Pharmacoresistance: Mechanisms of Pharmcoresistance☆

In 30% of epilepsy patients, seizure control by antiepileptic drugs (AED) is insufficient. The mechanisms underlying pharmacoresistance vary. The target hypothesis proposes that pharmacoresistance is caused by changes of the properties of drug targets. The transporter hypothesis argues that the expression or function of multidrug transporters in the brain is augmented, leading to impaired access of AEDs to central nervous system (CNS) targets. The leaky blood brain barrier hypothesis suggests that albumin entering the brain interstitial space buffers anticonvulsants or agents needed for their action such as GABA. In addition, the severity hypothesis suggesting that AEDs may not be strong enough in controlling intense seizures, network reorganization, and development of tolerance may contribute in some cases.