From the Guidelines
Medications that can cause elevated ammonia levels in the blood include valproic acid, phenobarbital, phenytoin, carbamazepine, certain antibiotics like amoxicillin, diuretics like furosemide, chemotherapy drugs such as 5-fluorouracil, asparaginase, and cytarabine, and antipsychotics like haloperidol and risperidone. These medications can impair the urea cycle, inhibit carbamoyl phosphate synthetase, alter gut flora, cause dehydration and electrolyte imbalances, lead to hepatotoxicity, or increase protein catabolism, resulting in elevated ammonia levels 1.
Key Medications Associated with Hyperammonemia
- Valproic acid (Depakote): impairs the urea cycle and inhibits carbamoyl phosphate synthetase
- Phenobarbital, phenytoin, and carbamazepine: anticonvulsants that may increase ammonia levels
- Amoxicillin and other penicillin derivatives: alter gut flora that produce ammonia
- Furosemide (Lasix): may indirectly raise ammonia levels by causing dehydration and electrolyte imbalances
- 5-fluorouracil, asparaginase, and cytarabine: chemotherapy drugs that can cause hepatotoxicity leading to ammonia elevation
- Haloperidol and risperidone: antipsychotics associated with hyperammonemia
Patient Risk Factors
Patients with underlying liver disease or urea cycle disorders are at higher risk for medication-induced hyperammonemia 1. Symptoms of elevated ammonia may include confusion, lethargy, vomiting, and in severe cases, encephalopathy or coma. The management of hyperammonemia is challenging and requires prompt identification and treatment, including the use of ammonia-scavenging agents and urea cycle intermediates 1.
Management of Hyperammonemia
The management of hyperammonemia involves stopping protein intake, providing adequate calories through intravenous glucose and lipids, and using nitrogen-scavenging agents and urea cycle intermediates 1. The choice of dialysis modality, including peritoneal dialysis (PD) and hemodialysis (HD), depends on institutional preference, local facilities, and the patient's condition 1.
From the FDA Drug Label
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured Hyperammonemia should also be considered in patients who present with hypothermia Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone There have been reports that valproic acid can induce hyperammonemia through inhibition of the synthesis of N-acetylglutamate, a co-factor for carbamyl phosphate synthetase
Medications that can cause elevated ammonia include:
- Valproic acid 2, 2, 3
- Topiramate (when co-administered with valproic acid) 2, 2
- Corticosteroids (may increase plasma ammonia levels in patients with impaired ability to form urea) 3
From the Research
Medications that can cause elevated ammonia
- Valproic acid (VPA) is a medication that can cause elevated plasma ammonia, leading to hyperammonemic encephalopathy in some individuals 4, 5, 6, 7, 8
Mechanism of hyperammonemia
- The exact mechanism of valproic acid-induced hyperammonemia is unclear, but it is thought to relate to the accumulation of toxic valproic acid metabolites and elevated ammonia levels 7
- Carnitine deficiency due to valproic acid is also proposed as a mechanism for hyperammonemia and the development of valproate-induced hyperammonemic encephalopathy (VHE) 6
Treatment of hyperammonemia
- Levocarnitine has been suggested for the treatment and prevention of VHE, and has been shown to be generally safe and effective in retrospective trials and case reports 4, 5, 6, 7
- Lactulose and combination therapy with levocarnitine have also been used for the treatment of hyperammonemia associated with valproic acid, but no significant difference in the reduction in ammonia levels was observed between these treatments 8