Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

Pharmacology of Antiepileptic Drugs

Summary: Several different types of chemical compounds are useful as antiepileptic drugs. Their mechanisms of action, as well as their physical structures, differ. Compounds such as carbamazepine, phenytoin, and probably valproate act by modifying ionic conductances, particularly sodium and calcium, in excitable membranes, thus limiting sustained high-frequency neuronal discharges. In contrast, barbiturates and benzodiazepines tend to affect 7-aminobutyric acid (GABA) mediation of the chloride channel opening. Knowledge of drug mechanisms is important for choosing the proper drug for various seizure types. In addition, an understanding of antiepileptic drug pharamcokinetics, nonther-apeutic effects, and interactions is essential for optimal therapy. The lack of uniform pharmacokinetics among patients and among different formulations of a drug can make it difficult to arrive at uniform criteria for both seizure control and determinations of toxicity. Both pharmacokinetic and pharmacodynamic interactions can occur between antiepileptic medications and other drugs. Three major types of side effects with anticonvulsants can be identified: dose-related alterations of neurologic function, idiosyncratic reactions, and nonidiosyncratic direct actions on other organ systems. These effects often compromise treatment.     

Treatment Considerations in Anticonvulsant Monotherapy

Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

Carbamazepine Efficacy in Adults With Partial and Generalized Tonic-Clonic Seizures

Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.     

Efficacy and Safety of Antiepileptic Drugs: A Review of Controlled Trials

Summary: Twenty randomized, double-blind, controlled clinical trials of antiepileptic drugs (AEDs) in mostly adult patients with mostly partial onset and/or generalized tonic-clonic seizures have been reported, with a total of 1,336 patients. None of these studies has demonstrated significant differences in antiepileptic efficacy between available antiepileptic drugs, but the results show that there are considerable individual differences between patients' responses to the same drug. While side effects are common with all of the antiepileptic drugs currently available, these are usually mild and reversible. Although some toxic effects may occur more frequently with certain drugs, there is sufficient overlap between the effects of various antiepileptic drugs that most side effects cannot be attributed with certainty to any one drug. Since side effects are generally dose-related, they can frequently be avoided or minimized by careful dosage titration and individualization of therapy.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Anticonvulsant Drugs and Cognitive Function: A Review of the Literature

Summary: Alterations of cognitive function are separate from disturbances of behavior seen in association with epilepsy. The nature of the cognitive disability may to a certain extent depend on the seizure type. Partial seizures, mainly derived from a temporal lobe focus, impair memory tasks, while generalized seizures seem to have more effect on attentional abilities. A number of studies, reviewed in this paper, suggest that anticonvulsant drugs further impair cognitive function. Maximal impairments are seen in patients receiving polytherapy: rationalization of polytherapy improves cognitive abilities. Studies in children and adults have allowed differentiation of the effects of various commonly used antiepileptic agents. Maximal cognitive deficits are seen with. phenytoin, while phenobarbital and sodium valproate induce moderate disturbances, and carbamazepine seems relatively free from such toxicity. Further research is needed on the interrelationship between types of seizure disorders, types of anticonvulsant medications, and cognitive function.     

Serum Bilirubin Levels with Antiepileptic Drugs

The incidence of reduced bilirubin levels in 168 outpatients with epilepsy, compared with levels in 69 controls, has been investigated. Highly significant (p less than 0.001) reductions in average bilirubin levels were noted for carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and multiple drug groups. A marginally significant (p less than 0.05) reduction in bilirubin levels occurred in patients treated with valproate (VPA) which, unlike the other drugs, has not been shown to induce hepatic enzymes.     

