Antiepileptic drugs: sodium valproate |
Sodium valproate is used for a number of indications, including:
- epilepsy—sodium valproate blocks voltage-dependent sodium channels, thus limiting the propagation of seizure discharges. Its action against absence seizures depends on blocking T-type calcium channels in the thalamus
- neuropathic pain—sodium valproate acts as a membrane stabiliser through sodium channel blockade as well as by inhibiting excessive firing of neurones through presynaptic and postsynaptic actions involving gamma-aminobutyric acid (GABA).The starting dose for neuropathic pain is 200 mg orally daily to twice daily, increasing as tolerated to a maximum of 1500 mg per day
- bipolar disorder—sodium valproate potentiates gamma-aminobutyric acid (GABA). Its mood stabilising action relates to its effects on protein kinase C. In acute mania, plasma sodium valproate concentrations of at least 300 micromol/L are necessary, while toxicity is likely at concentrations of 850 micromol/L or higher. Within that range, dosage should be determined by clinical response. No therapeutic plasma concentration range for the prophylactic treatment of recurrent bipolar disorder has been demonstrated, although plasma concentration ranges developed for its use as an antiepileptic are used as a guideline (350 to 700 micromol/L or 50 to 100 mg/L).
Pharmacokinetics: Sodium valproate has almost complete bioavailability and its peak concentration occurs 1 to 4 hours after a dose from an immediate-release formulation or 3 to 7 hours after an enteric-coated tablet. It has a high degree of protein binding (90%) and its half-life is in the range 8 to 12 hours. Steady-state concentrations are achieved after about 4 days. Sodium valproate undergoes extensive hepatic metabolism, with little unchanged drug excreted in the urine.
Adverse effects and precautions: Tremor, hair changes, sedation, and appetite stimulation with weight gain are the commonest adverse effects. Gastrointestinal symptoms such as anorexia, nausea and vomiting can occur. Note that the 200 mg and 500 mg tablets are enteric coated, producing reduced gastrointestinal symptoms. Sodium valproate alters platelet function and may cause thrombocytopenia; platelet status should be ascertained before major surgery. Dose-related, reversible elevations in hepatic enzyme levels also occur. Of greater concern are sodium valproate–associated idiosyncratic hepatotoxicity and pancreatitis, which may be fatal. The risk of hepatotoxicity is significantly higher in infants. Infants (2 years or less) taking multiple antiepileptic drugs in addition to sodium valproate and with mental retardation or congenital metabolic disorders such as carnitine or ornithine carbamoyltransferase deficiency appear to be particularly at risk of developing fatal hepatic failure. An incidence of fatal hepatotoxicity of 1 in 500 to 1 in 800 has been estimated for the above high-risk group when on polytherapy, compared to 1 in 37 000 for those outside the high-risk group.
Several studies have implicated chronic valproate use in females as being associated with the polycystic ovary syndrome (ie polycystic ovaries, polycystic ovarian dysfunction and hyperandrogenism resulting in the clinical features of chronic anovulation, menstrual disorders, hypofertility, hirsutism, acne, obesity and hair loss). However, whether there is a causative association with valproate use is still controversial. Polycystic ovaries (as opposed to the polycystic ovary syndrome) are relatively common in the community (up to 20% of women), and the incidence increases with increased adiposity.
Monitoring: Assessment of haematological, renal, electrolyte and hepatic function before commencing sodium valproate could prove a useful baseline; however, there is no consensus on the value of subsequent routine haematological and biochemical monitoring. For further information on monitoring, see Monitoring antiepileptic drug therapy (Appendix 7.1). For information on monitoring in bipolar disorder, see above.
Interactions: The risk of skin reactions, including Stevens-Johnson syndrome, is increased with concomitant use of lamotrigine . For further information on drug interactions with sodium valproate,
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