Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

40. Epilepsy

Susan J. Rogers and Jose E. Cavazos


KEY CONCEPTS

 Images Patient-specific treatment goals should be identified as early as possible.

 Images Accurate diagnosis and classification of seizure/syndrome type is critical to selection of appropriate pharmacotherapy.

 Images Patient characteristics such as age, comorbid conditions, ability to comply with the prescribed regimen, and presence or absence of insurance coverage can also influence the choice of antiepileptic drugs (AEDs).

 Images Pharmacotherapy of epilepsy is highly individualized and requires titration of the dose to optimize AED therapy (maximal seizure control with minimal or no side effects). Approximately 50% to 70% of patients can be maintained on one AED.

 Images If the therapeutic goal is not achieved with monotherapy, a second drug can be added or a switch to an alternative single AED can be made. If a second AED is added it should have a different mechanism of action from the first, although there is no clear evidence in humans to support this.

 Images Some patients eventually can discontinue AED therapy. Several factors predict successful withdrawal of AEDs.

 Images Surgery is the treatment of choice in selected patients with refractory focal epilepsy.

 Images The appropriate use of AEDs requires a thorough understanding of their clinical pharmacology, including mechanism of action, pharmacokinetics, adverse reactions, and drug interactions, as well as available dosage forms.


Epilepsy is a disorder that is best viewed as a symptom of disturbed electrical activity in the brain, which may have many etiologies. It is a collection of many different types of seizures that vary widely in severity, appearance, cause, consequence, and management. Seizures that are prolonged or repetitive can be life-threatening. Epilepsy is defined by the occurrence of at least two unprovoked seizures separated by 24 hours.1 The effect epilepsy has on patients’ lives can be significant and extremely frustrating. It is also important to recognize that seizures can be just one (albeit the most obvious) symptom of an epileptic disorder. Not uncommonly, patients have other comorbid disorders, including depression, anxiety, and potentially neuroendocrine disturbances. Patients with epilepsy also may display neurodevelopmental delay, memory problems, and/or cognitive impairment. Although, by convention, the focus of drug treatment is on the abolition of seizures, clinicians must also try to address these common comorbidities.

EPIDEMIOLOGY

Each year, 120 per 100,000 people in the United States come to medical attention because of a newly recognized seizure.1 At least 8% of the general population will have at least one seizure in a lifetime. However, it is common to have a seizure and not have epilepsy. The rate of recurrence of a first unprovoked seizure within 5 years ranges between 23% and 80%. Children with an idiopathic first seizure and a normal electroencephalogram (EEG) have a particularly favorable prognosis. Some seizures occur as single events resulting from withdrawal of CNS depressants (e.g., alcohol, barbiturates, and other drugs) or during acute neurologic illnesses or systemic toxic conditions (e.g., uremia or eclampsia). Some patients will have seizures only associated with fever. These febrile seizures do not constitute epilepsy.1

The age-adjusted incidence of epilepsy is 44 per 100,000 person-years. Each year, approximately 125,000 new epilepsy cases occur in the United States; only 30% are in people younger than 18 years of age at the time of diagnosis. There is a bimodal distribution in the occurrence of the first seizure, with one peak occurring in newborn and young children and the second peak occurring in patients older than 65 years of age. The relatively high frequency of epilepsy in the elderly is now being recognized.

ETIOLOGY

Seizures occur because a group of cortical neurons discharge abnormally in synchrony. Anything that disrupts the normal homeostasis or stability of neurons can trigger hyperexcitability and seizures. Thousands of medical conditions can cause epilepsy, from genetic mutations to traumatic brain injury. A genetic predisposition to seizures has been observed in many forms of primary generalized epilepsy. Patients with mental retardation, cerebral palsy, head injury, or strokes are at an increased risk for seizures and epilepsy. The more profound the degree of mental retardation as measured by the intelligence quotient (IQ), the greater is the incidence of epilepsy. In the elderly, the onset of seizures is typically associated with focal neuronal injury induced by strokes, neurodegenerative disorders (e.g., Alzheimer’s disease), and other conditions. In some cases, if an etiology of seizures can be identified and corrected, the patient may not require chronic antiepileptic drug (AED) treatment. Patients can also present with unprovoked seizures that do not have an identifiable cause, and thus by definition have idiopathic or cryptogenic epilepsy. Idiopathic etiology is the term used for suspected genetic cause, whereas cryptogenic etiology is used if no obvious cause is found for focal-onset seizures.

Many factors have been shown to precipitate seizures in susceptible individuals. Hyperventilation can precipitate absence seizures. Excessive sleep, sleep deprivation, sensory stimuli, emotional stress, and hormonal changes occurring around the time of menses, puberty, or pregnancy have been associated with the onset of or an increased frequency of seizures. A careful drug history should be obtained from patients presenting with seizures because theophylline, alcohol, high-dose phenothiazines, antidepressants (especially maprotiline or bupropion), and street drug use have been associated with provoking seizures. Perinatal injuries and small gestational weight at birth are also risk factors for the development of partial-onset seizures. Immunizations have not been associated with an increased risk of epilepsy.

PATHOPHYSIOLOGY

Seizures result from excessive excitation, or in the case of absence seizures, from disordered inhibition of a large population of cortical neurons.2 This is reflected on EEG as a sharp wave or spike. Initially, a small number of neurons fire abnormally. Normal membrane conductances and inhibitory synaptic currents break down, and excess excitability spreads, either locally to produce a focal seizure or more widely to produce a generalized seizure. This onset propagates by physiologic pathways to involve adjacent or remote areas. The clinical manifestations depend on the site of the focus, the degree of irritability of the surrounding area of the brain, and the intensity of the impulse.2

There are multiple mechanisms that might contribute to synchronous hyperexcitability, including: (a) alterations in the distribution, number, type, and biophysical properties of ion channels in the neuronal membranes; (b) biochemical modifications of receptors; (c) modulation of second messaging systems and gene expression; (d) changes in extracellular ion concentrations; (e) alterations in neurotransmitter uptake and metabolism in glial cells; and (f) modifications in the ratio and function of inhibitory circuits. In addition, local neurotransmitter imbalances could be a potential mechanism for focal epileptogenesis. Transitory imbalances between the main neurotransmitters, glutamate (excitatory) and γ-aminobutyric acid (GABA) (inhibitory), and neuromodulators (e.g., acetylcholine, norepinephrine, and serotonin) might play a role in precipitating seizures in susceptible patients.2

Control of abnormal neuronal activity with AEDs is accomplished by elevating the threshold of neurons to electrical or chemical stimuli or by limiting the propagation of the seizure discharge from its origin. Raising the threshold most likely involves stabilization of neuronal membranes, whereas limiting the propagation involves depression of synaptic transmission and reduction of nerve conduction.2

Prolonged seizures and continued exposure to glutamate can result in neuronal injury in vulnerable neuronal populations resulting in functional deficits, primarily in memory, and in permanent changes of wiring of the neuronal circuitry. Sprouting and reorganization of neuronal projections might lead to a chronic susceptibility to seizures, neuronal destruction, and brain damage. However, limited degree of neurogenesis in the hippocampal pathways has been induced by epileptic seizures. The role of these newly born neurons is not well understood.

CLINICAL PRESENTATION

The International League Against Epilepsy has proposed two major schemes for the classification of seizures and epilepsies: the International Classification of Epileptic Seizures and the International Classification of the Epilepsies and Epilepsy Syndromes.3,4 The International Classification of Epileptic Seizures (Table 40-1) combines the clinical description with certain electrophysiologic findings to classify epileptic seizures. Seizures are divided into two main pathophysiologic groups—partial seizures and generalized seizures—by EEG recordings and clinical symptomatology.

TABLE 40-1 International Classification of Epileptic Seizures

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CLINICAL PRESENTATION Epilepsy

General

In most cases, the healthcare provider will not be in a position to witness a seizure. Many patients (particularly those with CP or GTC seizures) are amnestic to the actual seizure event. Obtaining an adequate history and description of the ictal event (including time course) from a witness is critically important. With treatment the typical clinical presentation of the seizure may change

Symptoms

Symptoms of a specific seizure will depend on seizure type. Although seizures can vary between patients, they tend to be stereotyped within an individual

    • CP seizures can include somatosensory or focal motor features

    • CP seizures are associated with altered consciousness

    • Absence seizures can be almost nondetectable with only very brief (seconds) periods of altered consciousness

    • GTC seizures are major convulsive episodes and are always associated with a loss of consciousness

Signs

Interictally (between seizure episodes), there are typically no objective or pathognomonic signs

Laboratory Tests

There are currently no diagnostic laboratory tests for epilepsy. In some cases, particularly following GTC (or perhaps CP) seizures, serum prolactin levels can be transiently elevated. Laboratory tests can be done to rule out treatable causes of seizures (e.g., hypoglycemia, altered electrolyte concentrations, infections, etc.) that do not represent epilepsy

Other Diagnostic Tests

    • EEG is very useful in the diagnosis of various seizure disorders

    • An epileptiform EEG is found in only approximately 50% of the patients who have epilepsy

    • A prolactin serum level obtained within 10 to 20 minutes of a tonic–clonic seizure can be useful in differentiating seizure activity from pseudoseizure activity but not from syncope 5

    • Although magnetic resonance imaging (MRI) is very useful (especially imaging of the temporal lobes), a computed tomography (CT) scan typically is not helpful except in the initial evaluation for a brain tumor or cerebral bleeding

Partial (focal) seizures begin in one hemisphere of the brain and—unless they become secondarily generalized—result in an asymmetric motor manifestation. Partial seizures manifest as alterations in motor functions, sensory or somatosensory symptoms, or automatisms. Partial seizures with no loss of consciousness are classified as simple partial (SP). In some cases, patients will describe somatosensory symptoms as a “warning” prior to the development of a generalized tonic–clonic (GTC) seizure. These warnings are, in fact, SP seizures and frequently are termed auras.

Partial seizures with an alteration of consciousness are described as complex partial (CP). With CP seizures, the patient can have automatisms, periods of memory loss, or aberrations of behavior. Some patients with CP epilepsy have been mistakenly diagnosed as having psychotic episodes. CP seizures also can progress to GTC seizures. Patients with CP seizures typically are amnestic to these events. A partial seizure that becomes generalized is referred to as a secondarily generalized seizure.

Generalized seizures have clinical manifestations that indicate involvement of both hemispheres. Motor manifestations are bilateral, and there is a loss of consciousness. Generalized seizures can be further subdivided by EEG and clinical manifestations. Generalized absence seizures are manifested by a sudden onset, interruption of ongoing activities, a blank stare, and possibly a brief upward rotation of the eyes. They generally occur in young children through adolescence. It is important to differentiate absence seizures from CP seizures.

With GTC seizures there is a sudden sharp tonic contraction of muscles followed by a period of rigidity and clonic movements. During the seizure, the patient may cry or moan, lose sphincter control, bite the tongue, or develop cyanosis. After the seizure, the patient may have altered consciousness, drowsiness, or confusion for a variable period of time (postictal period) and frequently goes into a deep sleep. Tonic and clonic seizures can also occur separately.

Brief shock-like muscular contractions of the face, trunk, and extremities are known as myoclonic jerks. They can be isolated events or rapidly repetitive. A sudden loss of muscle tone is known as an atonic seizure, which may present as a head drop, the dropping of a limb, or a slumping to the ground. These patients often wear protective head ware to prevent trauma.

The International Classification of Epilepsies and Epilepsy Syndromes adds components such as age of onset, intellectual development, findings on neurologic examination, and results of neuroimaging studies to define epilepsy syndromes more fully. Syndromes can include one or many different seizure types (e.g., Lennox–Gastaut syndrome). The syndromic approach includes seizure type(s) and possible etiologic classifications (e.g., idiopathic, symptomatic, or unknown). Idiopathic describes syndromes that are presumably genetic but also those in which no underlying etiology is documented or suspected. A family history of seizures is commonly present, and neurologic function is essentially normal except for the occurrence of seizures. Symptomatic cases involve evidence of brain damage or a known underlying cause. A cryptogenic syndrome is assumed to be symptomatic of an underlying condition that cannot be documented. Unknown or undetermined is used when no cause can be identified. This syndromic classification requires more information and is more important for prognostic determinations and response to treatment than for a classification based simply on seizure type.

TREATMENT

Desired Outcomes

Images The ideal goal of treatment for epilepsy is complete elimination of seizures and no side effects with an optimal quality of life (QOL). Data from a large systematic review found that optimal QOL in epilepsy patients is defined by decreasing their seizure frequency and severity as well as addressing comorbid conditions, especially anxiety and depression.6 A large multicenter study found that in pharmacoresistant epilepsy patients, the adverse effects of their AEDs and depressive comorbidity were far more important in determining QOL than reducing the frequency of their seizures when seizure freedom cannot be obtained.7 In addition, other factors that can impact QOL in epilepsy patients include issues about driving, economic security, forming relationships, safety, social isolation, and social stigma.

The American Academy of Neurology (AAN) has developed eight quality performance measures for the clinician that define a high quality of care of these patients.8 In a recent survey of practicing neurologists, poor performance was found on three of these eight—counseling patients about AED side effects, discussion about depression, and their knowledge about referral of the intractable epilepsy patient for surgery.9 Lastly in helping to address QOL in epilepsy patients, an international consensus group has recently developed evidenced-based and practice-based statements to provide guidance on the management of neuropsychiatric conditions associated with epilepsy including depression.10


Clinical Controversy…

A significant amount of accumulating data suggests that treatment-resistant epilepsy may be intertwined with the presence of anxiety and/or depression in many epilepsy patients. In some patients the presence of bilateral hippocampal atrophy, diffuse cortical atrophy, or both in those persons with a history of depressive disorder at time of onset of epilepsy may provide a possible explanation for a very poor treatment response to AEDs. In addition, the issue of increased suicide rate seen in patients on AEDs may be influenced by the presence of these conditions. Until more valid data are collected in this area, it is the responsibility of the clinician treating the patient to make sure these conditions are carefully taken into account when selecting the appropriate AED therapy.

