Valpros Pedia Mechanism of Action

Pharmacologic Category: Anticonvulsant/antiepileptic.
Pharmacology: Pharmacodynamics: Sodium valproate is an anticonvulsant. Its anticonvulsant effect maybe related, at least in part, to increased brain concentrations of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA). This effect of sodium valproate on the GABA neurotransmitter is also believed to possibly contribute to its antimanic properties.
Pharmacokinetics: Absorption of valproate is rapid and complete. After oral administration, sodium valproate is rapidly converted to valproic acid and valproic acid dissociates to the valproate ion in the gastrointestinal tract. Peak plasma concentrations are achieved between 1 to 4 hours after a single oral dose. Absorption of valproic acid is not affected by co-administration with milk products. Food slightly delays its absorption; however, this does not affect the total absorption of the drug. When administered on an empty stomach, local gastric irritation may occur due to the transformation of sodium valproate to valproic acid.
Valproate is rapidly distributed; distribution appears to be restricted to plasma and rapidly exchangeable extracellular water.
Valproate has been detected in the cerebrospinal fluid (CST) (about 10% of serum concentrations), saliva (about 1% of plasma concentrations), and breast milk (about 1% to 10% of plasma concentrations). The drug crosses the placenta.
Plasma protein binding of valproate is concentration-dependent; the free fraction of the drug increases from 10% at a concentration of 40 mcg/mL to 18.5% at a concentration of 130 mcg/mL. Protein binding is approximately 90%.
The relationship between dose and total valproic acid concentration is nonlinear; concentration does not increase proportionally with dose, but increases to a lesser extent, because of saturable protein binding. The pharmacokinetics of unbound drug is linear. The half-life of sodium valproate is within the ranged 6 to 16 hours; its half-life in children is usually shorter.
Valproate is metabolized principally in the liver by beta (over 40%) and omega oxidation (up to 15% to 20%). The metabolites are excreted in urine; 30-50% of an administered dose is excreted as glucuronide conjugates. Less than 3% of an administered dose is excreted in urine unchanged. The major metabolite in urine is 2-propyl-3-ketopentanoic acid; minor urinary metabolites am 2-propylglutaric acid, 2-propyl-5-hydroxypentanoic acid, 2-propyl-3-hydroxypentanoic acid, and 2-propyl-4-hydroxypentanoic acid. Small amounts of drug are also excreted in feces and in expired air.
Valproate is eliminated by first-order kinetics. Mean plasma clearance of total or free valproic acid is 0.56 L/hr per 1.73 m2 or 4.6 L/hr per 1.73 m2, respectively.
Hepatic Insufficiency: Hepatic insufficiency impairs the ability to eliminate valproic acid. Compared with healthy individuals, the clearance of valproic acid was decreased by 50% in a limited number of patients with liver cirrhosis and by 16% in a limited number of patients with acute hepatitis. Valproic acid's half-life was increased from 12 to 18 hours.
Renal Insufficiency: Drug clearance of sodium valproate maybe reduced in patients with renal failure (i.e., creatinine clearance < 10 mL/min). Protein binding in these patients is substantially reduced; thus, monitoring total concentrations maybe misleading.
Geriatrics: The capacity of elderly patients to eliminate valproate has been shown to be reduced; intrinsic clearance reduced by 39% and free fraction increased by 44%. Accordingly, the initial dose should be reduced in the elderly (see Dosage & Administration).
Pediatrics: Pediatric patients (i.e., 3 months to 10 years old) have 50% higher clearance of the drug expressed by weight (i.e., mL/min per kg). However, the pharmacokinetic parameters of valproic acid in children > 10 years old approximate those in the adult population. Infants (i.e., < 2 months old) have a markedly decreased clearance of valproic acid compared with older children and adults. This may be due to the delayed development of metabolic enzyme systems and an increased volume of distribution of valproic acid in these patients.