Basic Pharmacology And Physiology Of Anti-Seizure Agents

A major goal of contemporary epilepsy research is the identification of therapies to prevent the development of recurrent seizures in individuals at risk, including those with brain injuries, infections, or neoplasms; status epilepticus; cortical dysplasias; or genetic epilepsy susceptibility. Epilepsy, the most common chronic neurological pathology, is symptomatically treated by present antiepileptic drugs (AEDs) in about two-thirds of the cases. Antiepileptic drugs, now commonly referred to as antiseizure drugs (ASDs), provide symptomatic benefit by preventing the occurrence of seizures in an individual at risk.

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A series of conceptual reconsiderations and therapeutic advances in recent years has resulted in meaningful changes in the classification, diagnosis, and treatment of epilepsy. The first step in evaluation of the person with epilepsy is determining whether the seizures are partial or generalized in onset; this determination will guide further evaluation and is mandatory in choosing an antiepileptic drug (AED). With 12 new AEDs and 1 device approved for use in epilepsy by the US Food and Drug Administration since 1993, the choice of AED has become more complex and it is impossible to predict whether a patient will respond favorably to a drug based on clinical features or clinical laboratory results. AEDs have many different mechanisms of action, but there does not seem to be a strong base of evidence to demonstrate that AED choice should be based on mechanism of action. Yet, a new secondary analysis of data from clinical trials of the new AED lacosamide suggests that combining this AED with another AED that has minimal or no activity at the sodium channel may lead to better tolerability and efficacy. The new AEDs have been tested in randomized controlled trials and compared with placebo; however, there are few head-to-head trials assessing the efficacy of various AEDs, and none of them provide evidence of a clear first choice drug or first add-on drug. Adverse effect profiles of the new generation of AEDs generally show better overall tolerability, but the choice of AED must be individualized (often based on comorbidities) because the adverse effect profiles of the newer AEDs differ widely. One area where the new AEDs consistently outperform the older AEDs is pharmacokinetic profile. Three new AEDs have no hepatic metabolism or protein binding, and others have minimal drug-drug interactions. Ultimately, selection of an appropriate agent involves matching a patient to a medication, or combination of medications, with the best record of efficacy while avoiding issues of tolerability and unwanted drug interactions (specifically tied to the needs of a given patient). Despite major advances in AED development, approximately one-third of people with epilepsy will have incomplete control of seizures no matter which AED is used alone or in combination, emphasizing the need for more effective AEDs. Patients with medication-resistant epilepsy may be candidates for epilepsy surgery, a highly effective treatment that is underutilized in this population.

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Disease-modifying therapies may prevent or delay the onset of spontaneous recurrent seizures in an individual at risk; they may reverse already established epilepsy; or they may prevent or ameliorate comorbidities, such as cognitive deficits that accompany some forms of epilepsy. The key difference distinguishing disease-modifying therapies from symptomatic therapies is that the benefit conferred by disease-modifying therapies persists after drug treatment is withdrawn. For the purposes of this article, we mainly focus on treatments that prevent or delay the onset of epilepsy; such a treatment is referred to as “antiepileptogenic”. Antiepileptogenesis can also refer to conditions in which epilepsy develops despite treatment, but it is less severe, that is the seizure frequency is reduced, seizures are of shorter duration, or the seizure type is milder. Furthermore, antiepileptogenic treatment may also result in amelioration of comorbidities associated with epilepsy

Recent studies of drug-resistant epilepsy have revealed the involvement of inflammation processes, functional glia changes and altered intercellular communication related to gap junctions. This provides further, albeit not exhaustive, examples of targets to consider for future AED discovery. A successful strategy aimed at overcoming resistance to AEDs necessitates an integrated vision encompassing the basic features of intractable epilepsies. To date, clinical trials have failed to demonstrate that antiseizure drugs have such disease-modifying activity. However, studies in animal models with levetiracetam and ethosuximide are encouraging, and clinical trials with these agents are warranted. Other promising strategies are inhibition of interleukin 1β signaling by drugs such as VX-765; modulation of sphingosine 1-phosphate signaling by drugs such as fingolimod; activation of the mammalian target of rapamycin by drugs such as rapamycin; the hormone erythropoietin; and, paradoxically, drugs such as the α2 adrenergic receptor antagonist atipamezole and the CB1 cannabinoid antagonist SR141716A (rimonabant) with proexcitatory activity. These approaches could lead to a new paradigm in epilepsy drug therapy where treatment for a limited period prevents the occurrence of spontaneous seizures, thus avoiding lifelong commitment to symptomatic treatment.

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