General Approach to Treatment

Images The general approach to treatment involves assessment of seizure type and frequency, identification of treatment goals, development of a care plan, and a plan for followup evaluation. During the assessment phase, it is critical to establish an accurate diagnosis of the seizure type and classification in order to select the appropriate initial AEDs. Patient-specific treatment goals must be identified, and these can change over time. Despite appropriate AED treatment, approximately 30% to 35% of patients are refractory to treatment. In this setting, seizure freedom may not be obtained, and more obtainable goals should be established (e.g., decrease in the number of seizures and minimized drug adverse effects).

Images Patient characteristics such as age, medical condition, ability to comply with a prescribed regimen, and insurance coverage also should be explored because these can influence AED choices or help to explain nonadherence to the regimen, a lack of response, or unexpected adverse effects.

Once the assessment is complete, for patients with new-onset seizures, the choice is whether to use drug therapy and, if so, which one. For a patient with long-standing epilepsy, adequacy of the current medication regimen must be evaluated. An AED should not be considered ineffective unless the patient has experienced unacceptable adverse effects with continued seizures.

Images If a decision is made to start AED therapy, monotherapy is preferred, and approximately 50% to 70% of all patients with epilepsy can be maintained on one drug.11 However, many of these patients are not seizure free. The percentage of patients who are seizure free on one drug varies by seizure type. After 12 months of treatment, the percentage who are seizure free is highest for those who have only GTC seizures (48% to 55%), lowest for those who have only CP seizures (23% to 26%), and intermediate for those with mixed seizure types (25% to 32%).11 Combining AEDs with different mechanisms of action to achieve freedom from seizures may be advantageous, although this approach is as yet unproven. Approximately 65% of patients can be expected to be maintained on one AED and be considered well controlled, although not necessarily seizure free.

Images Of the 35% of patients with unsatisfactory control, 10% will be well controlled with a two-drug treatment. Of the remaining 25%, 20% will continue to have unsatisfactory control despite multiple drug treatment. There may be a genetic predisposition to epilepsy that is refractory to drug therapy. Some of these patients may become candidates for surgery or vagal nerve stimulator.

Once the care plan is established, an AED is selected. Patient education and assurance of patient understanding of the plan are essential. Detailed directions regarding titration, what to do in the event of a treatment-emergent side effect, and what to do if a seizure occurs must be provided to patients. Documentation of the assessment, care plan, and educational process is essential. Providing the patient with a seizure and side-effect diary will assist in the followup and evaluation phase. At the followup stage of treatment (which can be done in the hospital, clinic, pharmacy, or by phone), the treatment goals must be reviewed. If the goal has been achieved, new goals should be identified. For example, if the GTC seizures are now controlled, the goal may be to control partial seizures. If a patient fails to respond to the first AEDs, trials with other AEDs should be attempted as appropriate. Completion of the evaluation often requires a reassessment of the patient and development of a new care plan taking into account patient compliance, efficacy, and safety of the initial treatment.

Medication noncompliance can be the single most common reason for treatment failure. It is estimated that up to 60% of patients with epilepsy are noncompliant.12 The rate of noncompliance is increased by the complexity of the drug regimen and by doses taken three and four times a day. Frequent uncontrolled seizures can also predispose a patient to noncompliance secondary to confusion over whether the drug was taken. Noncompliance is not influenced by age, sex, psychomotor development, or seizure type.12

Difference of opinion exists on the most appropriate time to initiate AED therapy. Treatment decisions vary depending on individual patient clinical characteristics and circumstances. Some clinicians start AED treatment after the first seizure, whereas others do not initiate treatment until a second, unprovoked seizure has occurred. Still others initiate prophylactic treatment following a CNS insult thought likely to cause epilepsy eventually (e.g., stroke or head trauma). Drug treatment may not be indicated when seizures have minimal impact on patients’ lives or when there has been only a single seizure. If a patient presents after a single isolated seizure, one of three treatment decisions can be made: treat, possibly treat, or do not treat. These decisions are based on the probability of the patient having a second seizure (Table 40-2). For patients with no risk factors, the probability of a second seizure is less than 10% in the first year and approximately 24% by the end of 2 years. If risk factors are present, the recurrence rate can be as high as 80% after 5 years.13 The decision on whether to start AED therapy often depends on patient-specific factors such as epilepsy syndrome, seizure etiology, presence of a neuroanatomic defect, and the EEG, as well as, the patient’s lifestyle and preferences. Patients who have had two or more seizures generally should be started on AEDs.

TABLE 40-2 Recurrence Risk for Patients Experiencing One Unprovoked Seizure

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When to Stop Antiepileptic Drugs

The AEDs used to control seizures may not need to be given for a lifetime. Polypharmacy can be reduced, and some patients can discontinue AEDs altogether. The drug considered less appropriate for the seizure type (or the agent deemed most responsible for adverse effects) should be discontinued first. In some cases, decreasing the number of AEDs can decrease side effects and increase cognitive abilities. This improvement in cognition may be small, especially if the patient is on a drug that primarily affects psychomotor speed with less effect on higher-order cognitive functioning.

Images Factors favoring successful withdrawal of AEDs include a seizure-free period of 2 to 4 years, complete seizure control within 1 year of onset, an onset of seizures after age 2 but before age 35, and a normal neurologic examination and EEG. Factors associated with a poor prognosis in discontinuing AEDs, despite a seizure-free interval, include a history of a high frequency of seizures, repeated episodes of status epilepticus (SE), a combination of seizure types, and development of abnormal mental functioning. A 2-year seizure-free period is suggested for absence and rolandic epilepsy, whereas a 4-year seizure-free period is suggested for SP, CP, and absence seizures associated with tonic–clonic seizures. AED withdrawal generally is not suggested for patients with juvenile myoclonic epilepsy (JME), absence with clonic–tonic–clonic seizures, or clonic–tonic–clonic seizures. The AAN has issued guidelines for discontinuing AEDs in seizure-free patients.14 After assessing the risks and benefits to both the patient and society, AED withdrawal can be considered in a patient meeting the following profile: seizure free for 2 to 5 years, a history of a single type of partial seizure or primary GTC seizures, a normal neurologic exam and normal IQ, and an EEG that has normalized with treatment. When these factors are present, the relapse rate is expected to be less than 32% for children and 39% for adults.

AED withdrawal should be done gradually, especially in patients with profound developmental disabilities. Some patients will have a recurrence of seizures as the AEDs are withdrawn. Sudden withdrawal is associated with the precipitation of SE. Withdrawal seizures are of particular concern for agents such as benzodiazepines and barbiturates. Seizure relapse has been reported to be more common if these AEDs are withdrawn over 1 to 3 months compared to over 6 months.

The risk of seizure relapse has been estimated at 10% to 70%. A meta-analysis determined that the relapse rate was 25% after 1 year and 29% after 2 years. Recurrence of seizures tends to occur early with at least one-half of the recurrences within 6 months of AED withdrawal and 60% to 90% within 1 year. Patients who relapse will generally become seizure free and in remission after AEDs are restarted although not necessarily immediately. The underlying epilepsy syndrome appears to determine prognosis for long-term remission.15


Clinical Controversy…

It is not entirely clear which patients with epilepsy will require lifelong treatment. Although many clinicians feel that AED therapy is lifelong, others would argue that certain patients with idiopathic epilepsy and a normal neurologic examination and EEG are candidates for AED withdrawal following a prolonged period of seizure freedom (e.g., greater than 2 to 3 years). A large amount of the data supporting discontinuing AEDs has been obtained from children. Some adults will be reticent to discontinue AED therapy even if the clinician is in favor of it because of the fear of having a seizure and the consequences (e.g., loss of driver’s license) that it would entail. The patient should agree and must be a willing participant in the plan to reduce or withdraw AED therapy.

Nonpharmacologic Therapy

Nonpharmacologic therapy for epilepsy includes diet, surgery, and vagus nerve stimulation (VNS). A vagal nerve stimulator is an implanted medical device that is Food and Drug Administration (FDA) approved for use as adjunctive therapy in reducing the frequency of seizures in adults and adolescents older than 12 years of age with partial-onset seizures that are refractory to AEDs. It is also used off-label in the treatment of refractory primary generalized epilepsy. The mechanisms of antiseizure actions of VNS are unknown. Human clinical studies have shown that VNS changes the cerebrospinal fluid (CSF) concentration of inhibitory and stimulatory neurotransmitters and activates specific areas of the brain that generate or regulate cortical seizure activity through increased blood flow. There is experimental evidence to suggest that the anticonvulsant effect of VNS is mediated by the locus coeruleus.16

The VNS device is relatively safe. It may also have a positive effect on mood and behavior, often independent of seizure reduction. The most common side effect associated with stimulation is hoarseness, voice alteration, increased cough, pharyngitis, dyspnea, dyspepsia, and nausea. Serious adverse effects reported include infection, nerve paralysis, hypoesthesia, facial paresis, left vocal cord paralysis, left facial paralysis, left recurrent laryngeal nerve injury, urinary retention, and low-grade fever. In the VNS studies, the percentage of patients who achieved a 50% or greater reduction in their seizure frequency (responders) ranged from 23% to 50%.

Images Surgery is the treatment of choice in selected patients with refractory focal epilepsy, especially those patients with seizures originating from the temporal lobe.17 The Early Randomized Surgery for Epilepsy trial resulted in freedom from seizures in 78% of newly refractory temporal lobe epilepsy patients, and none were seizure free in the group on standard drug therapy. Surgery reduces the risk of epilepsy-associated death, and it may also improve depression and anxiety in refractory epilepsy patients.18,19 A systematic review/meta-analysis of published evidence of temporal lobe patients with pharmacoresistant epilepsy concluded that the combination of surgery with medical treatment is four times as likely as medical treatment alone to achieve freedom from seizures.20 A National Institutes of Health Consensus Conference identified three absolute requirements for surgery. They are (a) an absolute diagnosis of epilepsy, (b) failure on an adequate trial of drug therapy, and (c) definition of the electroclinical syndrome. A focus in the temporal lobe has the best chance for a positive outcome; however, extratemporal foci can be excised successfully in more than 75% of patients. The procedure is not without risk. Learning and memory can be impaired postoperatively, and general intellectual abilities are also affected in a small number of patients. Surgery may be particularly useful in children with intractable epilepsy. Patients may need to continue AED therapy for a period of time following successful epilepsy surgery, but dosage reduction may be achieveable.21

The ketogenic diet, devised in the 1920s, is high in fat and low in carbohydrates and protein, and it leads to acidosis and ketosis. Protein and calorie intake are set at levels that will meet requirements for growth. Most of the calories are provided in the form of heavy cream and butter. No sugar is allowed. Vitamins and minerals are supplemented. Medium-chain triglycerides can be substituted for the dietary fats. Fluids are also controlled. It requires strict control and parent compliance. Although some centers find the diet useful for refractory patients, others have found that it is poorly tolerated by patients. Long-term effects include kidney stones, increased bone fractures, and adverse effects on growth.22 An international consensus statement has been published, which offers recommendations employing various forms of the ketogenic diet which may be more tolerable, including the use of the modified Atkins diet and the Low Glycemic Index Treatment.23 Subsequent data support the use of these variations in the ketogenic diet, as well as the medium chain triglyceride ketogenic diet in select patients.24

Pharmacologic Therapy

Optimal management of epilepsy requires that AED treatment be individualized. Different patient groups (e.g., children, women of child-bearing potential, and the elderly) may be better suited to receive one AED than another by virtue not only of seizure type but also of susceptibility or relative risk for certain adverse effects. These issues are highlighted further below.

Images Selection and optimization of AED therapy require not only an understanding of drug mechanism(s) of action and spectrum of clinical activity, but also an appreciation of pharmacokinetic variability and patterns of drug-related adverse effects. An AED must be effective for the specific seizure type being treated. The drug treatments of first choice depend on the type of epilepsy, drug-specific adverse effects, and patient preferences. Ultimately, AED effectiveness is the result of the interaction of each of these factors. A suggested algorithm for a general approach to the treatment of epilepsy is shown in Figure 40-1.

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FIGURE 40-1 Algorithm for the treatment of epilepsy. (AED, antiepileptic drug; QOL, quality of life.)

Table 40-3 provides evidenced-based treatment recommendations by three professional/regulatory bodies.2528 In addition, recommendations from a U.S. panel of experts, which included more recent drug treatment data compared to the AAN–American Epilepsy Society (AES) recommendations are included.29

TABLE 40-3 Drugs of Choice for Specific Seizure Disorders

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The mechanism of action of most AEDs can be categorized as (a) affecting ion channel kinetics, (b) augmenting inhibitory neurotransmission, or (c) modulating excitatory neurotransmission. Augmentation in inhibitory neurotransmission includes increasing CNS concentrations of GABA, whereas efforts to decrease excitatory neurotransmission are primarily focused on decreasing (or antagonizing) glutamate and aspartate neurotransmission. AEDs that are effective against GTC and partial seizures probably reduce sustained repetitive firing of action potentials by delaying recovery of sodium channels from activation. Drugs that reduce corticothalamic T-type calcium currents are effective against generalized absence seizures. Myoclonic seizures respond to drugs that enhance GABAA-receptor inhibition. In addition to mechanism of action, awareness of pharmacokinetic properties (Table 40-4), adverse effects (Table 40-5), and AED metabolic pathway as well as inducer or inhibitory effects on liver (Table 40-6) can aid in the optimization of AED therapy. Pharmacokinetic interactions are a common complicating factor in AED selection. Interactions can occur in any of the pharmacokinetic processes: absorption, distribution, metabolism, or elimination. Caution should be used when AEDs are added to or withdrawn from a drug regimen.

