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  1. Home
  2. Books
  3. Antiepileptic Drugs
  • Cited by 2
Publisher:
Cambridge University Press
Online publication date:
September 2009
Print publication year:
2005
Online ISBN:
9780511545023
DOI:
https://doi.org/10.1017/CBO9780511545023
Subjects:
Neurology and Clinical Neuroscience, Medicine
Information

Book description

This book reviews the use of antiepileptic drugs focusing on the interactions between these drugs and between antiepileptics and other drugs. These interactions can be beneficial or can cause harm. The aim of this book is to increase awareness of the possible impact of combination pharmacotherapies. Pharmacokinetic and pharmacodynamic interactions are discussed supported by clinical and experimental data. The book consists of five sections covering the general concepts and advantages of combination therapies, the principles of drug interactions, the mechanisms of interactions, drug interactions in specific populations or in patients with co-morbid health conditions, and concludes with a look at the future directions for this field of research. The book will be of interest to all who prescribe antiepileptics to epileptic and non-epileptic patients, including epileptologists, neurologists, neuro-pediatricians, psychiatrists and general practitioners.

Reviews

'The book contains a wealth of information both for everyday practice and for more theoretical aspect. Interactions between AED … covered in great detail. … Why is this book so important? The authors explain it in their foreword. As a substantial proportion of patients with epilepsy will not become seizure free with one drug, combination therapy is necessary and therefore often used.'

Source: Official Journal of the European Paediatric Neurology Society

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Contents

Page 1 of 2

Contents
  • 1 - Combination therapy of diseases: general concepts
    pp 3-15
  • View abstract

    Summary

    Combination therapy has been used since therapeutics was first practiced. A scientific basis for the value of combination therapy was established in the 1940s. This chapter treats the term polytherapy as synonymous with combination therapy, a term that is more widely accepted across the spectrum of therapeutics and throughout Europe and the USA. Combinations of medicines with different spectra of adverse drug reactions may allow reduction of dose of each compound to levels that are less likely to produce clinically relevant toxicity. One of the principles of combination therapy in cancer is that the agents should have non-overlapping toxicity. The use of combination therapy means that the patient has to take more tablets, unless the drugs have been formulated in a combined preparation. Combination therapy is an essential therapeutic tool, although one that can all too often be misused, to the detriment of the patient.
  • 2 - Combination therapy with antiepileptic drugs: potential advantages and problems
    pp 16-25
  • View abstract

    Summary

    The primary reason why two or more drugs are used together is the failure of monotherapy to control the seizures. It is assumed that combined antiepileptic drugs (AEDs) work to increase efficacy either by an additive and/or synergistic effect or by achieving infra-additive adverse effects allowing a higher dose to be administered. Combination therapy is clearly indicated when two or more seizure types exist that fail to respond to any one agent. A potential advantage of combination therapy is to add efficacy at the same time using AEDs with counteracting adverse effects. Combinations of AEDs may produce pharmacodynamically active metabolites not present in clinically relevant concentrations when drugs are used as monotherapy. In some cases combining an enzyme-inducing drug such as phenytoin (PHT) with carbamazepine (CBZ) or valproate (VPA) increases the clearance, often requiring a much larger dose to achieve blood levels comparable to those achieved with monotherapy.
  • 3 - Pharmacogenetic aspects
    pp 26-44
    • By Matthew C. Walker, Pharmacology and Therapeutic Unit, Department of Clinical and Experimental Epilepsy, Institute of Neurology, Queen Square, London, UK, Michael R. Johnson, Division of Neurosciences and Psychological Medicine, Imperial College London, Charing Cross Hospital, London, UK, Philip N. Patsalos, Pharmacology and Therapeutic Unit, Department of Clinical and Experimental Epilepsy, Institute of Neurology, Queen Square, London, UK
  • View abstract

    Summary

    Pharmacogenetics and pharmacogenomics are fields which show how the genetic make-up of an individual can influence drugs effects. Genetic polymorphisms can influence antiepileptic drug (AED) responses and, during polytherapy, their interaction profile by influencing metabolism, central nervous system penetration, pharmacodynamics and adverse events. This chapter considers the evidence for each of these and reviews the uses and pitfalls of genetic screening. The point of action for AEDs is the brain, and so AEDs have to be able to cross the blood-brain barrier. GABAA receptors are the target for a number of AEDs since alterations in GABAA receptor-mediated transmission have been implicated in the pathogenesis of epilepsy. The predictive value of a pharmacogenetic test can be viewed from a genetic epidemiological perspective. Clinical and cost effectiveness of pharmacogenetic tests may need to be established in prospective randomized trials and their use may require new professional standards of testing and test interpretation.
  • 4 - Pharmacokinetic principles and mechanisms of drug interactions
    pp 47-56
    • By Philip N. Patsalos, Pharmacology and Therapeutics Unit, Department of Clinical and Experimental Epilepsy, Institute of Neurology, London, UK; The National Society for Epilepsy, Chalfont St Peter, UK
  • View abstract