Clinically Significant Carbamazepine Drug Interactions: An Overview

Summary: Knowledge of the principles of drug action and distribution contributes to an understanding of the occurrence of drug interactions. The pharmacologic action of most drugs is postulated to occur by the formation of a drug-receptor complex at the site of action that is capable of altering the physiologic response of the target system. The therapeutic response observed depends on the sum of the numerous factors that can affect the disposition pattern of a drug. In an individual, the response to a given drug dose remains relatively constant, but in a large population, a fixed dose can produce a range of plasma concentrations and therefore varied clinical responses. For most drugs, there is a linear relationship between the total dose and the plasma concentration achieved at steady state. Saturation, or zero-order, kinetics accounts for nonlinear increases in drug concentration with dosage increase. Drug-drug interactions with carbamazepine include several types. (1) Autoinduction of carbamazepine metabolism increases the carbamazepine clearance rate, decreases the half-life, and decreases serum concentrations; the clinician must reevaluate a patient's serum levels at 4 to 6 weeks after initiation of therapy. (2) Carbamazepine induces the metabolism of other antiepileptic drugs, enhancing the clearance of phenytoin, primidone, valproic acid, clonazepam, and ethosuximide. (3) Other drugs added to the epileptic patient's drug regimen may induce the metabolism of carbamazepine, causing increased serum concentrations. (4) Inhibition of carbamazepine metabolism by other drugs can also occur; symptoms of drug intoxication rapidly follow. Interactions occur between carbamazepine and macrolide antibiotics, cimetidine, propoxyphene, and isoniazid. Drug-drug interactions are preventable. It is the responsibility of every physician to be alert to the potential for their occurrence whenever a change in the epileptic patient's drug regimen is made.     

Effect of Antiepileptic Drugs on Growth of Murine Lymphoid Tumor Cells in Single-Cell Culture

The effect of three commonly used antiepileptic drugs (AEDs), phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA), on the growth of lymphoid tumor cells was assessed in vitro. A single-cell culture method was used to determine growth rates by direct visualization. The amount of free drug was determined by ultrafiltration to ascertain its correlation to therapeutic drug levels. VPA slowed the growth of B-myeloma (FO) and T-lymphoma (AKR-1) cells significantly within the range of therapeutic drug levels. CBZ and PHT likewise inhibited cell growth in both lineages but at two to four times the therapeutic level of free drug. CBZ was shown to have long-term effects on FO and AKR-1 cells, demonstrated by the reduced growth rates of cloned lines for 2-3 months after drug removal. Cloned sublines of myeloma cells secreting lambda light chain (J558L) treated with CBZ or PHT had a higher frequency of lambda light chain secretion loss mutations than the nontreated parent line.     

Antiepileptic Drugs in Mood-Disordered Patients

Summary:  Bipolar disorder is a common, recurrent, often severe mental disorder that, without adequate treatment, is associated with high rates of morbidity and mortality. We review the evidence on the efficacy of a spectrum of antiepileptic drugs (AED) in bipolar disorder. Most studies have been carried out with carbamazepine (CBZ), valproate (VPA), and lamotrigine (LTG). All three of these AEDs have been shown to be of value in the management of patients with bipolar illnesses. VPA and CBZ seem to exert stronger antimanic effects and, to a lesser degree, acute antidepressant efficacy. LTG seems to be effective against depression and mania, with a more robust activity against depression. No firm evidence supports a role for vigabatrin, tiagabine, topiramate, or levetiracetam in these disorders.     

Pharmacokinetic Considerations in Prescribing Antiepileptic Drugs

Summary: Each antiepileptic drug has a characteristic pharmacokinetic profile, and the unique properties of each must be considered when selecting the optimal agent for a particular patient. Detailed pharmacologic data are obtained during the preapproval evaluation of a drug, particularly in early phase studies in healthy volunteers. Each drug is then evaluated in the target population in later phase trials and in certain populations, such as children and individuals with various types of organ failure. Key considerations are bioavailability, protein binding, metabolism and elimination, and drug interactions. Important pharmacokinetic considerations in the selection and use of these drugs are presented in this review, with examples from currently available drugs.     

Pharmacokinetic Considerations with the Use of Antiepileptic Drugs in Patients with HIV and Organ Transplants

Purpose of Review

Antiepileptic drugs are frequently administered to patients with HIV infection or in recipients of organ transplants. The potentially serious drug-drug interactions between the “classic” antiepileptic drugs, antiretrovirals, and immunosuppressants have been extensively studied. Evidence-based information on the second and third generation of antiepileptic drugs is almost non-existent. The purpose of this review is to analyze the pharmacokinetic profile of these newer agents to assess their potential for drug interactions with antiretrovirals and immunosuppressants.