TABLE 40-4 Antiepileptic Drug Pharmacokinetic Data

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TABLE 40-5 Antiepileptic Drug Side Effects and Monitoring

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TABLE 40-6 Antiepileptic Drugs Elimination Pathways and Major Effects on Hepatic Enzymes

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Adverse effects of AEDs can be divided into acute and chronic (see Table 40-5). Acute effects can be dose/serum concentration-related or idiosyncratic. Concentration-dependent effects are common and troublesome but not usually life-threatening. Neurotoxic adverse effects are encountered commonly and can include sedation, dizziness, blurred or double vision, difficulty with concentration, and ataxia. In many cases, these effects can be alleviated by decreasing the dose or avoided in some cases by titrating the dose upward very slowly. Most idiosyncratic reactions are mild, but they can be more serious if the hypersensitivity involves one or more organ systems. Other idiosyncratic side effects including hepatitis or blood dyscrasias are serious but rare.

Acute organ failure, when it occurs, generally occurs within the first 6 months of AED therapy. Unfortunately, laboratory screening evaluations of blood and urine typically are not helpful in predicting or detecting the early stage of severe reactions and generally are not recommended in asymptomatic patients. An exception to this is in the screening of patients of Southeast Asian heritage for HLA-B*1502 antigen who are to receive carbamazepine and possibly phenytoin, lamotrigine, and oxcarbazepine. There is a strong association between the presence of this antigen and Stevens–Johnson syndrome as well as toxic epidermal necrolysis.38 In addition the HLA genotype HLA-A*3101 has been found to be associated with multiple carbamazepine-induced cutaneous reactions in Chinese, Japanese, and European populations.38 In any patient, laboratory assessment, including white blood cell (WBC) counts and liver function tests, may be reasonable if the patient reports an unexplained illness (e.g., lethargy, vomiting, fever, or rash).7 It is important to note that patients dosed and maintained within “therapeutic ranges” are also capable of experiencing toxicities to AEDs.32 Another potential long-term adverse effect of AED treatment is osteomalacia and osteoporosis.39,40 The bone disorders associated with AED use are a heterogeneous group of disorders, ranging from asymptomatic high-turnover disease, with findings of normal bone mineral density, to markedly decreased bone mineral density sufficient to warrant the diagnosis of osteoporosis. While the etiology of these osteopathies is uncertain, it has been hypothesized that certain drugs, including phenytoin, phenobarbital, carbamazepine, oxcarbazepine, felbamate, and valproic acid, may interfere with vitamin D metabolism; at least for the CYP3A4 inducers this activity may be explained by recent findings of an inducible CYP3A4-dependent vitamin D pathway.41 Whether the other AEDs cause these effects is unknown, however, current evidence suggests that lamotrigine does not. Common laboratory findings in these patients include elevated bone-specific alkaline phosphatase concentration, intact parathyroid hormone, and decreased serum calcium and 25-OH vitamin D concentrations. Patients receiving these drugs should receive supplemental vitamin D and calcium, as well as bone mineral density testing if other risk factors for osteoporosis are present.

Comparative data now exist between some of the older AEDs, carbamazepine, phenytoin, and valproic acid and the newer agents, levetiracetam, lamotrigine, and topiramate (low dose) that suggest the older agents increase circulatory vascular risk markers, which may contribute to acceleration of atherosclerosis and that this effect is treatment duration dependent.42,43

The comparative effects of AEDs on cognition have been difficult to evaluate because of differences or inconsistencies in study design, seizure types studied, control for serum drug concentrations, and the neuropsychologic tests used. In general, there are not large differences between the older drugs, although the barbiturates, phenobarbital and primidone, appear to cause more cognitive impairment than other commonly used AEDs.44,45 Phenytoin, particularly when serum concentrations are above the commonly accepted therapeutic range, may have a greater effect on motor function and speed. Among the older AEDs, valproic acid may cause less impairment of cognition. Improvement in cognition has been reported in patients switched from phenytoin or phenobarbital to valproic acid. However, these improvements are subtle if patients are in the same relative area of the therapeutic range. Patients changed from polytherapy to monotherapy also may demonstrate improvement in cognition. Some of the newer agents are believed to cause fewer neurobehavioral or cognitive effects. Among the newer AEDs, gabapentin and lamotrigine have been shown in several studies to cause fewer cognitive impairments compared with older agents, such as carbamazepine.4648 Conversely, topiramate may cause substantial cognitive impairment, particularly when used at high doses or during rapid dose escalation.48 In addition, these patients may not be fully aware of their deficits.49,50 AED treatment itself may sometimes worsen seizures due to improper AED selection for a specific seizure type or syndrome or can represent a paradoxical toxic effect of the drug.51

Because most adult patients have localization-related (partial-onset) seizures, the most widely used AEDs traditionally have been carbamazepine, phenobarbital, phenytoin, and valproic acid. For CP seizures, these AEDs have similar efficacy.52,53 Of these, carbamazepine and phenytoin are the most commonly prescribed AEDs for partial seizures in the United States. This preference is largely based on data derived from two landmark trials conducted through the Veterans Administration (VA) Epilepsy Cooperative Study Group. In the first of these trials, patients with new-onset partial or generalized epilepsy were randomized to receive either carbamazepine, phenobarbital, phenytoin, or primidone.52 After 3 years, patients who received either carbamazepine or phenytoin were equally likely, and patients on phenobarbital or primidone were least likely to have remained on their originally assigned treatment. Thus, carbamazepine and phenytoin were considered the drugs of first choice in patients with new-onset partial or generalized seizures. Carbamazepine was associated with fewer side effects. A followup study using almost identical methods compared carbamazepine and valproic acid.53 Carbamazepine- and valproic acid-treated groups had equal retention rates for tonic–clonic seizures. Carbamazepine was superior to valproic acid for efficacy in the treatment of partial seizures. Valproic acid caused slightly more adverse effects.

Based primarily on these trials, carbamazepine has been recognized as the AED of first choice for partial seizures. Several of the newer generation AEDs are now proving to be reasonable alternatives. The newer AEDs were first approved as adjunctive therapy for patients with refractory partial seizures. Monotherapy trials with several of these newer agents including lamotrigine, gabapentin, topiramate, oxcarbazepine, and levetiracetam have now been completed.5456 Comparisons between lamotrigine and older agents, including carbamazepine and phenytoin as initial monotherapy for partial seizures have been conducted in Europe, and the results suggest comparable effectiveness and perhaps better tolerability for lamotrigine, particularly in elderly patients. In a large, unblinded, randomized, controlled trial in hospital-based outpatient clinics in the United Kingdom, lamotrigine was found to be clinically better than carbamazepine for time to treatment failure outcomes in newly diagnosed patients with partial seizures; lamotrigine was determined to be a cost-effective alternative to carbamazepine. Other drugs studied in this trial were gabapentin, oxcarbazepine, and topiramate.57 Results from a VA cooperative trial designed to compare gabapentin, lamotrigine, and carbamazepine in newly diagnosed elderly patients with partial seizures found that lamotrigine efficacy is comparable with that of both gabapentin and carbamazepine, and is better tolerated than carbamazepine but equal to gabapentin in this population.58 Clinical data suggest that in newly diagnosed patients, oxcarbazepine is as effective as phenytoin, valproic acid, and immediate-release carbamazepine, with perhaps fewer adverse effects. Close examination of the conversion to monotherapy trials suggests that oxcarbazepine demonstrates efficacy even in patients who previously had an inadequate response to carbamazepine, in spite of their structural similarity. Lastly, levetiracetam in a 1-year study was found to have equal efficacy and tolerability when studied against controlled-release carbamazepine.59

In addition, several monotherapy trials using an active control or pseudoplacebo design also have been conducted. Although these study designs provide evidence of efficacy for the newer drugs, because the comparison is between active drug and placebo in patients who continue to have seizures in spite of current treatment with standard AEDs, it is difficult to compare the efficacy of the newer drugs directly with the older AEDs. Generally speaking, the newer AEDs appear to have comparable efficacy to the older agents and are perhaps better tolerated. A recent systematic review and meta-analysis attempted to compare the efficacy and tolerability of the newer AEDs in treatment of refractory partial epilepsy as add on therapy with another AED or placebo; although the results provided indirect evidence, the authors found topiramate and probably levetiracetam more efficacious in controlling seizure frequency and gabapentin less efficacious compared to all other new AEDs. In addition, tolerability was poorer with oxcarbazepine and topiramate whereas gabapentin and levetiracetam were better tolerated with the most common side effects comparable between the new AEDs.60

To date, among the newer generation agents, lamotrigine, oxcarbazepine, and topiramate have received FDA approval for use as monotherapy in patients with partial seizures. Phenobarbital and primidone are also useful in partial seizures, but sedation and cognitive adverse effects limit their utility. Felbamate, which has monotherapy approval, is effective but has been associated with some significant side effects. Interpretation of monotherapy trials with the newer AEDs can be daunting owing to the unique study designs and specific patient populations employed. Withholding an effective AED (i.e., giving placebo) in patients with epilepsy is generally considered unethical. Primarily generalized seizures such as absence seizures may respond differently pharmacologically than other seizure types. Phenytoin, phenobarbital, and carbamazepine, although effective in GTC and partial seizures, are ineffective for absence seizures, and in some cases, can precipitate an increase in seizure frequency. Absence seizures are best treated with ethosuximide, valproic acid, and perhaps lamotrigine. For levetiracetam, topiramate, and zonisamide, additional data are needed to confirm efficacy. Oxcarbazepine, gabapentin, and tiagabine do not appear to be effective in treating absence seizures, and can worsen this condition in some patients. If the patient has a combination of absence and other generalized or partial seizures, valproic acid or lamotrigine is the preferred first choice because they are effective for absence and other seizure types. If valproic acid is ineffective in treating a mixed seizure disorder that includes absence, ethosuximide could be used in combination with another AED.

The traditional treatment of tonic–clonic seizures is phenytoin; however, carbamazepine and valproic acid are increasingly used because these AEDs have a lower incidence of side effects with equal efficacy. Valproic acid generally is considered the drug of first choice for atonic seizures and for JME. Lamotrigine and perhaps topiramate and zonisamide can be alternative agents for these seizure types. Levetiracetam is FDA approved as adjunctive treatment of myoclonic seizures in patients with JME.

Results of a large, unblinded, randomized, controlled trial conducted in patients with new-onset generalized and unclassified epilepsy outpatients in the United Kingdom has helped to define the role of the newer generation drugs. These researchers found that for idiopathic generalized epilepsy, valproic acid was significantly better tolerated than topiramate and more efficacious than lamotrigine.61 A post hoc analysis of this trial delineated clinical factors significant in influencing treatment failure and in achieving a 12 month remission.62

Serum concentrations of the older AEDs should be viewed as a tool with which to optimize therapy for an individual patient, not as a therapeutic end point in itself. The serum concentration is a target that should be correlated with clinical response. The desired outcome is the cessation of seizures without side effects. Seizure control can occur before the “minimum” of the published therapeutic range is achieved, and side effects can appear before the “maximum” of the range is achieved. Some patients may need and tolerate concentrations beyond the maximum. The therapeutic range for AEDs can be different for different seizure types. Serum concentrations may need to be higher to control CP seizures than to control tonic–clonic seizures. Clinicians should define a therapeutic range for an individual patient above which there are side effects and below which the patient experiences seizures. Then serum levels can be useful to document lack of efficacy, loss of efficacy, noncompliance, and to determine how much room there is to increase a dose based on expected toxicity. Depending on the AED, serum levels can also be useful in patients with significant renal and/or hepatic disease, patients taking multiple drugs, and women who are pregnant or taking oral contraceptives (OCs). Therapeutic concentration ranges have not been clearly defined for some of the second-generation AEDs.

Therapeutic Considerations in the Elderly and Young

Use of AEDs in the elderly and young can pose special challenges.32 Avoidance of AEDs that interact with other medications that the elderly are often taking is of upmost importance. Many of the AEDs are inducers or inhibitors of the cytochrome P450 (CYP450) system, which can adversely affect the drug level of concomitantly administered drugs. Hypoalbuminemia is common in the elderly, and can make monitoring and adjustment of serum drug levels of highly albumin-bound AEDs, such as phenytoin, valproic acid, and tiagabine, problematic. The elderly also experience body mass changes, such as an increase in fat to lean body mass or decrease in body water, which can affect the volume of distribution of some drugs, and therefore possibly the elimination half-life. In addition, declining renal and/or hepatic function can occur in the elderly, which can require a lower dose of the AED. Lastly, the pharmacodynamic response to AEDs can change with aging such that elderly patients may be more sensitive to various neurocognitive adverse effects. Also, elderly patients’ seizures may be controlled at relatively lower total serum concentrations.

For neonates and infants, an increase in the total body water to fat ratio and a decrease in serum albumin and α-acid glycoprotein can result in volume of distribution changes that can affect the elimination half-life of the AEDs. In addition, newborns up to the age of 2 to 3 years display decreased efficiency in renal elimination, with newborns being the most affected. Hepatic activity is also reduced in this population. However, by age 2 to 3 years, hepatic activity is more robust than that seen in adults. Therefore, children require higher doses of many of the AEDs than adults, whereas neonates and infants require lower doses. Lastly, rapidly changing and sometimes inconsistent metabolism in the patient groups above make therapeutic drug monitoring especially important even though the definition of therapeutic blood level is less certain in these patients than in adults.

