There are approximately 45 million people in the world with epilepsy and the global incidence is 0.05%. Known causes of epilepsy include stroke, head trauma, tumors, and infections; however, in many cases the cause is unknown. During seizure activity, patients risk injury, quality of life impediments, developmental delays, and learning difficulties. While antiepileptic drugs (AEDs) remain the mainstay of treatment, 30% of patients with epilepsy are refractory to treatment. AEDs have a wide variety of side effects that may decrease the quality of life and impair brain development.
Many AEDs directly block voltage-gated sodium channels. Alternative mechanisms include indirect voltage-gated calcium channels blockers, γ-aminobutyric acid (GABA) modifiers, or intracellular synaptic vesicle release modulators.
Phenytoin, carbamazepine, lamotrigine, and topiramate primarily affect sodium channels. Gabapentin and pregabalin, despite being GABA analogs, indirectly block voltage-gated calcium channels. Other antiepileptic drugs target the GABA system, including GABA receptors and GABA transport mechanisms. Examples include valproic acid, clonazepam, zonisamide, and tiagabine. Carbonic anhydrase inhibitors, such as zonisamide and topiramate, use bicarbonate ions to modulate the GABA response. Levetiracetam and brivaracetam are used to treat refractory epilepsy. The proposed mechanisms of action are modulation of synaptic vesicle release for potassium channels, calcium channels, or sodium channels.
The most common neurologic side effects are sedation, dizziness, ataxia, vertigo, and visual disturbances such as diplopia or blurred vision. Common nonneurologic side effects include GI irritation, skin rash, edema, and hepatic toxicity. Most AEDs exhibit these side effects. AEDs should be discontinued slowly to prevent rebound effects.
Some AEDs induce the cytochrome p-450 enzymes, particularly CYP34. Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproic acid are known inducers. For other drugs metabolized in the liver, the AED inducers will increase drug metabolism and therefore decrease anticipated action. Oral contraceptives and neuromuscular blocking drugs (NMBD) are examples of drugs affected by concomitant use of AEDs. Patients who are taking phenytoin require four to five times the usual dosages of steroid-based NMBDs to maintain paralysis; however, benzylisoquinoline NMBDs have not shown the same effect.
Many AEDs bind serum plasma proteins. The free fraction of AEDs can be greatly increased by hypoalbuminemia or by other medications with a high affinity to plasma proteins. This can lead to increased free fraction of AEDs and subsequently an increase in side effects or toxicity.
Phenytoin decreases excitatory glutamate release due to inhibition of sodium channels. Phenytoin not only treats grand mal epilepsy, but also treats partial and tonic-clonic seizures. It is highly protein bound with only 10% free-drug in circulation. Due to nonlinear kinetics and a narrow therapeutic range, phenytoin can be difficult to dose. It is metabolized by the liver and a small fraction is excreted in the ...