Recent Findings

As a group, the newer generations of antiepileptic drugs have shown a more favorable drug interaction potential compared to the “classic” ones. A group of moderate enzyme-inducing drugs includes eslicarbazepine acetate, oxcarbazepine, rufinamide, and topiramate. These drugs are not as potent inducers as the “classic” drugs but may potentially decrease the serum concentrations of some antiretrovirals and immunosuppressants. Antiepileptic drugs with no or minimal enzyme-inducing properties include brivaracetam, gabapentin, lacosamide, lamotrigine, levetiracetam, perampanel, pregabalin, and vigabatrin.

Summary

The newer generations of antiepileptic drugs have expanded the therapeutic options in patients with HIV infection or organ transplants.

     

Effects of Antiepileptic Drugs on Hormones

Summary: : A hormone is an intrinsic substance carried via the blood to a target organ which is then functionally stimulated. Similar to extrinsically administered medications, the metabolism and function of the hormones may be altered by antiepileptic drugs (AEDs). The proposed mechanisms are (a) enhanced metabolism (natural steroids, synthetic steroids, e.g., decadron and birth control pills, thyroxine, and vitamin D₃), (b) altered protein bonding (thyroxine, sex hormones), (c) impaired release into the systemic circulation (calcitonin, insulin, vitamin K clotting factors) and (d) altered end-organ effect. The AEDs most likely to interact with hormones are barbiturates, carbamazepine, and phenytoin.     

Valproate Metabolites in Serum and Urine During Antiepileptic Therapy in Children with Infantile Spasms: Abnormal Metabolite Pattern Associated with Reversible Hepatotoxicity

The purpose of this study was to identify abnormal metabolite patterns of valproate (VPA) as possible early indicators of VPA-induced liver toxicity. In a prospective study, we determined serum and urine levels of VPA metabolites by gas chromatography-mass spectrometry (GC-MS) during the course of therapy in 25 children treated for infantile spasms with high VPA doses (less than or equal to 100 mg/kg body weight/day). Most patients had similar metabolite profiles: The main metabolites in serum were the beta-oxidation products (2-en-VPA and 3-keto-VPA) and the major diunsaturated metabolite 2,3'-dien-VPA. Glucuronide conjugates and the oxidation products represent the most abundant metabolites in urine. Other metabolites, including the potential hepatotoxin 4-en-VPA, were detected only in low concentrations. Two children had transiently aberrant metabolite profiles, indicating altered beta-oxidation, (levels of 2-en-VPA, 2,3'-dien-VPA, and 3-en-VPA were markedly increased) in connection with hepatomegaly and increased liver enzyme activities at a time when both had febrile infections and were receiving dexamethasone comedication. At no time were increased levels of 4-en-VPA or its derivatives detected. Establishing the VPA metabolite profile may aid in evaluation of patients who show signs and symptoms of liver dysfunction during VPA therapy. The present study shows that initial stages of hepatotoxicity reactions to VPA may be accompanied by characteristic changes in VPA metabolism; early detection of such abnormal metabolite patterns might decrease the risk of severe hepatic injury.     

Polytherapy, Monotherapy, and Carbamazepine

Summary: Despite the widespread and traditional use of polytherapy in the treatment of epilepsy, there is little evidence of its advantages over monotherapy. Among other undesirable effects, it can produce subtle cognitive and behavioral changes and sometimes even exacerbate the epilepsy. Recent studies provide evidence that in many patients seizures can be controlled by carefully monitored monotherapy: Approximately 75% of newly diagnosed, previously untreated epileptic patients will enter a 2-year remission with this form of treatment. The theory has even been advanced that early control of seizures may help prevent the evolution of drug-resistant, chronic epilepsy. In some patients with chronic epilepsy, multiple-drug therapy can be reduced to single-drug treatment, usually with an improvement in cognitive function and without increase in seizures. Trials conducted to date have shown no evidence of superiority of any one major antiepileptic drug over another in control of a particular seizure type. The choice of antiepileptic drug for monotherapy may therefore be influenced by differences in toxic effects associated with individual agents. On the basis of clinical and psychometric evidence, carbamazepine has been shown to cause fewer adverse effects than other antiepileptic drugs on cognitive function, mood, and behavior.