Therapeutic Considerations in Women (and Men)

Many hormones influence brain electrical excitability, and estrogen and progesterone may interact in complex ways to alter neuronal excitability and protein synthesis. Estrogen has a slight proconvulsant effect, whereas progesterone exerts a mild anticonvulsant effect. Estrogen has a mild inhibitory effect on GABA receptors, potentiates excitatory glutaminergic activity, and can promote the development of kindling. Progesterone has the opposite effect and appears to potentiate GABA receptor activity and reduce neuronal discharge rates. AEDs, especially hepatic metabolizing enzyme inducers, increase the metabolism of these hormones and induce the production of sex hormone-binding globulin. This may lead to decreases in the unbound fraction of the hormone. Enzyme-inducing AEDs, including topiramate and oxcarbazepine at higher doses, can cause treatment failures in women taking OCs owing to induction of the metabolism of ethinyl estradiol and progestin. This may also be an issue with rufinamide, lamotrigine, clobazam, and felbamate, all which have a small effect in decreasing the bioavailability of OCs. A supplemental form of birth control, in addition to OCs, is advised if breakthrough bleeding occurs. However medroxyprogesterone depot injection, copper intrauterine devices, and hormone-releasing intrauterine systems are not affected by AEDs. There are no data available on the efficacy of the transdermal contraceptive patch or the emergency contraceptive pill in patients taking these AEDs, but it has been suggested that women use twice the normal dose of the postcoital pill.63 Valproic acid, benzodiazepines, except clobazam, and most of the newer AEDs, such as gabapentin, levetiracetam, tiagabine, zonisamide, vigabatrin, and lacosamide, are not enzyme inducers and have not been implicated in reducing contraceptive effectiveness. Of note, OCs lower lamotrigine’s serum level significantly and lower valproic acid’s level about 20%.32

In some women, vulnerability to seizures is highest just before and during the menstrual flow (catamenial seizures) and at the time of ovulation. The increased susceptibility to seizures during those catamenial periods is associated with a slight increase of estrogen relative to progesterone. The risk of catamenial epilepsy is estimated at 12.5%, but it may be as high as 50% in women with epilepsy. This pattern of seizure exacerbation can also be related to progesterone withdrawal and changes in the estrogen-to-progesterone ratio. Conventional AEDs should be used as primary agents but intermittent supplementation with higher dose of AED or benzodiazepines should be considered. Acetazolamide also has been used during catamenial periods but with variable and limited success. Hormonal therapy with progestational agents, particularly cyclic natural progesterone therapy, may be effective.

Reproductive endocrine disorders are common in women with epilepsy and include menstrual irregularity, infertility, sexual dysfunction, and in some patients polycystic ovary syndrome (PCOS).64 Potential mechanisms for these disturbances include disruption of the hypothalamic–pituitary–adrenal (HPA) axis via seizure discharges in limbic structures and/or AEDs.64 AEDs, particularly the enzyme-inducing agents (e.g., carbamazepine, phenytoin, and phenobarbital), also may affect HPA function by altering the metabolism of the neuroactive sex hormones, including testosterone. Valproic acid is associated with increasing changes in sex hormone concentrations that causes hyperandrogenism and polycystic changes regardless if the patient has epilepsy, especially in women who have gained weight or those who start valproic acid at age less than 20 years.64

During pregnancy there may be increased maternal seizures, pregnancy complications, and adverse fetal outcome.65 Approximately 25% to 30% of pregnant women have increased seizures, whereas seizures decrease in a similar number. However, the risk of seizures is significantly less if the patient has been seizure free 12 months prior to the pregnancy.66 Increased seizure frequency may result from either a direct effect on seizure threshold or a reduction in AED concentration. An increase in clearance has been reported for phenytoin, carbamazepine, phenobarbital, ethosuximide, lamotrigine, oxcarbazepine, levetiracetam, topiramate, and clorazepate during pregnancy. Protein binding may also be reduced. The altered disposition of AEDs can begin as early as the first 10 weeks of pregnancy, and may require up to 4 weeks postpartum to normalize (longer for carbamazepine and phenobarbital than for phenytoin).

Women with epilepsy have a higher incidence of adverse pregnancy outcomes. Although the risk of congenital malformations is 4% to 6% (twice as high as in nonepileptic women), more than 90% of pregnancies in epileptic mothers have satisfactory outcomes. Older data, much of which included AED polytherapy, indicated that barbiturates and phenytoin may cause congenital heart malformations, orofacial clefts, and other malformations. From these data the risk of neural tube defect with valproic acid and carbamazepine was estimated to be 0.5% to 1%, respectively, and appeared to be related to drug exposure during gestational days 0 to 28. Other adverse pregnancy outcomes associated with maternal seizures, but not necessarily caused by AEDs, are growth, psychomotor, and mental retardation. Women with epilepsy are also more likely to have miscarriages, and 10% to 20% of infants are born with low birth weight. Updated practice parameters are available to aid in the counseling and management of pregnant women with epilepsy.6769

Although data exist which question the effectiveness of folic acid supplementation, it is currently believed that some teratogenic effects may be prevented by adequate folate intake; therefore, prenatal vitamins with folic acid (0.4 to 5 mg/day) should be given to any woman of child-bearing potential who is taking AEDs.65 Also, that higher folate doses should be used in women with a history of a previous pregnancy with a neural tube defect or taking valproic acid. Higher AED doses and serum concentrations, polytherapy, and a family history of birth defects appear to increase the teratogenic risk of AEDs. Deciding on the most effective single-drug treatment prior to conception is vitally important. Current data strongly suggest that an increased risk of adverse outcomes in women with epilepsy is due to teratogenic effects of AEDs and not epilepsy since studies show that epileptic women who do not take AEDs have the same risk of birth defects as infants born to control, seizure free women.70 The most concerning effects are found with the use of valproic acid in the pregnant patient. Data gathered from pregnancy registries and long-term studies suggest that valproic acid exposure is associated with a 1% to 2% risk of neural tube defects, a 10- to 20-fold increase over the general population, and an increased risk of neurodevelopmental deficits, reduced verbal abilities, and poorer attentional tasks; it appears that these effects are dose-dependent with major congenital malformation risk significantly increasing at 600 mg/day and largest risk observed at doses that exceed 1,000 mg/day. However, individual susceptibility is genetically determined, and teratogenicity can occur at much lower doses in some persons. Data are still limited on the newer agents, although topiramate may have a negative effect on birth weight and cause an increase risk in oral cleft and hypospadias in the fetus.70 Some AEDs can cause neonatal hemorrhagic disorder, which can be prevented by administrating 10 mg/day vitamin K orally to the mother during the last month of pregnancy and/or administering parenteral vitamin K to the newborn at delivery.69

Most AEDs pass into the breast milk, and concentrations are measureable in breastfeeding infants. In general, the degree of protein binding of a given AED allows for prediction of its concentration in breast milk. AEDs with less protein binding accumulate more in breast milk. Treatment with AEDs is not necessarily a reason to discourage breastfeeding. In fact, an argument could be made that since AEDs should rarely be discontinued abruptly, breastfeeding is a reasonable way to allow for a downward titration of a medication that the baby was exposed to for the past 9 months. Infants born to women taking any AED (particularly barbiturates or benzodiazepines) should be closely observed for signs of excess sedation, irritability, or poor feeding.65 An ongoing multicenter observational study of breastfeeding women taking AED monotherapy has failed to show significant cognitive effects in children exposed in utero to various AEDs—carbamazepine, lamotrigine, phenytoin, or valproic acid, although there was some negative effect on cognition noted for phenytoin.71

The perimenopausal period can be associated with worsening of seizures. At menopause, seizures often improve in frequency, particularly in women with a catamenial seizure pattern. According to current data, conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate may increase the frequency of epileptic seizures. It is suggested that a combination of single estrogenic compound such as 17-β-estradiol along with a natural progesterone should be considered in women who need hormone replacement therapy for disruptive menopausal symptoms.72 Data suggest that men with epilepsy have reduced fertility, and that carbamazepine, oxcarbazepine, and valproic acid are associated with sperm abnormalities in these men while levetiracetam appears to slightly increase serum testosterone.73 In addition, valproic acid seems to cause testicular atrophy resulting in reduced testosterone volume.74

Clinical Considerations with Specific Drugs

Tables 40-4 through 40-7 list specific data (including pharmacokinetics, adverse effects, metabolism, and dosing) for each of the commonly used AEDs. Below we summarize the pharmacology, advantages and disadvantages, and perspectives on the place in therapy of some specific AED.

TABLE 40-7 Antiepileptic Drugs Dosing and Target Serum Concentration Ranges

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Carbamazepine

Pharmacology and Mechanism of Action Carbamazepine is believed to act primarily by enhancing fast inactivation of voltage-gated sodium channels. In addition, interaction with voltage-gated calcium and potassium channels might also contribute to its activity.75

Pharmacokinetics The absorption of carbamazepine from immediate-release tablets is slow and erratic because of its low water solubility. There is also large variability in the peak-to-trough concentrations of up to 40%. There is no first-pass metabolism. Food, especially fat, may enhance the bioavailability of carbamazepine. Carbamazepine suspension is absorbed faster than the tablets.76 Controlled-release (Tegretol-XR) and sustained-release (Carbatrol) preparations are also available, and they are bioequivalent in twice-daily (every 12 hours) dosing to immediate-release carbamazepine dosed four times daily (every 6 hours). Compared with immediate-release carbamazepine, both these formulations have lower peaks and higher troughs, which may decrease side effects and improve seizure control. Carbatrol can improve QOL measurements compared to the immediate-release product.77 Patients should be told to take Tegretol-XR with food and that the casing will be excreted in the feces. It cannot be broken or crushed. Tegretol-XR and Carbatrol appear to be bioequivalent; however, there is less variability in the absorption of Carbatrol.76

Carbamazepine is a neutral and highly lipophilic drug that is highly protein bound to α1-acid glycoprotein and albumin. The major metabolite of carbamazepine is carbamazepine-10,11-epoxide, which has anticonvulsant activity in animals and humans. The formation of the 10,11-epoxide is influenced by concurrent use of other enzyme-inducing or enzyme-inhibiting drugs; thus the 10,11-epoxide concentration may change with the administration of other drugs (e.g., valproate and felbamate) with no change in parent carbamazepine concentration.

Carbamazepine induces its own metabolism (autoinduction), thereby decreasing its half-life after chronic therapy. The presence of enzyme-inducing drugs reduces the half-life even more. The enzyme-induction effect begins within 3 to 5 days of starting therapy and takes 21 to 28 days to complete. Therefore, it is possible to achieve initial concentrations that are within the therapeutic range but have concentrations fall despite continued therapy and good compliance. Some patients who respond well to initial therapy may be labeled refractory or noncompliant if the autoinduction phenomenon is not considered. The autoinduction reverses rapidly if carbamazepine is discontinued. Carbamazepine also displays diurnal variation in its serum level with evening levels lower than morning levels. It appears that carbamazepine is cleared significantly faster in females than males and in Caucasians compared to African Americans, and therefore variable dosing may be needed.77

Adverse Effects Carbamazepine side effects can parallel the rise and decline of serum concentrations daily. Neurosensory side effects are the most common (35% to 50% of patients). These side effects are more common during initiation of therapy and can dissipate with continued treatment. Carbamazepine can also cause nausea, which can be caused by a local effect of the drug on the GI tract, in which case food may help, or it can be caused by an effect on the brainstem, which may ultimately require discontinuation of the drug. Dosage manipulation, including the use of the controlled-or sustained-release preparations, should be tried before the patient is considered to be intolerant of carbamazepine. Carbamazepine can cause hyponatremia, the incidence of which increases with age, however, its occurrence is lower than that seen with oxcarbazepine. Periodic determinations of serum sodium concentration are recommended, especially in the elderly.76

Leukopenia is the most common hematologic side effect, with an incidence as high as 10%. It usually is transient, even when the drug is continued, and can be caused by a redistribution of WBCs rather than a decrease in their production.76 In about 2% of patients, leukopenia is persistent, but even patients with WBC counts of 3,000/mm3 (3 × 109/L) or less do not seem to have an increased incidence of infection. A clinical guide is to continue carbamazepine therapy unless the WBC count drops to less than 2,500/mm3 (2.5 × 109/L) and the absolute neutrophil count drops to less than 1,000/mm3 (1 × 109/L).

Drug Interactions Because of concentration-dependent efficacy and side effects, drug interactions with carbamazepine often are very significant. Drugs that inhibit CYP3A4 potentially may increase carbamazepine serum concentrations. Carbamazepine can induce the metabolism of other drugs.

Dosing and Administration The variable contributions of the 10,11-epoxide metabolite and free-carbamazepine concentrations have restricted a precise definition of the therapeutic range. Loading doses of carbamazepine are indicated only for critically ill patients. During dosage titration, it must be remembered that carbamazepine clearance increases with time. Doses may be started at one-fourth to one-third the anticipated maintenance dose and increased every 2 to 3 weeks. Because of the auto- and heteroinduction of carbamazepine metabolism, it is necessary to administer the drug two to four times per day. Carbamazepine tablets should not be stored in places where they would be exposed to high heat or high humidity.76

Advantages Carbamazepine has been well studied. Oral solid and liquid dosage forms are available. The oral solid dosage form is available as an immediate-release tablet, as a sustained-release capsule, and a controlled-release tablet. The sustained-and controlled-release dosage forms allow for twice-daily dosing to reduce the peak-to-trough fluctuations. Compared with other first-generation AEDs, carbamazepine causes minimal cognitive impairment.

Disadvantages Carbamazepine has an active metabolite that can contribute to efficacy and toxicity. Other drugs can alter the concentration of this metabolite without changing the concentration of the parent carbamazepine. It induces its own metabolism, which complicates dosage titration. It also induces the metabolism of other medications, and other drugs may interact with it and/or its active metabolite. There is no parenteral formulation. There are clinically meaningful CNS side effects including sedation and nausea. One prospective study, however, found fewer side effects with the sustained-release formulation compared to the immediate-release formulation.78 When ingested during the first trimester of pregnancy, carbamazepine has been associated with a slight risk of spina bifida. Chronic carbamazepine use has also been associated with decreases in bone mineral density and 25-hydroxy (OH) vitamin D. The generic formulations of immediate-release tablets have been associated with breakthrough seizures when brands have been switched.

Place in Therapy Carbamazepine is considered a first-line therapy for patients with newly diagnosed partial seizures and for patients with primary generalized convulsive seizures who are not in an emergent situation.

