From the FDA Drug Label
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy.
The medications that can increase ammonia levels are:
- Valproic acid: can cause hyperammonemia, especially when used concomitantly with topiramate.
- Topiramate: when used with valproic acid, can increase the risk of hyperammonemia. 1 1 1
From the Research
Valproic acid is the most well-known medication that can increase ammonia levels, and patients taking this medication should be closely monitored for signs of hyperammonemia, especially if they have underlying liver disease or are taking other medications that may interact with valproic acid 2.
Medications that Increase Ammonia Levels
Several medications can increase ammonia levels in the body, which may be particularly concerning for patients with liver disease or urea cycle disorders.
- Valproic acid (Depakote), a common antiepileptic medication, is one of the most well-known medications that can elevate ammonia levels through inhibition of carbamoyl phosphate synthetase 1, a key enzyme in the urea cycle 3.
- Other antiepileptic drugs like phenytoin, phenobarbital, and carbamazepine may also increase ammonia levels, though less commonly than valproic acid.
- Certain antibiotics, particularly those containing asparaginase used in cancer treatment, can raise ammonia levels by increasing protein catabolism.
- Diuretics like furosemide and thiazides may indirectly increase ammonia by causing dehydration and prerenal azotemia.
- Multiple antipsychotics including haloperidol and risperidone have been associated with hyperammonemia.
Risk Factors and Management
The prevalence of asymptomatic hyperammonemia is higher than symptomatic hyperammonemia, and various risk factors have been identified, including concomitant medications, liver injury, and defects in carnitine metabolism 2.
- Discontinuation of valproic acid is the most effective treatment for hyperammonemia, with a success rate of 56.3% 4.
- Lactulose initiation is also a common treatment modality, but its effectiveness is lower compared to discontinuation of valproic acid.
- Patients taking medications that can increase ammonia levels should be monitored for signs of hyperammonemia, such as confusion, lethargy, vomiting, or neurological changes, especially if they have underlying liver disease.
Recent Studies
A recent systematic review found that valproic acid-associated hyperammonemia is a common adverse effect that may occur within the therapeutic range of valproic acid, and further studies are required to determine the benefit of routine ammonia level monitoring and to guide the management of valproic acid-associated hyperammonemia 2.
- Another study found that the incidence of hyperammonemia is relatively high, and there is a dose-dependent association between valproic acid and blood ammonia level 5.
- A case report also highlighted the potential risk of hyperammonemia resulting from the combination of valproic acid and quetiapine, although further studies are needed to confirm this hypothesis 6.