CHAPTER 2-155: VALPROIC ACID

INTRODUCTION

Valproic acid (Depakene or Depakote [divalproex sodium]) is a structurally unique anticonvulsant. It is used for the treatment of absence seizures, partial complex seizures, and generalized seizure disorders and is a secondary agent for refractory status epilepticus. It is also used commonly for the prophylaxis and treatment of acute manic episodes and other affective disorders, chronic pain syndromes, and migraine prophylaxis.

MECHANISM OF TOXICITY

1. Valproic acid is a low–molecular-weight (144.21) branched-chain carboxylic acid (pKa = 4.8) that increases levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and prolongs the recovery of inactivated sodium channels. These properties may be responsible for its action as a general CNS depressant. Valproic acid also alters fatty acid metabolism, with impairment of mitochondrial beta-oxidation and disruption of the urea cycle, and can cause hyperammonemia, hepatotoxicity, metabolic perturbations, pancreatitis, cerebral edema, and bone marrow depression. Some of these effects may be associated with carnitine deficiency.

2. Pharmacokinetics

   1. Valproic acid is rapidly and completely absorbed from the GI tract. There is a delay in the absorption with the preparation Depakote (divalproex sodium) because of its delayed-release formulation as well as the intestinal conversion of divalproex to two molecules of valproic acid.

   2. At therapeutic levels, valproic acid is highly protein bound (80–95%) and confined primarily to the extracellular space, with a small (0.1–0.5 L/kg) volume of distribution (Vd). In overdose and at levels exceeding 90 mg/L, saturation of protein-binding sites occurs, resulting in a greater circulating free fraction of valproic acid and a larger Vd.

   3. Valproic acid is metabolized predominantly by the liver and may undergo some degree of enterohepatic recirculation. The elimination half-life is 5–20 hours (average, 10.6 hours). In overdose, the half-life may be prolonged to as long as 30 hours (there are case reports of up to 60 hours, but this may have been due to delayed absorption). A level exceeding 1,000 mg/L may not drop into the therapeutic range for at least 3 days. In addition, active metabolites (eg, the neurotoxic 2-en-valproic acid and the hepatotoxic 4-en-valproic acid) produced via beta-oxidation and omega-oxidation pathways may contribute to prolonged or delayed toxicity.

TOXIC DOSE

The usual daily dose for adults is 1.2–1.5 g to achieve therapeutic serum levels of 50–150 mg/L, and the suggested maximum daily dose is 60 mg/kg. Acute ingestions exceeding 200 mg/kg are associated with a high risk for significant CNS depression, and ingestions exceeding 400 mg/kg are associated with coma, respiratory depression, cerebral edema, and hemodynamic instability. The lowest published fatal dose is 15 g (750 mg/kg) in a 20-month-old child, but adult patients have survived after ingestions of 75 g.

CLINICAL PRESENTATION

1. Acute overdose

   1. Acute ingestion commonly causes GI upset, variable CNS depression (confusion, disorientation, obtundation, and coma with respiratory failure), and occasionally hypotension with tachycardia and a prolonged QT interval. The pupils may be miotic, and the ...