Clobazam

Pharmacology and Mechanism of Action Clobazam is a 1,5-chlorinated benzodiazepine derivative. The drug potentiates GABA’s effect at the GABA receptor, increasing chloride current by increasing channel opening; the αsubunit of GABA-A is especially important in the drug’s activity.

Pharmacokinetics Clobazam is 80% to 90% protein bound. The drug is metabolized in the liver to N-desmethylclobazam primarily, which is an active metabolite; the metabolite achieves plasma concentrations three to five times higher than clobazam, but it has 1/5 the activity. Clobazam and N-desmethylclobazam have elimination half-lifes of 36 to 42 hours and 71 to 82 hours, respectively.

Adverse Effects CNS effects are the most common side effects with clobazam. With abrupt discontinuation, a withdrawal syndrome can be seen which consists of convulsions, psychosis, hallucinations, behavioral disorder, tremor, and anxiety; milder symptoms can present as dysphoria, anxiety, and insomnia.

Drug Interactions Clobazam inhibits CYP2D6; therefore, drugs metabolized by this enzyme may require dosage reduction. It is a weak inducer of CYP3A4 and may lower the serum levels of some OC’s, which are metabolized by this enzyme.

Dosing and Administration Dosing is weight based, so patients who are less than or equal to 30 kg are started at 5 mg/day and increased slowly to 20 mg/day, while those weighing more than 30 kg are started at 10 mg/day and increased slowly to 40 mg/day; doses greater than 5 mg should be given in two divided doses. Dosing in geriatric patients is initiated as in patients weighing less than or equal to 30 kg, but increased up to 40 mg depending on the weight of the patient. Poor metabolizers of CYP2C19 are dosed like geriatric patients.

Advantages Clobazam is a potent chlorinated benzodiazepine that is more efficacious than clonopin in the treatment of Lennox–Gastaut. As with other benzodiazepines, tolerance can develop to its effectiveness in treatment of epilepsy, however 30% of patients do not develop tolerance, so the drug can often be used for years.

Disadvantages It is a class IV controlled substance. Patients must be carefully weaned off the drug to avoid a significant withdrawal symptoms. The drug is much less effective than clonazepam in treatment of myoclonic jerks and absence seizures. There is no liquid or parenteral formulation available.

Place in Therapy Adjunctive treatment of seizures associated with Lennox–Gastaut syndrome.

Ethosuximide

Pharmacology and Mechanism of Action Ethosuximide is believed to exert its primary action through inhibition of T-type calcium channels.75

Pharmacokinetics Metabolism occurs in the liver by hydroxylation, and the metabolites are believed to be inactive. There is some evidence of nonlinear pharmacokinetics at higher concentrations.

Adverse Effects The most frequently reported side effects are nausea and vomiting (up to 40% of patients), which may be minimized by administration of smaller and more frequent doses.79

Drug Interactions Because ethosuximide is not protein bound, displacement interactions do not occur. Valproic acid may inhibit the metabolism of ethosuximide, but only if the metabolism of ethosuximide is near saturation.

Dosing and Administration A loading dose is not required. Titration over 1to 2 weeks to maintenance doses of 20 mg/kg per day usually results in therapeutic concentrations. Data suggest that patients can be managed successfully on once-a-day therapy; however, GI distress appears to be dose related, and the total daily dose is usually divided into two equal doses.79

Advantages This drug is very effective in the treatment of absence seizures. It is generally well tolerated and has few pharmacokinetic interactions.

Disadvantages Ethosuximide has a very narrow spectrum of activity.

Place in Therapy Ethosuximide is still a first-line treatment for absence seizures.

Ezogabine

Pharmacology and Mechanism of Action The primary mechanism of action of ezogabine is as a selective positive allosteric modulator (opener) of KCNQ2-5 channels, which stabilizes the resting membrane potential and reduces brain excitability.80

Pharmacokinetics Ezogabine’s oral bioavailability is 60%; high fat food does not affect the extent of its absorption but increases its maximal blood drug concentration (Cmax) 38% and delays its time to maximal blood drug concentration (Tmax) by 0.75 hour. Ezogabine has a 30% lower trough serum level in the evening than in the morning. The drug undergoes glucuronidation and acetylation with the major metabolite, n-acetyl metabolite (NAMR) being less active than the parent drug in animal models. Elderly subjects show a 40% to 50% higher area under the drug concentration time curve (AUC) and a 30% higher half-life compared to younger subjects, and therefore dosage reduction is recommended.

Adverse Effects CNS effects are the most common side effects seen with ezogabine. More concerning is urinary retention, which occurs usually within the first 6 months, but onset can be later; special caution is advised if the drug is used in persons with benign prostatic hypertrophy, those already on anticholinergics, or those persons unable to communicate clinical symptoms. In addition, the drug can cause QT prolongation, with increased occurrence within 3 hours of administration. Caution is advised in those already taking drugs that can increase the QT interval and persons with congestive heart failure, ventricular hypertrophy, hypokalemia, or hypomagnesemia.

Drug Interactions Ezogabine can increase lamotrigine clearance by 22% and decrease AUC by 18% while NAMR may inhibit renal clearance of digoxin. Ezogabine serum levels may be reduced 35% by phenytoin and 31% by carbamazepine. Lastly, alcohol may increase systemic exposure, Cmax and AUC, of ezogabine, resulting in an increase in adverse drug effects.

Dosing and Administration The drug must be titrated up slowly to avoid CNS effects and given three times a day. If the drug is discontinued, it should be titrated down over at least 3 weeks.

Advantages Ezogabine works by an entirely different mechanism, and therefore may be valuable when added to another AED as adjunctive therapy.

Disadvantages It is a class V controlled substance. The drug may interfere with both urine and serum bilirubin clinical lab assays causing falsely elevated readings. Its tendency to cause urinary retention and QT prolongation in some patients requires special vigilance when prescribing the drug. There are no liquid or parenteral formulations available, and the drug must be taken three times per day.

Place in Therapy Given the drug’s novel mechanism of action, it should be used adjunctively in select patients who fail to respond optimally to other AEDs for treatment of partial seizures.

Felbamate

Pharmacology and Mechanism of Action At therapeutic doses, felbamate appears to act by blocking N-methyl-D-aspartate (NMDA) synaptic responses and by modulating GABAA receptors. At higher doses it may modulate sodium channels and inhibit high-voltage activated calcium channels.75

Pharmacokinetics Felbamate is rapidly and well absorbed. The absorption is unaffected by food or antacids. Approximately 40% to 50% of a dose of felbamate is metabolized by hydroxylation and conjugation pathways in the liver, and the remainder is excreted unchanged in the urine. It displays linear pharmacokinetics.80

Adverse Effects The most frequently reported side effects prior to marketing were anorexia, weight loss, insomnia, nausea, and headache (sometimes severe). Anorexia and weight loss may be especially problematic in children and in patients with diminished caloric intake. After marketing, felbamate was found to be associated with aplastic anemia and acute liver failure. The onset was between 68 and 354 days of therapy. The approximate rate of occurrence of aplastic anemia is 1 in 3,000 and of hepatitis is 1 in 10,000. Data suggest a possible increased risk for aplastic anemia in patients, especially women, with a history of cytopenia, AED allergy or significant toxicity, viral infection, and/or immunologic problems.25,26,81

Drug Interactions Felbamate can induce or inhibit the metabolism of the older AEDs. Interactions between warfarin and felbamate have also been reported.80

Dosing and Administration The starting dose of felbamate is increased at 2-week intervals.

Advantages Felbamate has a broad spectrum of activity and a unique mechanism of action. It is approved for treating atonic seizures in patients with the Lennox–Gastaut syndrome and is also effective in treating patients with partial seizures.

Disadvantages The use of felbamate is limited by the association with aplastic anemia and hepatotoxicity, as well as multiple drug interactions.

Place in Therapy It should be reserved for patients not responding to other AEDs.

Gabapentin

Pharmacology and Mechanism of Action Gabapentin was designed to be a GABA agonist but does not react at the GABA receptor, alter GABA uptake, or interfere with GABA transaminase. Gabapentin appears to bind to an amino acid carrier protein and to act at a unique receptor. It inhibits high-voltage activated calcium channels.75 It elevates human brain GABA levels, possibly via alterations in GABA synthesis or reversal of the neuronal GABA transporter, resulting in nonvesicular release of GABA.82

Pharmacokinetics Gabapentin is a substrate of the L-amino acid carrier protein in the gut (system L) and in the CNS.83 This carrier protein transports the drug across the gut membrane by an active process. The binding of gabapentin to this system is saturable, and gabapentin therefore displays dose-dependent bioavailability that appears to vary considerably between individuals.84 Food, including protein-rich meals, does not appear to interfere with gabapentin oral absorption.85,86 Concentrations in human CSF are 5% to 35% of plasma levels, and tissue concentrations are approximately 80% of plasma levels.

Because gabapentin is eliminated exclusively by the kidneys, dosage adjustments are necessary in patients with significantly impaired renal function.

Adverse Effects CNS effects, as well as weight gain, are the most common side effects seen with gabapentin. Aggressive behavior has been reported in children.87 A withdrawal reaction characterized by anxiety, insomnia, nausea, sweating, and increased pain has also been reported with abrupt discontinuation in patients taking it for pain.

Drug Interactions Gabapentin does not induce or inhibit liver enzymes; therefore, drug interactions are not likely to occur. There is a 10% reduction in the clearance of gabapentin in patients taking cimetidine and a 20% reduction in the bioavailability if aluminum antacids are taken simultaneously with gabapentin. These interactions are unlikely to be clinically significant.

Dosing and Administration Typical starting doses of gabapentin are 300 mg at bedtime on the first day, increasing to 900 mg/day over 3 days. Faster titration rates (e.g., starting at 300 to 900 mg three times daily) have been well tolerated.87 Data suggest gabapentin should be given at least four times a day when the total daily dose is 3,600 mg or greater.88 It does not appear to be absorbed rectally. Patients with end-stage renal disease maintained on hemodialysis should receive an initial 300- to 400-mg dose with 200 to 300 mg gabapentin given after every 4 hours of hemodialysis.

Advantages Gabapentin has multiple mechanisms of action and is mechanistically different from first-generation AEDs. It is not metabolized and is excreted unchanged by the kidney. It has a broad therapeutic index with minimal CNS adverse effects and few drug interactions. Doses can be escalated rapidly. It is available in liquid dosage form.

Disadvantages Gabapentin is absorbed by an active process that saturates at higher doses. This may require more frequent daily dosing for patients who need doses greater than 3,600 mg/day. Doses exceeding the 3,600 mg/day maximum listed in the package insert may be required in some patients to achieve seizure remission. There is no parenteral formulation.

Place in Therapy Gabapentin is a second-line agent for patients with partial seizures who have failed initial treatment. In addition, although monotherapy has no proven efficacy in previously diagnosed refractory patients, it may have a role in patients with less severe seizure disorders, such as new-onset partial epilepsy, particularly in the elderly. Gabapentin also has been shown to be useful for chronic pain and other nonepileptic conditions.

Lacosamide

Pharmacology and Mechanism of Action Lacosamide is a functionalized amino acid with unknown mechanism of action, but two mechanisms are suggested.35 It selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyper-excitable neuronal membranes and inhibition of repetitive neuronal firings. In addition, it binds to collapsin response mediator protein (CRMP-2), a phosphoprotein mainly expressed in the CNS, and it is involved in neuronal differentiation and control of axonal outgrowth. The role of CRMP-2 binding in seizure control is unknown.

Pharmacokinetics Lacosamide is rapidly and almost completely absorbed after oral administration, and food does not affect its bioavailability. There is a linear relationship between daily doses and serum concentrations up to 800 mg/day. No dosage adjustment is necessary in children or the elderly. Moderate hepatic and renal impairment have both been shown to increase systemic drug exposure up to approximately 40%.35

Adverse Effects CNS and GI effects are the most common side effects seen with lacosamide, and they are dose related. The drug can also cause a small increase in median PR interval (5 to 9 milliseconds) on the electrocardiogram (ECG).

Drug Interactions The blood level of lacosamide is decreased by approximately 15% to 20% by enzyme-inducing AEDs.33 It is a substrate of CYP2C19; however, there are no known drug interactions between lacosamide and drugs metabolized by CYP2C19. The drug does not appear to affect the serum concentration of OCs containing ethinyl estradiol and levonorgestrel.35

Dosing and Administration The starting dose is 100 mg/day in two divided doses, with dose increase by 100 mg/day every week until a daily dose of 200 to 400 mg has been reached. Studies have shown that a dose of 600 mg daily may be efficacious for some patients, but at the expense of more CNS side effects.

Advantages There is an IV form of lacosamide available for short-term replacement that appears to be safe, well tolerated, and easy to administer as well as a liquid dosage form. It does not affect the serum level of other AEDs, and its serum level is minimally affected by enzyme-inducing AEDs. It has novel mechanism(s) of action.

Disadvantages Lacosamide is a class V controlled substance.

Place in Therapy It is a potent second-line agent that should be considered in those patients who have failed first-line AEDs.

Lamotrigine

Pharmacology and Mechanism of Action Lamotrigine inhibits voltage-dependent sodium channels; it also inhibits high voltage-activated calcium channels and attenuates release of glutamate and to a lesser extent, GABA and dopamine.75

Pharmacokinetics Lamotrigine is completely and rapidly absorbed, with a bioavailability of 98%. Food does not significantly affect absorption. It is also absorbed following rectal administration, but the bioavailability is approximately 50% of that of oral dosage forms. Lamotrigine clearance is higher in children and lower in the elderly compared with young adults. There are only modest differences in the pharmacokinetics of lamotrigine in the elderly versus younger subjects. Hepatic disease, depending on severity, can influence lamotrigine pharmacokinetics. Approximately 17% of a lamotrigine dose can be removed by hemodialysis, with the half-life being reduced to approximately 13 hours. For patients on dialysis, the half-life is much more prolonged between dialyses. The half-life is prolonged in patients with renal failure.

