From the Guidelines
Medications such as valproic acid, carbamazepine, and certain antibiotics like fluoroquinolones can cause hyperammonemia by interfering with ammonia metabolism or increasing its production. Hyperammonemia is a serious condition that can result in moderate to severe neurological impairment and cerebral edema, and it is essential to identify the underlying cause, including medications that may be contributing to the condition 1. The urea cycle is responsible for removing ammonia from the body, and certain medications can inhibit enzymes in this cycle, leading to a build-up of ammonia. For example, valproic acid, an anticonvulsant medication, can inhibit the urea cycle, leading to hyperammonemia 1. Other medications, such as carbamazepine, can also impair ammonia elimination, increasing the risk of hyperammonemia. Some antibiotics, like fluoroquinolones, can also contribute to hyperammonemia by interfering with the urea cycle. Additionally, medications like asparaginase, used in chemotherapy, can increase ammonia production, while barbiturates and certain diuretics like acetazolamide can also elevate ammonia levels. It is crucial to monitor patients taking these medications for symptoms of hyperammonemia, such as confusion, lethargy, vomiting, and in severe cases, seizures or coma, and to adjust their medication regimen accordingly. Key medications that may cause hyperammonemia include:
- Valproic acid
- Carbamazepine
- Fluoroquinolones
- Asparaginase
- Barbiturates
- Acetazolamide
- Salicylates in high doses
- Glycine-containing solutions used during surgery. These medications can increase the risk of hyperammonemia, either by inhibiting the urea cycle, increasing ammonia production, or interfering with renal excretion of ammonia, highlighting the need for careful monitoring and management of patients taking these medications 1.
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 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 may cause hyperammonemia (elevated ammonia levels) are:
- Valproic acid
- Topiramate (when used concomitantly with valproic acid) 2
From the Research
Medications that May Cause Hyperammonemia
- Valproic acid: Studies have shown that valproic acid can cause hyperammonemia, even at therapeutic doses and serum levels 3, 4, 5, 6, 7.
Risk Factors for Hyperammonemia
- Higher dosages of valproic acid: Research has found that higher dosages of valproic acid are associated with an increased risk of hyperammonemia 7.
- Total drug load of concurrent antiseizure medications: A study found that a higher total drug load of concurrent antiseizure medications is an independent predictor of hyperammonemia 7.
- Use of topiramate: The use of topiramate has been identified as an independent risk factor for hyperammonemia in patients taking valproic acid therapy 7.
- Use of phenobarbital: Hyperammonemia was also associated with the use of phenobarbital in a study of epilepsy patients treated with valproic acid therapy 7.
Treatment and Management
- L-Carnitine supplementation: L-Carnitine supplementation has been shown to be beneficial in reducing ammonia levels and reversing hyperammonemia in patients taking valproic acid 4, 5, 6.
- Withdrawal of valproic acid: In some cases, withdrawal of valproic acid may be necessary to manage hyperammonemia 3.
- Monitoring of ammonia levels: It is essential to monitor ammonia levels in patients taking valproic acid, especially those with risk factors for hyperammonemia 3, 4, 7.