Which medications in the drug class Urea Cycle Disorder Treatment Agents are used in the treatment of Hyperammonemia?

Updated: Nov 09, 2018
  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS  more...
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Urea Cycle Disorder Treatment Agents

This group consists of sodium benzoate, sodium phenylacetate, and sodium phenylbutyrate. These drugs lower blood ammonia concentrations by conjugation reactions involving acylation of amino acids. Sodium phenylbutyrate is a prodrug and is metabolized to phenylacetate. Phenylacetate then conjugates with glutamine to form phenylacetylglutamine, which is then excreted by the kidneys. On a molar basis, 1 mole of phenylacetate removes 2 moles of nitrogen.

Sodium phenylbutyrate (Buphenyl)

Phenylacetate was introduced after benzoate but now has been replaced by phenylbutyrate because former has bad odor. Adverse effects include menstrual disturbances (23% of patients), anorexia, pH disturbance, hypoalbuminemia, disturbance in phosphate metabolism, Fanconi syndrome, bad taste, and offensive body odor. Available in powder and tablet forms.

Carglumic acid (Carbaglu)

Also called N -carbamoyl-L-glutamate, carbamylglutamic acid, or carglutamic acid. Structural analogue of N -acetylglutamate, which enters cells and enables activation of CPS I (first enzyme of urea cycle) in vivo. Decreases hyperammonemia by converting ammonia into urea. More resistant to enzymatic degradation by hydrolysis compared with N -acetylglutamate.

Carglumic acid was recently approved by the FDA as adjunctive therapy for acute hyperammonemia and maintenance therapy for chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS), a rare genetic disorder resulting in hyperammonemia. [27]

Available as a 200-mg dispersible tab. Tab is scored and can be split to provide accurate dose.

Sodium phenylacetate and sodium benzoate (Ammonul)

Benzoate combines with glycine to form hippurate, which is excreted in urine. One mole of benzoate removes 1 mole 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 mole is identical to that of urea (2 moles of nitrogen). Ammonul must be administered with arginine for carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) 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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