects.- I. Antiaggressive and/or Anxiolytic Effects.- II. Antineuralgic Effects.- III. Antidiuretic Effects.- IV. Effects on Alcohol-Withdrawal Symptoms.- V. Antiarrhythmic Effects.- VI. Antimaniacal Effects.- VII. Other Effects.- E. Pharmacokinetics.- I. Absorption.- II. Distribution.- III. Metabolism.- IV. Elimination.- F. Drug Interactions.- G. Toxicology.- I. Acute Toxicity Studies.- II. Subacute and Chronic Toxicity Studies.- III. Reproduction Studies.- IV. Mutagenicity Studies.- V. Carcinogenicity Studies.- References.- 17 Valproic Acid.- A. Chemistry and Physicochemical Properties.- B. Antiepileptic Activity.- I. Valproic Acid in Experimental Models of Epilepsy.- II. Mechanism of Anticonvulsant Action of Valproic Acid.- C. Central Nervous System Effects Besides the Anticonvulsant Effect.- D. Pharmacodynamic Properties Outside the Central Nervous System.- E. Pharmacokinetics.- I. Absorption and Bioavailability.- II. Distribution and Protein Binding.- III. Elimination.- F. Drug Interactions.- I. Effect of Valproic Acid on Other Drugs.- II. Effect of Other Drugs on Valproic Acid.- G. Toxicity.- References.- 18 Oxazolidinediones.- A. Introduction.- B. Anticonvulsant Effects.- I. Chemically Induced Convulsions.- II. Electrically Induced Convulsions.- III. Convulsions Produced by Other Methods.- C. Central Nervous System Effects Besides the Anticonvulsant Effect..- I. Influence on the Electroencephalogram.- II. Influence on Behavior.- D. Biochemical Effects.- I. Transmitter.- II. Other Effects.- E. Pharmacodynamic Properties Outside the Central Nervous System.- F. Pharmacokinetics.- I. Absorption.- II. Distribution.- III. Metabolism.- IV. Excretion.- G. Interactions.- H. Toxicity.- References.- 19 Succinimides.- A. Introduction.- B. Anticonvulsant Effects.- I. Chemically Induced Convulsions.- II. Electrically Induced Convulsions.- III. Convulsions Induced by Other Methods.- C. Central Nervous System Effects Besides the Anticonvulsant Effect.- I. Influence on the EEG.- II. Influence on Behavior.- III. Effects on Neurochemical Processes.- D. Pharmacodynamic Properties Outside the Central Nervous System.- E. Pharmacokinetics.- I Absorption.- II. Distribution.- III. Metabolism.- IV. Elimination.- F. Interactions.- G. Toxicity.- References.- 20 Benzodiazepines.- A. Introduction.- B. Chemical Structure of Benzodiazepines.- C. Methods of Determination.- D. Kinetics.- I. Absorption and Distribution.- II. Metabolism and Elimination Half-lives.- E. Anticonvulsant Properties.- F. Relationship Between Anti-Pentylenetetrazol Activity and Brain Concentrations of Benzodiazepines.- G. Relationship Between Benzodiazepine Concentrations in the Brain and High-Affinity Drug-Binding Sites.- References.- 21 Carbonic Anhydrase Inhibitors.- A. Introduction.- B. Anticonvulsant Effect.- C. Clinical Use and Limitations.- D. Toxicity.- References.- 22 Acetylurea Derivatives.- A. Introduction.- B. Chemistry.- I. Synthesis and Physicochemical Properties.- II. Structure-Activity Relations.- C. Experimental Pharmacology.- I. Anticonvulsant Activity.- II. Other Pharmacodynamic Properties.- III. Pharmacokinetics.- IV. Drug Interactions.- V. Effects on Clinical Laboratory Tests.- D. Toxicity.- I. Acute Administration.- II. Chronic Administration.- E. Conclusions.- References.- 23 Electrophysiological Effects of Antiepileptic Drugs.- A. Introduction.- B. Phenytoin.- I. Neuronal Membranes.- II. Synaptic Transmission.- III. Brain.- IV. Summary.- C. Barbiturates.- I. General Remarks.- II. Membrane Excitability.- III. Synaptic Transmission.- IV. Spinal Cord.- V. Brain.- VI. Summary.- D. Carbamazepine.- I. Nerve Fibers.- II. Synaptic Transmission.- III. Brain.- IV. Summary.- E. Valproic Acid.- I. Ganglia and Spinal Cord Neurons.- II. Brain.- III. Summary.- F. Oxazolidinediones.- I. Nerve Fibers and Ganglia.- II. Spinal Cord.- III. Synaptic Transmission in the Spinal Trigeminal Nucleu.- IV. Brain.- V. Summary.- G. Succinimides.- I. Synaptic Transmission.- II. Brain: Focal Seizure Activity.