Valpros Pedia Mechanism of Action

Antiepileptic (Fatty Acid Derivative).
Pharmacology: Pharmacodynamics: Sodium valproate is an anticonvulsant. Although its mechanism of action is not fully established, its activity in epilepsy may be related to the blockade of voltage-dependent sodium channels and increased brain levels of gamma-aminobutyric acid (GABA), potentiating its inhibitory effect. This mechanism will explain its clinical effect on mania. Its effects on the neuronal membrane is not known.
Pharmacokinetics: Equivalent doses of intravenous (IV) and oral sodium valproate products are expected to result in equivalent minimum/maximum drug concentrations (C_min/C_max) and total systemic exposure to the valproate ion when valproate IV is administered as a 60-minute infusion. The effect of the formulation on the valproate ion absorption is of minor clinical importance under steady state conditions attained in chronic use for the treatment of epilepsy.
Sodium valproate is rapidly converted to valproic acid in the stomach. Valproic acid is rapidly and almost completely absorbed from the gastrointestinal tract. Peak serum levels are achieved 1 to 4 hours after a single oral dose. Food slightly delays absorption, but does not affect total absorption. Milk products does not affect drug absorption.
In most adult patients, doses of 1,200 to 1,500 mg per day resulted to therapeutic plasma levels of 50 to 100 mcg/mL. However, the therapeutic or toxic plasma concentrations has not been definitely established. The onset of therapeutic effects is within several days to more than a week from treatment initiation.
Sodium valproate is readily distributed, most likely in the circulation and rapidly exchangeable extracellular water. The plasma protein binding of valproate high (90%; 60% to albumin), concentration-dependent, and is reduced in the presence of other drugs. Thus, valproate may displace certain protein-bound drugs (see Interactions). The kinetics of the unbound drug is linear. However, due to its saturable plasma protein binding, the relationship between the dose and the total valproate concentration is nonlinear; increasing the dose may decrease the extent of protein binding and may lead to variable changes in its clearance and elimination. Valproate crosses the placenta and is also distributed in the cerebrospinal fluid (CSF) and breast milk. Relative to the plasma levels, its concentrations in the CSF and in breast milk are found to be 5% to 15% and about 1% to 10%, respectively.
Valproate is mainly metabolized by the liver, undergoing glucuronidation via UGT1A6, UGT1A9, and UGT2B7 as major pathway of biotransformation (40%). In adult patients on monotherapy, 30% to 50% of the administered dose appears in the urine as a glucuronide conjugate. The other major metabolic pathway is the mitochondria β-oxidation, accounting for >40% of the administered dose. Less than 15% to 20% of the dose is eliminated through omega-oxidation (cytochrome P450-dependent), while <3% of the dose is excreted unchanged in the urine.
Valproate is eliminated by first-order kinetics. The serum half-life of valproic acid ranges from 5 to 20 hours (average 10.6 hours). The mean plasma clearance for total and free valproate are 0.56 L/hr/1.73 m² and 4.6 L/hr/1.73 m², respectively. The volume of distribution (Vd) for total and free valproate are 11 L/1.73 m² and 92 L/1.73 m², respectively. The major urinary metabolite is 2-propyl-3-ketopentanoic acid. The minor metabolites are 2-propylglutaric acid, 2-propyl-5-hydroxypentanoic acid, 2-propyl-3-hydroxypentanoic acid, and 2-propyl-4-hydroxypentanoic acid. Small amounts of the drug are also excreted in feces and exhaled air. Very small amounts of unmetabolized parent drug is excreted in the urine.
Special Populations: Renal Impairment: Protein binding of valproic acid is substantially decreased in patients with renal impairment, which can result to misleading total valproate concentration monitoring. The unbound clearance of valproate is slightly reduced in patients with renal failure [creatinine clearance (CrCl) <10 mL/minute]. Hemodialysis causes a decrease in the valproate concentrations by about 20%.
Hepatic Impairment: Liver disease is associated with decreased albumin concentration, resulting to reduced protein binding and higher unbound fractions (2- to 2.6-fold increase) of valproate. In addition, liver disease impairs the capacity to eliminate valproate. The increase in half-life from 12 to 18 hours was also observed in patients with liver cirrhosis or acute hepatitis.
Children: Compared to children and adults, infants 2 months old and below have a significantly decreased ability in eliminating valproate due to the delayed development of glucuronyltransferase and other enzyme systems involved in valproate elimination. The decreased plasma protein in infants resulted to increased Vd.
Patients between 3 months and 10 years have 50% higher clearances expressed on weight compared to adults. Children over the age of 10 years have pharmacokinetic parameters that approximate those of adults. The half-life of valproate is usually shorter in children.
Elderly: Elderly patients have decreased capacity to reduce valproate compared to younger adults (22 to 26 years old). The intrinsic clearance of the drug is reduced by 39%, while the free fraction is increased by 44%. The protein binding of valproic acid is also reduced in the elderly.