Pharmacology
Summary
Epilepsy is a chronic neurological disorder characterized by recurrent seizures stemming from aberrant neuronal discharges in the brain. These seizures can be genetic or triggered by various factors including, neoplasms, stroke, or trauma. They are primarily classified into two categories: focal and generalized Focal seizures can be differentiated into focal aware seizures and focal impaired awareness seizures, each with the possibility of motor involvement. On the other hand, generalized seizures involve both hemispheres from onset and are categorized based on the presence or absence of motor symptoms. Proper classification is vital for effective management, especially in the selection of broad-spectrum antiepileptics.
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Broad-spectrum antiepileptics come in various forms, and are designed to treat a wide range of seizure types. Valproate functions by inhibiting voltage-dependent sodium channels, blocking T-type calcium channels, and augmenting GABA release. Topiramate and lamotrigine, similar to valproate, primarily achieve their therapeutic effect by inhibiting voltage-gated sodium channels, which subsequently impedes high-frequency neuronal firing. The racetams represent another class of antiepileptics; notable examples include levetiracetam, used for focal and generalized seizures, as well as myoclinic seizures and brivaracetam, prescribed primarily for focal-onset seizures. As far as side effect: valproate is associated with GI distress (e.g. nausea, vomiting) can cause increased appetite and tremor (at higher doses). Topiramate can cause weight loss, kidney stones, and acute angle-closure glaucoma. Lamotrigine may cause diplopia or blurred vision, and can rarely cause Stevens-Johson syndrome. Levetiracetam and evetiracetam are associated with dizziness, drowsiness, nausea, and other neuropsychiatric side effects.
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Lesson Outline
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FAQs
Valproate works by blocking sodium (Na+) channels and t-type calcium channels, which helps to prevent repetitive neuronal discharge. It also increases GABA levels in the CNS through enhanced GABA release via GABA(B) receptor agonism, inhibition of GABA transaminase, and activation of glutamic acid decarboxylase. This broad action makes it effective in treating both generalized and focal seizures.
Valproate can cause gastrointestinal distress, increased appetite and weight gain, tremors (at higher doses), hyperammonemia, and rarely, fatal hepatotoxicity. It can also cause pancreatitis (rare) and is teratogenic. Taking valproate with food can help to reduce GI side effects. Baseline liver function tests and frequent subsequent monitoring can help detect hepatotoxicity early.
Topiramate works by blocking voltage-dependent sodium channels, which helps to stabilize presynaptic neuronal membranes. It also blocks NMDA-glutamate receptors. Additionally, topiramate allosterically binds to the GABA-A receptor at a non-benzodiazepine binding site. This wide-ranging action helps to control both focal and generalized seizures, amongst other conditions.
Lamotrigine acts as a broad-spectrum antiepileptic drug by blocking voltage-gated sodium channels. It may also inhibit the release of glutamate and aspartate. These actions make it useful in managing focal and generalized seizures, Lennox Gastaut syndrome, absence seizures (less effective than valproate and ethosuximide). It is also used in the long-term management of bipolar disorder.
Levetiracetam and brivaracetam bind to synaptic vesicle glycoprotein 2A (SV2A), which makes them effective for various types of seizures. These drugs can cause dizziness, drowsiness, nausea, and neuropsychiatric effects like depression, hostility, aggression, and agitation. The risk for neuropsychiatric effects is greater for people with a history of psychiatric problems or learning difficulties. The serum concentration of brivaracetam can decrease with the concomitant use of CYP450 inducers, such as phenytoin, carbamazepine, and phenobarbital.
