Question 17

Compare and contrast phenytoin, sodium valproate and levetiracetam under the following headings.

a)    Mechanism of action    (20% marks)

b)    Pharmacokinetics    (20% marks)

c)    Adverse effects    (30% marks)

d)    Therapeutic monitoring    (30% marks)

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College answer

Not available.


This question feels like some kind of refugee from the First Part syllabus. Certainly, anticonvulsants are well-explored in the primary papers, where numerous SAQs ask trainees to compare the properties of these substances.

Phenytoin Sodium valproate Levetiracetam
Mechanisms of action
  • By binding to voltage gated sodium channels and stabilising them in their inactive state, phenytoin decreases the excitability of excitable tissues and prevents the generation and propagation of action potentials.
  • Multiple anticonvulsant mechanisms: sodium valproate increases the activity of GABA (mainly by inhibiting its catabolism) and stabilises neuronal membranes by its activity on sodium channels, as well as reducing the high-frequency firing of neurons by voltage-gated sodium, potassium, and calcium channel blockade.
  • Multiple effects on multiple excitatory and inhibitory neurotransmitters and ion channels. Appears to have some selectivity for abnormally firing tissue, i.e. this drug is selective for epileptic brain tissue. The precise mechanism of its effect remains unknown
  • 50-90% bioavailability
  • 90% protein bound
  • VOD = 1.6-2.5L
  • Hepatic metabolism (CYP450) into an inactive metabolite
  • 100%  bioavailability
  • 90% protein bound
  • VOD=0.2 L/kg
  • Hepatic metabolism: extensively metabolised by microsomal glucuronide conjugation
  • 100%  bioavailability
  • 10% protein bound
  • VOD=0.5-0.7 L/kg
  • Minimally metabolised; about 30% of the drug is excreted in the urine
Adverse effects
  • Acute toxic effects: Ataxia, nystagmus and tremor, slurred speech, cardiac toxicity 
  • Toxicity with chronic use: Gingival hyperplasia, hypersensitivity rash, folate deficiency, peripheral neuropathy, drug-induced lupus, bone marrow suppression.
  • Also: DRESS syndrome, toxic epidermal necrolysis, Stephens-Johnson syndrome.
  • Hepatoxicity
  • SIADH,
  • thrombocytopenia
  • hyperammonaemia
  • aplastic anaemia

Side effects are neurocognitive and behavioural. These may include:

  • change in mood
  • depression
  • anxiety
  • restlessness or fatigue,
  • personality changes,
  • cognitive decline, 
  • increased risk of suicide. 
Therapeutic monitoring
  • Narrow therapeutic range; needs monitoring
  • Normal level = 10 to 20 μ/mL
  • Narrow therapeutic range; needs monitoring
  • Normal level = 
  • No need for monitoring: levels do not correlate with effect or with toxicity


Jones, Gary L., Gary H. Wimbish, and William E. McIntosh. "Phenytoin: basic and clinical pharmacology." Medicinal research reviews 3.4 (1983): 383-434.

Isbister, Geoffrey K., et al. "Valproate overdose: a comparative cohort study of self poisonings." British Journal of clinical pharmacology 55.4 (2003): 398-404.

Stockis, Armel, et al. "Clinical pharmacology of levetiracetam for the treatment of epilepsy." Expert review of clinical pharmacology 2.4 (2009): 339-350.