Sodium valproate
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Sodium valproate is primarily used as an anti-epileptic medication but is sometimes used in bipolar disorder and off license for migraine prophylaxis. Sodium valproate is considered the first-line choice for generalised tonic-clonic seizures, myoclonic jerks and atonic or tonic seizures in males and females unable to have children (highly teratogenic). It is also considered first line in all patients (male and female) for treating Dravet syndrome and Lennox-Gastaut syndrome.
Vaproate is also thought to act via several other mechanisms including:
Contraindications
The protein binding of valproate is reduced by hypoalbuminemia, ureamia, increasing total valproate concentration, free fatty acid-containing therapies (e.g. propofol, IV fat emulsion), and certain medications (e.g. aspirin which is also highly protein bound and may displace valproate) resulting in an increased free fraction.
These circumstances may lead to the measured total valproate concentration not reflecting the elevated free fraction and are more commonly encountered in critically ill patients. Clinicians should be aware of this as toxicity may occur despite apparently normal or only slightly abnormal valproate levels.
In addition to valproate toxicity other less strongly protein-bound drugs (e.g. warfarin) can be displaced by valproate, which may elevate their free plasma levels and increase the therapeutic effect or lead to toxicity of the concomitant drug.
Also note that the liver is a major site of valproate metabolism (see below), so drugs that inhibit cytochrome P450 enzymes (e.g. erythromycin, fluoxetine, and cimetidine) can increase valproate levels.
Mechanism of action
Valproate's precise mechanism of action is unclear but its main mechanisms of action appear to be:- Inhibition of GABA transaminase reducing GABA metabolism and increasing GABAergic neurotransmission (remember GABA is an inhibitory neurotransmitter)
- Blockade of voltage-gated sodium ion channels (reduces neuronal excitability)
Vaproate is also thought to act via several other mechanisms including:
- Inhibiting histone deacetylases (alters gene transcription: genomic effect is wide with 461 genes being up or down-regulated)
- Reduce fatty acid incorporation into glycolipids increasing action potential threshold
- Inhibition of excitatory glutamergic transmission (glutamate is an amino acid and the major excitatory neurotransmitter in the nervous system)
- Inhibition of inositol (a secondary messenger involved in neurotransmission)
- Activation of multiple kinase pathways
Contraindications
- Acute porphyrias
- Known or suspected mitochondrial disorders (higher rate of acute liver failure and liver-related deaths)
- Personal or family history of severe hepatic dysfunction
- Active liver disease
- Urea cycle disorders (risk of hyperammonaemia)
- Women and girls of childbearing potential (unless conditions of Pregnancy Prevention Programme are met)
Sodium valproate and pregnancy
Valproate is highly teratogenic and evidence supports that use in pregnancy leads to neurodevelopmental disorders (approx. 30–40% risk) and congenital malformations (approx. 10% risk).
Valproate is highly teratogenic and evidence supports that use in pregnancy leads to neurodevelopmental disorders (approx. 30–40% risk) and congenital malformations (approx. 10% risk).
Cautions
- Liver dysfunction
- Systemic lupus erythematous
Liver toxicity
Liver dysfunction (including fatal hepatic failure) has occurred in association with valproate therapy (with an increased risk in children < 3 years old and patients with metabolic or degenerative disorders, organic brain disease or severe seizure disorders associated with mental retardation).
Liver dysfunction usually presents in the first 6 months of treatment and is more common in those on multiple anti-epileptic drugs. Raised liver enzymes during valproate treatment are usually transient but patients should be reassessed clinically and liver function (including prothrombin time) monitored until return to normal. Valproate should be discontinued if there is an abnormally prolonged prothrombin time.
Liver dysfunction (including fatal hepatic failure) has occurred in association with valproate therapy (with an increased risk in children < 3 years old and patients with metabolic or degenerative disorders, organic brain disease or severe seizure disorders associated with mental retardation).
Liver dysfunction usually presents in the first 6 months of treatment and is more common in those on multiple anti-epileptic drugs. Raised liver enzymes during valproate treatment are usually transient but patients should be reassessed clinically and liver function (including prothrombin time) monitored until return to normal. Valproate should be discontinued if there is an abnormally prolonged prothrombin time.
Side effects
| Common | Uncommon | Rare |
|---|---|---|
| Abdominal pain Agitation Alopecia Anaemia Abnormal behaviour Impaired concentration Confusion Deafness Diarrhoea Drowsiness Haemorrhage Hallucination Headache Hepatic disorders Hypersensitivity Hyponatraemia Memory loss Menstrual cycle irregularities Movement disorders Nail disorder Nausea and vomiting Nystagmus Oral disorders Seizures Stupor Thrombocytopenia Tremor Urinary disorders Weight gain | Androgenetic alopecia Angioedema Bone disorders inc fracture Bone marrow disorders Coma Encephalopathy Hair changes Hypothermia Leucopenia Pancreatitis Paraesthesia Parkinsonism Peripheral oedema Pleural effusion Renal failure SIADH Skin reactions Vasculitis Virilism | Agranulocytosis Cerebral atrophy Cognitive disorder Dementia Diplopia Gynaecomastia Hyperammonaemia Hypothyroidism Infertility male Learning disability Myelodysplastic syndrome Nephritis tubulointerstitial Obesity Polycystic ovaries Red blood cell abnormalities Rhabdomyolysis Severe cutaneous adverse reactions (SCARs) Systemic lupus erythematosus (SLE) Urine abnormalities |
Pancreas toxicity
Pancreatitis is a rare but potentially serious side effect. Valproate treatment should be stopped if symptoms of pancreatitis develop.Valproate and protein binding
Valproate is highly protein-bound to albumin, with the biologically active free (unbound) fraction expected to be 5–10% of the total concentration.The protein binding of valproate is reduced by hypoalbuminemia, ureamia, increasing total valproate concentration, free fatty acid-containing therapies (e.g. propofol, IV fat emulsion), and certain medications (e.g. aspirin which is also highly protein bound and may displace valproate) resulting in an increased free fraction.
These circumstances may lead to the measured total valproate concentration not reflecting the elevated free fraction and are more commonly encountered in critically ill patients. Clinicians should be aware of this as toxicity may occur despite apparently normal or only slightly abnormal valproate levels.
In addition to valproate toxicity other less strongly protein-bound drugs (e.g. warfarin) can be displaced by valproate, which may elevate their free plasma levels and increase the therapeutic effect or lead to toxicity of the concomitant drug.
Also note that the liver is a major site of valproate metabolism (see below), so drugs that inhibit cytochrome P450 enzymes (e.g. erythromycin, fluoxetine, and cimetidine) can increase valproate levels.
Metabolism
- Hepatic metabolism 30-50%
- Mitochondrial β-oxidation 40%
- Other oxidative pathways 15-20%
- Excreted unchanged in the urine <3%