Therapeutic Drug Monitoring of Phenytoin in Clinical Practice
Summary
Phenytoin remains a mainstay in the management of seizure disorders but presents considerable challenges owing to its narrow therapeutic index, high protein binding and nonlinear pharmacokinetics. Therapeutic drug monitoring (TDM) of phenytoin is routinely employed to balance seizure control against the risk of toxicity, which can manifest as ataxia, cognitive impairment and cardiac arrhythmias. Measurement of total plasma concentration alone may misrepresent the pharmacologically active unbound fraction in patients with hypoalbuminaemia or altered protein binding. Direct assays for free phenytoin yield the most accurate guide to dose adjustment but require specialised laboratory resources. In many clinical settings, predictions based on the Sheiner–Tozer equation are used to adjust total phenytoin concentrations for serum albumin, improving the precision of therapeutic decisions. Emerging approaches include the use of informatics tools integrated into electronic health records to flag patients at risk of misclassification and novel assays employing mass spectrometry for rapid, multi-matrix analysis. Optimisation of phenytoin dosing through TDM is a global priority, with implications for intensive care, paediatric and resource-limited settings and for patients requiring extracorporeal support.
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Therapeutic Drug Monitoring of Phenytoin in Clinical Practice publication trend
The graph below shows the total number of articles in therapeutic drug monitoring of phenytoin in clinical practice across all publications each year (not limited to Nature Index journals).
Technical terms
Total phenytoin concentration: The combined amount of protein-bound and unbound drug in plasma.
Free phenytoin concentration: The portion of drug not bound to plasma proteins and pharmacologically active.
Therapeutic window: The plasma concentration range within which phenytoin is effective without undue toxicity.
Sheiner–Tozer equation: A formula used to adjust total phenytoin concentration for variations in serum albumin.
LC-MS/MS: Liquid chromatography–tandem mass spectrometry, an analytical technique for precise drug quantification.
Venoarterial ECMO: A form of extracorporeal membrane oxygenation providing cardiac and respiratory support.
Plasma exchange: A procedure that removes and replaces patient plasma to eliminate pathogenic substances.
References
- Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations. BMC Medical Informatics and Decision Making (2012).
- Development and Validation of an LC‐MS/MS Method and Comparison with a GC‐MS Method to Measure Phenytoin in Human Brain Dialysate, Blood, and Saliva. Journal of Analytical Methods in Chemistry (2018).
- Phenytoin Pharmacokinetics During Venoarterial Extracorporeal Membrane Oxygenation and Plasma Exchange. Cureus (2021).
- Therapeutic drug monitoring of phenytoin and valproic acid in critically ill patients at Windhoek Central Hospital, Namibia. African Journal of Laboratory Medicine (2022).
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