The Pharmacologic Basis of Antiepileptic Drug Action

Abstract

Summary:The development of medications used in the treatment of epilepsy has accelerated over the past decade, and has benefited from a parallel growth in our knowledge of the basic mechanisms underlying neuronal excitability and synchronization. This understanding of the pharmacologic basis of antiepileptic drug (AED) action has, in large part, arisen from recent advances in cellular and molecular biology, coupled with avenues of drug discovery that have departed somewhat from the largely empiric approaches of the past. Physicians now have available to them an ever-growing armentarium of AEDs, neTherapy with antiepileptic drugs (AEDs) remains the mainstay of treatment of patients with epilepsy. Before the Victorian era, therapeutic approaches to epilepsy were largely based on superstition and charlatanism. The first demonstrably effective chemotherapy relied on the use of nonspecific depressants of the central nervous system. Sir Charles Locock introduced bromides in the mid-nineteenth century for the treatment of catamenial epilepsies, and phenobarbital (PB) was adopted in 1912 after the observations of Hauptmann (l), who used that compound to sedate a ward of noisy psychiatric patients and those with epilepsy during the night. Introduction of more specific AEDs for clinical application followed the availability of the first animal-seizure model: the maximal electroshock (MES) model (2). The history of AED design has recently been reviewed in some detail (3).The relation of the human epilepsies to the animal models commonly used for AED development, and to the cellular membrane physiology underlying neuronal excitability, continues to be an imperfect one (Fig. 1) cessitating a firmer appreciation of their mechanisms of action if more rational approaches toward both clinical application and research are to be adopted. An important example in this regard is the concept of rational polypharmacy for patients with epilepsy who are refractory to monotherapy. This review summarizes our current understanding of the molecular targets of clinically significant AEDs, comparing and contrasting their differing mechanisms of action. Key Words: Antiepileptic drug-AED-Anticonvulsant-Mechanism-%-zure-Epilepsy-Ion channel.threshold pentylenetetrazol (PTZ) test in mice (see Table 1) have been carefully standardized (4). The MES model has served to identify AEDs that are functionally similar to phenytoin (PHT), and most of these compounds display in common the ability to inactivate voltage-dependent Na+ channels in a use-dependent fashion. Such compounds suppress sustained repetitive firing in cultured neurons. Activity in this model seems highly predictive of the ability of those AEDs to protect against partial and secondarily generalized tonic-clonic seizures (Fig. 2). Carbamazepine (CBZ), as well as several newer agents such as felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), and topiramate (TPM), fit this model of AED activity. Some of these (i.e., PHT, CBZ, LTG) may also attenuate the release of excitatory neurotransmi...

Anticonvulsant activity of Bacopa monniera in rodents

“…This may indicate a GABAergic mechanism as the effect of diazepam was potentiated and similar to a full protective dose of diazepam (4 mg/kg BW, ip). This model reveals that BM may be clinically effective against generalized-spike-wave absence epilepsies (Rho, Raman, 1999).…”

“…The dose of BM did not stop hind limb extension, but decreased it by nearly half the extension time in controls. This indicates its ability to prevent the spread of seizure in the central nervous system (Rho, Raman, 1999).…”

“…The probable protection in this model (Rho & Raman, 1999) is mediated either by: 1) Suppression of Ca 2+ conductance across low threshold T-type Channels, or 2) Enhancement of GABA A receptor mediated Cl -conductance.…”

Antiepileptic Drugs 2012: Recent Advances and Trends

“…Therefore, much work is needed to answer vital common clinical questions regarding AEDs, such as (1) Which drug should be used (first-generation or a new agent)? (2) Are there certain agents that should be tried before surgery? (3) Can a certain combination of medications yield better seizure control than a single agent?…”

“…However, because 2 of the AEDs have novel mechanisms of action, it is important to appreciate a somewhat simplistic overview of how AEDs work to appreciate the complexity of this therapy. Figure 1 diagrams where AEDs are believed to exert their therapeutically relevant effects, 1,2 with an emphasis on presynaptic effects. Currently available AEDs are thought to affect several molecules at the excitatory synapse.…”