Pharmacology
Summary
Narrow-spectrum antiepileptics are primarily effective against focal seizures and focal seizures with secondary generalization. Carbamazepine stands out, functioning by increasing voltage-dependent sodium channels inactivation, subsequently inhibiting the prolonged high-frequency firing of neurons. Notable adverse effects encompass dose-related issues like diplopia and ataxia, SIADH, and hematologic concerns such as agranulocytosis. Furthermore, carbamazepine, as a potent broad-spectrum inducer of the hepatic cytochrome P450 system, can precipitate Steven-Johnson syndrome/toxic epidermal necrolysis (SJS-TEN), especially in individuals carrying the HLA-B*1502 allele.
Oxcarbazepine, which functions similar to carbamazepine, offers a more favorable side-effect profile, characterized by fewer CNS adversities and diminished drug interactions. Phenytoin is another narrow-spectrum antiepileptic that increases voltage-dependent sodium channels inactivation. Phenytoin may cause gingival hyperplasia, hirsutism, and drug-induced lupus syndrome. IV phenytoin also plays a vital role in maintenance therapy for status epilepticus, while IV benzodiazepines like diazepam and lorazepam are used to acutely treat this dire medical emergency. Vigabatrin and tiagabine, two agents that modulate GABA transmission, are used as adjunctive treatment options for focal seizures.
Lesson Outline
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FAQs
Carbamazepine, oxcarbazepine, and phenytoin are all narrow-spectrum antiepileptics primarily used to treat focal seizures and generalized tonic-clonic seizures. Their primary mechanism involves increasing voltage- and use-dependent Na+ channel inactivation, thereby reducing neuronal excitability and controlling seizure activities. Besides their role in seizure management, carbamazepine is a first-line therapy for trigeminal neuralgia. Oxcarbazepine may be chosen over carbamazepine for its improved side effect profile and less drug-drug interactions.
Side effects of carbamazepine include ataxia, diplopia, syndrome of inappropriate ADH (SIADH), and agranulocytosis. Given the risk of bone marrow suppression, carbamazepine is contraindicated in patients with a history of bone marrow depression. Carbamazepine also influences several CYP450 enzymes, including causing a decrease in substrate serum levels. This includes induction of CYP3A4, which can lower the serum levels of hormonal contraceptives. It also may cause Stevens-Johnson syndrome and DRESS syndrome, and is a known teratogen.
While both agents belong to the narrow-spectrum antiepileptic category, oxcarbazepine offers fewer CNS side effects and drug interactions than carbamazepine. This makes it an appealing alternative for those intolerant to carbamazepine. Despite its advantages, oxcarbazepine isn't without risks; it can lead to severe skin reactions like Stevens-Johnson Syndrome and DRESS. As with carbamazepine, it has teratogenic potential, though clinical studies on this aspect are limited.
Phenytoin poses a spectrum of potential side effects including ataxia, diplopia, gingival hyperplasia, and hirsutism. It shares with carbamazepine and oxcarbazepine the potential for causing drug-induced lupus. Additionally, phenytoin can be the culprit behind severe skin reactions like Stevens-Johnson Syndrome and DRESS syndrome. It has teratogenic effects, notably leading to conditions like cleft palate in newborns if taken during pregnancy. Like carbamazepine, phenytoin affects the serum levels of hormonal contraceptives due to CYP3A4 induction. Prolonged use can lead to reduced bone mineral density, making monitoring and supplementation necessary for long-term therapy.
Tiagabine and vigabatrin operate by enhancing the brain concentrations of GABA, an inhibitory neurotransmitter. Vigabatrin achieves this by irreversibly inhibiting GABA transaminase, reducing GABA degradation, whereas tiagabine prevents GABA reuptake, thereby elevating its levels in the synaptic cleft.
Status epilepticus represents a severe form of seizure activity that persists for an extended duration without interceding recovery. The acute treatment involves intravenous benzodiazepines like diazepam or lorazepam. For maintenance, IV phenytoin is typically used. In refractory cases, IV phenobarbital, a barbiturate, may also beconsidered.