    Summary

    This chapter reviews the pharmacokinetic principles that are important to drug interactions and relates these to the major mechanisms of drug interactions. Although drug interactions with antiepileptic drugs (AEDs) are rare during absorption, such interactions can be important in some cases. Interactions involving the distribution of drugs are difficult to ascertain. Distribution of AEDs from the blood compartment to the brain is very necessary for a successful therapeutic outcome. Metabolism is the most important mechanism of elimination and accounts for the majority of clinically relevant drug interactions with AEDs. By far the most important pharmacokinetic interactions with AEDs are those which are related to induction or inhibition of drug metabolism. Although drug interactions affecting renal excretion are rare with AEDs, AEDs that undergo extensive renal elimination in unchanged form may be susceptible to interactions affecting the excretion process.
  • 5 - Predictability of metabolic antiepileptic drug interactions
    pp 57-92
    • By Edoardo Spina, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy, Emilio Perucca, Clinical Pharmacology Unit, University of Pavia, Pavia, Italy, Rene Levy, Department of Pharmaceutics, University of Washington, Seattle, WA, USA
  • View abstract

    Summary

    Knowledge of the main enzyme systems involved in the biotransformation of antiepileptic drugs (AEDs) is essential for understanding the principles and mechanisms of metabolically based drug interactions involving these drugs. In recent years, the major cytochrome P450 (CYP) isoenzymes have been characterized at the molecular level and their different substrates, inhibitors and inducers have been identified. Drug interactions involving CYP isoforms and other drug-metabolizing enzymes may result from one of two processes, enzyme induction or inhibition. The potential for metabolic drug interactions is an important aspect to be considered during the development of new drugs. Initially, the simplest approach to the in vitro study of drug metabolism was through use of purified enzymes. Prediction of interactions that may affect the test drug requires knowledge of the enzyme systems and knowledge of the influence of other drugs on such enzyme systems.
  • 6 - Influence of food and drugs on the bioavailability of antiepileptic drugs
    pp 93-110
  • View abstract

    Summary

    This chapter deals with interactions which occur before pharmaceutical interactions and during pharmacokinetic interactions absorption. The delivery of drugs into the circulation may be altered by physicochemical interactions that occur prior to absorption. Several drugs can interfere with the physiologic conditions and function of the gastrointestinal tract, and therefore alter the absorption of other drugs. Phenytoin is the most studied of the antiepileptic drugs (AEDs), principally because it has been in use the longest. Food has been found to have variable but modest, usually enhancing, effects on phenytoin absorption. Epileptic patients receiving phenytoin have been reported to exhibit a significantly smaller diuretic response to furosemide. The gastrointestinal absorption of carbamazepine formulations is slow, erratic and unpredictable. Over the past few years, eight new AEDs felbamate, gabapentin, lamotrigine, oxcarbazepine, topiramate, zonisamide, vigabatrin, and levetiracetam have reached the market and are licensed for clinical use.
  • 7 - Interactions between antiepileptic drugs
    pp 111-138
  • View abstract

    Summary

    Old and new antiepileptic drugs (AEDs) are associated with a wide range of pharmacokinetic drug-drug interactions. Classical pharmacokinetic interactions are enzyme induction, enzyme inhibition and displacement from protein binding. Numerous studies have been performed showing that phenobarbital (PB) decreases concentrations of other concomitantly given AEDs. The interaction of phenytoin (PHT) with valproic acid (VPA) is somewhat complex as it primarily concerns protein binding. In the last decade, a series of new AEDs have become available for the treatment of epileptic patients. The experience of several decades with the classic AEDs has shown that interactions may have severe clinical consequences. Reports on AED interactions usually focus on the increase or decrease of serum concentrations. Most interactions correspond to the pharmacokinetic properties of the compounds, but it should be borne in mind that rare interactions may also play an important role in the individual.
  • 8 - Interactions between antiepileptic and non-antiepileptic drugs
    pp 139-178
    • By Jerzy Majkowski, Center for Epilepsy Diagnosis and Treatment Foundation of Epileptology, Warsaw, Poland, Philip N. Patsalos, Pharmocology and Therapeutics Unit, Department of Clinical and Experimental Epilepsy, Institute of Neurology, London; The National Society for Epilepsy, Chalfont St Peter, UK
  • View abstract

