Many of the traditional AEDs, including carbamazepine and phenytoin, elicit their mechanisms of action through the inhibition of voltage-gated sodium channels. These channels serve as critical components for the initiation and propagation of action potentials, facilitating neurotransmitter release and signal transmission to postsynaptic neurons. Voltage-gated channel inhibitors may exert their effects through stabilization of the channel in the inactive state via transient interactions with the core or membrane-bound portions of the channel.
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Certain AEDs are postulated to function solely through this mechanism, while several combine this activity with other molecular mechanisms to modulate neurotransmission. The GABA A receptor is a ligand-gated chloride channel that, when activated by GABA or another small molecule, hyperpolarizes the membrane, thereby suppressing action potentials in the postsynaptic neuron. Additionally, gabapentin is structurally similar to GABA, and stimulates GABA release through multiple interactions, one of which may be inhibition of voltage-gated calcium channels 7.
Several other molecular mechanisms are used by AEDs that target a diverse set of proteins and processes.
Levetiracetam and its recently approved chemical analog brivaracetam are thought to exert their effects through binding to SV2A, a neurotransmitter reporter found in synaptic vesicles and endocrine granules. Thus, these drugs may be similar to those with GABA-related mechanisms. Notably, both levetiracetam and brivaracetam have improved toxicity profiles compared with earlier generation AEDs. AMPA receptors are ligand-gated ion channels that mediate fast excitatory neurotransmission. Further, the primary mechanism of action of third-generation AED perampanel is through the noncompetitive antagonism of the AMPA receptor.
NMDA receptor hypofunction and overstimulation have been implicated in a wide range of neurological disorders, including dementia, neuropathic pain, schizophrenia, and epilepsy 9. Major epilepsy groups have published and continue to update clinical guidelines for the diagnosis and treatment of epilepsy. In , the American Academy of Neurology and American Epilepsy Society published a joint guidance based on a systematic review of 47 qualifying studies on the treatment of adults with a first unprovoked seizure In these studies, the first-generation AEDs carbamazepine, phenytoin, and phenobarbital were most often used.
However, no difference in quality of life or rate of long-term 2—5 years seizure remission was found between immediate and delayed AED therapy initiation. These findings suggest that therapeutic drug monitoring TDM may be beneficial to ensure sufficient exposure and minimize toxicities, thereby increasing efficacy and quality of life regardless of when pharmacotherapy is initiated.
Although most clinical trials and guidelines focus on epilepsy in adult populations, children account for roughly one-quarter of all epilepsy cases. The guidelines published in by the American Academy of Neurology and the Practice Committee of the Child Neurology Society provide similar recommendations for children as those provided for adults An important consideration in the initiation of daily pharmacotherapy in a pediatric population is the potential impact of drug administration on the child's psychosocial development. Although fewer trials have been conducted in pediatric populations, the effects of AED therapy are similar in children as in adults.
AED therapy likely reduces the risk of a second seizure, but it does not necessarily improve long-term remission success. A survey of clinical trials evaluating the efficacy of AEDs for various types of epilepsy was first published by the ILAE in 12 and updated in Notably, data were enriched and recommendations made primarily for focal seizures and pediatric absence seizures.
For other epilepsy types, such as generalized onset tonic-clonic and juvenile myoclonic epilepsy, only low levels of evidence were available. Overall, well-designed randomized controlled trials are lacking in epilepsy, and this makes it difficult to determine which AEDs are the most effective for each type of epilepsy.
As such, empirical use of AEDs is necessary when recommended first-line drugs are not effective and literature data are limited. The goals for AED therapy postdiagnosis are to prevent further seizures while minimizing adverse and off-target drug effects. Generally, AED monotherapy is initiated and patient response is monitored. If seizure control is not achieved initially, monotherapy is attempted with a different AED. Transitioning between monotherapies requires vigilant monitoring for efficacy and potential toxicity. Once monotherapy options have been exhausted, combination therapy with an adjunctive AED is commonly pursued for disease management.
