Pharmacokinetics of drugs used in critically ill adults

Critically ill patients exhibit a range of organ dysfunctions and often require treatment with a variety of drugs including sedatives, analgesics, neuromuscular blockers, antimicrobials, inotropes and gastric acid suppressants. Understanding how organ dysfunction can alter the pharmacokinetics of drugs is a vital aspect of therapy in this patient group. Many drugs will need to be given intravenously because of gastrointestinal failure. For those occasions on which the oral route is possible, bioavailability may be altered by hypomotility, changes in gastrointestinal pH and enteral feeding. Hepatic and renal dysfunction are the primary determinants of drug clearance, and hence of steady-state drug concentrations, and of efficacy and toxicity in the individual patient. Oxidative metabolism is the main clearance mechanism for many drugs and there is increasing recognition of the importance of decreased activity of the hepatic cytochrome P450 system in critically ill patients. Renal failure is equally important with both filtration and secretion clearance mechanisms being required for the removal of parent drugs and their active metabolites. Changes in the steady-state volume of distribution are often secondary to renal failure and may lower the effective drug concentrations in the body. Failure of the central nervous system, muscle, the endothelial system and endocrine system may also affect the pharmacokinetics of specific drugs. Time-dependency of alterations in pharmacokinetic parameters is well documented for some drugs. Understanding the underlying pathophysiology in the critically ill and applying pharmacokinetic principles in selection of drug and dose regimen is, therefore, crucial to optimising the pharmacodynamic response and outcome.