Chapter 19

### INTRODUCTION

Valproic acid (VPA) is a broad-spectrum, carboxylic acid-derived anticonvulsant that has been used in the treatment of epilepsy, bipolar disease, schizophrenia, and migraine headache. Its main mechanism of action is not well understood, but it is thought that it increases the amount of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in the central nervous system (CNS). It comes in several different preparations and salt forms (Table 19-1). Divalproex sodium is a mixture of equal parts of the acid and sodium salts of valproic acid. The delayed-release (Depakote) and extended-release (Depakote ER) formulations are not bioequivalent.1 A 20 percent increase in the daily dose is recommended when switching from Depakote to Depakote ER to account for the differences in rate and extent of absorption.

TABLE 19-1Valproic Acid Formulations

### DOSING

Dosing is done in terms of valproic acid content. For seizure disorders, initial oral dosing for patients 10 years of age and older is 10–15 mg/kg/day. Dosing intervals for the oral and parenteral preparations are typically every 8–12 hours (although dosing every 6 hours may be needed in some patients), with the exception of the extended-release formulation, which can be administered once or twice daily. The daily dose can be titrated weekly by 5–10 mg/kg/day to a maximum recommended dose of 60 mg/kg/day. Loading doses are not recommended for the oral VPA formulations due to intolerable gastrointestinal side effects; however, intravenous loading doses of valproate sodium 25 mg/kg are commonly given for patients in status epilepticus. Intravenous loading doses can be given at a rate of 1.5–3 mg/kg/min, but faster rates of up to 6 mg/kg/min appear to be safe.2,3,4 Therapeutic drug monitoring (TDM) is used in conjunction with the clinical exam to optimize seizure control and minimize toxicity. Measuring serum concentrations is routinely performed via immunoassay, and the therapeutic range is reported as 50–100 mcg/mL, although individual patients may have optimal responses outside these ranges. Concentrations higher than 150 mcg/mL are associated with a high incidence of CNS side effects. Free (unbound) concentrations are also available with a therapeutic range reported to be 6–22 mcg/mL with toxicity occurring above 50 mcg/mL. Trough levels (obtained prior to a dose) are preferred to assure that minimum therapeutic concentrations are maintained. Diurnal variations in the serum concentration of VPA have been reported, so it is important to ...

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