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Anticonvulsant/Antiepileptic.
Pharmacology: Mechanism of Action: Valproic Acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).
Pharmacodynamics: The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate may not provide a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.
Epilepsy: The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations.
Mania: In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 85 and 125 mcg/mL.
Pharmacokinetics: Valproic acid and its salts are rapidly absorbed from the gastrointestinal tract; the rate, but not the extent, of absorption is delayed if given with or after food. Valproic acid is extensively metabolised in the liver, a large part by glucuronidation and the rest by a variety of complex pathways. It does not appear to enhance its own metabolism, but metabolism may be enhanced by other drugs which include hepatic microsomal enzymes. Valproic acid is extremely bound to plasma proteins. The extent of protein binding is concentration dependent and is stated to be about 90 to 95% at total concentrations of 50 micrograms/mL, falling to about 80 to 85% at 100 micrograms/mL. Reported half lives for valproic acid have ranged from about 5 to 20 hours; the shorter half-lives have generally been recorded in epileptic patients receiving multiple drug therapy. The target range of total plasma valproic acid is usually quoted as being 40 to 100 micrograms/mL (280 to 700 micromoles/litre) but routine monitoring of plasma concentrations are not generally considered to be of use as an aid to assessing control. Valproic acid crosses the placental barrier and small amounts are distributed into breastmilk.