    Summary

    Clinically important drug interactions occur essentially at two levels, at the pharmacokinetic level and at the pharmacodynamic level. This chapter describes the clinically significant interactions between antiepileptic drugs (AEDs) and non-AEDs. The interactions can be classified into three groups according to their risk of interaction with AEDs. Carbamazepine is a potent hepatic enzyme inducer and, as well as inducing its own metabolism via an action on CYP3A4, it also induces the metabolism of many other drugs that are CYP3A4 substrates. There are no clinical data to suggest ethosuximide induces or inhibits the metabolism of other non-AEDs. As a new AED, knowledge of the interaction profile of felbamate with non-AEDs is limited. Zonisamide undergoes extensive metabolism, via CYP3A4, and approximately 30% of zonisamide is excreted in urine as unchanged zonisamide. To date, there are no reports of zonisamide affecting the pharmacokinetics of non-AEDs.
  • 9 - Pharmacodynamic principles and mechanisms of drug interactions
    pp 181-192
    • By Blaise F. D. Bourgeois, Harvard Medical School, Division of Epilepsy and Clinical Neurophysiology, Children's Hospital, Boston, MA, USA
  • View abstract

    Summary

    Pharmacodynamic interactions consist of the quantitative or qualitative alterations of any effect of a drug on any organ when these alterations are caused by the presence of another drug in the body. In order for two drugs to have a pharmacodynamic interaction, they have to share at least one common pharmacodynamic property or they have to share an identifiable clinical effect. Whenever a patient takes two or more medications simultaneously, there is the potential for some type of pharmacodynamic interaction. There can be doubt that one of the main disadvantages of antiepileptic combination therapy is an increase in the intensity or number of side effects. This chapter discusses the clinical significance of pharmacodynamic interactions and their advantages and disadvantages. A literature review of data in animals and in humans was used to determine whether appropriate antiepileptic drugs (AED) combinations can be selected on the basis of their mechanism of action.
  • 10 - Methods for assessing pharmacodynamic interactions
    pp 193-207
    • By Blaise F. D. Bourgeois, Harvard Medical School, Division of Epilepsy and Clinical Neurophysiology, Children's Hospital, Boston, MA, USA
  • View abstract

    Summary

    Assessing a pharmacodynamic interaction between two drugs requires a valid quantitative measurement of a specific drug effect for the two drugs individually, as well as a quantitative measurement of the effect of the two drugs administered together. The isobolographic analysis is widely used to determine the various types of pharmacodynamic interaction in experimental animal models, in particular for antiepileptic drugs. Besides the isobolographic analysis, various other methods have been used to assess pharmacodynamic interactions. One of them is the fractional effective concentration (FEC) index. The difficulties encountered in the assessment of pharmacodynamic interactions in experimental animals are compounded when interactions are to be studied clinically in patients, especially for antiepileptic drugs. The discussion on designs of clinical trials to study pharmacodynamic interactions between antiepileptic drugs is based on the assumption that the studies are to be clinically relevant.
  • 11 - Experimental studies of pharmacodynamic interactions
    pp 208-227
    • By Stanislaw J. Czuczwar, Department of Pathophysiology, Medical University and Isotope Laboratory, Institute of Agricultural Medicine, Jaczewskiego, Lublin, Poland
  • View abstract

    Summary

    There have been many experimental studies dealing with combinations of conventional antiepileptic drugs. In the early 1980s, intensive experimental studies were initiated on the possible anticonvulsant activity of ionotropic glutamate receptor antagonists. Although many calcium channel inhibitors actually potentiated the anticonvulsant activity of conventional antiepileptic drugs, in many cases significant side effects were evident. Experimental data may provide a good background for the add-on treatment of epilepsy. Experimental studies provide evidence that a combination of two antiepileptic drugs may produce antagonistic, additive, and supra-additive (synergistic) anticonvulsant effects. A drug combination producing a supra-additive seizure protection should be of clinical interest. Existing experimental evidence points to a favorable synergistic interaction between valproate and phenytoin or topiramate and carbamazepine, or felbamate and all major antiepileptic drugs. The experimental data may be helpful for choosing drug combinations potentially beneficial in epileptic patients.
  • 12 - Clinical studies of pharmacodynamic interactions
    pp 228-240
  • View abstract