Of note, many of the second- and third-generation AEDs were initially approved as adjunctive therapies; however, recent data suggest that many of the third-generation AEDs are also effective as first-line monotherapies 15 , While these drugs may be preferred by patients due to a lower incidence of side effects, most are not currently approved as first-line therapies for epilepsy.
Given the large number of drugs and overlapping mechanisms of action within drug classes, AED selection can be a significant challenge. Current guidelines in the US and Europe provide multiple options for first-line, second-line, and adjunctive therapeutic options for each type of seizure, as outlined in Table 2 There are many key factors that must be considered when selecting a therapy, either for initial or combination therapy, all of which are specific to the patient Recommended antiepileptic drugs first-line, adjuvant, and secondary by seizure type.
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Addition of an adjunctive AED, or incorporation of an AED into an existing drug regimen, requires an assessment of potential drug—drug interactions. This topic is beyond the scope of this review, and reference texts are available that enumerate the many AED drug—drug interactions that have been established and observed 19 , In brief, most AEDs are at least partially metabolized by liver enzymes, and many AEDs either inhibit or induce hepatic cytochrome P enzyme activity. Drug doses must be carefully selected and adjusted to achieve desired therapeutic concentrations.
The importance of monitoring AED concentrations in blood has been recognized for several decades. AEDs have a narrow therapeutic window and display wide interindividual variability with regard to pharmacokinetics. One challenging aspect of AED therapy is that their clinical efficacy is variable, even among patients with the same serum drug concentrations. Given these considerations and the common use of multiple AEDs, TDM is an important aspect of pharmacological epilepsy treatment.
In particular, they recommended establishing a patient-specific effective range, termed the therapeutic range, after AED therapy is initiated, and assessing drug concentrations every 6—12 months or when changes to the clinical situation warranted. To date, only 2 published randomized trials have compared epilepsy patients with and without routine TDM for guiding AED dosing. Neither trial found an improvement in overall outcome with routine TDM 24 , These results do not, however, address the utility of TDM in selected clinical situations, such as during medication modifications, in which the information provided is likely more impactful.
Further, the need for TDM of third-generation AEDs has not been definitively established and may thus be used in a different context than for first- or second-generation AEDs. Due to short half-lives, many AEDs are associated with a high pill burden to sustain therapeutic concentrations. For some second-generation AEDs, extended-release formulations have been approved and marketed for epilepsy and other indications. These include gabapentin, lamotrigine, levetiracetam, oxcarbazepine, and topiramate. Reviews of available pharmacokinetic data suggest that the overall PK data for extended-release formulations compares favorably to immediate-release formulations, with reductions in peak-to-trough fluctuations Although small studies have shown that patients rate tolerability and quality of life higher when switched to extended-release formulations, there is no large-scale evidence of increased safety 26 , The potential advantages of once-daily administration include increased compliance, more stable blood concentrations, and patient preference for more convenient dosing.
Although AEDs elicit their mechanisms of action in the non-protein bound, or free, form, laboratory assays typically report total drug concentrations in serum or plasma. Free drug measurements are not indicated or clinically useful for non-highly bound molecules, such as phenobarbital. However, when a molecule is highly protein bound, such as is the case with phenytoin, measurement of free drug concentrations can provide additional information regarding therapeutic efficacy or toxicity.
Anemia, hypoalbuminemia, and uremia can all displace drug—protein interactions, thereby increasing free drug concentrations. Thus, for highly protein-bound AEDs, when plasma protein concentrations are altered, such as during pregnancy, or low, such as in elderly patients, free drug measurements can be clinically useful for drug monitoring 28 , Non-protein bound drug may be separated using methodologies such as ultrafiltration before analysis with downstream laboratory methods.
Immunoassays are commonly employed in the measurement of many first-generation AEDs. While many vendors have automated antibody-based assays available for canonical AEDs like phenytoin and carbamazepine, immunoassay offerings for many second- and third-generation compounds are more limited. Homogeneous immunoassays are available for second-generation AEDs, including lamotrigine 30 , levetiracetam 31 , gabapentin 32 , topiramate 33 , and zonisamide Offerings via third-party vendors, such as the aforementioned assays available through ARK Diagnostics, may be integrated into automated laboratory platforms to streamline laboratory work flows.