Adverse Effects CNS effects, including headache, are the most frequently reported side effects seen with lamotrigine. Adverse effects are more common when lamotrigine is given in combination with other AEDs (e.g., diplopia when given concomitantly with carbamazepine or tremor with valproic acid) compared with monotherapy, and they can be pharmacodynamic in nature. Lamotrigine can cause rash, which usually appears in the first 3 to 4 weeks of therapy. Patients who have developed a rash with another AED are more likely to develop a rash with lamotrigine.89 The rash typically is generalized, erythematous, and morbilliform. However, a Stevens–Johnson reaction also has been reported. Some rashes, especially those which develop early, can necessitate the withdrawal of lamotrigine.90 Risk factors for the emergence of more serious rashes appear to be concomitant use of valproic acid and situations where high initial doses or rapid dosage escalation is used. Data from several European monotherapy trials suggest that when dosed appropriately, the incidence of rash from lamotrigine is similar to that of older agents such as carbamazepine and phenytoin. The incidence is higher in children than in adults.

Drug Interactions Lamotrigine does not inhibit liver enzymes and has a low potential for pharmacokinetic interactions with other drugs. It has been found to decrease the bioavailability of the progesterone component (levonorgestrel) of a combination OC by 19%. The clinical relevance of this interaction has not been determined.91

Concomitant treatment with OCs can lead to a reduction in the serum concentrations of lamotrigine because of an induction of lamotrigine glucuronidation by ethinyl estradiol.92 In addition, lamotrigine serum levels can significantly increase during the week off OC treatment in some patients.93

Valproic acid substantially inhibits the metabolism of lamotrigine, with maximal inhibition occurring at valproic acid doses and serum concentrations of 500 mg/day and 40 to 50 mcg/mL (280 to 350 μmol/L), respectively.94 A pharmacodynamic interaction can occur with concurrent carbamazepine therapy, causing an increase in CNS side effects.

Dosing and Administration In patients who are taking enzyme-inducing drugs, lamotrigine can be started more rapidly than in patients receiving valproic acid. The maintenance doses are also different. Managing dosing is critical owing to the relationship between rash, concomitant valproic acid treatment, and the dose escalation rate. Removal of inducers from a lamotrigine regimen may necessitate decreases in lamotrigine dose, whereas removal of valproic acid can necessitate an increase in the lamotrigine dose. Dispersible and oral disintegrating tablets are available for patients who cannot swallow an oral solid tablet.

Advantages Lamotrigine is potentially a broad-spectrum AED, having efficacy in partial seizures and several types of generalized seizures. Pediatric dosage forms are available as a chewable dispersible tablet and an oral disintegrating tablet. It is also available as an extended release product for once daily dosing. It neither induces nor inhibits the metabolism of other AEDs. Lamotrigine has linear pharmacokinetics and is not highly protein bound. It is generally well tolerated in both children and elderly patients and does not cause weight gain.

Disadvantages Lamotrigine is associated with rash, especially in patients who start at a high dose, have rapid dose escalation, and/or are taking concurrent valproic acid. Therefore, the initial doses must be low (especially if the patient is on valproic acid) and escalated slowly to maximize safety. There is no parenteral dosage form.

Place in Therapy Lamotrigine is useful as both adjunctive treatment in patients with partial seizures and as monotherapy. Lamotrigine monotherapy appears to have comparable effectiveness with more traditional AEDs such as carbamazepine and phenytoin. In addition, it may be a useful alternative for primary generalized seizure types such as absence and as adjunctive therapy for primary GTC seizures, the latter of which is an approved indication.

Levetiracetam

Pharmacology and Mechanism of Action The mechanism of action of levetiracetam has yet to be delineated; however, the drug is not active in the classic models used to test AEDs. The drug binds in the brain to the synaptic vesicle protein SV2A, which is believed to be important in its activity.95 Limited animal data suggest that levetiracetam may have antiepileptogenic effects, meaning that it may prevent the development of epilepsy under certain circumstances, however confirmation of this research is needed.96

Pharmacokinetics Absorption of levetiracetam is rapid and complete following oral administration, and it is not significantly affected by food or enteral nutrition formulas.97 Renal elimination of unchanged parent drug accounts for the majority of clearance (66%), with the remainder being metabolized via nonhepatic enzymatic hydrolysis to inactive metabolites. This pathway involves neither the CYP450 or UGT isozyme systems. Because it is eliminated renally, clinicians should anticipate age-related reductions in clearance in elderly patients. Conversely, levetiracetam clearance appears to be approximately 40% higher in children than in adults. In addition, patients with severe liver cirrhosis should initially receive one-half the recommended starting dose because of a 57% decrease in clearance.98 Levetiracetam is excreted into breast milk in potentially clinically important amounts.99 Data are sparse regarding serum concentration–effect relationships.

Adverse Effects CNS effects are the most common side effects seen with levetiracetam, and they are usually mild. In children and young adults, agitation, irritability, or somnolence/lethargy are the most frequently reported CNS side effects.100 The mechanism underlying these effects is unknown.

Drug Interactions Levetiracetam neither inhibits nor induces the CYP450, UGT, or epoxide hydrolase enzyme systems, and in vitro data predict a low potential for pharmacokinetic interactions. It does not appear to significantly interact with other AEDs, warfarin, digoxin, or OCs.

Dosing and Administration Levetiracetam is available orally and parenterally. The IV product has not been tested for intramuscular (IM) use, and therefore, should not be administered IM. Typically the initial dose is given twice daily, with dosage increments every 2 weeks. To minimize CNS side effects, dosing may be initiated at one-half the suggested initial dose, given once a day. The IV formulation should be given at the same frequency and dose as the oral product. Although not FDA approved, the oral dose of levetiracetam has been titrated up rapidly to 3,000 mg in 3 days in some intractable seizure patients with improvement seen after day 2.101

Advantages Levetiracetam is felt to have a novel, although unknown, mechanism of action. It has linear pharmacokinetics and is not metabolized by the CYP450 system. No significant drug interactions, including with OCs, have been reported. Initial doses may be effective. The drug appears to be well tolerated, with transient sedation being the most troublesome adverse effect.

Disadvantages Dose adjustments are needed for patients with decreased renal function, and slower dose escalation may be needed to avoid CNS adverse effects. Behavioral problems can limit therapy in some patients.

Place in Therapy Levetiracetam is indicated for patients with partial seizures who have failed initial therapy. Its role as monotherapy for partial seizures remains to be clarified. It is approved for adjunctive treatment of myoclonic seizures in patients with JME and as adjunctive treatment of primarily generalized seizures in patients with idiopathic generalized epilepsy.

Oxcarbazepine

Pharmacology and Mechanism of Action Oxcarbazepine, which is structurally related to carbamazepine, is a prodrug that is rapidly converted to the active 10-monohydroxy derivative (MHD). The mechanism of action of oxcarbazepine is similar to that of carbamazepine. Oxcarbazepine and MHD block voltage-sensitive sodium channels, modulate the voltage-activated calcium currents, and increase potassium conductance. Oxcarbazepine can display differing affinities for both sodium channels and Ca2+ channels compared with older drugs such as carbamazepine.102 Whereas carbamazepine may modulate L-type Ca2+ channels, oxcarbazepine appears to modulate N- and P-type Ca2+ channels.103 Whether these differences lead to differing patterns of clinical effectiveness is uncertain. It has no significant interactions with neurotransmitters or modulation of receptor sites.

Pharmacokinetics Oxcarbazepine is absorbed completely, and MHD is inactivated by glucuronide conjugation and eliminated by the kidneys. Oxcarbazepine and its active metabolite do not undergo autoinduction. The relationship between dose and serum concentration is linear. Children 2 to 6 years of age need larger doses (per kg) to achieve the same serum concentration, suggesting a more rapid clearance. Cmax and bioavailability of MHD in elderly volunteers were higher than in younger volunteers, and the elimination rate was slower, possibly reflecting decreased renal elimination. Patients with significant renal impairment may require a dosage reduction.

Adverse Effects CNS effects are the most frequent side effects seen with oxcarbazepine. In comparative trials, oxcarbazepine generally caused fewer side effects than phenytoin, valproic acid, or carbamazepine. Dizziness may be more common in elderly patients than in young adults. CNS adverse effects appear to be far more common at doses greater than 1,200 mg/day. Hyponatremia, defined as a plasma sodium concentration of less than 125 mmol/L, has been reported in up to 25% of patients taking oxcarbazepine and occurs more often in elderly patients. Clinicians should be particularly watchful in patients receiving concomitant sodium-depleting drugs such as diuretics. Hyponatremia appears to occur less frequently in children. Clinicians should consider monitoring serum sodium levels following the initiation of oxcarbazepine, and they should instruct patients regarding the symptoms of hyponatremia. Approximately 25% to 30% of patients who develop a rash with carbamazepine will experience a similar reaction with oxcarbazepine.25,26,81 The tolerability of oxcarbazepine has not been compared with that of extended-release formulations of carbamazepine that have lower peaks and potentially fewer side effects than immediate-release carbamazepine formulations.

Drug Interactions Oxcarbazepine decreases the bioavailability of ethinyl estradiol and levonorgestrel.104 Women concurrently taking OCs should be counseled about the potential for contraceptive failure. Unlike carbamazepine, there are no interactions between cimetidine, erythromycin, or warfarin and oxcarbazepine. The administration of oxcarbazepine in doses greater than 1,200 mg with phenytoin has resulted in a 40% increase in the concentration of phenytoin, consistent with inhibition of CYP 2C19. Oxcarbazepine treatment may modestly reduce lamotrigine serum concentrations, suggesting induction of UGT isozymes.105

The replacement of carbamazepine with oxcarbazepine may result in a drug interaction because an enzyme-inducing drug is being removed.

Dosing and Administration Doses and titration schedules differ regarding whether the drug is used for mono- or adjunctive therapy in adults versus children. Although not FDA approved, doses up to 60 mg/kg/day have been used in infants and children younger than 4 years of age to successfully control partial-onset seizures.106 In patients being converted from carbamazepine, the typical maintenance dose of oxcarbazepine is 1.5 times the carbamazepine dose or less, if patients are on large doses of carbamazepine, due to autoinduction of carbamazepine but not oxcarbazepine.

Advantages The efficacy of oxcarbazepine is comparable with that of carbamazepine, phenytoin, and valproic acid. It may be better tolerated than phenytoin as monotherapy and therefore, less likely to be discontinued.107 There is broad international experience with this drug.

Disadvantages About 30% of patients who have experienced a rash with carbamazepine have a cross-reaction with oxcarbazepine. There are more reports of hyponatremia with oxcarbazepine, especially in patients at risk. Replacing carbamazepine with oxcarbazepine can result in interactions owing to the removal of an enzyme inducer. Enzyme-inducing drugs can increase the clearance of MHD.

Place in Therapy Oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children as young as 4 years of age. It is also a potential first-line drug for patients with primary generalized convulsive seizures. Oxcarbazepine may also be effective in patients not demonstrating a response to carbamazepine.

Phenytoin

Pharmacology and Mechanism of Action The primary mechanism of action of phenytoin is believed to be its ability to inhibit voltage-dependent sodium channels.75

Pharmacokinetics The pharmacokinetics of phenytoin are complex. For a more in-depth understanding, the reader is referred to a more extensive review.108 The oral absorption of phenytoin is almost complete. Dissolution is the rate-limiting step, and absorption may be saturable at higher doses, such as those used for oral loading. Absorption following IM administration of phenytoin is erratic and delayed, and IM injections are painful; however, IM absorption following fosphenytoin is rapid and well tolerated.

Phenytoin enters the brain rapidly and is redistributed to other body tissues, including breast milk and the placenta. Phenytoin competes for albumin sites with other highly protein-bound drugs. It is essential to know the patient’s serum albumin level in interpreting the serum concentrations of phenytoin.109 Patients with significant renal dysfunction will have altered phenytoin protein binding. Obesity increases the volume of distribution.

Phenytoin is metabolized in the liver by parahydroxylation. The major isoforms responsible for the metabolism of phenytoin are CYP2C9 and CYP2C19; the former displays polymorphism, which may affect the response to phenytoin.75 Phenytoin displays Michaelis–Menten pharmacokinetics, and the metabolism of phenytoin saturates at doses used clinically. The clinical importance of this is that a small change in dose can result in a disproportionally large increase in serum concentrations, potentially leading to toxicity. In some patients the metabolism of phenytoin can saturate even at low serum concentrations within the therapeutic range. The long-held belief that the metabolism of phenytoin decreases with age in adults has been challenged.110

Adverse Effects CNS effects are the most frequent side effects seen with phenytoin. Most of these effects usually are transient and can be minimized by slow dosage titration. At very high concentrations of greater than 50 mcg/mL (200 μmol/L), phenytoin can exacerbate seizures.

It is unclear whether the chronic side effects of phenytoin are concentration or duration dependent. One of the more common chronic side effects is gingival hyperplasia. Good oral hygiene can minimize gingival hyperplasia and should be encouraged. Other chronic effects include vitamin D deficiency, osteomalacia, carbohydrate intolerance, immunologic disturbances, hypothyroidism, and peripheral neuropathy. Phenytoin is associated with rare hypersensitivity or idiosyncratic reactions resulting in rashes, Stevens–Johnson syndrome, pseudolymphoma, bone marrow suppression, lupus-like reactions, and hepatitis.111

Drug Interactions Phenytoin is associated with numerous drug interactions involving altered absorption, metabolism, and protein binding that can enhance or reduce its effects. It is an inducer of both CYP450 and UGT isozymes. The absorption of phenytoin can be increased or decreased with the administration of food depending on the composition of the meal. The bioavailability of phenytoin suspension can be decreased in patients receiving continuous enteral nutrient tube feedings. However, a single-dose study of simultaneous administration of enteral feeding found no difference in phenytoin bioavailability, suggesting that the mechanism was something other than physical contact.108

Phenytoin decreases folic acid absorption. Replacement of folic acid can reduce phenytoin concentration and result in loss of efficacy.108

Dosing and Administration Four oral dosage forms are available, and changing dosage forms can lead to changes in phenytoin serum concentrations. Whether or not a dosage form uses the parent drug or salt form should be considered when changing from one dosage form to another. One hundred milligrams of phenytoin acid is equal to 92 mg of phenytoin sodium. Phenytoin capsules are designated as immediate-release or extended-release. Only the extended-release capsules should be used in once-daily dosing. Particle size rather than formulation may determine the rate of absorption.

