Contraindications: Significant hepatic dysfunction; known urea cycle disorders; use in prophylaxis of migraine headaches in pregnant women;
POLG-Related Mitochondrial Disease
The gene that encodes pol γ, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO).
-related mitochondrial disease Serious Side Effects:
Roughly 5-10% of patients on valproate long term will develop an asymptomatic, self-limiting transaminitis. Valproate can cause several forms of hepatotoxicity. More than 100 fatal cases of valproate-induced liver injury been reported in the literature. Three clinically distinguishable forms of hepatotoxicity (besides simple transaminitis) can occur with valproate.
Hyperammonemia with minimal or no evidence of hepatic injury: This syndrome typically presents with progressive and episodic confusion followed by obtundation and coma. The time to onset is often within a few weeks of starting valproate or increasing the dose, but it can present months or even years after starting the medication. The diagnosis is made by the finding of elevations in serum ammonia with normal (or near normal) serum aminotransferase and bilirubin levels. Valproate levels are usually normal or minimally high. The syndrome resolves within a few days of stopping valproate, but may reverse more rapidly with carnitidine supplementation or renal hemodialysis.
Acute hepatocellular injury with jaundice: typically accompanied by hepatocellular or mixed pattern of enzyme elevations. This acute liver injury pattern usually has its onset within 1 to 6 months of starting valproate. The pattern of serum enzyme elevations can be hepatocellular or mixed; sometimes the serum aminotransferase levels are not markedly elevated, despite the severity of injury. Immunoallergic features (fever, rash, eosinophilia) are usually absent, but rare cases with prominent features of hypersensitivity have been reported. Multiple instances of fatal acute hepatic failure due to valproate have been published and valproate is regularly listed as a cause of drug induced acute liver failure. Liver histology is distinctive and reveals a microvesicular steatosis with central lobular necrosis, mild to moderate inflammation and cholestasis. In cases with a prolonged course, fibrosis, bile duct proliferation and regenerative nodules may be present. Prospective studies using historical controls suggest that carnitidine (particularly intravenously) may be beneficial if given soon after presentation.
Reye-like syndrome described in children on valproate who develop fever and lethargy (suggestive of a viral infection) followed by confusion, stupor and coma, with raised ammonia levels and marked ALT elevations but normal or minimally elevated bilirubin levels. Metabolic acidosis is also common and the syndrome can be rapidly fatal. Valproate may simply be an aspirin-like agent capable of triggering Reye syndrome if it is being taken when the child develops either influenza or varicella infection.
All three forms of valproate hepatotoxicity have features of mitochondrial injury and liver histology, and usually demonstrates microvesicular steatosis with variable amounts of inflammation and cholestasis. Young age (<2 years), presence of other neurological conditions and concurrent use of other anticonvulsants appear to be important risk factors for acute liver failure due to valproate. Valproate has been rarely associated with anticonvulsant hypersensitivity syndrome and generally is a safe alternative in patients with that syndrome caused by the aromatic anticonvulsants.
1° MOA: ↑'s inhibitory effect of GABA, possibly by activation of glutamic acid decarboxylase or inhibition of GABA-transaminase; blockade of high-frequency repetitive firing by slowing the rate of Na+ recovery from inactivation, blocks the low-threshold T-type Ca2+ channel.
- inhibits metabolism of lamotrigine; so when coadministered lamotrigine dose should be halved
aspirin increases levels by ↓ its protein binding
highly (≥90%) bound to plasma proteins & ∴ subject to displacement interactions, e.g. phenytoin, carbamazepine, warfarin, tolbutamide, diazepam (unbound levels ↑ twofold)
- first-line treatment for mania and mixed states; may not be as effective for treating bipolar depression
extended release is ~80% as bioavailable as IR, so plasma levels will ↓ ~20% when converting from immediate to extended-release
- selenium & zinc supplementation may help prevent hair loss
more effective in preventing mania than treating depressive episodes, "a better ceiling than a floor"
Category D—*AVOID* High rate of neural tube defects; the absolute risk of producing a child with neural tube defects when used between the 17th and 30th days after fertilization is 1%–2%! Also associated with ↓ IQ scores and autism.
Though RID's up to as high as 15% have been measured, the American Academy of Pediatrics classified valproic acid as compatible with breastfeeding
Elderly are especially prone to somnolence
No dosage adjustment necessary
Contraindicated in patients with hepatic impairment
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Last updated March 25 2019 15:25:58. Disclaimer: This website does not provide medical advice, nor is it a substitute for clinical judgment.
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