Valproic acid hyperammonemia

Although carnitine administration may partially ameliorate hyperammonemia, it is expensive, and there are only limited data to support routine supplemental use in patients taking valproic acid. 

Hyperammonemia and encephalopathy associated with concomitant valproic acid use Administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In most cases, symptoms and signs abated with discontinuation of either drug. 

Valproic acid causes hair loss in about 5% of patients, but this effect is reversible. Transient gastrointestinal effects are common, and some mild behavioral effects have been reported. Metabolic effects, including hyperglycemia, hyperglycinuria, and hyperammonemia, have been reported. An increase in body weight also has been noted. Valproic acid is not a CNS depressant, but its administration may lead to increased depression if it is used in combination with phenobarbital, primidone, benzodiazepines, or other CNS depressant agents. 

The relationship of hyperammonemia to valproic acid-associated encephalopathies has been questioned after a study of ammonia concentrations in 55 asymptomatic patients taking valproic acid showed that 29 had ammonia concentrations above the reference range, the highest being 140 pmol/l (1180). 

It is difficult to establish a relation between valproate encephalopathy and increased serum ammonium concentrations. Valproate-induced hyperammonemic encephalopathy has been reported in several single case reports, but still it is difficult to ascertain whether hyperammonemia or valproic acid is the cause of the encephalopathy. In one case valproate was used in combination with lithium, which in itself could have caused encephalopathy by displacement of protein binding or other mechanisms, regardless of hyperammonemia (1181). In a second case it was also impossible to evaluate the effect of hyperammonemia on the level of consciousness, since it involved a woman who took valproic acid (30 g) in addition to... 

Murphy JV, Marquardt K. Asymptomatic hyperammonemia in patients receiving valproic acid. Arch Neurol 1982 39(9) 591-2. 

McCall M, Bourgeois JA. Valproic acid-induced hyperammonemia a case report. J Clin Psychopharmacol 2004 24(5) 521-6. 

Mallet L, Babin S, Morais JA. Valproic acid-induced hyperammonemia and thrombocytopenia in an elderly woman. Ann Pharmacother 2004 38(10) 1643-7. 

Of as yet unknown consequence to the brain and nervous system, there are many studies indicating that valproic acid promotes a variety of potentially dangerous viruses (e.g., Fan et al., 2005). Both valproic acid and carbamazepine cause a small increase in the rate of major congenital malformations in infants (Wide et al., 2004). Acute and potentially fatal pancreatitis has been reported with valproic acid (e.g., Grauso-Eby et al., 2003). Liver failure is a known problem as well. Valproic acid is known to cause hyperammonemia with encephalopathy (e.g., McCall et al., 2004). Severe and even lethal skin disorders can occur with all of the antiseizure medications now used as mood stabilizers. The various adverse effects of valproic acid and other mood stabilizers are not nearly as benign as physicians believe in their eagerness to switch patients from lithium. 

McCall, M., Bourgeois, J. (2004). Valproic acid-induced hyperammonemia A case report. Journal of Clinical Psychopharmacology, 24, 521—526. 

A rare complication is fulminant hepatitis. Children <2 years of age with other medical conditions who were given multiple antiseizure agents were especially likely to suffer fatal hepatic injury there were no deaths reported for patients >10 years old who received only valproate. Acute pancreatitis and hyperammonemia have been associated with the use of valproic acid. Valproic acid can produce teratogenic effects such as neural tube defects. 

B. Specific drugs and antidotes. There is no specific antidote. Naloxone (see p 469) has been reported to increase arousal, but inconsistently, with greatest success in patients with serum valproic acid levels of 185-190 mg/L. L-Camitine (p 426) has been used to treat valproic acid-induced hyperammonemia. 

A. Hyperammonemia, encephalopathy, or hepatotoxicity related to valproic acid therapy. 

A. Severe valproate-induced hepatotoxicity, hyperammonemia, coma, or acute valproic acid overdose. Early intervention with iV (rather than orai)... 

Valproic acid has been suspected to cause some adverse reactions through reduced serum biotinidase enzyme activity. The activity of this enzyme was determined in 57 children taking valproic acid, eight of whom had hyperammonemia and three of whom, all female, had hair loss in 17 children taking car-bamazepine and in 75 age- and sex-matched healthy controls no significant differences were found between the groups [328. ... 

Okamura N. Effect of CPS14217C> A genotype on valproic-acid-induced hyperammonemia. Pediatr Int 2010 52(5) 744-8. 

---