If oral administration is not feasible, IV administration of phenytoin is preferred, as IM administration can cause tissue necrosis. Fosphenytoin is a prodrug for phenytoin and is available as a parenteral dosage form. Fosphenytoin is ordered in phenytoin equivalents (PE), the actual dose of phenytoin acid desired. It is very water-soluble and is converted rapidly to phenytoin systemically. Fosphenytoin can be given rapidly IV and IM with reliable absorption and minimal pain. It is significantly better tolerated than phenytoin.

Because of saturable absorption, an oral loading dose, such as 20 mg/kg, should be divided into four equal doses and given at 6-hour intervals. Subsequent dosage adjustments should be done cautiously owing to its nonlinear elimination. One author has suggested that if the serum concentration is less than 7 mcg/mL (28 μmol/L), the daily dose should be increased by 100 mg; if the serum concentration is between 7 and 12 mcg/mL (28 and 48 μmol/L), the daily dose can be increased by 50 mg; and if the serum concentration is greater than 12 mcg/mL (48 μmol/L), the daily dose can be increased by 30 mg or less. These increases are reported to result in less than 10% of patients achieving a phenytoin serum concentration greater than 25 mcg/mL (99 μmol/L).112

Advantages After more than 66 years, phenytoin’s risk-to-benefit ratio is well established. It is available in oral solid, oral liquid, extended-release oral solid, and parenteral (phenytoin and fosphenytoin) dosage forms, allowing flexibility in dosing and use in emergent situations. In some patients, the extended-release dosage form can be given once a day with good seizure control.

Disadvantages Phenytoin displays Michaelis–Menten pharmacokinetics, meaning that the metabolism saturates at doses given clinically thus complicating dose titration. Also, phenytoin is an inducer of CYP450 isozymes, is metabolized by CYP450 enzymes, and is highly protein bound. Therefore, many drug interactions are associated with coadministration of this agent. It also has multiple significant adverse effects.

Place in Therapy Phenytoin has long been a first-line AED for primary generalized convulsive and partial seizures. However, its place in therapy is being reevaluated as more experience is gained with newer AEDs.

Pregabalin

Pharmacology and Mechanism of Action It is proposed that pregabalin’s binding to the subunit of the voltage-gated calcium channel may be responsible in large part for the drug’s activity. This binding results in a decrease in the release of several excitatory neurotransmitters, including glutamate, noradrenaline, substance P, and calcitonin gene-related peptide.113

Pharmacokinetics Pregabalin is a substrate of the L-amino acid carrier protein in the CNS. It does not display dose-dependent bioavailability. Food decreases the rate of absorption but not the bioavailability of the drug.114

Pregabalin is eliminated primarily by renal excretion as an unchanged drug, and therefore dosage adjustment is required in patients with significantly impaired renal function. In anuric patients, 50% of the dose is removed by 4 hours of hemodialysis.

Adverse Effects CNS effects, as well as weight gain, are the most frequently reported side effects seen with pregabalin. It is unknown if pregabalin causes aggressive behavior in children. A withdrawal reaction characterized by anxiety, nervousness, and irritability has been noted in patients being treated for generalized anxiety upon abrupt discontinuation of the drug.115

Drug Interactions Because pregabalin is predominantly excreted unchanged in the urine and undergoes negligible metabolism, drug interactions are unlikely.

Dosing and Administration Starting doses of pregabalin are divided into twice or thrice daily intervals. The manufacturer recommends that patients with end-stage renal disease maintained on hemodialysis receive a 25 to 75 mg daily dose with 25 to 75 mg given after every 4 hours of hemodialysis.

Advantages Pregabalin is somewhat more potent than gabapentin without the dose-limited GI absorption properties. It has minimal CNS side effects and no drug interactions.

Disadvantages It is a class V controlled substance. Like gabapentin it can cause weight gain and peripheral edema, especially as the dose is increased. There is no parenteral formulation available.

Place in Therapy Pregabalin is a second-line agent for patients with partial seizures who have failed initial treatment. It is also useful for chronic neuropathic pain and generalized anxiety disorder.115

Rufinamide

Pharmacology and Mechanism of Action Rufinamide suppresses neuronal hyperexcitability through prolongation of the inactivation phase of voltage-gated sodium channels.116

Pharmacokinetics Oral absorption is relatively slow with a Tmax of 4 to 6 hours. At low doses (600 mg), the drug is relatively well absorbed (85%) when taken with food; however, the percentage of drug absorbed decreases with higher doses. Twice-daily dosing is recommended due to the slow absorption properties and the drug’s short half-life (6 to 10 hours).36 It is extensively metabolized with no active metabolites, with primary biotransformation by carboxylesterases. Although clinical data indicate that children and adults have similar pharmacokinetics, population pharmacokinetic modeling suggests that in the absence of interacting comedication the drug may have a higher clearance in children.116

Adverse Effects CNS effects are the most common side effects seen with rufinamide. These effects are dose-dependent. Rufinamide may increase the incidence of convulsions in some patients, and may precipitate SE. Multiorgan hypersensitivity has occurred within 4 weeks of starting treatment in patients younger than 12 years of age.

Drug Interactions Rufinamide is a weak inhibitor of CYP2E1 and a weak inducer of CYP3A4; the later effect may be responsible for modestly lower levels of carbamazepine and triazolam when given concomitantly with rufinamide. It may decrease the AUC of combination OCs containing ethinyl estradiol and norethindrone; however, it is not known if this is due to induction of CYP3A4 or uridine diphosphate glucuronosyl transferase (UDP-GT), or both. Rufinamide is responsible for a modest increase in the clearance of lamotrigine, phenobarbital, and phenytoin, and the effect is greater in children than adults. Carbamazepine, phenytoin, primidone, and phenobarbital significantly increase the clearance of rufinamide; however, it is believed this interaction is not entirely due to CYP450 enzyme induction. Valproic acid significantly decreases the clearance of rufinamide and elevates serum levels of rufinamide by 70%.

Dosing and Administration The initial dose of rufinamide is 400 to 800 mg/day given in divided doses with an increase in dose every other day until a maximum dose of 45 mg/kg/day or 3,200 mg/day (whichever is less) is obtained.

Advantages The drug is effective for seizures associated with Lennox–Gastaut syndrome without causing cognitive and psychiatric adverse effects. The dose can be rapidly escalated.

Disadvantages Drug interactions are common with rufinamide, and patients with Lennox–Gastaut are usually on multiple medications. It displays decreased absorption at higher doses and when taken on an empty stomach. The drug has caused convulsions and SE in some patients.

Place in Therapy As an adjunctive agent in controlling seizures in Lennox–Gastaut syndrome after patients have failed valproic acid, topiramate, and lamotrigine.

Tiagabine

Pharmacology and Mechanism of Action Tiagabine is a potent specific inhibitor of GABA uptake into neuronal elements, thus, enhancing the action of GABA by decreasing its removal from the synaptic space.117

Pharmacokinetics Tiagabine is absorbed quickly and nearly completely after oral administration. There is a linear relationship between dose and serum concentrations. Children eliminate tiagabine slightly faster than adults. Hepatic impairment causes higher and more prolonged plasma concentrations of total and unbound drug. Renal dysfunction does not change its pharmacokinetics.117 Tiagabine displays diurnal variation in its serum level, with evening levels lower than morning levels.

Adverse Effects CNS and GI effects are the most frequent side effects seen with tiagabine. Adverse events usually are mild to moderate and transient, and most occur during dose titration.118 CNS side effects can be diminished by taking tiagabine with food, thus slowing the absorption rate. It has increased the incidence of nonconvulsive SE in patients with chronic refractory partial epilepsy.119 In addition, there are reports of SE or new-onset seizures occurring in patients without a history of epilepsy.

Drug Interactions Food decreases the rate but not the extent of absorption. Tiagabine is displaced from protein by naproxen, salicylates, and valproate. However, tiagabine does not displace phenytoin, valproic acid, amitriptyline, tolbutamide, or warfarin.117

Dosing and Administration A clear dose–response has been demonstrated, and the minimal effective adult dose level is 30 mg/day. The initial dose is increased weekly.

Advantages Tiagabine has a known mechanism of action. It is the first drug marketed in the United States that acts only on GABA reuptake. It has linear pharmacokinetics and is not reported to interact with other drugs.

Disadvantages Initially high and rapid dosage escalation is associated with increased CNS side effects. Therefore, the drug must be started at a low dose and titrated gradually to response. Lower doses may be needed in patients with liver disease. Tiagabine is metabolized by CYP3A4 enzymes, and other drugs may alter its clearance. There is no parenteral formulation.

Place in Therapy Tiagabine is second-line therapy for patients with partial seizures who have failed initial therapy. It does not appear to have a role in primary generalized seizure types.

Topiramate

Pharmacology and Mechanism of Action Topiramate has multiple modes of action involving voltage-dependent sodium channels, GABA-receptor subunits, high-voltage calcium channels, and kainate/α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subunits.75 It also inhibits carbonic anhydrase, which likely is not a major mechanism of action.75

Pharmacokinetics Although generally considered to have linear absorption and elimination pharmacokinetics, a greater than proportional increase in both Cmax and AUC has been observed and probably is explained by saturable binding to erythrocytes.120 Approximately 50% of the dose is excreted renally unchanged; however, its metabolism is increased by approximately 50% when given with enzyme-inducing AEDs. Renal tubular reabsorption may be involved prominently in the renal handling of topiramate.

Adverse Effects CNS effects are the most frequent side effects reported with topiramate, including “thinking abnormally,” which rarely has included psychosis. Most of these occurred during rapid titration and at higher doses.121Word-finding difficulties can be a problem with topiramate and can occur in a significant number of patients, especially patients with left posterior temporal lobe epilepsy or SP seizures.122Concomitant therapy with topiramate, valproic acid, or phenobarbital can cause cognitive dysfunction. Nephrolithiasis has occurred in 1.5% of patients receiving topiramate, which is two to four times the incidence in the general population. Patients should be encouraged to maintain adequate fluid intake in order to minimize this problem. Topiramate can cause metabolic acidosis at doses as low as 50 mg/day. Risk factors for this condition include renal disease, severe respiratory disorders, SE, diarrhea, surgery, and the ketogenic diet. Metabolic acidosis in part may explain the anorexia and weight loss seen with this drug.82

Drug Interactions Oral clearance of digoxin is slightly increased when topiramate is added. Topiramate coadministration can cause increased phenytoin serum concentrations in some patients. The variable response can be explained by the intersubject variability in the proportion of phenytoin clearance attributed to CYP2C19 metabolism and whether the patient is a homozygous or heterozygous carrier of the mutant allele responsible for the CYP2C9 and/or CYP2C19 “poor metabolizer” phenotype. Topiramate can modestly increase the oral clearance of valproic acid and increase formation of the 4-ene-valproic acid metabolite. However, the clinical significance of this interaction is unclear. Topiramate increases the clearance of ethinyl estradiol in a dose-dependent manner. Topiramate doses of less than 200 mg/day are unlikely to alter OC pharmacokinetics.123

Dosing and Administration Topiramate should be titrated slowly to avoid adverse events with dosage increments every 1 to 2 weeks. For patients on other AEDs, doses greater than 600 mg/day do not appear to lead to improved efficacy and can cause increased adverse effects; however, higher doses may prove beneficial to individual patients who tolerate them.124

Advantages Topiramate has multiple mechanisms of action and is a broad-spectrum AED. Elimination is primarily renal, but hepatic metabolism occurs, especially if given concomitantly with enzyme inducers. It has linear pharmacokinetics and few drug interactions.

Disadvantages With rapid dosage escalation, topiramate can compromise cognitive functioning, including impaired word finding and impaired short-term memory. Therefore, initial doses should be low, and titration must be slow. Renal stones and weight loss have been associated with topiramate use. The dose should be decreased in patients with renal impairment. There is no parenteral formulation.

Place in Therapy Topiramate is a first-line AED for partial seizures as an adjunct and/or monotherapy. It is also approved for the treatment of tonic–clonic seizures in primary generalized epilepsy.

Valproic Acid/Divalproex Sodium

Pharmacology and Mechanism of Action Alterations of the synthesis and degradation of GABA do not fully explain the antiseizure activity of valproic acid. Valproic acid may potentiate postsynaptic GABA responses, may have a direct membrane-stabilizing effect, and may affect potassium channels.125

Pharmacokinetics Valproic acid appears to be absorbed completely from available oral dosage forms when administered on an empty stomach.125 However, the rate of absorption differs among preparations. Peak concentrations occur in 0.5 to 1 hour with the syrup, 1 to 3 hours with the capsule, and 2 to 6 hours with the enteric-coated tablet.125 The extended-release formulation (Depakote-ER) is FDA approved for patients with migraine headache and epilepsy. The bioavailability of this formulation is approximately 15% less than that of enteric-coated divalproex sodium (Depakote).

Valproic acid is extensively bound to albumin, and this binding is saturable. Accordingly, the valproic acid free fraction will increase as the total serum concentration increases. Because of this saturable binding, measurement of unbound serum concentrations may be a better monitoring parameter than the total valproic acid serum concentration, especially at higher concentrations or in patients with hypoalbuminemia.

