PHARMACOKINETIC ALTERATIONS AFTER SEVERE HEAD-INJURY - CLINICAL RELEVANCE

Pharmacological therapy, present and future, will undoubtedly continue to play a large role within the overall management of patients with s evere head injury. Nevertheless, limited clinical data are available t o evaluate the effect of severe head injury on pharmacokinetics. The d isruption of the blood-brain barrier secondary to trauma and/or subseq uent hyperosmolar therapy can be expected to result in higher than exp ected brain drug concentrations. Aggressive dietary protein supplement ation may result in increased oxidative drug metabolism These effects may counterbalance inhibitory influences on drug metabolism secondary to cytokine release during the acute phase response. Alterations in pr otein binding can also be anticipated with the hypoalbuminaemia and in creases in alpha(1)-acid glycoprotein typically observed in these pati ents. Based on studies in other patient populations, moderate hypother mia, a treatment strategy in patients with head injury, can decrease d rug metabolism. The pharmacokinetics of the following drugs in patient s with severe head injury have been studied: phenytoin, pentobarbital (pentobarbitone), thiopental (thiopentone), tirilazad, and the agents used as marker substrates, antipyrine, lorazepam and indocynanine gree n (ICG). Several studies have documented increases in metabolism over time with phenytoin, pentobarbital, thiopental, antipyrine and lorazep am. Increases in tirilazad clearance were also observed but attributed to concurrent phenytoin therapy. No changes in the pharmacokinetics o f ICG were apparent following head injury. With the frequent use of po tent inhibitors of drug metabolism (e.g. cimetidine, ciprofloxacin) th e potential for drug interaction is high in patients with severe head injury. Additional pharmacokinetic investigations are recommended to o ptimise pharmacological outcomes in patients with severe head injury.