The Pharmacology and Clinical Efficacy of Antiseizure Medications: From Bromide Salts to Cenobamate and Beyond

Abstract

Epilepsy is one of the most common and disabling chronic neurological disorders. Antiseizure medications (ASMs), previously referred to as anticonvulsant or antiepileptic drugs, are the mainstay of symptomatic epilepsy treatment. Epilepsy is a multifaceted complex disease and so is its treatment. Currently, about 30 ASMs are available for epilepsy therapy. Furthermore, several ASMs are approved therapies in nonepileptic conditions, including neuropathic pain, migraine, bipolar disorder, and generalized anxiety disorder. Because of this wide spectrum of therapeutic activity, ASMs are among the most often prescribed centrally active agents. Most ASMs act by modulation of voltage-gated ion channels; by enhancement of gamma aminobutyric acid-mediated inhibition; through interactions with elements of the synaptic release machinery; by blockade of ionotropic glutamate receptors; or by combinations of these mechanisms. Because of differences in their mechanisms of action, most ASMs do not suppress all types of seizures, so appropriate treatment choices are important. The goal of epilepsy therapy is the complete elimination of seizures; however, this is not achievable in about one-third of patients. Both in vivo and in vitro models of seizures and epilepsy are used to discover ASMs that are more effective in patients with continued drug-resistant seizures. Furthermore, therapies that are specific to epilepsy etiology are being developed. Currently, ~ 30 new compounds with diverse antiseizure mechanisms are in the preclinical or clinical drug development pipeline. Moreover, therapies with potential antiepileptogenic or disease-modifying effects are in preclinical and clinical development. Overall, the world of epilepsy therapy development is changing and evolving in many exciting and important ways. However, while new epilepsy therapies are developed, knowledge of the pharmacokinetics, antiseizure efficacy and spectrum, and adverse effect profiles of currently used ASMs is an essential component of treating epilepsy successfully and maintaining a high quality of life for every patient, particularly those receiving polypharmacy for drug-resistant seizures.

Fig. 1

Chemical structures of clinically approved antiseizure drugs discussed in this review

Fig. 2

Introduction of antiseizure drugs (ASMs) to the market from 1853 to 2020. Licensing varied from country to country. Figure shows the year of first licensing or first mention of clinical use in Europe, the USA, or Japan. We have not included all derivatives of listed ASMs nor ASMs used solely for the treatment of status epilepticus. The first generation of ASMs, entering the market from 1857 to 1958, included potassium bromide, phenobarbital, and a variety of drugs mainly derived by modification of the barbiturate structure, including phenytoin, primidone, trimethadione, and ethosuximide. The second-generation ASMs, including carbamazepine, valproate, and benzodiazepines, which were introduced between 1960 and 1975, differed chemically from the barbiturates. The era of the third-generation ASMs started in the 1980s with “rational” (target-based) developments such as progabide, vigabatrin, and tiagabine, i.e., drugs designed to selectively target a mechanism thought to be critical for the occurrence of epileptic seizures. Note that some drugs have been removed from the market. Modified from Löscher and Schmidt [11]. For further details, see Löscher et al. [30]. ACTH adrenocorticotropic hormone

Fig. 3

The clinical spectrum of antiseizure drugs. For details see text. i.v. intravenous

Fig. 4

Choice of antiseizure medications (ASMs) in adults and children. Common first monotherapy refers to the first treatment choice in a patient without any specific factors precluding the use of this. Monotherapy alternatives refer to ASMs chosen when certain patient- or ASM-related factors preclude the use of the first-choice ASM. Data from various sources [63, 64, 67, 68] and guidelines discussed in these papers. Note that several additional childhood epilepsy syndromes are not illustrated in this figure. ACTH adrenocorticotropic hormone

Fig. 5

Mechanism of action of clinically approved antiseizure medications (ASMs) [162]. Updated and modified from Löscher and Schmidt [167] and Löscher et al. [33]. Asterisks indicate that these compounds act by multiple mechanisms (not all mechanisms shown here). Some ASMs, e.g., fenfluramine, are not shown here, but their mechanism(s) of action are described in Table 2. AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, GABA γ-aminobutyric acid, GABA-T GABA aminotransferase, GAT-1 GABA transporter 1, KCNQ Kv7 potassium channel family, NMDA N-methyl-D-aspartate, SV2A synaptic vesicle protein 2A