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 topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels.
Medications that caused elevated ammonia include:
- Valproic acid
- Concomitant administration of topiramate and valproic acid 1, 1, 1 The clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders.
From the Research
Valproic acid is the most common medication associated with elevated ammonia levels, and its use should be carefully monitored, especially in patients with underlying liver disease or those taking concomitant medications such as phenytoin or topiramate, as suggested by the most recent study 2.
Medications Causing Elevated Ammonia
Several medications can cause elevated ammonia levels in the blood, including:
- Valproic acid (Depakote), a common antiepileptic drug, which is one of the most frequent causes, particularly at higher doses or with long-term use 2
- Other anticonvulsants like phenytoin, phenobarbital, and carbamazepine, which can also increase ammonia levels 2
- Certain antibiotics including tetracyclines and fluoroquinolones, which may elevate ammonia
- Diuretics such as furosemide and thiazides, which can cause hyperammonemia by altering kidney function
- Chemotherapy drugs like 5-fluorouracil, asparaginase, and cytarabine, which are known to increase ammonia levels during treatment
- Multiple antipsychotics including haloperidol and risperidone, which have been implicated in ammonia elevation
Mechanism of Ammonia Elevation
Ammonia elevation occurs because these medications either:
- Interfere with the urea cycle (the body's main pathway for removing ammonia)
- Increase protein catabolism
- Alter gut bacteria that produce ammonia
Patient Susceptibility
Patients with underlying liver disease are particularly susceptible to medication-induced hyperammonemia, as they may have impaired ammonia clearance mechanisms 2.
Symptoms of Elevated Ammonia
Symptoms of elevated ammonia may include:
- Confusion
- Lethargy
- Vomiting
- In severe cases, coma
Management
If a medication is suspected of causing elevated ammonia, healthcare providers should consider:
- Dose reduction
- Medication substitution
- Monitoring ammonia levels, particularly in patients with underlying liver disease or those taking concomitant medications such as phenytoin or topiramate, as suggested by the most recent study 2.