⚡ Seizure Pathophysiology
- Seizure = paroxysmal, hypersynchronous electrical discharge in cerebral cortex
- Cellular hallmarks
- Prolonged neuronal depolarization
- Sustained high-frequency repetitive firing (SHFRF)
- Followed by prolonged post-ictal hyperpolarization
- Imbalance between excitation (glutamate) and inhibition (GABA)
- Excess glutamate → NMDA/AMPA receptor overactivation
- Reduced GABAA-mediated Cl⁻ influx → diminished inhibition
- Ion channel dysfunction
- Voltage-gated Na⁺ channels: sustained opening → repetitive firing
- T-type Ca²⁺ channels: burst firing in thalamocortical circuits (absence seizures)
- K⁺ channel defects impair repolarization
- Therapeutic goal = restore normal electrical rhythm without suppressing physiological neural activity.
🔬 Anticonvulsant Mechanisms
Na⁺ Channel Blockade
- Bind to inactivated state of fast voltage-gated Na⁺ channels
- Increase refractory period → reduce sustained repetitive firing
- Representative drugs
- Phenytoin
- Carbamazepine
- Lamotrigine
- Topiramate (also blocks AMPA)
GABA Potentiation
- Enhance GABAA-mediated Cl⁻ influx → hyperpolarization
- Barbiturates: prolong Cl⁻ channel opening
- Benzodiazepines: increase frequency of Cl⁻ channel opening
- Valproic acid: inhibits GABA transaminase (↑ GABA levels)
Glutamate Receptor Blockade
- Reduce excitatory neurotransmission
- AMPA receptor blockade
- Topiramate
- Lamotrigine
- NMDA receptor blockade
- Felbamate
T‑Type Ca²⁺ Channel Blockade
- Block low-threshold (T-type) Ca²⁺ channels in thalamic neurons
- Suppresses thalamocortical burst firing → absence seizures
- Representative drugs
- Ethosuximide (selective)
- Valproic acid (also blocks)
Na⁺ block
→
↓ firing
+
GABA ↑
→
↓ excitability
→
seizure suppression
📋 Seizure Types & First‑Line Agents
| Seizure Type | Preferred Agents | Key Notes |
|---|---|---|
| Focal (partial) – simple or complex | Valproic acid · Phenytoin · Carbamazepine · Lamotrigine | Lamotrigine often better tolerated long‑term |
| Generalized tonic‑clonic | Valproic acid · Phenytoin · Carbamazepine · Lamotrigine | Carbamazepine may exacerbate absence/myoclonic |
| Absence (petit mal) | Ethosuximide · Valproic acid | Ethosuximide is highly selective for absence |
| Status epilepticus | IV Lorazepam · IV Diazepam · IV Phenytoin · IV Fosphenytoin | Fosphenytoin is water‑soluble, faster infusion |
- Do not use carbamazepine or phenytoin for absence seizures — they are ineffective and may worsen.
