Valproic Acid/Divalproex Sodium Pharmacology and Mechanism of Action Initially it was believed that valproic acid increased GABA

by inhibiting its degradation or by activating its synthesis. Although this may explain in part the effects of valproic acid, the time course for the increase in GABA compared with the onset of anticonvulsant effects indicates that alterations of the synthesis and degradation of GABA do not fully explain the antiseizure activity of valproic acid. It has been proposed that valproic acid may potentiate postsynaptic GABA responses, may have a direct membranestabilizing effect, and may affect potassium channels. Pharmacokinetics Valproic acid appears to be absorbed completely from available oral dosage forms when administered on an empty stomach.115 However, the rate of absorption differs among preparations. Peak concentrations occur in 0.5 to 1 hour with the syrup, 1 to 3 hours with the capsule, and 2 to 6 hours with the enteric-coated tablet.115 The extended-release formulation (Depakote-ER) is FDA approved for use in both patients with migraine headache and epilepsy. It should be noted, however, that the bioavailability of this formulation is approximately 15% less than that of enteric-coated divalproex sodium (Depakote). Valproic acid is extensively bound to albumin, and this binding is saturable. Accordingly, the valproic acid free fraction will increase as the total serum concentration increases. Because of this saturable binding, measurement of unbound serum concentrations may be a better monitoring parameter than the total valproic acid serum concentration, especially at higher concentrations or in patients with hypoalbuminemia. The primary route of valproic acid metabolism is -oxidation, although up to 40% of a dose may be excreted as the glucuronide. At least 10 metabolites of valproic acid have been identified. Some of these may have weak anticonvulsant activity, and at least one metabolite may be responsible for the hepatotoxicity reported with valproic acid. One of the lesser oxidative metabolites, 4-eneVPA, causes significant hepatotoxicity in rats. The formation of this metabolite is increased when valproic acid is given with enzymeinducing drugs. Valproic acid displays diurnal elimination with lower evening serum levels occurring than morning levels. Adverse Effects The most frequently reported side effects are gastrointestinal complaints (up to 20%), including nausea, vomiting, and anorexia, as well as weight gain. Pancreatitis is rare. The gastrointestinal complaints may be minimized but not totally alleviated with the enteric-coated formulation or by giving the drug with food Alopecia and hair changes are temporary, and hair growth returns even with continued dosing. Weight gain can be significant for many patients and is associated with an increase in fasting insulin and leptin serum levels.116 The increase in serum insulin is believed to be caused by the inhibition of metabolism of insulin by the liver. This has led to the development of insulin resistance in obese male and female subjects. Valproic acid causes minimal cognitive impairment.The most serious side effect reported with valproic acid is hepatotoxicity. Hyperammonemia is common (50%) but does not necessarily imply liver damage; however, fatalities have been attributed to valproic acid hepatotoxicity. Most deaths have occurred in patients who were younger than 2 years of age, mentally retarded, and receiving multiple AEDs. Hepatotoxicity occurred early in the course of therapy. Patients who complain of nausea, vomiting, lethargy, anorexia, and edema in the first 6 to 12 months of therapy should have liver function tests done. Multiple-AED therapy can alter the metabolism of valproic acid, leading to increased formation of the potentially liver-toxic 4-ene-VPA. Valproic acid has been shown to alter carnitine metabolism, and it has been postulated that a deficiency of carnitine alters fatty acid oxidation that could lead to both liver toxicity and hyperammonemia. However, valproic acid hepatotoxicity has occurred in a patient taking supplemental carnitine, and a prospective study demonstrated no effect on well-being when carnitine was added. Although carnitine can ameliorate hyperammonemia in part, it is expensive, and there are only limited data to support routine supplemental use in patients

taking valproic acid.Thrombocytopenia and alterations in platelet aggregation occur in the patients receiving valproic acid, and these phenomena are related to serum concentration. These blood coagulopathies can occur more frequently in children than in adults.120 Drug Interactions Because it is highly protein bound, other highly protein-bound drugs can displace valproic acid. Free fatty acids and aspirin can alter valproic acid binding by displacement. Valproic acid is an enzyme inhibitor that can inhibit specific cytochrome P450 isozymes, epoxide hydrolase, and UGT isozymes. The addition of valproic acid to phenobarbital results in a 30% to 50% decrease in the clearance of phenobarbital and significant toxicity if the dose of phenobarbital is not reduced. Dosing and Administration Valproic acid in some patients may have a half-life sufficiently long to permit once-daily dosing with enteric-coated divalproex, more frequent dosing is the norm. Based on half-life data, twice-daily dosing is feasible with any valproic acid dosage form; however, children and other patients taking enzyme inducers can require dosing three to four times daily.63 The serum concentrationdose relationship is curvilinear (e.g., the concentration-dose ratio decreases with increasing dose) probably because of increasing free concentrations and a resulting increase in clearance. Valproic acid is available as a soft gelatin capsule, an enteric-coated tablet, a syrup, a sprinkle capsule, an extended-release formulation designed for once-daily dosing, and an IV formulation for replacement of oral therapy or in situations where rapid loading of valproic acid is deemed necessary.115 This parenteral formulation must not be given intramuscularly because it can cause tissue necrosis. The sprinkle capsule, designed to be opened and mixed with food, has a slower rate of absorption, which results in fewer fluctuations in the peak-to-trough ratio. The syrup is absorbed more rapidly than any solid dosage form. The enteric-coated tablet is not sustained-release; it consists of sodium divalproex, which must be metabolized in the gut to valproic acid. It is enteric coated to reduce the incidence of gastrointestinal distress. The enteric coating does cause delayed absorption, although once the enteric coating dissolves, sodium divalproex has absorption, metabolism, and elimination rates similar to those of the gelatin capsule. If a patient is switched from Depakote to Depakote-ER, the dose should be increased by 14% to 20%. Depakote-ER may be given once daily. Advantages Valproic acid is available in multiple dosage formulations. The IV formulation is especially well tolerated. It has a wide therapeutic index and can be considered a broad-spectrum AED. It also can be useful in other neurologic or psychiatric disorders, including migraine headache and bipolar disorder. Disadvantages Some patients report significant weight gain with valproic acid, and this can limit compliance. Valproic acid is also associated with other side effects, such as alopecia, tremor, pancreatitis, polycystic ovary disease, and thrombocytopenia. It has been associated with hepatic necrosis in young children. Valproic acid is an enzyme inhibitor and is involved in multiple drug-drug interactions. Place in Therapy Valproic acid is first-line therapy for primary generalized seizures such as myoclonic, atonic, and absence seizures. It can be used as both monotherapy and adjunctive therapy for partial seizures, and it can be very useful in patients with mixed seizure disorders. Reference: Pharmacotherapy A Pathophysiologic Approach Seventh Edition