Continuing Education Activity

Antiepileptic drug-level monitoring has been a standard practice in managing seizures since the introduction of antiepileptic drugs or antiseizure medications. Conforming antiepileptic drug levels to predefined therapeutic margins proves elusive, as clinicians often inflate these values. This activity discusses the effectiveness, diversity, and relevance of monitoring antiepileptic drug levels across various clinical milieus.

The diagnosis of epilepsy primarily hinges on clinical evaluation, supported by adjunctive investigative modalities such as electroencephalogram and magnetic resonance imaging. Similarly, gauging antiepileptic drug efficacy relies on clinical appraisal, with antiepileptic drug levels as supplementary information in specific scenarios. A comprehensive understanding of evolving guidelines and research, coupled with adept critical analysis skills, are vital for deciphering antiepileptic drug levels within the context of individual patient presentations and treatment objectives. Furthermore, fostering a patient-centered approach mandates accounting for distinctive patient characteristics and preferences, coupled with effective communication regarding treatment regimens and the rationale behind antiepileptic drug monitoring. Equipping healthcare professionals with in-depth knowledge of antiepileptic drug monitoring protocols empowers them to actively engage in shared decision-making with patients, ultimately fostering superior treatment outcomes.

Objectives:

• Evaluate the misconception surrounding the practice of maintaining antiepileptic drugs within laboratory-defined therapeutic ranges.

• Identify the efficacy, variability, and utility of monitoring antiepileptic drug levels in various settings.

• Assess the clinical assessment of antiepileptic drug efficacy.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes for patients who might benefit from antiepileptic drug monitoring.

Introduction

Antiepileptic drug-level monitoring has been a common clinical practice since the advent of antiepileptic drugs or antiseizure medications.[1] Maintaining antiepileptic drugs within laboratory-defined therapeutic ranges is a myth, with professionals overestimating values in most clinical settings.

Epilepsy is primarily diagnosed through clinical evaluation, with diagnostic modalities such as electroencephalogram and magnetic resonance imaging considered complementary investigations.[2] The assessment of antiepileptic drug efficacy should also be clinical, and the antiepileptic drug level should be utilized as a complementary tool in selected situations.

Function

Patient-Specific Antiepileptic Drug Levels

A single antiepileptic drug level can reasonably be assessed while the patient is seizure-free, serving as a benchmark for future reference if seizure control deteriorates or symptoms suggestive of toxicity develop.[3] Regular monitoring of valproic acid levels is crucial in cases of toxicity, with intervals typically set every 2 to 4 hours until a decrease in serum valproate levels is observed.[4]

Breakthrough Seizures

In cases of patients with epilepsy who have remained stable over a period and present with unprovoked breakthrough seizures, assessing drug levels may provide valuable guidance for treatment decisions.[5]

Status Epilepticus

In managing status epilepticus, the primary goal is to abort the attack using a benzodiazepine followed by an antiepileptic drug load, often with phenytoin. Monitoring antiepileptic drug levels in this setting could guide further loading if clinically indicated.[5]

Drug Substitution

Variations exist between different generic and brand-name antiepileptic drugs. Therefore, guidelines recommend against switching between different generics and brands. However, monitoring antiepileptic drug levels can aid in dose adjustments when substitution is necessary.[6]

Pharmacokinetics

The efficacy of antiepileptic drugs can be influenced by factors such as pregnancy, liver and renal diseases, drug interactions in polypharmacy, and aging. Therefore, drug levels can assist in dose adjustments to achieve a seizure-free quality of life.[3]

Issues of Concern

Variability in Antiseizure Medication Levels

Multiple clinical studies have been conducted to test the efficacy of monitoring antiepileptic drug levels in various clinical settings. One such study involved 114 inpatients in the United Kingdom. The medications studied included phenytoin, valproate, carbamazepine, lamotrigine, and phenobarbitone. To a lesser extent, other levels had been ordered, such as benzodiazepines, topiramate, gabapentin, and vigabatrin. The findings of the study indicated that antiepileptic drug levels proved beneficial with phenytoin, carbamazepine, and phenobarbitone. Lamotrigine has different therapeutic ranges, making interpretation of the levels difficult and leading to inappropriate dosage adjustments.[7] Valproate has a short half-life, making its measurement low-yield and primarily reflective of short-term compliance.

