VIVA: Pharmacology - Nervous system

Question 1

Describe the pharmacokinetics of sodium valproate

Answer 1

4 to pass:
- Can be administered IV or orally
- Well-absorbed orally with bioavailability of >80%
- Peak blood levels within 2hrs
- Highly protein bound and low volume of distribution 0.15L/kg
- Extensively metabolised in liver and excreted as glucuronide conjugate in urine (30-50% of dose)
- Long half-life 9-18hrs

Question 2

What are the adverse effects of sodium valproate?

Answer 2

1. GIT:
   - Nausea, vomiting, abdominal pain
   - Reflux
   - Asymptomatic elevation of LFTs
2. CNS:
   - Fine tremor
   - Ataxia
   - Sedation
   - Fatal encephalopathy if there is also genetic abnormality of urea metabolism
3. Less common:
   - Weight gain
   - Increased appetite
   - Hair loss
   - Rash
4. Rare but serious:
   - Idiosyncratic hepatic failure (risk highest <2yrs old)
   - Idiosyncratic thrombocytopaenia
   - Teratogenic if given in 1st trimester (e.g. neural tube defects, cardiovascular/facial/digital abnormalities)
   - Hypernatraemia

Question 3

Sodium valproate exhibits capacity-limited protein binding kinetics. What is this?

Answer 3

• Sodium valproate is highly bound to plasma proteins (90%) at lower concentrations (75mg/L)
• This mechanism is saturated at higher concentrations (150mg/L) leading to an increase in free drug (70% bound)
• This will result in apparent increased clearance of drug at higher doses and reduction in half-life (variable clearance)
• Thus dosage is preferred as a sustained release preparation