The primary route of valproic acid metabolism is β-oxidation, although up to 40% of a dose may be excreted as the glucuronide. At least 10 metabolites of valproic acid have been identified. Some of these may have weak anticonvulsant activity, and at least one metabolite may be responsible for the hepatotoxicity reported. One of the lesser oxidative metabolites, 4-ene-VPA, causes hepatotoxicity in rats. The formation of this metabolite is increased when valproic acid is given with enzyme-inducing drugs.125 Valproic acid displays diurnal elimination with lower evening serum levels occurring than morning levels. It crosses into the placenta, and concentrations may be up to five times higher in cord serum blood than in the mother due to higher binding in the fetal compartment.126

Adverse Effects The most frequently reported side effects are GI (up to 20%), including nausea, vomiting, anorexia, as well as weight gain. Pancreatitis is rare. GI complaints may be minimized, but not totally alleviated, with the enteric-coated formulation or by giving the drug with food. Alopecia and hair changes are temporary, and hair growth returns even with continued dosing. Weight gain can be significant for many patients and is associated with an increase in fasting insulin and leptin serum levels.127 The increase in serum insulin is believed to be caused by the inhibition of metabolism of insulin by the liver.128This has led to the development of insulin resistance in obese male and female subjects.125 Valproic acid causes minimal cognitive impairment.125

The most serious side effect reported with valproic acid is hepatotoxicity. Hyperammonemia is common (50%) but does not necessarily imply liver damage. Most liver failure deaths have occurred in patients who were younger than 2 years of age, had mental retardation, and received multiple AEDs. Hepatotoxicity occurred early in the course of therapy. Patients who complain of nausea, vomiting, lethargy, anorexia, and edema in the first 6 to 12 months of therapy should have liver function evaluated. Multiple AEDs can alter the metabolism of valproic acid, leading to increased formation of the potentially liver-toxic 4-ene-VPA. Valproic acid has been shown to alter carnitine metabolism, and it has been postulated that a deficiency of carnitine alters fatty acid oxidation that could lead to both liver toxicity and hyperammonemia.129 However, valproic acid hepatotoxicity has occurred in a patient taking supplemental carnitine, and a prospective study demonstrated no effect on well-being when carnitine was added. Although carnitine can ameliorate hyperammonemia in part, it is expensive, and there are only limited data to support routine supplemental use in patients taking valproic acid.130

Thrombocytopenia and alterations in platelet aggregation occur in the patients receiving valproic acid, and these phenomena are related to serum concentration. These blood coagulopathies may occur more frequently in children than in adults.131

Drug Interactions Because it is highly protein bound, other highly protein-bound drugs (e.g., free fatty acids and aspirin) can displace valproic acid.

Valproic acid can inhibit specific CYP450 isozymes, epoxide hydrolase, and UGT isozymes. The addition of valproic acid to phenobarbital results in a 30% to 50% decrease in phenobarbital clearance and significant toxicity if the dose of phenobarbital is not reduced. Data also suggest that combination OCs may increase the clearance of valproic acid and lower serum levels by 20%.32 In addition, carbapenems, especially meropenem, can lower valproic acid levels.132

Dosing and Administration Valproic acid in some patients may have a half-life long enough for once-daily dosing with enteric-coated divalproex, but more frequent dosing is the norm. Based on half-life data, twice-daily dosing is feasible with any valproic acid dosage form; however, children and patients taking enzyme inducers can require dosing three to four times daily. The serum concentration–dose relationship is curvilinear (e.g., the concentration–dose ratio decreases with increasing dose) probably because of increasing free concentrations and a resulting increase in clearance.

Valproic acid is available as a soft gelatin capsule, an enteric-coated tablet, a syrup, a “sprinkle capsule,” an extended-release formulation designed for once-daily dosing, and an IV formulation for replacement of oral therapy or in situations where rapid loading is necessary.125 This parenteral formulation must not be given IM because it can cause tissue necrosis. The sprinkle capsule, designed to be opened and mixed with food, has a slower rate of absorption, which results in fewer fluctuations in the peak-to-trough ratio. The syrup is absorbed more rapidly than any solid dosage form. The enteric-coated divalproex tablet is not sustained release. It must be metabolized in the gut to valproic acid. The enteric coating reduces GI distress. The enteric coating causes delayed absorption, although once the enteric coating dissolves, sodium divalproex has absorption, metabolism, and elimination rates similar to those of the gelatin capsule. If a patient is switched from Depakote to Depakote-ER, the dose should be increased by 14% to 20%. Depakote-ER may be given once daily.

Advantages Valproic acid is available in multiple dosage formulations. The IV formulation is especially well tolerated. It has a wide therapeutic index and is considered a broad-spectrum AED. It is also used in other neurologic or psychiatric disorders (e.g., migraine headache, bipolar disorder).

Disadvantages Some patients report significant weight gain with valproic acid, which may limit compliance. It has other side effects, such as alopecia, tremor, pancreatitis, PCOS, and thrombocytopenia. It has been associated with hepatic necrosis in young children. As an enzyme inhibitor, it is involved in multiple drug–drug interactions.

Place in Therapy Valproic acid is first-line therapy for primary generalized seizures, including myoclonic, atonic, and absence seizures. It can be used as both monotherapy and adjunctive therapy for partial seizures, and it can be very useful in patients with mixed seizure disorders.

Vigabatrin

Pharmacology and Mechanism of Action Vigabatrin is an amino acid that is a structural analog of GABA. It is a racemic mixture consisting of two enantiomers with only the S(+)-enantiomer active. Vigabatrin is a selective, irreversible inhibitor of GABA-transaminase, the enzyme that degrades GABA, thereby increasing GABA levels in the CNS.133

Pharmacokinetics Vigabatrin undergoes virtually no metabolism and is excreted unchanged in the urine. It is rapidly absorbed from the GI tract, and food has no effect on its absorption. Serum vigabatrin levels are linearly related to dosage, but therapeutic levels are not related to duration of effect; duration of effect is directly related to regeneration of the enzyme which metabolizes GABA. Since vigabatrin undergoes virtually no metabolism and is excreted renally, dosage adjustment is necessary in renally impaired patients. Children have a higher vigabatrin clearance than adults and therefore require higher mg/kg doses.32

Adverse Effects Vigabatrin may aggravate seizures, particularly absence and myoclonic seizures in patients with generalized epilepsies. Patients with history of depression, psychosis, or behavioral disturbances may be at greater risk to develop psychiatric effects.133 Vigabatrin causes progressive, irreversible, bilateral concentric visual field constriction in a high percentage of patients. It may also reduce visual acuity in a dose-related and life exposure-related manner. Vigabatrin is associated with weight gain and edema, peripheral neuropathy, somnolence, and fatigue. In up to 11% of patients (up to age 3 years) treated with high doses of the drug for infantile spasms, magnetic resonance imaging (MRI) findings have been strongly suggestive of intramyelinic edema in select brain areas. These findings appear to be reversible, and their significance is unclear.134

Drug Interactions Vigabatrin induces CYP2C and therefore decreases phenytoin plasma levels by approximately 20%. One study noted at least a 10% increase in serum carbamazepine levels in the majority of patients started on adjunctive therapy with vigabatrin, which has not been supported in clinical trials.

Dosing and Administration Vigabatrin’s initial dose in adults for refractory CP seizures is 1,000 mg/day given in two divided doses with an increase by 500 mg/day weekly until 3,000 mg/day is reached. Initial dose in infants and children for infantile spasms is 50 mg/kg/day given in two divided doses with an increase by 25 to 50 mg/kg/day every 3 days to a maximum dose of 150 mg/kg/day.

Advantages Vigabatrin has been widely studied and used in numerous countries throughout the world.

Disadvantages Adverse effects are sizeable and significant. It is available only through a restricted distribution program (SHARE program), which requires providers and patients to register. Vision should be checked at baseline and every 3 months for up to 3 to 6 months after drug discontinuation.

Place in Therapy Vigabatrin is a first-line agent for infantile spasms, particularly those with tuberous sclerosis as the etiology. It is a third-line adjunctive agent for refractory partial epilepsy.

Zonisamide

Pharmacology and Mechanism of Action Zonisamide, a sulfonamide, is believed to exert its antiepileptic effect by inhibition of slow sodium channels, by blockade of T-type Ca2+ channels, and possibly by inhibition of glutamate release. It also has a weak carbonic anhydrase inhibitory effect.135

Pharmacokinetics Zonisamide is well absorbed and reaches a maximum concentration in 2 to 5 hours. It is metabolized by CYP3A4 and to a much lesser extent by CYP2C19 and CYP3A5. Approximately 30% is excreted unchanged in the urine. Zonisamide is distributed to most tissues, but the drug is concentrated in the red blood cells. It crosses the placenta. The concentration in breast milk is similar to that in the plasma.135

Adverse Effects CNS effects, including word-finding problems and irritability, as well as GI effects are the most common side effects seen with zonisamide. Adverse effects may be more common during rapid dose escalation. Because it is structurally related to sulfonamides, hypersensitivity reactions can occur (0.02% of patients), and zonisamide should be used with caution (if at all) in patients with a confirmed allergy to sulfonamide compounds. A 2.6% incidence of symptomatic kidney stones has been reported in patients treated in the United States.136 Because of reports of modest, reversible declines in renal function in some patients, monitoring of renal function may be advisable for certain patients. Oligohidrosis has been reported. In addition, modest weight loss has been reported with this agent.25,26,81

Drug Interactions Zonisamide does not inhibit or induce the CYP450 system.

Dosing and Administration Zonisamide is given once or twice daily, however, once-daily dosing causes greater fluctuations in serum concentrations and perhaps more side effects. The dose should be increased every 2 weeks to response. Zonisamide is stable for 48 hours when mixed with water, apple juice, or pudding.

Advantages Zonisamide has multiple mechanisms of action and may be a broad-spectrum AED. There is broad international experience with this drug. It has a very long half-life, which is suitable for once- or twice-daily dosing. Patients may experience modest weight loss.

Disadvantages The dose of zonisamide should be titrated slowly to patient response. Renal stones and oligohidrosis have been reported. In addition, cognitive impairment can occur, especially if the dosage is escalated rapidly. It should be avoided in patients allergic to “sulfa drugs.”

Place in Therapy Zonisamide is approved for the adjunctive treatment of partial seizures. Zonisamide is potentially effective in a variety of partial and primary generalized seizure types.


Clinical Controversy…

The place in therapy of the newer drugs is still being determined. The cost of the newer AEDs generally is much higher than that of the older drugs. Given that, in general, the efficacy of the newer drugs is comparable with that of the older agents, many clinicians (and patients) have been slow to adopt this newer generation of drugs, however this is changing as more generic new AEDs become available. It is important to recognize that overall effectiveness encompasses both efficacy and tolerability assessments. Generally speaking, the newer generation of AEDs possess fewer adverse effects and seems to be better tolerated than older, far less expensive agents such as the barbiturates. Some may also have less costly long-term adverse effects such as effects on bone metabolism or the fetus, and they may cause fewer drug interactions, which require higher doses of drugs to avoid treatment failures. These differences may well justify the shrinking difference in cost. Whether to switch to newer generation AEDs needs to be determined on an individual patient basis.

PERSONALIZED PHARMACOTHERAPY

The most important aspect in the use of AEDs in persons with epilepsy is to tailor the choice of drug to the patient’s seizure type(s), concomitant medical problem(s) including concurrent medications, the patient’s economic status, and age. Evaluation of the patient’s renal and hepatic function is key to employing the best AED(s) in the treatment. The use of a generic AED may work well in one patient, but not in another. Assessment of QOL in the individual patient ultimately may be more meaningful than measuring blood levels of the AEDs. It is clear that the cheapest drug in epilepsy (e.g., phenobarbital) is not the best because of the number of side effects. Because epilepsy treatment continues to be highly individualized, the drug or combination of drugs that controls seizures with the least number of side effects will be the drug of choice for that patient, no matter how expensive the drug acquisition cost.

Since many patients with epilepsy require minimal variation in blood concentrations to prevent seizures and avoid side effects, generic prescribing for epilepsy remains controversial. Issues related to generic use have been clearly delineated in the literature.137,138 What has yet to be determined is whether bioequivalence translates into therapeutic equivalence in the use of generic AEDs and whether there is a subset of patients where this is not true.

Just as important is treating the epileptic pregnant patient, since this requires special knowledge of which AEDs’ pharmacokinetic profiles are affected by pregnancy, so dosage adjustment can be instituted to avoid breakthrough seizures.

In recent years much progress has been made in delineating patients who are at greater risk to develop severe adverse hypersensitivity reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis through HLA allele testing (see Pharmacologic Therapy section). Ongoing work is also being done to identify patients who may be at risk to develop multiorgan hypersensitivity syndrome using lymphocyte testing, although a test is not yet commercially available.

To date, there are very few epileptic syndromes that can be identified by genetic testing; however, research is still ongoing in this area. The genetic risk of epilepsy is quite complex, that is, multiple genetic and environmental factors seem to contribute to epilepsy risk. In addition, reliable genetic markers for drug efficacy have not been identified, since the occurrence of AED resistance is probably multifactorial.

EVALUATION OF THERAPEUTIC OUTCOMES

A therapeutic range should be established for each patient to define concentrations that result in minimal side effects and optimal seizure control. This therapeutic plasma concentration range should be used to identify the appropriate patient-specific dose. Patients should be monitored long term for seizure control, comorbid conditions, social adjustment (including QOL assessments), drug interactions, compliance, and adverse effects. Periodic screening for comorbid neuropsychiatric disorders such as depression and anxiety is also important. Clinical response is more important than the serum drug concentrations.

Outcomes can be assessed by regular clinical monitoring, drug utilization review, and QOL assessments. Clinical monitoring involves identifying the number and type of seizures. Patients should record the severity and the frequency of seizures in a seizure diary. There should be a decrease in the number and/or severity of seizures. Patients and family should be questioned regularly to determine whether they are truly seizure free.

ABBREVIATIONS

Images

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