Important considerations, however, include potential increased cost per assay and decreased efficiency due to limited reagent stability and laboratory needs. Further, like all immunoassays, they can be subject to interferences and cross-reactivity with similar compounds. In the absence of commercially available methods for all AEDs, mass spectrometry is an alternative approach for AED quantification. Such laboratory tests may be targeted for a single AED or may be multiplexed in design. In the literature, there are a plethora of methods described for the quantification of individual AEDs in biological matrices, with the majority of these methods utilizing mass spectrometry.
Simultaneous quantification of analytes is challenging due to the potential for similar retention times, variable ionization efficiency, and overlapping precursor and product ions. Chromatographic times varied from 6—12 min 35 , 38 , With an increased number of drugs to separate, analytical run times may exceed 17 min per sample 36 , Most patients on multi-AED therapy are prescribed 2 or 3 AEDs at a time, and these combinations are tailored to the individual patient. If developed for clinical use, a multiplexed assay covering most AEDs could be applied to nearly all patients and reduce the number of separate tests ordered.
When potential interferences with an immunoassay are of concern, methodologies that utilize chromatography could be used, as these provide physical separation of serum components. While AEDs are developed and studied for their ability to address epilepsy, they are also commonly used for other indications. In fact, the majority of AEDs are prescribed to patients without an epilepsy diagnosis, mostly for the treatment of psychiatric disorders 40 , While the use of AEDs in psychiatric disorders is widespread, only 4 AEDs are approved by the FDA for psychiatric indications pregabalin for generalized anxiety disorder and carbamazepine, lamotrigine, and valproic acid for bipolar disorder.
Beyond this small number of drugs and limited indications, the use of AEDs in psychiatric disorders is considered off-label. Support and guidance for how AEDs can be used is derived mainly from open-label studies, small uncontrolled trials, and case reports Additionally, the incidence of psychiatric disorders, particularly depression, among patients with epilepsy is higher than that of the general population and thus appropriate AED therapy may be used to treat both conditions Other common indications for AED use are neuropathic pain and headaches.
Gabapentin and pregabalin are approved for postherpetic neuralgia lingering pain from complications of shingles , while pregabalin is also approved for the treatment of peripheral diabetic neuralgia. Carbamazepine is the first-line treatment for trigeminal neuralgia severe episodic facial pain ; however, the progressive nature of the disease decreases carbamazepine's effectiveness over time The Canadian Pain Society recently recommended gabapentin, pregabalin, and carbamazepine as first-line therapies and other anticonvulsants as fourth-line therapies for neuropathic pain AEDs are used for pain relief from headaches, particularly migraine headaches.
While both topiramate and valproic acid are approved for the treatment of migraines, several other AEDs, such as carbamazepine, clonazepam, levetiracetam, vigabatrin, and zonisamide, are commonly prescribed off-label for this purpose Unfortunately, clinical data for most AEDs for the prevention of migraines are limited. The best clinical evidence is available for topiramate and valproic acid, both of which reduce migraine frequency when compared with placebo in multiple clinical trials Several polymorphisms are known to have pharmacogenetic effects for one or more AEDs.
These effects include alterations to pharmacokinetic parameters and increased risk of serious adverse effects. Within the HLA-B15 serotype, one polymorphism has been identified that increases the risk of certain severe adverse effects of some AEDs. CYP2C9 3 polymorphisms have been demonstrated to decrease the rate of metabolism of phenobarbital, phenytoin, and valproic acid Despite high-quality evidence, prospective CYP2C9 genotyping is not commonly performed, with clinical practice generally relying on monitoring serum drug concentrations and clinical presentation CYP2C19 variants can also impact AED metabolism, with a substantial effect on phenobarbital and to a lesser extent on phenytoin.