    Summary

    This chapter addresses the clinical impact of pharmacodynamic (PD) interactions of antiepileptic drugs (AEDs) and the strategies that have been used to discover these interactions. It outlines trials that have provided, or have attempted to provide, relevant data on PD interactions that impact on efficacy. The most common studies of additive effects of AEDs are the randomized placebo-controlled add-on studies of the new AEDs. Negative-PD interactions, also called supra-additivity for side effects, may occur when two drugs with similar side-effect profiles exceed the threshold for that side effect in combination but not individually. Several studies of specific AED combinations have demonstrated an increase in side effects. PD interactions may also increase the likelihood of non-dose-related side effects and serious idiosyncratic reactions. To date, the best data for a potentially supra-additive effect on efficacy are for the combination of lamotrigine and valproate (VPA).
  • 13 - Clinical studies of pharmacodynamic interactions between antiepileptic drugs and other drugs
    pp 241-254
    • By Gaetano Zaccara, Unit of Neurology, Santa Maria Nuova Hospital, Florence, Italy, Andrea Messori, Drug Information Centre, Careggi Hospital, Florence, Italy, Massimo Cincotta, Unit of Neurology, Santa Maria Nuova Hospital, Florence, Italy
  • View abstract

    Summary

    This chapter discusses the clinical data concerning pharmacodynamic (PD) interactions of antiepileptic drugs (AEDs) with antidepressants (ADs), antipsychotics (APs), central nervous system (CNS) stimulants, anesthetic agents, analgesics and anti-inflammatory drugs. Experimental and clinical data suggest that AEDs and ADs have similar mechanisms of action which could result in favorable and/or unfavorable PD interactions depending on the particular agents involved. AP and AEDs are frequently co-administered and PD interactions concerning their effects on psychosis and seizure threshold are possible. At low doses, stimulants are co-administered with AEDs in the epileptic patient and seem to have beneficial PD interactions. Among anesthetic agents, lidocaine is of particular interest. Treatment of anesthetic-induced convulsions can be particularly difficult because of many possible unfavorable PD interactions. AEDs, analgesics and anti-inflammatory drugs can often be co-administered for the treatment of some forms of pain.
  • 14 - Antiepileptic drug interactions in children
    pp 257-272
  • View abstract

    Summary

    This chapter reviews the characteristics of the various interactions between the various antiepileptic drugs (AEDs), including those that are in development and what is presently known regarding their mechanism. It highlights the benefits this knowledge can offer to optimize the treatment for each type of epilepsy in children. A number of AEDs have been shown to be effective as monotherapy for various types of epilepsy, in which they may therefore be administered as first-line drug. In infancy, Dravet syndrome may worsen with the addition of carbamazepine (CBZ), phenobarbital (PB), lamotrigine (LTG), or vigabatrin (VGB). The coadministration of AED and chemotherapeutic drugs (CTD) may lead either to reduced activity or increased toxicity of an AED. Although the rule of monotherapy as the strategy of choice clearly applies to the majority of pediatric patients suffering from epilepsy, it remains difficult to maintain it for patients with pharmacoresistant epilepsy.
  • 15 - Antiepileptic drug interactions in the elderly
    pp 273-293
    • By Jeannine M. Conway, James C. Cloyd, Epilepsy Research and Education Program, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA
  • View abstract

    Summary

    Antiepileptic drugs (AEDs) are frequently prescribed in the elderly due to the high prevalence of AED-treatable neuropsychiatric disorders in this age group. There are several factors associated with AED therapy in the elderly that substantially increase the risk of clinically significant drug interactions. The elderly exhibit altered pharmacodynamics resulting in greater sensitivity to both pharmacological and toxicological drug effects. The use of polypharmacotherapy leaves the elderly patient at an increased risk for adverse events. There are no known drug interactions between anticoagulants/antiplatelets and the following AEDs: gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), tiagabine (TGB), or zonisamide (ZNS). A number of AEDs either induce or inhibit drug metabolizing enzymes and, in turn, their metabolism is affected by many co-medications. Several of the newer AEDs do not appear to interact with other medications, while others are affected by enzyme induction of inhibition but do not appear to alter the disposition of co-medications.
  • 16 - Antiepileptic drug interactions in pregnancy
    pp 294-324
    • By Mark S. Yerby, North Pacific Epilepsy Research, Oregon Health Sciences University, Portland, Oregon, USA
  • View abstract

