Valproate Associate Fulminant Hepatic Failure

B

• Structure similar to short-chain fatty acid
• First-line treatment for absence seizures
• Also widely used as a mood stabilizer in psych illness – esp bipolar affective disorder

• Blocks inactivated Na channels and GABAergic effects
• VPA metabolism is complex
• 95% hepatic metabolism
• VPA => VPA-coA => VPA-carnitine => cross mito membrane => VPA-coA => b-oxidation
• Valproyl-carnitine shuttles across mitochondrial membrane via carnitine translocase
• In mito, valproyl-carnitine is converted back to valproyl-coA which enters a slower version of beta oxidation which eventually yields 3-en-VPACoA. (effects on beta ox can cause Reyes-like syndrome)
• 4 types of hepatic effects: transient reversible transaminitis, reversible hyperammonemia, toxic hepatitis, Reye like syndrome

• VPA also decreases carnitine stores – formation of valproyl-carnitine increases renal carnitine excretion and inhibits carnitine transporter at cell membrane
• Low cellular carnitine has two main effects: inhibits transport of long-chain fatty acids across mito membrane for beta-ox and inhibits urea cycle. (hyperammonemia)

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