- III. Summary.- H. Benzodiazepines.- I. Facilitation of GABAergic Transmission.- II. Excitable Membranes and Synaptic Transmission in the Periphery.- III. Spinal Cord.- IV. Brain.- V. Summary.- J. Miscellaneous.- I. Carboanhydrase Inhibition: Acetazolamide.- II. Local Anesthetics.- References.- Clinical Pharmacology of Antiepileptic Drugs.- 24 Clinical Pharmacokinetics of Antiepileptic Drugs.- A. Hydantoin Drugs.- I. Phenytoin.- II. Mephenytoin (Methoin).- III. Ethotoin.- B. Barbiturates and Chemically Related Anticonvulsants.- I. Phenobarbital (Phenobarbitone).- II. Methylphenobarbital (Mephobarbital).- III. Eterobarbital.- IV. Primidone.- C. Carbamazepine.- D. Valproic Acid.- E. Succinimides.- I. Ethosuximide.- II. Methsuximide.- III. Phensuximide.- F. Benzodiazepines.- I. Diazepam.- II. Clonazepam.- G. Oxazolidinediones.- I. Trimethadione (Troxidone).- II. Paramethadione.- H. Acetazolamide.- J. Sulthiame.- K. Pheneturide.- References.- 25 Monitoring Antiepileptic Drug Levels.- A. Introduction.- B. Justification for Monitoring Plasma Concentration Levels of Antiepileptic Drugs.- C. The Concept of the Therapeutic Level.- D. Clinical Evaluation of Therapeutic Levels.- E. Therapeutic Plasma Concentration Ranges for the Individual Antiepileptic Drugs.- I. Phenytoin.- II. Carbamazepine.- III. Phenobarbital.- IV. Primidone.- V. Ethosuximide.- VI. Benzodiazepines.- VII. Valproic Acid.- VIII. Other Antiepileptic Drugs.- F. Protein Binding and Monitoring Antiepileptic Drug Levels.- G. Monitoring Antiepileptic Drug Therapy by Measurements in Biological Fluids Other than Plasma.- I. General Considerations.- II. Monitoring Salivary Levels of Antiepileptic Drugs.- III. Monitoring Antiepileptic Drugs in Tears.- H. Active Metabolites and Monitoring Antiepileptic Drug Levels.- I. Phenytoin.- II. Carbamazepine.- III. Phenobarbital.- IV. Primidone.- V. Ethosuximide.- VI. Benzodiazepines.- VII. Valproic Acid.- J. Pharmacodynamic Aspects of Monitoring Antiepileptic Drug Levels..- K. Practical Problems of Monitoring Antiepileptic Drug Levels.- I. Timing of Sampling.- II. Handling of Blood Samples and Results.- L. Utilization of the Monitoring of Antiepileptic Drug Levels.- References.- 26 Clinical Use of Antiepileptic Drugs.- A. Introduction.- B. Use of Antiepileptic Drugs in Epilepsy.- I. Indications for the Use of Antiepileptic Drugs.- II. Aim of Antiepileptic Drug Therapy.- III. Selection of an Antiepileptic Drug.- IV. Use of Antiepileptic Drugs in Practice.- V. Combinations of Antiepileptic Drugs.- VI. Indications for Cessation of Antiepileptic Drug Therapy.- C. Use of Antiepileptic Drugs for Indications Other than Epilepsy.- I. Migraine.- II. Tic Douloureux.- III. Other Varieties of Pain.- IV. Hyperinsulinism.- V. Dyskinesia.- VI. Cardiac Arrhythmia.- VII. Myotonia.- VIII. Miscellaneous.- References.- 27 Adverse Effects.- A. Introduction.- B. Mechanism of Adverse Effects.- I. Dose-Dependent Side Effects.- II. Drug-Induced Diseases.- C. Adverse Effects.- I. Adverse Effects of Individual Antiepileptic Drugs.- II. Antiepileptic Drug-Induced Diseases.- References.- 28 Antiepileptic Drug Interactions.- A. Interactions Affecting the Kinetics of Antiepileptic Drugs.- I. Drugs Which May Affect the Gastrointestinal Absorption of Antiepileptic Drugs.- II. Drugs Which May Affect the Plasma Protein Binding of Antiepileptic Drugs.- III. Drugs Which May Inhibit the Metabolism of Antiepileptic Drugs.- IV. Drugs Which Stimulate the Metabolism of Antiepileptic Drugs.- V. Drugs Which May Affect the Renal Excretion of Antiepileptic Drugs.- B. Interactions Affecting the Kinetics of Other Drugs.- I. Drugs Whose Gastrointestinal Absorption May Be Affected by Antiepileptic Drugs.- II. Drugs Whose Plasma Protein Binding May Be Affected by Antiepileptic Drugs.- III. Drugs Whose Metabolism May Be Inhibited by Antiepileptic Drugs.- IV. Drugs Whose Metabolism May Be Stimulated by Antiepileptic Drugs.- V. Interactions Resulting in Altered Drug Excretion in Urine.- References.