What medications can increase ammonia levels?

Medications That Can Increase Ammonia Levels

Valproic acid is the most well-documented medication that can significantly increase ammonia levels, potentially causing hyperammonemic encephalopathy even at therapeutic doses and with normal liver function. 1

Primary Medications That Increase Ammonia Levels

1. Valproic Acid (Depakote, Depakene)

• Mechanism: Inhibits urea cycle enzymes and depletes carnitine, leading to impaired ammonia metabolism 1, 2
• Risk factors:
  • Concomitant use of other anticonvulsants, especially phenytoin and topiramate 1, 3
  • Underlying urea cycle disorders (e.g., ornithine transcarbamylase deficiency) 4
  • Congestive heart failure 3
  • Epilepsy 3
  • Higher valproic acid doses and serum concentrations 5, 3
  • Longer duration of valproic acid therapy 5

2. Other Anticonvulsants

• Phenytoin: Increases risk of hyperammonemia when used with valproic acid 3
• Topiramate: When combined with valproic acid, increases risk of hyperammonemia with or without encephalopathy 1
• Carbamazepine and phenobarbital: May contribute to hyperammonemia when used in combination with valproic acid 5

3. Mood Stabilizers

• Concomitant use with valproic acid increases risk of elevated ammonia levels 6

4. Antipsychotics

• Risperidone and blonanserin: Associated with elevated ammonia levels when used with valproic acid 6

Clinical Manifestations of Hyperammonemia

Symptoms and Signs

• Confusion and lethargy
• Vomiting
• Changes in mental status
• Ataxia, dysarthria, tremors
• Seizures
• Coma in severe cases 7, 1

Diagnostic Thresholds

• Normal ammonia levels: ≤35 µmol/L (<60 µg/dL)
• Hyperammonemia: >100 µmol/L (170 µg/dL) in neonates, ≥50 µmol/L (85 µg/dL) in term infants, children, and adolescents
• Severe hyperammonemia: >200 µmol/L (341 µg/dL) - associated with poor neurological outcomes 7

Monitoring and Management

Monitoring

• Check ammonia levels in patients taking valproic acid who present with alterations in mental status 2
• Monitor serum valproic acid levels, particularly with concurrent use of phenytoin or topiramate 3
• Consider monitoring carnitine levels in patients on long-term valproic acid therapy 5

Management of Medication-Induced Hyperammonemia

1. Discontinue the offending medication if clinically significant hyperammonemia occurs 1
2. L-carnitine supplementation may be beneficial in reducing ammonia levels in valproic acid-induced hyperammonemia 2
3. Lactulose can be used for treatment of hyperammonemic encephalopathy 8
4. Rifaximin is an effective add-on therapy to lactulose for management of hepatic encephalopathy 8
5. Nitrogen scavengers may be considered in severe cases 7
6. Continuous kidney replacement therapy may be required for severe hyperammonemia regardless of cause 7

High-Risk Populations

• Patients with underlying urea cycle disorders 4
• Patients with liver disease or dysfunction 1
• Elderly patients 1
• Patients on polytherapy with multiple anticonvulsants 5
• Patients with congestive heart failure 3

Clinical Pitfalls to Avoid

• Do not assume normal liver function tests rule out hyperammonemia
• Hyperammonemia can occur even with therapeutic valproic acid levels 2
• Be particularly vigilant when combining valproic acid with other anticonvulsants, especially phenytoin and topiramate 1, 3
• Consider the possibility of an underlying urea cycle disorder in patients who develop severe hyperammonemia with valproic acid 4
• Remember that hypothermia can be a manifestation of hyperammonemia and should prompt ammonia level testing 1