Medication Summary
Because the enzyme defect interrupts the urea cycle, alternative means of waste nitrogen disposal are required. Some medications assist in excreting nitrogen and serve as an alternative to urea to reduce waste nitrogen levels. Administer only in a large medical facility with close laboratory monitoring.
Urea Cycle Disorder Treatment Agents
Class Summary
These are used in management of severe, uncompensated metabolic alkalosis.
Arginine (R-Gene)
Enhances production of ornithine, which facilitates incorporation of waste nitrogen into the formation of citrulline and ASA.
Sodium phenylacetate and sodium benzoate (Ammonul)
Benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mol is identical to that of urea (2 mol of nitrogen). Ammonul must be administered with arginine for carbamyl phophate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or ASA lyase deficiencies. Indicated as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea cycle enzyme deficiencies. Serves as an alternative to urea to reduce waste nitrogen levels.
Glycerol phenylbutyrate (Ravicti)
Glycerol phenylbutyrate is a nitrogen-binding agent for chronic management of adult and pediatric patients (including newborns) with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. It is a pre-prodrug that is metabolized by ester hydrolysis and pancreatic lipases to phenylbutyrate and then by beta oxidation to phenylacetate. Glutamine is conjugated with phenylacetate to form phenylacetylglutamine, a nitrogen waste product that is excreted in the urine. It is not indicated for treatment of hyperammonemia.
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Compounds comprising the urea cycle are numbered sequentially, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (ASA) (4); the reaction is mediated by ASA synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.
