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CHAPTER 2-12: ANTICONVULSANTS, NEWER

Freda M. Rowley

INTRODUCTION

Developed for the treatment of partial and generalized seizure disorders, these second- and third-generation anticonvulsants are finding wider use in the treatment of chronic and neuropathic pain syndromes; mood disorders, including bipolar and generalized anxiety disorders; and migraine headache prophylaxis. Serious adverse effects with the therapeutic use of ezogabine (retinal pigment abnormalities, blue skin discoloration), felbamate (aplastic anemia, hepatic failure) and vigabatrin (permanent visual field deficits) have led to restrictions in their use.

Characteristics of several of these drugs are listed in Table II–7.

TABLE II–7.ANTICONVULSANT DRUGS (NEWER)
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TABLE II–7. ANTICONVULSANT DRUGS (NEWER)
Drug Usual Elimination Half-life (h) Usual Daily Dose (mg/d) Reported Potential Toxic Effects
Ezogabine 7–11 300–1,200 CNS depression, dizziness, ataxia; agitation, aggressive behavior (>2.5 g), hallucinations, seizures; QT prolongation, dysrhythmias
Felbamate 20–23 1,800–4,800 Mild CNS depression, nystagmus, ataxia; tachycardia; nausea and vomiting; delayed (>12 h) crystalluria, hematuria, renal dysfunction
Gabapentin 5–7 900–3,600 Somnolence, dizziness, ataxia, myoclonus, slurred speech, diplopia; tachycardia, hypotension or hypertension; diarrhea
Lacosamide 13 200–600 CNS depression, headache, dizziness, ataxia, nystagmus, nausea and vomiting; QRS widening, AV block, hypotension, tachycardia; transient transaminase elevation
Lamotrigine 22–36 200–500 Lethargy, dizziness, ataxia, stupor, nystagmus, hypertonia, seizures; hypotension, tachycardia, QRS prolongation; nausea and vomiting; hypokalemia; hypersensitivity: fever, rash (Stevens– Johnson syndrome), hepatitis, renal failure
Levetiracetam 6–8 1,000–3,000 Drowsiness, ataxia
Perampanel 52–129 2–12 CNS depression, dizziness, ataxia, vertigo; agitation, euphoria, seizures; hyponatremia, nausea, and vomiting
Pregabalin 6-9 50–600 CNS depression, dizziness, headache, ataxia, agitation, confusion, seizures; nausea and vomiting; hypotension, peripheral edema
Tiagabine 7–9 30–70 Somnolence, confusion, agitation, dizziness, ataxia, tremor, clonus, seizures, status epilepticus
Topiramate 21 200–600 Sedation, confusion, slurred speech, ataxia, tremor, anxiety, agitation, seizures; hypotension; hyperchloremic non–anion gap metabolic acidosis
Vigabatrin 4–8 2,000–4,000 Sedation, confusion, coma, agitation, delirium, psychotic disturbances (hallucinations, delusions, paranoia)
Zonisamide 50–68 100–400 Somnolence, ataxia, agitation; bradycardia, hypotension; respiratory depression

MECHANISM OF TOXICITY

Anticonvulsants suppress neuronal excitation by one of four major mechanisms.

  1. Blockade of voltage-gated sodium channels by lamotrigine, topiramate, zonisamide, and felbamate. Lacosamide selectively enhances slow inactivation of these channels.

  2. Blockade of voltage-gated calcium channels by gabapentin, levetiracetam, and zonisamide. Pregabalin binds to the alpha-2 delta subunit of L-type calcium channels.

  3. Inhibition of excitatory amines. Lamotrigine inhibits glutamate release via sodium channel effects on presynaptic membranes. Felbamate is a competitive glutamate antagonist at the N-methyl-D-aspartate (NMDA) receptor. Perampanel is a selective noncompetitive antagonist at postsynaptic amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors.

  4. Gamma-aminobutyric acid (GABA) enhancement. Tiagabine inhibits GABA transporter GAT-1, preventing reuptake into presynaptic neurons. Vigabatrin inhibits GABA transaminase, blocking GABA metabolism. Gabapentin and pregabalin are GABA analogs that have no known activity at GABA receptors.

  5. Pharmacokinetics (see Tables II–7 and II–66)

TOXIC DOSE VARIES

with each medication. A 4-year-old boy had a 10-minute tonic–clonic seizure after the ingestion of 52 mg (3 mg/kg) of ...

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