• DOI:10.1212/WNL.44.5.787
• Corpus ID: 75925846

New antiepileptic drugs

@article{Harden1994NewAD,
  title={New antiepileptic drugs},
  author={Cynthia Harden},
  journal={Neurology},
  year={1994},
  volume={44},
  pages={787 - 787}
}

• C. Harden
• Published 1 May 1994
• Medicine
• Neurology

Antiepileptic drugs (AEDs) were first developed by empiric drug testing, without any basic understanding of epileptic processes. Bromide salts were used for epilepsy in the last century with the notion that this medicine would suppress sexual desire, which-according t o prevailing scientific thought in the 1860s-would in turn suppress seizure activity.l However, the sedative action of bromides correlated with seizure reduction, which led to the discovery in 1912 of another sedative with efficacy in seizure disorders, phenobarbital. The continued search for similar molecules with antiseizure activity but less sedating side effects led to the development of phenytoin, ethosuximide, and other succinimides, as well as benzodiazepines and carbamazepine. Valproate is a much simpler molecule serendipitously discovered as having antiseizure properties when it was used as a solvent in a drug-screening program.2 Valproate was approved for use in the United States in 1978; until late 1992, there were no other novel AEDs submitted for approval to the FDA.3 The development of animal seizure models was a major step in the discovery of hydantoins (most notably phenytoin) in the 1930s. Animal models were crucial in guiding the development of all subsequent AEDs-primidone in the 1940s, benzodiazepines and succinimides in the 1950s, carbamazepine in the 1960s, and valproate in the 1 9 7 0 ~ . ~ ~ Testing drugs in animal models remains important in AED development, perhaps more so now than in the past since a drug’s anticonvulsant profile in animal seizure models provides insight into its cellular mechanism of action. Two of the most widely used animal models are the maximal electroshock test and the pentylenetetrazol test, which both are highly reproducible and relatively standardized. A drug’s effectiveness in preventing seizures in the maximal electroshock test correlates with its ability to prevent partial and secondarily generalized seizures in humans; this model may evaluate the ability of a drug to prevent seizure spread. Drugs that show efficacy in this model, like phenytoin and carbamazepine, often block. voltage-dependent sodium channels. The pentylenetetrazol test evaluates the ability of a drug to prevent clonic seizures and may correlate with action against absence seizures. Effective activity in this model often indicates that a drug is affecting the inhibitory neurotransmitter gammaaminobutyric acid (GABA) system in the brain, possibly by enhancing GABA levels or altering GABA receptors.2 Developments in understanding the cellular mechanisms of epileptogenesis have enabled investigators to elucidate the mechanisms of action of available AEDs and have launched the development of AEDs targeted to act a t the molecular structure of neuronal membranes. Current understanding of the mechanisms of available antiepileptic drugs is that their action is mainly through one of three mechanisms: (1) altering voltage-dependent ion channels involved in action potential propagation or burst generation, (2) augmenting of GABA-mediated inhibition, or (3) interfering with amino acid-mediated excitation.2 The electrophysiologic basis for epileptic discharges consists of a depolarization shift (DS). The DS is generated by a n abnormal, large, synchronous excitatory postsynaptic potential in a small area of cortex, followed by activation of intrinsic voltage-dependent sodium and calcium membrane currents. This step results in a burst of action potential discharges. Epileptic foci are subsets of neurons with endogenous bursting characteristics that act as “pacemakers” to the DS. Neurons in the CA2 and CA3 pyramidal cells in the hippocampus, neurons of layers 4 and 5 of the neocortex, and neurons in chronic neocortical epileptogenic foci have spontaneous electrical bursting characteristics that may endow these sites with high epileptogenic p~ ten t i a l .~ Among the traditional anticonvulsant drugs, phenytoin and carbamazepine exert their effects through an electrochemical mechanism, since both block the voltage-dependent sodium channels of the action potential. The succinimides, used primarily in absence epilepsy, act on the calcium channels in the thalamus. Phenytoin also blocks voltage-dependent calcium channels. The actions of these drugs