Hyperammonemia Medication

Updated: Sep 29, 2021
  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA  more...
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Medication Summary

The medical management of urea cycle disorders used to be limited to dietary modifications, which were not sufficient in many patients. Introduction of compounds that promote alternate pathways for nitrogen excretion was a big breakthrough. As nitrogen is converted to compounds other than urea, the load on the urea cycle is reduced.

  • Sodium phenylbutyrate: Patients with CPS, OTC, or AS deficiency should receive sodium phenylbutyrate at a dose of 450-600 mg/kg/day.

  • Citrulline: Patients with CPS or OTC deficiency should receive citrulline (150-200 mg/kg/day for < 20 kg and 3-4 g/m2/day if >20 kg) as a source of arginine; because citrulline is elevated in ASS and ASL deficiencies, it should not be given to patients with an unknown diagnosis. After stabilization, citrulline 170 mg/kg/day is given to patients with OTC and CPS deficiency.

  • Arginine: It is administered IV together with sodium phenylacetate and sodium benzoate solution as part of the initial hyperammonemia treatment. In patients ≤20 kg, CPS and OTC deficiency or if a specific defect in the urea cycle has not been identified, administer arginine hydrochloride bolus 200 mg/kg in patients who weigh less than 20 kg and 4 g/m2 for patients over 20 kg, infused over 90 min; this is followed by a maintenance dose of 200 mg/kg/day in patients under 20 kg and 4 g/m2/day for patients over 20 kg. In ASS and ASL deficiency, the maintenance dose recommended is 600 mg/kg/day if less than 20 kg and 12 g/m2/day if over 20 kg. After stabilization, an arginine base (500 mg/kg/day PO) is recommended for AS and AL deficiency.


Urea Cycle Disorder Treatment Agents

Class Summary

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Phenylacetate was introduced after benzoate but now has been replaced by phenylbutyrate because former has bad odor.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)

Carglumic acid acts as an activator of carbamoyl phosphate synthetase (CPS 1), improves or restores the function of the urea cycle, and facilitates ammonia detoxification and urea production. It is indicated 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. Also, carglumic acid is used as adjunctive therapy to standard-of-care for acute hyperammonemia due to propionic acidemia or methylmalonic acidemia.

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.



Class Summary

These agents control nausea and vomiting associated with IV administration of sodium benzoate and phenylacetate.

Ondansetron hydrochloride (Zofran)

Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with sodium benzoate and phenylacetate and carglumic acid.

Granisetron (Granisol, Sancuso)

Used for prevention of chemotherapy-induced nausea and vomiting. At chemoreceptor trigger zone, blocks serotonin peripherally on vagal nerve terminals and centrally. Prevents nausea and vomiting associated with sodium benzoate and phenylacetate and carglumic acid.

Palonosetron (Aloxi)

Selective 5-HT3 receptor antagonist with long half-life (40 h). Blocks 5-HT3 receptors peripherally and centrally in chemoreceptor trigger zone. Prevents nausea and vomiting associated with sodium benzoate and phenylacetate and carglumic acid.

Dolasetron (Anzemet)

Prevents nausea and vomiting by binding to 5-HT3-receptors located on chemoreceptor trigger zone and vagal neurons in GI tract. Prevents nausea and vomiting associated with sodium benzoate and phenylacetate and carglumic acid.