Pharm 101: Valproate



  • 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
  • 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

Pharmacology 101

Top 200 drugs

MBBS (UWA) CCPU (RCE, Biliary, DVT, E-FAST, AAA) Adult/Paediatric Emergency Medicine Advanced Trainee in Melbourne, Australia. Special interests in diagnostic and procedural ultrasound, medical education, and ECG interpretation. Editor-in-chief of the LITFL ECG Library. Twitter: @rob_buttner

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