Valproic Acid Toxicity


(with permission from Dr. Valerie Demekhin to repost)


VPA is well absorbed from the GI tract with bioavailability of 80 – 90%. Peak concentrations are usually reached in 6 hours (except for enteric coated Depakote DR/ER formulations which peak in up to 24 hours). VPA is 90% protein bound at therapeutic concentrations, but the percentage decreases to up to 35% as the VPA concentration exceeds 300 mg/L due to saturation of binding sites.

Less than 3% of valproic acid is excreted in urine (we do not worry about renal adjustment or accumulation regardless of renal function) but the drug undergoes extensive liver metabolism.

Hepatic metabolism is complex and utilizes the same enzymes as mitochondrial lipid metabolism. Glucuronidation, mitochondrial ß- oxidation, and cytosolic ω- oxidation account for 50%, 40%, and 10% respectively of VPA. ß- oxidation occurs in mitochondrial matrix and starts with passive diffusion of VPA across mitochondrial membrane and ends with transport of metabolites in opposite directions using acetylCoA and carnitine as transporters.

ß- oxidation of VPA depletes carnitine stores; VPA metabolites trap mitochondrial CoA that leads to decreased ATP production (negatively affects carnitine transporters). Depletion of carnitine and the limited pool of free CoA lead to excessive ß- oxidation and ultimately to hyperammonemia (CPS I excess).

Electrolytes, blood gases, liver function tests, platelets, and serum lactate and serum ammonia concentrations should be monitored in all patients. Hyperammonemia (>80 μg/dL or >35 μmol/L) occurs in up to 80% of patients receiving chronic VPA therapy.

Management of VPA toxicity includes supportive management and discontinuation of therapy. Carnitine should be administered in the event of hyperammonemia or hepatotoxicity. IV carnitine is preferred in symptomatic patients, while oral carnitine is sufficient asymptomatic patients. The LD is 100 mg/kg over 30 minutes followed by 15 mg/kg over 10 – 30 minutes every 4 hours until clinical improvement occurs. However, it is important to acknowledge that the recommendations are based on toxicology emergency cases where doses ingested and the levels are far above what we see in the hospital. The indications for treatment are usually hyperammonemia, lethargy, coma or hepatic dysfunction. For patients with acute overdose but without clinical findings of toxicity, oral carnitine can be administered with a dose of 100 mg/kg day (up to 3 grams) divided every 6 hours.

Oral carnitine reverses carnitine deficiency and results in resolution of ammonia levels and improves lethargy in chronically treated VPA patients. Unanswered questions are the duration of L-carnitine supplementation and the effect of its administration on the VPA level.



  1. Goldfrank, Doyon, Toxicologic emergencies. Chapter 48: antiepileptics. 10th
  2. Howland MA. L-Carnitine. In: Goldfrank’s Toxicological Emergencies, 9th, McGraw Hill Medical, New York 2011. p.711.
  3. Ohtani, Carnitine deficiency and hyperammonemia with valproic acid therapy. J Pediatr 1982;101(5):782.
  4. Gidal Diet and valproate induced transient hyperammonemia: affect of L-carnitine. Pediatr Neurol 1997;16(4):301.
  5. Jackie Raskind, The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother 2000;34:630-8.a


Valerie Demekhin, Pharm.D., BCPS
Dr. Demekhin participates in multidisciplinary patient care rounds and provides pharmacotherapy services in the neurosurgery, neurology and epilepsy care unit. Dr. Demekhin precepts PGY-1 pharmacy residents for the neurology/neurosurgery rotation. In addition, she is a member of stroke and neurology committees. Dr. Demekhin is an active member within American College of Clinical Pharmacy (ACCP), Society of Critical Care Medicine (SCCM), American Society of Health System Pharmacists (ASHP), New York City Society of Health-System Pharmacists (NYSCHP) and Royal Counties Society of Health System Pharmacists (RCHSP). She serves as a journal review for Journal of Pharmacy Practice and has presented on topics such as pulmonary arterial hypertension, management of toxicological emergencies (calcium channel and beta blockers overdose, role of lipids in toxicology world, sulfonylurea overdose,, management of hypertensive urgencies and emergencies, therapeutic hypothermia, sepsis and stroke.

Dr. Demekhin’s areas of interest include toxicology, sedation, infectious diseases, stroke, and surgery/neurosurgery.




Additional Notes:

Hyperammonemia/encephalopathy: Hyperammonemia and/or encephalopathy, sometimes fatal, has been reported following the initiation of valproate therapy and may be present with normal transaminase levels.

Ammonia levels should be measured in patients who

  1. develop unexplained lethargy and vomiting, or
  2. develop changes in mental status or
  3. present with hypothermia.


Discontinue therapy if ammonia levels are increased and evaluate for possible urea cycle disorder (UCD). Hyperammonemic encephalopathy has been reported in patients with UCD, particularly ornithine transcarbamylase deficiency. Use is contraindicated in patients with known UCD.

Evaluation of UCD should be considered for the following patients prior to the start of therapy:

  • History of unexplained encephalopathy or coma;
  • encephalopathy associated with protein load;
  • pregnancy or postpartum encephalopathy;
  • unexplained mental retardation;
  • history of elevated plasma ammonia or glutamine;
  • history of cyclical vomiting and lethargy;
  • episodic extreme irritability, ataxia;
  • low BUN or protein avoidance;
  • family history of UCD or unexplained infant deaths (particularly male); or
  • signs or symptoms of UCD (hyperammonemia, encephalopathy, respiratory alkalosis).

Hyperammonemia and/or encephalopathy may also occur with concomitant topiramate therapy in patients who previously tolerated monotherapy with either medication.



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