Pharm
Valproic Acid Toxicity
search
Valproic Acid Toxicity
, Valproate Toxicity, Depakote Toxicity, VPA Toxicity
See Also
Valproic Acid
(
Depakote
)
Mechanism
Valproate
is a simple
Fatty Acid
2-n-propylpentanoic acid
Eight carbon branched-chain carboxylic acid
Metabolism: Three primary mechanisms
Hepatic Glucuronidation (50%)
Glucuronic acid conjugation occurs in the liver
Primary metabolism pathway
Non-hepatic metabolism
Mitochondrial Beta-oxidation (40%)
Primary and preferred non-hepatic pathway
Valproate
undergoes
Fatty Acid
beta-oxidation in the mitochondria
Requires acetyl-coA to enter mitichondria
Requires carnitine to cross Mitochondrial innder-membrane
Microsomal omega hydroxylation (<5% under normal cicumstances)
Carnitine independent metabolism pathway
Results in formation of Delta^4-
Valproic Acid
which is hepatotoxic
Contributes to high
Serum Ammonia
levels
Excretion
Urine is primary excretion pathway for the metabolized form of
Valproate
Pathophysiology
Toxicity
Precipitating factors
Valproic Acid
in excess or
Carnitine deficiency (depleted when starting
Valproic Acid
)
Injury mechanisms
Microsomal omega hydroxylation replaces mitochondrial beta oxidation
Occurs with carnitine deficiency
Results in hepatotoxic
Valproate
metabolites (Delta^4-
Valproic Acid
)
Results in build-up of
Valproate
in the cytoplasm
Increased
Valproate
levels
Direct cellular injury
Microvesicular
Steatosis
Metabolic Acidosis
Cerebral edema (with increased
Seizure
risk) due to metabolite (4-en-
Valproic Acid
)
Risk factors
Carnitine deficiency
Valproic Acid
started within last few weeks (carnitine depletion uncompensated)
Increased
Fatty Acid
metabolism (faster carnitine deficiency)
Ketogenic diet or Atkins Diet
Poor nutritional intake
Signs
Altered Level of Consciousness
Seizure
s
May paradoxically occur with
Valproate
Overdose
Labs
Serum Ammonia
Increased levels
Serum Ammonia
may also be increased up to 80 in non-toxic chronic
Valproic Acid
therapy
Serum
Valproic Acid
May be normal despite toxicity (especially when carnitine deficient)
Monitor serial levels if elevated in large
Overdose
Patient observation until asymptomatic and serum
Valproate
acid levels drop to normal or fall 20-30% from prior level
Liver Function Test
s
Elevated in carnitine deficiency, with increased
Valproate
metabolism by microsomal omega hydroxylation
Venous Blood Gas
(or
Arterial Blood Gas
)
Metabolic Acidosis
in significant
Overdose
(due to acidic molecule)
Management
Stop
Valproic Acid
Consider L-Carnitine (see below)
Large ingestion management
Multi-dose Charcoal (50g every 2-4 hours) indications
Presentation within 1 hour of large reported
Valproate
ingestion AND
No airway compromise
Hemodialysis Indications
Very high
Valproic Acid
levels (e.g. >800)
Severe
Metabolic Acidosis
Ongoing
Seizure
s
Management
L-Carnitine
Indications
Massive
Valproic Acid
Overdose
Symptoms suggestive of Valproic Acid Toxicity
Valproic Acid
level >120
Serum transaminase increase (AST, ALT)
Increased
Serum Ammonia
Consider
Serum Ammonia
>80 as abnormal if taking
Valproic Acid
chronically
Dosing
L-Carnitine 50-100 mg/kg (up to 2 grams) IV every 8 hours
References
Bohan (2001) Neurology 56(10): 1405-9 [PubMed]
Prevention
Stop
Valproic Acid
if symptoms suggestive of toxicity
Consider L-Carnitine supplementation (by prescription, OTC formulation too low dose)
L-Carnitine 50-100 mg/kg (up to 2 grams) orally three times daily
L-Carnitine is well tolerated, but may cause GI upset or fishy odor to skin
L-Carnitine is derived from animal proteins (as well as some plants such as avocado) with only the L-Isomer active
References
Hatten and Orman in Majoewsky (2013) EM:Rap 13(7): 3-4
Silva (2008) J Inherit Metab Dis 31(2):205-16 [PubMed]
Type your search phrase here