From the Guidelines
Dialysis can be effective in treating phenytoin neurotoxicity despite its high protein binding, as it removes the free (unbound) fraction of the drug, which can be increased in toxicity due to saturation of protein binding sites and conditions like uremia, hypoalbuminemia, and acidosis. The effectiveness of dialysis in removing phenytoin is not directly addressed in the provided study [ 1 ], which focuses on the use of extracorporeal treatment for poisoning with beta-adrenergic antagonists. However, the principle that dialysis removes the free fraction of a drug applies broadly. In the context of phenytoin toxicity, the free fraction of the drug is what contributes to its neurotoxic effects, and dialysis can help reduce this fraction by removing the free drug from the blood, thereby allowing bound drug to dissociate from proteins and be removed as well.
Key factors influencing the effectiveness of dialysis in phenytoin toxicity include the saturation of protein binding sites, the presence of conditions that decrease protein binding such as uremia, hypoalbuminemia, and acidosis, and the use of high-flux dialysis modalities. The study [ 1 ] discusses the importance of considering the dialyzability of drugs based on their pharmacokinetic properties, including protein binding and endogenous clearance, which is relevant when assessing the potential benefit of dialysis in drug toxicity.
In clinical practice, the decision to use dialysis in phenytoin neurotoxicity should be based on the severity of the toxicity, the presence of conditions that alter phenytoin protein binding, and the availability of dialysis facilities. High-flux hemodialysis and hemoperfusion are considered effective modalities for removing phenytoin, especially in severe cases where supportive care alone is insufficient to manage toxicity. It's crucial to monitor patients closely during dialysis, as the procedure can have significant effects on drug levels and patient outcomes.
The provided study [ 1 ] emphasizes the importance of considering the specific pharmacokinetic properties of each drug when evaluating the potential benefit of extracorporeal treatments, which is a principle that applies to the management of phenytoin toxicity as well. By understanding how dialysis can effectively remove the free fraction of phenytoin and how this can impact overall drug levels and toxicity, clinicians can make informed decisions about the use of dialysis in managing severe phenytoin neurotoxicity.
From the Research
Effectiveness of Dialysis in Treating Phenytoin Neurotoxicity
- Despite phenytoin being highly bound to protein, dialysis can be effective in treating neurotoxicity due to several factors 2, 3, 4, 5.
- Studies have shown that extracorporeal treatments, such as hemodialysis and hemoperfusion, can reduce phenytoin levels and improve clinical outcomes in cases of severe overdose 2, 6, 3, 4.
- The effectiveness of dialysis in removing phenytoin is thought to be due to the ability of activated charcoal to dissociate bound phenytoin from plasma proteins, allowing it to be adsorbed and removed 5.
- The EXTRIP Workgroup has recommended the use of extracorporeal treatment in select cases of severe phenytoin poisoning, including cases with prolonged coma or incapacitating ataxia 3.
Mechanism of Phenytoin Removal
- Phenytoin is highly bound to albumin, but the binding constant is relatively small, allowing for dissociation and adsorption to activated charcoal 5.
- Hemoperfusion with activated charcoal has been shown to be effective in removing phenytoin, even in cases where protein binding is significant 4, 5.
- The use of high-flux hemodialysis in combination with hemoperfusion has also been shown to be effective in reducing phenytoin levels and improving clinical outcomes 4.
Clinical Applications
- Extracorporeal treatments, such as hemodialysis and hemoperfusion, should be considered in cases of severe phenytoin overdose, particularly in cases with prolonged coma or incapacitating ataxia 3.
- Early and frequent charcoal hemoperfusion may be beneficial in cases of phenytoin toxicity, as it can help to reduce phenytoin levels and improve clinical outcomes 6.