6.5 Anticonvulsants
Anticonvulsants (antiepileptic drugs, AEDs) suppress seizure activity by modulating neuronal excitability. Mechanisms include sodium channel blockade, GABA enhancement, and calcium channel inhibition.
Sodium Channel Blockers
Mechanism
Prolong inactivated state of voltage-gated Na⁺ channels
↓ Repetitive firing of action potentials (use-dependent blockade)
Preferentially affect hyperexcitable neurons
Phenytoin (Dilantin)
First-line for tonic-clonic and partial seizures
Pharmacokinetics: Zero-order kinetics at therapeutic doses (saturable)
Side effects: Gingival hyperplasia, hirsutism, nystagmus, ataxia
Chronic: Folate deficiency, osteoporosis, CYP450 inducer
Carbamazepine (Tegretol)
Partial and tonic-clonic seizures, also trigeminal neuralgia, bipolar
Strong CYP450 inducer (auto-induces own metabolism)
Side effects: Diplopia, ataxia, hyponatremia (SIADH)
Serious: Aplastic anemia, agranulocytosis (rare, monitor CBC)
Lamotrigine (Lamictal)
Broad spectrum: partial, absence, tonic-clonic, bipolar maintenance
Generally well-tolerated
Risk: Stevens-Johnson syndrome (SJS) with rapid titration—slow dose escalation required
GABA Enhancers
Benzodiazepines
Diazepam, lorazepam: IV for status epilepticus (emergency)
Clonazepam: Absence and myoclonic seizures
GABAA positive allosteric modulators
Tolerance develops—not ideal for chronic use
Phenobarbital
GABAA direct agonist (↑ duration of Cl⁻ opening)
Effective for neonatal seizures, status epilepticus
Highly sedating, CYP450 inducer, cognitive effects
Largely replaced by newer agents
Vigabatrin
Irreversible GABA transaminase inhibitor → ↑ GABA
Infantile spasms (West syndrome), refractory partial seizures
Risk: Irreversible peripheral visual field defects—requires ophthalmologic monitoring
Tiagabine
Inhibits GABA transporter (GAT-1) → ↑ synaptic GABA
Adjunct for partial seizures
Valproic Acid (Valproate, Depakote)
Mechanism
Multiple mechanisms: Na⁺ channel blockade, ↑ GABA (via ↑ GAD, ↓ GABA-T), T-type Ca²⁺ blockade
Clinical Use
Broad spectrum: all seizure types (absence, myoclonic, tonic-clonic, partial)
Also: bipolar disorder, migraine prophylaxis
Side Effects
GI upset, weight gain, tremor, hair loss, thrombocytopenia
Serious: Hepatotoxicity (especially in children <2 years), pancreatitis
Teratogenic: Neural tube defects (spina bifida)—contraindicated in pregnancy
Calcium Channel Modulators
Ethosuximide
Blocks T-type (low-voltage-activated) Ca²⁺ channels in thalamus
First-line for absence seizures (3 Hz spike-wave)
NOT effective for other seizure types
Side effects: GI upset, headache, lethargy
Gabapentin & Pregabalin
Bind α₂δ subunit of voltage-gated Ca²⁺ channels
↓ Neurotransmitter release at presynaptic terminals
Adjunct for partial seizures, neuropathic pain
Generally well-tolerated (sedation, dizziness, weight gain)
Newer Anticonvulsants
Levetiracetam (Keppra)
Binds synaptic vesicle protein SV2A—unique mechanism
Broad spectrum, no drug interactions, renally cleared
Side effects: irritability, behavioral changes, somnolence
Topiramate (Topamax)
Multiple mechanisms: Na⁺ blockade, GABA↑, glutamate↓, carbonic anhydrase inhibition
Seizures, migraine prophylaxis, weight loss
Side effects: cognitive impairment ("Dopamax"), paresthesias, kidney stones
Oxcarbazepine
Keto-analog of carbamazepine, similar efficacy
Better tolerated, less drug interactions, but more hyponatremia
Lacosamide
Enhances slow inactivation of Na⁺ channels
Adjunct for partial-onset seizures
Risk: PR interval prolongation
Status Epilepticus Management
Medical Emergency
Continuous seizure >5 minutes or recurrent seizures without recovery
First-line: Benzodiazepines (lorazepam IV, diazepam IV/rectal, midazolam IM)
Second-line: Phenytoin/fosphenytoin IV, valproate IV, or levetiracetam IV
Refractory: Phenobarbital, propofol, or midazolam infusion (ICU setting)
Airway management and supportive care critical