Conversely, phenytoin has a long half-life; hence, the antiepileptic drug level reflects long-term usage. The newer antiepileptic drugs have broader indications and are safer compared to the older ones. However, some of these newer agents lack generalizable reference ranges. For these reasons, level monitoring with newer agents is not useful.[8] Furthermore, variability in antiepileptic drug levels exists within patient populations and between clinical settings and is often based on the type and severity of the seizure.[9] 

A study demonstrated that antiepileptic drug levels vary considerably among patients treated for idiopathic generalized tonic-clonic seizures with phenytoin. While some patients achieve a seizure-free quality of life with certain antiepileptic drug levels, others may experience symptoms of toxicity. Thus, it is impractical to generalize the efficacy of antiepileptic drug-level monitoring.[10]

Drug-Drug Interactions Affecting Antiseizure Medications

Clinicians should be aware of the pharmacokinetics of medications, particularly in cases of polypharmacy. Medications utilizing metabolic pathways through the liver are often affected by interactions, which are commonly observed in medications such as valproic acid and carbamazepine. Non-seizure medications are also an important consideration, especially in hospital settings. Carbapenem can reduce valproic acid levels significantly and cause breakthrough seizures.[11] In such cases, it is important to monitor levels to guide therapy. Enzyme-inhibiting medications such as valproic acid can affect the metabolism of lamotrigine, increasing the level and its half-life. Conversely, medications such as estrogen-containing oral contraceptives reduce lamotrigine levels by increasing glucuronidation.[12][13][14] New-generation antiseizure medications such as gabapentin, levetiracetam, pregabalin, and vigabatrin are excreted unchanged by the kidneys and show minimal potential for drug-drug interactions.[15]

Clinical Monitoring Versus Drug-Level Monitoring

Multiple studies have concluded that clinical monitoring could optimally achieve seizure control. An investigation examined patients taking phenytoin and compared medication adjustments based on clinical assessment in one group to adjustments based on drug level in the other group. The study found that the majority of cases could be managed clinically, with only a few patients benefiting from drug-level monitoring.[16] This study was conducted using an old antiepileptic drug with a long half-life; therefore, antiepileptic drug levels are more closely correlated with medication compliance. Attempts to achieve therapeutic levels in seizure-free patients with subtherapeutic levels have not shown any difference in seizure control and have been associated with increased neurotoxicity.[10]

Antiseizure Medication Compliance

Compliance with epilepsy treatment plans is challenging due to the chronic nature of the disease, often requiring long-term pharmacologic therapy. Non-compliance manifests in various forms, with erratic non-compliance, characterized by inconsistent dosing, being the most prevalent. This inconsistency results in unreliable therapeutic antiepileptic drug levels and variability in seizure control.[17] Some patients exhibit white coat adherence, wherein they take their medications 1 or more days before their medical appointments, often resulting in antiepileptic drug levels within the normal ranges. In general, compliance studies are limited by their short-term nature and are difficult to correlate with actual behavior, which is known to vary over long periods in chronic conditions such as epilepsy.[18] 

Compliance and adherence are terms used interchangeably to describe the status of not taking the medication or following the treatment plan.[19] Compliance implies a paternalistic approach and fails to consider the patient's perspective. Adherence reflects the patient's role and perspective in the treatment plan. Compliance or adherence to a treatment plan is a complex process stemming from the strength of the relationships between physicians, patients, and the healthcare system. Compliance is paternalistic, passive, and episodic. Conversely, adherence is collaborative, active, and continuous. Therefore, many clinicians prefer to use the term adherence over compliance to position the patient at the center of their treatment plan and emphasize a holistic approach to achieving positive long-term outcomes when treating complex chronic conditions such as epilepsy.[20]

Other Ways to Promote Antiepileptic Drug-Level Monitoring

To effectively guide patients in managing their medications, clinicians must investigate the reasons for non-adherence and assist patients in overcoming them. However, it depends on the patient's ability to adhere to their medications eventually. Various methods can be employed to assess compliance, including:

• Patient reporting, which depends on the patient recalling, their reliability as a historian, and the pattern of compliance with other medications
• Monitoring drug levels, which has traditionally been used as the only reliable way to monitor adherence by most clinicians
• Utilization of diaries [21]
• Direct observation of medication administration
• Pill counts
• Implementation of behavioral interventions and intensive reminders [22] 

There are many effective ways to help patients adhere to their medication other than monitoring drug levels. However, relying solely on drug level monitoring presents challenges, as it can be expensive, unreliable, and, in some cases, lead to unnecessary dosage adjustments, potentially increasing the risk of adverse effects.

Clinical Significance

Achieving optimal outcomes in the treatment of epilepsy rarely requires monitoring of antiepileptic drug levels.[23] Although this has been a common clinical practice for years, newer antiepileptic drugs and more recent evidence suggest that the value of antiepileptic drug-level monitoring is low except for the few scenarios mentioned above. Clinical monitoring within the broader context of a supportive, patient-centered treatment plan based on a therapeutic physician-patient relationship is the key to success.

• Although levetiracetam and brivaracetam levels are not routinely monitored, it is important to note that they may be altered during the first trimester.[24] Monitoring of levetiracetam serum levels is important during pregnancy.[25]

• Due to its complex pharmacokinetics, adjusting phenytoin dosage accurately in critically ill patients with low albumin levels is challenging. The commonly used Sheiner-Tozer equation often fails to predict free phenytoin concentration accurately, potentially leading to inappropriate dosing.

