Emergency medications for inborn errors of metabolism (IEMs)

Emergency medications for inborn errors of metabolism (IEMs) 
Emergency medications for inborn errors of metabolism (IEMs) in infants and children include drugs to eliminate toxic metabolites and/or amino acids and enzyme cofactors to compensate for metabolic deficiencies. These and other drugs may be required to maintain and treat the underlying IEM. Some IEMs are treated with replacement enzymes that are FDA approved, designated as orphan drugs, or investigational. 

Ammonium Detoxicants. Treatment of hyperammonemia; enhances elimination of nitrogen. This drug is FDA approved for treatment of hyperammonemia due to urea cycle defects and is available only from a specialty wholesaler, Ucyclyd Pharma (888-829-2593). 

  • Sodium phenylacetate and sodium benzoate (Ammonul). Indicated for acute hyperammonemic and associated encephalopathy due to urea cycle defects. For ammonia levels >500-600 mcg/dL, hemodialysis is the preferred treatment; however, sodium phenylacetate and sodium benzoate should be considered if dialysis cannot be initiated immediately. 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 mole is identical to that of urea (2 mol of nitrogen). Ammonul should be administered with arginine-HCL for carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) deficiencies and should not be given for arginase deficiency. Approved as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea cycle enzyme deficiencies. Preparation contains 100 mg/mL each of sodium phenylacetate and sodium benzoate and comes in 50-mL vials. Must dilute IV dose in at least 25 mL/kg of dextrose 10% up to 600 mL. Do not mix directly with other medications, but it may be piggybacked. Give in addition to daily fluid requirement but decrease maintenance fluid by volume of Ammonul given.

Amino Acid. Essential amino acid used for certain urea cycle defects.

  • Arginine (R-Gene). Enhances production of ornithine, which facilitates incorporation of waste nitrogen into the formation of citrulline and argininosuccinate. Provides 1 mol of urea plus 1 mol ornithine per mol of arginine when cleaved by arginase. Preparation is 10% arginine hydrochloride. Can be mixed with sodium phenylacetate and sodium benzoate. If administering separately, mix with sodium bicarbonate.

Enzyme Cofactor. Enzyme cofactors are used to enhance the activity of cofactor-dependent enzymes.

  • Pyridoxine. Precursor of pyridoxal, which functions in the metabolism of proteins, carbohydrates, and fats. Also aids in the release of liver- and muscle-stored glycogen and in the synthesis of GABA (within the CNS) and heme. Involved in synthesis of GABA within the CNS. Indicated for seizures of unknown etiology unresponsive to conventional anticonvulsants and for seizures in patients with known pyridoxine-dependent IEM. Give undiluted or mix with other solutions. Incompatible with alkaline or oxidizing solutions and iron salts. Not to be mixed with sodium bicarbonate.

Nutritional Supplement. This agent is used for the treatment of primary and secondary carnitine deficiency.

  • Levocarnitine (Carnitor). An amino acid derivative, synthesized from methionine and lysine, required in energy metabolism. Can promote excretion of excess fatty acids in patients with defects that bioaccumulate acyl-CoA esters. Carnitine is indicated for most organic acidemias and is controversial for fatty acid oxidation defects

Helpful Web sites for finding information on orphan drug designation include the following:

  • National Organization for Rare Disorders (NORD) (lists more than 1000 rare diseases)
  • United States FDA’s Other Sources of Rare Disease/Orphan Product Information (list of Web sites that provide information on rare diseases and orphan drugs)
  • United States FDA’s List of Orphan Drug Designations and Approvals


    • Dickson PI, Tolar J. The individual (single patient) IND for inborn errors of metabolism. Mol Genet Metab. 2014 Oct 13.
    • Fernandes J, Saudubray JM, Van den Berghe G. Inborn Metabolic Diseases: Diagnosis and Treatment. 3rd ed. Springer-Verlag: 2000.

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