Therapeutic Drug Monitoring of Phenytoin Rationale and Current Status

Abstract

The rationale fo r measuring serum drug concentrations as a guide to therapy is based on 2 assumptions: that there is a direct relationshi p between the drug concentra tion in serum and the concentration of the free drug at the receptor site. and that this de term ines the therapeutic effect (Koch-Weser 1975). This has evolved to the curre nt target concentra tion st rategy (Sheiner & Tozer 1978: Spector et a1. 1988) in which dosage adjustments are made to bring patients' serum drug concen trations into t he ta rge t or "therapeutic' ra nge. Concentrations below or above this range are considered to be ei ther ·subtherapeutic' or ·toxic'. respectively. Recently. Spector et a1. (1988) have questioned the val ue of routine therapeutic drug monitoring in generaL citing the aminoglycosides and digoxin as specific exam ples.It has been argued that therapeutic drug monito ri ng of phenytoin is panicularly justifiable because of its narrow therapeutic range and saturable eli minat ion kinetics (Morrow & Richens 1989: Perrucca & Richens 198I a). The clinical pharmacoki netics of phenytoi n are well known. and have been reviewed b y o t hers (Mani n et a1. 1977: Richens 1979: Winter & Tozer 1986). During the past 10 yea rs. therapeutic d rug monitoring of phenytoin has become rout ine i n the management of patients with epilepsy_ The therapeutic range is generally considered t o be 40 to 80 ~mol / L. and many clinicians employ the target concent ration strategy to individualise their patients· dosages. This anicle crit ically examines the basis fo r therapeutic mon ito ring of phenytoin and the appropriateness of the target concentration strategy. It considers the pharmacokinet ic methods available for the individualisation of phenytoin dosage and, in panicular. the potential advan tagt!s of Bayesian forecasting. It also exam ines the stat us o f the debate whether free or tOlal phenytoin concentration should be monitored. Finally, the authors consider the evidence for the cli nical utility of therapeutic monitori ng of phenytoin. and the need fo r fut ure research.

Differences between the Measured and Calculated Free Serum Phenytoin Concentrations in Epileptic Patients

“…Total concentration is easily measured, and then free concentration is predicted using that value. The therapeutic range of the free phenytoin serum concentration is about 10% of that of the total phenytoin serum concentration and varies from 3.3 to 9.6 µmol/L (0.83 - 2.27 mg/L) 7,8. Only a few specialized laboratories offer to analyze the free phenytoin concentration because it is a more expensive and time-consuming test.…”

“…The concentration of albumin in serum is decreased with inflammation, chronic liver disease, or malnutrition. The presence of hypoalbuminemia is known to reduce the protein binding of phenytoin in plasma,8,10 and both the ratio of free/total phenytoin concentration and the total phenytoin concentration may be altered. Therefore, it is difficult to accurately estimate the free phenytoin concentration from the total concentration.…”

Diphenytoin, riluzole and lidocaine: Three sodium channel blockers, with different mechanisms of action, decrease hippocampal epileptiform activity

“…We analyzed changes in interburst interval, burst length, and CA3 burst synchronization. In general, DPH has been identified as a prototypic, sodium channel, anticonvulsant compound and has been used clinically for partial and generalized seizures (Griffith and Taylor, 1988a; Johannessen, 2002; Korn et al, 1987; Levine and Chang, 1990; Oliver et al, 1977; Schneiderman and Evans, 1986; Schneiderman and Schwartzkroin, 1982). RLZ has been shown to block the persistent sodium current (I NaP ; Cheah et al, 2010; Harvey et al, 2006; Miles et al, 2005; Theiss et al, 2007; Urbani and Belluzzi, 2000) whereas, LIDO has demonstrated the ability to inhibit voltage-gated sodium channels during abnormal membrane depolarization (Ragsdale et al, 1996).…”

Selected pharmacokinetic issues of the use of antiepileptic drugs and parenteral nutrition in critically ill patients

“…[103,104]; patients with uraemia [105]; drug-drug interactions; displacement of the drug from its plasma protein binding by another drug [106,107]; and patients with chronic liver disease [108]. …”