• To address this, the corrected phenytoin level can be calculated using the formula: Corrected phenytoin = obtained phenytoin level / ((adjustment x albumin) + 0.1). Here, adjustment = 0.275; if creatine clearance is <20 mL/min, adjustment = 0.2.

• This study compared the Sheiner-Tozer equation with direct measurement of free phenytoin concentration using high-performance liquid chromatography in such patients, revealing discrepancies between the 2 methods. Direct measurement of free phenytoin concentration is recommended for individualizing phenytoin dosage in critically ill patients with low albumin levels.[26]

Other Issues

In the current environment of patients seeking healthy foods and herbal and non-proprietary medications, therapeutic drug monitoring can pose challenges. A comprehensive understanding of the patient's medication regimen is essential to consider potential drug-drug interactions and minimize undesired changes in antiepileptic drug levels. The recent increase in the use of cannabidiol as an antiepileptic drug has heightened the need for frequent monitoring of certain medications, such as clobazam, during concomitant therapy.[27] In combination with valproate or clobazam, cannabidiol can cause increased liver enzymes, notably alanine aminotransferase and aspartate aminotransferase; therefore, patients receiving this combination may benefit from additional liver enzyme monitoring. Animal studies have shown cannabidiol to increase clobazam anticonvulsant activity through CYP3A4 activity, but only when an anticonvulsant dose of cannabidiol was used. Despite increased serum clobazam concentrations, administering sub-therapeutic doses of cannabidiol did not result in heightened anticonvulsant effects.[23][28][29]

Trough Versus Free levels

Trough levels and free levels of antiepileptic drugs are crucial parameters for therapeutic drug monitoring in patients with epilepsy.

Trough levels represent the concentration of antiepileptic drugs in the blood at the lowest point, typically just before the next dose is due. This consideration is especially important in antiepileptic drugs with short half-lives. These levels are significant as they indicate the minimum concentration of the drug between doses, ensuring that therapeutic levels are maintained throughout the dosing interval. For antiepileptic drugs, maintaining adequate trough levels is essential for preventing breakthrough seizures and optimizing therapeutic efficacy.

On the other hand, free levels denote the concentration of the unbound, pharmacologically active fraction of the drug in the bloodstream. Measuring free levels becomes crucial when protein binding may be altered, such as during severe systemic illness or drug interactions. When protein binding is altered, it can influence the availability of the active form of the drug, potentially leading to inaccurate assessments of therapeutic efficacy based on total drug concentrations alone. Considerable variability exists in the free fraction of phenytoin, carbamazepine, and valproic acid among individuals, particularly when influenced by concurrent disease or drug interactions. Alterations in binding can render total concentrations unreliable indicators of pharmacologically active drug levels in plasma, potentially leading clinicians to make inappropriate dosage adjustments. Prioritizing the measurement of free drug concentration can mitigate interpretative errors and may be the preferred method for monitoring therapy in specific patient populations.[30][31][32]

Enhancing Healthcare Team Outcomes

Nurse practitioners, internists, primary care providers, neurologists, or emergency department physicians frequently encounter patients undergoing treatment with antiepileptic drugs. In the past, it was widely believed that routine drug monitoring of antiepileptics was beneficial, but except for a few cases, this practice is no longer recommended. Instead, clinical monitoring within the context of a supportive, patient-centered, interprofessional team treatment plan based on a therapeutic clinician-patient relationship with the support of nurses and pharmacists is the key to success. A systematic review emphasizes that not every antiepileptic drug requires therapeutic drug monitoring. Therapeutic drug monitoring can enhance clinical care, particularly for antiepileptic drugs such as phenytoin with complex pharmacokinetics, but its requirement differs based on the drug and individual patient factors.[33]

This interprofessional team includes physicians, neurologists, nurse practitioners, physician assistants, nurses, and pharmacists. In addition to verifying appropriate dosing and performing medication reconciliation, pharmacists should emphasize the importance of medication compliance to patients and the need for close follow-up. If there is evidence of non-compliance, pharmacists should discuss the situation with clinicians managing the case. Pharmacists and nurses should assist in educating patients about the adverse effects of the drugs so that they know when to report back to clinicians; they must also be alert to signs of therapeutic failure, which must be documented and reported to other team members as necessary so that regimen modification can be implemented if required. Only through such an interprofessional team approach with open communication channels between all team members can the morbidity of anticonvulsants be reduced and safe outcomes be achieved.

Nursing, Allied Health, and Interprofessional Team Interventions

Nurses responsible for administering antiepileptic drugs should independently verify the dose and route of administration. They should also understand the potential adverse effects of the drugs and educate patients to enhance safety measures. If a dose does not appear reasonable, the nurse should contact the prescribing clinician immediately.

Nursing, Allied Health, and Interprofessional Team Monitoring

Several anticonvulsants have the potential to cause adverse cardiac effects when administered intravenously.[34] Thus, patients should be placed on a cardiac monitor, and their vital signs should be measured frequently. Any adverse effects should be immediately reported to the prescriber.