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Valproic acid is an agent that is chemically related to free fatty acids and is used in the treatment of generalized, partial, and absence (petit mal) seizures. As such, it has the widest spectrum of activity compared to the other currently available antiepileptic drugs (Table 12-1).1,2 Now available in intravenous, as well as oral, form, valproic acid can be used for the acute treatment and chronic prophylaxis of seizures.3,4 Valproic acid is also a useful agent for the treatment of bipolar affective disorders and the prevention of migraine headaches.5

Table 12-1 International Classification of Epileptic Seizures with Treatment Recommendations

Although the precise mechanism of action for valproic acid is unknown, its antiepileptic effect is thought to result from its ability to increase concentrations of the neuroinhibitor γ-aminobutyric acid (GABA), to potentiate the postsynaptic response to GABA, or to exert a direct effect on cellular membranes.6

The generally accepted therapeutic range for total valproic acid steady-state concentrations is 50–100 μg/mL, although some clinicians suggest drug concentrations as high as 175 μg/mL with appropriate monitoring of serum concentrations and possible adverse effects. Valproic acid is highly protein bound to albumin with typical values of 90–95%.7,8 Plasma protein binding of valproic acid is saturable within the therapeutic range, which results in less protein binding and higher unbound fraction of drug at higher concentrations. The concentration-dependent protein binding of valproic acid causes the drug to follow nonlinear pharmacokinetics (Figure 12-1). This type of nonlinear pharmacokinetics is fundamentally different than that observed during phenytoin administration. Phenytoin hepatic metabolism becomes saturated, which causes Michaelis-Menten pharmacokinetics to take place. As a result, when phenytoin doses are increased, total and unbound steady-state concentrations increase more than a proportional amount (e.g., when the dose is doubled, serum concentrations may increase three- to five-fold or more). In the case of valproic acid, when the dose is increased total drug steady-state concentration ...

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