    Summary

    This chapter reviews some of the clinically important issues surrounding pregnancy and antiepilepsy drugs (AED) exposure. One-quarter to one-third of woman with epilepsy (WWE) will have an increase in seizure frequency during pregnancy. A number of adverse outcomes of pregnancy are known to occur more often in infants of mothers with epilepsy (IME). Five clinical syndromes have been reported in IMEs: fetal trimethadione syndrome, FHS, a primidone embryopathy, a fetal valproate syndrome and a fetal carbamazepine syndrome. There have been case reports of anomalies associated with exposure to the newer, AEDs, but no drug-specific syndrome of anomalies described. While pregnancy, maternal seizures and AEDs pose risks for successful pregnancy outcome, the majority of patients can and do have healthy children. Valproic acid (VPA) has in addition to the underlying increased risk for malformations an additional risk for development of neural tube defects (NTDs).
  • 17 - Antiepileptic drug interactions in handicapped and mentally retarded patients
    pp 325-340
    • By Matti Sillanpää, Departments of Child Neurology and Public Health, University of Turku, Turku, Finland
  • View abstract

    Summary

    This chapter emphasizes the context in which pharmacokinetic and pharmacodynamic interactions are likely to occur during the treatment of epilepsy in handicapped and mentally retarded patients. The diagnosis of epileptic seizures may be difficult in mentally retarded patients, because they cannot in many cases express themselves and therefore fail to tell about their perceived symptoms. The main groups of reasons for intractability of seizures are related to actions by the physician, to the patient, to the epilepsy itself, and to the drugs. Epilepsy in mental retardation commonly presents with several seizure types, drug resistance, concomitant psychiatric symptoms and syndromes with various enzyme abnormalities, which increase the risk of interactions. The outcome of drug therapy may be difficult to assess in the mentally retarded, for example in patients with infantile spasms. The impact of the newer antiepileptic drugs may consist of a better tolerability with fewer interactions.
  • 18 - Antiepileptic drugs and sex steroids
    pp 341-349
    • By Richard H. Mattson, Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
  • View abstract

    Summary

    In 1972 Kenyon sent a letter to the British Medical Journal describing a patient with epilepsy treated with phenytoin (PHT) who became pregnant despite taking usual amounts of oral contraceptive (OC) pills. Following the initial case report by Kenyon, three other cases of OC failure were cited by Janz and Schmidt. Antiepileptic drug (AED)-induced clearance and increased sex-hormone-binding globulin (SHBG) may result in lower free testosterone with resultant decrease in libido, potency and spermatogenesis. Most pharmacokinetic studies have suggested the estrogens and progestins in the OC pill were cleared approximately twice as rapidly in women patients receiving enzyme-inducing AEDs compared to normal controls. The safest way of dealing with the problem of unwanted loss of OC effectiveness is to avoid AEDs that affect the clearance of sex steroids. Increased clearance and possible loss of contraceptive effect is found with felbamate (FBM) and oxcarbazepine (OXC).
  • 19 - Antiepileptic drug interactions in patients requiring psychiatric drug treatment
    pp 350-368
    • By Michael R. Trimble, The National Hospital for Neurology and Neurosurgery, Institute of Neurology, Queen, Square, London, UK, Marco Mula, Amadeo Avogadro University, Novara, Italy
  • View abstract

    Summary

    In recent years a number of newer antidepressant drugs have been introduced into clinical practice. The new generation of antipsychotic drugs essentially fall into two categories; those that are clozapine related, which included olanzapine and quetiapine, and others such as risperidone. It is also known that many patients with epilepsy receive psychotropic drugs, sometimes but not always on account of psychiatric symptoms. Neuroleptics, such as phenothiazines, are metabolized by intestinal sulfoxidases, although CYP2D6 plays an important role in chlorpromazine and thioridazine metabolism. Antidepressants have been extensively evaluated in relation to the general problem of their proconvulsant activity. Historically, antipsychotic drugs have been considered proconvulsants possibly because of their D2-receptor blocking activity. As far as antidepressant drugs are concerned, fluoxetine and nefazodone interactions are probably the most relevant in epilepsy from a clinical point of view.
  • 20 - Antiepileptic drugs in non-epileptic health conditions: possible interactions
    pp 369-391
    • By Jerzy Majkowski, Center for Epilepsy Diagnosis and Treatment Foundation of Epileptology, Warsaw, Poland
  • View abstract

    Summary

    This chapter emphasizes the spectrum and scale of antiepileptic drugs (AED) usage in medical disciplines other than epilepsy, and to increase awareness of unpredicted drug interactions when combination therapy with two/three drugs is used. There are many pharmacological reasons why AEDs have therapeutic effects in non-epileptic neurological and psychiatric conditions. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients creates the risk of drug interactions. In many countries folk medicine is frequently used for various reasons. Carbamazepine (CBZ) is one of the most commonly used AEDs in epilepsy and other neurological and psychiatric disorders. Many drug interactions can be demonstrated but only a few of them are so clinically significant that they require adjustment of drug dosages. Case reports of toxic effects due to drug interactions are presented in the chapter as a warning signal calling for attention when polytherapy has to be used.

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