Hyperammonemia Associated with Valproic Acid Concentrations

Abstract

Valproic acid, a branched short-chain fatty acid, has numerous action mechanisms which turn it into a broad spectrum anticonvulsant drug and make its use possible in some other pathologies such as bipolar disorder. It is extensively metabolized in liver, representing β-oxidation in the mitochondria one of its main metabolic route (40%). Carnitine is responsible for its entry into the mitochondria as any other fatty acid. Long-term high-dose VPA therapy or acute VPA overdose induces carnitine depletion, resulting in high levels of ammonia in blood. As a high correlation between salivary valproic acid levels and plasma ultrafiltrate levels was found in humans, saliva becomes a promising monitoring fluid in order to study valproic acid pharmacokinetics and its toxic effect. Extended-release (twice daily) formulations of valproic acid or carnitine supplementation are the proposed two therapeutic strategies in order to reverse hyperammonemia.

Valproic Acid-Induced Hyperammonemia with Encephalopathy (VIHE): A Case Report

“…Ammonia levels and drug levels should be checked immediately if a patient develops lethargy or any neurological symptoms. Ammonia levels are best monitored in the blood, while VPA levels can be best monitored in saliva, so both levels are closely checked timely [4] .…”

Severe hyperammonaemic encephalopathy resulting from the overlap between hepatic and valproate encephalopathy

“…Carnitine metabolism and action has been postulated to be integral to the development of valproate toxicity. Sodium valproate through a number of proposed mechanisms results in the depletion of free carnitine; this, in turn, has been postulated to result in direct detrimental effects on hepatocyte metabolism as well as resulting in altered sodium valproate metabolism within the hepatocyte with the build of multiple metabolites, some of which are believed to be responsible for the development of toxicity again through altered hepatocyte metabolism 2. Carnitine deficiency can occur for a number of other reasons including poor nutritional intake such as associated with alcoholism or decreased synthesis due to severe liver dysfunction or increased requirements during critical illness, all of which were present in our patient 3 4.…”

Estudio Multicéntrico Español: Niños Con Hiperamoniemia No Asociada a Errores Innatos Del Metabolismo

“…Probablemente, es un efecto más frecuente que el realmente descrito en la literatura, al que no se le ha prestado la atención que requiere, y que no siempre está asociado a niveles altos del fármaco en sangre. De hecho, algunos autores han referido que el tiempo de tratamiento, la dosis, los niveles en suero del fármaco e incluso los niveles de amonio no parecen estar relacionados con el inicio o la severidad de la encefalopatía (8) y que es necesario un control regular de los niveles de los fármacos en sangre o saliva para evitar este efecto secundario (9). En el presente trabajo, se destaca una muestra multicéntrica con diferentes edades de presentación en el ámbito pediátrico y de diversas causas asociadas a la hiperamoniemia secundaria con la que los autores queremos resaltar la importancia de pensar en esta posibilidad ya que aparece con una sintomatología grave, para actuar precozmente y con un tratamiento adecuado.…”

“…La carnitina también puede ser utilizada en determinados casos de EH, ya que disminuye el efecto tóxico hepático de la encefalopatía inducida por VPA (3,9). Respecto a la alimentación, las fórmulas enterales y/o parenterales suelen ser libres de carnitina y la suma de administración de varios antiepilépticos y un bajo peso son factores de riesgo para la deficiencia de carnitina en niños con epilepsia.…”