Valproate

Key examples

• Sodium valproate
• Valproic acid

 

Common indications

• Epilepsy, as a first choice drug for the control of generalised or absence seizures and as a treatment option for focal seizures.
• Bipolar disorder, for the acute treatment of manic episodes and prophylaxis against recurrence.

 

Mechanisms of action

• The mechanism of action of valproate is incompletely understood.
• It appears be a weak inhibitor of neuronal sodium channels, stabilising resting membrane potentials and reducing neuronal excitability (see Phenytoin). It also increases the brain content of γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter, which regulates neuronal excitability.

 

Important adverse effects

• The most common dose-related adverse events are gastrointestinal upset (such as nausea, gastric irritation and diarrhoea), neurological and psychiatric effects (including tremor, ataxia and behavioural disturbances), thrombocytopenia and transient increase in liver enzymes. 
• Hypersensitivity reactions include hair loss, with subsequent regrowth being curlier than original hair. 
• Rare, life-threatening idiosyncratic adverse effects include severe liver injury, pancreatitis, bone marrow failure and antiepileptic hypersensitivity syndrome (see Carbamazepine).

 

Warnings

• Valproate should be avoided where possible in women of child-bearing age, particularly around the time of conception and in the first trimester of pregnancy. 
• It is the antiepileptic drug associated with the greatest risk of fetal abnormalities, including neural tube defects, craniofacial, cardiac and limb abnormalities and developmental delay. 
• It should be avoided in patients with hepatic impairment and dose reduction is required in patients with severe renal impairment.

 

Important interactions

• Valproate inhibits hepatic cytochrome P450 enzymes, increasing plasma concentration and toxicity of drugs metabolised by P450 enzymes, including, for example, warfarin and other antiepileptic drugs. Valproate is itself metabolised by these enzymes. As such, valproate concentration is reduced and risk of seizures may be increased by cytochrome P450 inducers (e.g. phenytoin, carbamazepine), and also by carbapenems. 
• Adverse effects are increased by cytochrome P450 inhibitors (e.g. macrolides, protease inhibitors) and drugs that displace it from protein binding sites (e.g. aspirin). 
• The efficacy of antiepileptic drugs is reduced by drugs that lower the seizure threshold (e.g. SSRIs, tricyclic antidepressants, antipsychotics, tramadol).