Valproate Flashcards
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.
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.
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).
Prescribing
Valproate is formulated as a sodium salt, which is prescribed in epilepsy, and as valproic acid, licensed for bipolar disorders. Valproate dose is equivalent in the two formulations, but care is required when switching between them. The usual daily starting dose of valproate is 600 mg for epilepsy and 750 mg for bipolar disorder, taken in 1–3 divided doses. The dose is increased to a usual daily maximum of 1–2 g.
Administration
Oral valproate is formulated as a bewildering array of normal or enteric-coated tablets, capsules, granules and oral solutions. Some formulations can be crushed (tablets) or mixed with food (granules), whereas modified-release and enteric-coated formulations should be swallowed whole without chewing. It is important to give the patient appropriate instructions for the formulation chosen. Intravenous valproate can be used temporarily where oral administration is not possible. It can be given either as a slow IV injection or by infusion.
Communication
Explain that the aim of treatment is to reduce frequency of seizures. Warn patients that they may have some indigestion or tummy upset when starting valproate, but that these will settle in a few days and can be reduced by taking tablets with food. As the most serious potential adverse effects are unpredictable, patients should seek urgent medical advice for unexpected symptoms including lethargy, loss of appetite, vomiting or abdominal pain (may indicate liver poisoning) or bruising, a high temperature or mouth ulcers (may indicate blood abnormalities). For women, discuss contraception and pregnancy (see Clinical tip). Advise patients not to drive unless they have been seizure-free for 12 months (or have only had seizures when asleep over 3 years). They should not drive for 6 months after changing or stopping treatment.
Monitoring
Monitor efficacy by comparing seizure frequency before and after starting treatment or dose adjustment. Monitor safety by patient report. Measurement of liver function (including prothrombin time) before and during the first 6 months of treatment may be useful. Plasma valproate concentrations (usually 40–100 mg/L) do not correlate well with therapeutic effect. They should therefore only be measured to check for adherence or toxicity.
