Pharm 101: Valproate

Class

Anticonvulsant

Pharmacodynamics

• Exact mechanism of action is unknown
• Proposed mechanisms:
  • Sodium channel blockade which inhibits sustained high frequency firing of neurons
  • Blockade of NMDA receptor mediated excitation
  • Increased GABA levels

Pharmacokinetics

• Bioavailability > 80%
• 90% plasma protein bound
• Volume of distribution 0.15L/kg
• Extensive liver metabolism (95%)
• Half life 9-18 hours
• Extensive drug interactions with other anticonvulsants:
  • Inhibits metabolism of phenobarbitol and ethosuximide
  • Increases free concentration of phenytoin by displacing from plasma proteins
  • Increases levels of carbamazepine epoxide (active metabolite of carbamazepine)
  • Decreases clearance of lamotrigine (prolongs half life 2-3x)

Clinical uses

• Anticonvulsant:
  • Generalised tonic-clonic seizures, partial seizures, absence seizures
  • First line for myoclonic seizures
  • Intravenous use for status epilepticus
• Migraine prophylaxis

Adverse effects

• Gastrointestinal disturbance (nausea/vomiting) is common.
• CNS: tremor, nystagmus
• Alopecia and weight gain (reversible)
• Lethargy:
  • Interferes with conversion of ammonia to urea
  • Causes lethargy associated with increased blood ammonia concentrations
  • Caution in genetic defects of urea metabolism
• Fatal hepatic toxicity:
  • Usually within four months of initiation
  • Most common in patients < 2 years of age
  • Precaution in liver disease or in combination with other hepatotoxic drugs
  • LFT derangement in 40%
• Thrombocytopaenia (although abnormal bleeding rare)
• Pregnancy complications:
  • 1-2% risk of spina bifida with first trimester use
  • Cardiovascular, orofacial and digital abnormalities
  • Cognitive mpairment

Further Reading

• Nickson C. Sodium Valproate Overdose. LITFL