Retigabine A Promising New Antiepileptic Drug with a Novel Mechanism of Action
Retigabine A Promising New Antiepileptic Drug with a Novel Mechanism of Action
Epilepsy affects up to 1% of the world’s population. It is not a singular disease, but a variety of disorders reflecting underlying brain dysfunction that may result from myriad causes. The latest proposal by the International League Against Epilepsy (ILAE) defines epilepsy as the occurrence of at least one seizure with an enduring alteration in the brain structure or function, which increases the likelihood of future seizures.1 An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal, excessive and synchronous neuronal activity in the brain.
Depending on the pattern of neuronal involvement, the symptomatology (or semiology) of a seizure may consist of a wide range of sudden and transitory phenomena, which may include alterations of consciousness or motor, sensory, autonomic and psychic events. Based on the semiology and corresponding electroencephalographic and brain imaging changes, seizures can be broadly classified into partial (originating from a focal area of the cortex) and generalised (widespread involvement of bilateral cortical regions at the outset). Over the last decade, considerable advances have been made in our understanding of the molecular biology underlying seizure generation and propagation.2 These have been accompanied by the licensing of a range of new antiepileptic drugs (AEDs).3 However, despite these efforts, up to a third of patients continue to have seizures or intolerable side effects, and thus can be considered to have refractory epilepsy.4 Uncontrolled seizures are associated with increased morbidity and mortality, posing a large economic burden on individuals and society. There continues, therefore, to be a need to develop more AEDs with novel mechanisms of action.5
Pharmacology
Voltage-gated ion channels generate and control much of the electrical activity of neurons.6 Inward currents are mediated by Na+ and Ca++ channels. Blockers of these channels represent important classes of AEDs and include phenytoin, carbamazepine, lamotrigine, oxcarbazepine, gabapentin and pregabalin. Examples of AEDs with other mechanisms of action include those influencing gamma-aminobutyric acid (GABA) (e.g. sodium valproate, vigabatrin, tiagabine) and glutamate (e.g. topiramate, felbamate) neurotransmission. Levetiracetam binds to synaptic vesicle protein (SV2A) and may alter neurotransmitter trafficking by an as yet unknown mechanism.
Potassium Channels
As a counterbalance to the role of Na+ and Ca++ channels in generating action potentials, K+ channels serve as ‘brakes’ that limit neuronal excitability. M-current is a slowly activating, low-threshold K+-mediated flux that repolarises the neuronal membrane and controls the generation and frequency of the action potential.7
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