💊 Primary Anticonvulsants
Phenytoin
- Mechanism: blocks inactivated Na⁺ channels → prevents seizure propagation
- Uses: focal, tonic‑clonic, status epilepticus
- PK:
- Variable oral absorption
- Nonlinear (zero‑order) elimination at therapeutic doses
- Induces CYP450 (auto‑induction not prominent)
- Highly protein‑bound (albumin)
- Adverse effects:
- CNS depression (nystagmus, ataxia, sedation)
- Gingival hyperplasia
- Hirsutism
- Osteomalacia (↓ vitamin D metabolism)
- Megaloblastic anemia (↓ folate absorption)
- Aplastic anemia — monitor CBC
- Teratogenicity: cleft lip/palate, fetal hydantoin syndrome
Carbamazepine
- Mechanism: identical to phenytoin (Na⁺ channel blockade)
- Uses:
- Focal and tonic‑clonic seizures
- DOC for trigeminal neuralgia
- Bipolar disorder (mood stabilization)
- PK: potent CYP450 inducer (including its own metabolism → auto‑induction)
- Adverse effects:
- CNS depression (diplopia, dizziness, sedation)
- Osteomalacia
- Megaloblastic anemia
- Aplastic anemia / agranulocytosis
- Exfoliative dermatitis (Stevens‑Johnson risk)
- SIADH → dilutional hyponatremia
- Teratogenicity: cleft lip/palate, spina bifida
Valproic Acid
- Mechanism: Na⁺ blockade + GABA transaminase inhibition + T‑type Ca²⁺ blockade
- Uses:
- Broad-spectrum: focal, tonic‑clonic, absence
- Bipolar mania
- Migraine prophylaxis
- PK: inhibits CYP450 (↑ levels of other drugs)
- Adverse effects:
- Hepatotoxicity (toxic metabolite – risk highest in young children)
- Thrombocytopenia
- Pancreatitis
- Alopecia (reversible)
- Weight gain
- Teratogenicity: spina bifida (neural tube defect)
Ethosuximide
- Mechanism: selective T‑type Ca²⁺ channel blockade in thalamus
- Use: absence seizures only
- Adverse effects: GI upset, drowsiness, headache; rarely aplastic anemia
- Valproic acid is the broadest-spectrum AED, but its hepatotoxicity and teratogenicity limit use in some populations.
🧪 Other Anticonvulsants
Lamotrigine
- Na⁺ channel blockade + glutamate (AMPA) receptor inhibition
- Uses: focal, tonic‑clonic, Lennox‑Gastaut, bipolar maintenance
- Slow titration required to reduce rash risk
- Adverse effect: Stevens‑Johnson syndrome (rash, fever, mucosal involvement)
Topiramate
- Na⁺ channel blockade + AMPA blockade + GABA enhancement
- Uses: focal seizures (adults & children >2 yr), migraine prophylaxis
- Adverse effects: weight loss, cognitive slowing, paresthesias, metabolic acidosis, nephrolithiasis
Felbamate
- Na⁺ channel blockade + NMDA receptor blockade
- Use: refractory seizures (often adjunctive)
- Serious adverse effects: aplastic anemia, hepatotoxicity — reserved for refractory cases
Gabapentin
- Binds α₂δ subunit of voltage‑gated Ca²⁺ channels → ↓ neurotransmitter release
- May enhance GABAergic effects (indirect)
- Uses: focal seizures (adjunct), neuropathic pain (postherpetic neuralgia)
- Renally excreted; no hepatic metabolism
- Adverse effects: sedation, dizziness, peripheral edema
🧠 Clinical Pearls & Drug Interactions
- Additive CNS depression: all AEDs potentiate other CNS depressants (ethanol, benzodiazepines, opioids)
- Abrupt withdrawal: may precipitate rebound seizures or status epilepticus — taper slowly
- Oral contraceptive efficacy: reduced by CYP450‑inducing AEDs (phenytoin, carbamazepine, topiramate, felbamate)
- Use alternative or high‑dose OCP / backup contraception
- Pregnancy: all AEDs carry teratogenic risk
- Valproate: highest risk (neural tube defects, cognitive impairment)
- Folate supplementation (4–5 mg/day) recommended preconception
- Monitoring:
- CBC, LFTs, serum levels (for phenytoin, carbamazepine, valproate)
- Bone density (vitamin D / calcium) with long‑term enzyme inducers
- Phenytoin has zero‑order kinetics at therapeutic doses — small dose increments cause disproportionate level increases and toxicity.
- For status epilepticus: IV lorazepam is first‑line; fosphenytoin is preferred over phenytoin due to better water solubility and faster infusion.
Enzyme Induction vs. Inhibition
| Drug | CYP450 Effect | Clinical Consequence |
|---|---|---|
| Phenytoin | Inducer | ↓ warfarin, OCP, corticosteroids |
| Carbamazepine | Inducer (auto‑induction) | ↑ own clearance; ↓ OCP, warfarin |
| Valproic acid | Inhibitor | ↑ lamotrigine, phenytoin, phenobarbital levels |
| Topiramate | Inducer (mild) | ↓ OCP efficacy |
| Felbamate | Inducer & inhibitor | Complex interactions; monitor levels |