PHARMACOKINETICS OF DRUGS USED IN CRITICALLY ILL ADULTS

Critically ill patients exhibit a range of organ dysfunctions and ofte n require treatment with a variety of drugs including sedatives, analg esics, neuromuscular blockers, antimicrobials, inotropes and gastric a cid suppressants. Understanding how organ dysfunction can alter the ph armacokinetics of drugs is a vital aspect of therapy in this patient g roup. Many drugs will need to br given intravenously because of gastro intestinal failure. For those occasions on which the oral route is pos sible, bioavailability may be altered by hypomotility, changes in gast rointestinal pH and enteral feeding. Hepatic and renal dysfunction are tile primary determinants of drug clearance, and hence of steady-stat e 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 decrea sed activity of the hepatic cytochrome P450 system in critically ill p atients. Renal failure is equally important with both filtration and s ecretion clearance mechanisms being required ed for the removal of par ent drugs and their active metabolites. Changes in the steady-state vo lume of distribution are often secondary to renal failure and may lowe r the effective drug concentrations in the body. Failure of the centra l nervous system, muscle, the endothelial system and endocrine system may also affect the pharmacokinetics of specific drugs. Time-dependenc y of alterations in pharmacokinetic parameters is well documented for some drugs. Understanding the underlying pathophysiology in the critic ally ill and applying pharmacokinetic principles in selection of drug and dose regimen is, therefore, crucial to optimising the pharmacodyna mic response and outcome.