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
Pharm 101 700

Pharmacology 101

Top 200 drugs

MBBS CCPU (RCE, Biliary, DVT, E-FAST, AAA) Rob is an Emergency Medicine Advanced Trainee based in Melbourne, Australia. He has special interests in medical education, ECG interpretation, and the use of diagnostic and procedural ultrasound in the undifferentiated and unwell patient.

Follow him on twitter: @rob_buttner | ECG Library |

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