Initial studies also suggest that CYP2C19 variants may decrease the rate of zonisamide metabolism Polymorphisms of UGT2B7 significantly decrease serum valproic acid levels in epilepsy patients UGT1A4 is the main enzyme responsible for the glucuronidation of lamotrigine. The UGT1A4 L48V variant decreases serum lamotrigine concentrations and affects its overall efficacy in both pediatric and adult patients 49 , Overall, the translation of genotypes of relevant genes to dose adjustments for individual patients remains challenging, partly due to lack of conclusive evidence as well as clear guidelines.
Due to their range of neurotransmission-modulating mechanisms, AEDs have been successfully used not only for the treatment of epilepsy but also for various psychiatric conditions and certain types of pain. Identifying an effective AED for an individual patient involves empirical testing of different drugs, often guided by TDM. Multiple assay modalities are available for determining serum concentrations of AEDs.
Furthermore, pharmacogenetics testing can be applied during consideration of AED therapy or when investigating unexpected clearance kinetics. Overall, AEDs are an important drug type that must be carefully prescribed and monitored to achieve successful treatment in a variety of conditions. Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
Skip to main content. Review Article Mini-Review. Claire E. Knezevic , Mark A. DOI: Abstract Background: Antiepileptic drugs AEDs have been used for the treatment of epilepsy and other neurological disorders since the late 19th century. Impact Statement Understanding the molecular mechanisms of action of antiepileptic drugs, as well as the role of the clinical laboratory in monitoring drug concentrations, can aid in the successful selection and management of epilepsy, in its myriad presentations. View this table: View inline View popup. Table 1. FDA approval years and molecular mechanisms of antiepileptic drugs.
Overview of neurotransmitter activity at the pre- and postsynaptic junction. Epilepsy treatment guidelines Major epilepsy groups have published and continue to update clinical guidelines for the diagnosis and treatment of epilepsy. AED therapy The goals for AED therapy postdiagnosis are to prevent further seizures while minimizing adverse and off-target drug effects. Table 2. Analytical methodologies Immunoassays. Mass spectrometry In the absence of commercially available methods for all AEDs, mass spectrometry is an alternative approach for AED quantification.
Use of AEDs in nonepileptic disease states While AEDs are developed and studied for their ability to address epilepsy, they are also commonly used for other indications.
go to link Genetic variables in drug metabolism Several polymorphisms are known to have pharmacogenetic effects for one or more AEDs. Krasowski, CLN, June Role of Sponsor: No sponsor was declared. References 1. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE commission for classification and terminology. Epilepsia ; 58 : — OpenUrl CrossRef. ILAE official report: a practical clinical definition of epilepsy.
Epilepsia ; 55 : — Recommendation for a definition of acute symptomatic seizure. Epilepsia ; 51 : — 5. The history of barbiturates a century after their clinical introduction. Neuropsychiatr Dis Treat ; 1 : — Patsalos PN. Antiepileptic Drug Interactions. A Clinical Guide. London, UK: Springer; Genton P, Roger J. Antiepileptic drug monotherapy versus polytherapy: a historical perspective. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a year longitudinal cohort study.
JAMA Neurol. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Long-term safety and efficacy of zonisamide versus carbamazepine monotherapy for treatment of partial seizures in adults with newly diagnosed epilepsy: results of a phase III, randomized, double-blind study. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Instruction manual for the ILAE operational classification of seizure types.
The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. Update ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial immunotherapy for epileptic seizures and syndromes. Epilepsies ; 54 3 Antiepileptic drug immunotherapy for epilepsy: a network meta-analysis of individual participant data. Cochrane Epilepsy Group Vigabatrin versus carbamazepine monotherapy for epilepsy.
Cochrane Database Syst Rev Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review. Cochrane Database Syst Rev.
Topiramate versus carbamazepine monotherapy for epilepsy: an individual participant data review. Lamotrigine versus carbamazepine monotherapy for epilepsy: an individual participant data review. Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review. Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures: an individual participant data review.
Oxcarbazepine versus phenytoin monotherapy for epilepsy. Comparative efficacy of antiepileptic drugs for patients with generalized epileptic seizures: systematic review and network meta-analyses. Int J Clin Pharm. Somerville ER. Some treatments cause seizure aggravation in idiopathic epilepsies especially absence epilepsy.
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