Valproic Acid Mechanism of Action

Mechanism

• Valproic acid is used to treat generalized, partial, and absence seizures, as well as migraines and psychiatric disorders.
• It has a wider spectrum of activity than other antiepileptic drugs.

Pharmacokinetic

• Bioavailability: • Intravenous: 100% • Oral: 100% • Sustained Release Tablet: 90% • Extended Release Tablet: 80-90%
• Volume of Distribution (Vd): • Pediatric: 0.22 (+ 0.05) L/kg • Adults: 0.15 (+ 0.10) L/kg
• Therapeutic range: • Seizures: 50-100 mg/L • Psychiatric Disorder: 50-125 mg/L

Volume of Distribution (Vd)

• Valproic acid is highly bound to serum albumin (90-95%).
• Binding becomes saturated within the therapeutic range (above 50 mg/L), leading to nonlinear pharmacokinetics.
• Factors affecting unbound valproic acid fraction: • Hypoalbuminemia • Liver disease • Nephrotic syndrome • Cystic fibrosis • Trauma • Malnourishment • Elderly • Displacement by endogenous or exogenous substances

Metabolism

• Valproic acid metabolism is induced by other drugs that enhance hepatic enzyme activity.
• One metabolite, 4-hydroxy-valproic acid, may be associated with hepatotoxicity.
• Elimination: mostly through hepatic metabolism (>95%) and minimally through renal route (<5%).
• Clearance (CL) correlates better with ideal body weight than total body weight in obese patients.
• Liver dysfunction reduces valproic acid clearance.

Half-Life

• Pediatric: 6-8 hours
• Adult: 12-18 hours

Time to Peak

• Oral: 1-3 hours (before meal), 6-8 hours (after meal)
• Intravenous: at the end of 1 hour infusion

Indication and Therapeutic Range

• Generalized, partial, and absence seizures: 50-100 mg/L
• Mania, anxiety, depression, psychosis, and substance-abuse withdrawal: 50-125 mg/L

Therapeutic Dose

• Initial dose: 10-15 mg/kg/day PO
• Dose increase: 5-10 mg/kg/week to achieve optimal clinical response
• Maximum dose: 60 mg/kg/day

Special Considerations

• Valproic acid concentrations above 100 mg/L may be required in patients with partial seizures.
• IV Valproate is not recommended for post-traumatic seizure prophylaxis in patients with acute head trauma.
• Valproate should be withdrawn gradually to minimize the potential of increased seizure frequency.

Renal and Hepatic Impairment

• Renal impairment: no dosage adjustment necessary, but renal function needs to be monitored closely.
• Hepatic impairment: patients with existing liver disease should be classified according to liver dysfunction index (Child-Pugh score) before initiation of the drug.

Interaction

• Valproic acid is an enzyme inhibitor and is subject to enzyme induction.

Monitoring

• Steady state: 2-4 days
• Sampling time: 30 minutes or just before next dose
• Monitoring is recommended in certain conditions, including: • Initiation of therapy • Change in dosing regimen • Addition of other antiepileptic drugs • Change in patient's clinical course • Claims of valproic acid side effects

Monitoring Parameters

• Liver enzymes
• Full blood count with platelets
• Serum ammonia (with symptoms of lethargy, mental status change)
• Body weight
• Blood pressure
• Heart rate

Adverse Drug Reactions

• Side effects: alopecia, pancreatitis, hyperammonemic encephalopathy, hepatotoxicity, weight gain
• Patients at higher risk: young patients, especially those with hepatic failure