Influence of critical illness on pharmacokinetics

Question 5 from the first paper of 2011 asked the candidates to discuss the effects of critical illness on drug absorption and drug clearance. In brief, in can say that critical illness delays or impairs absorption, and delyas or impairs clearance. With deeper probing, one can also remember that changes in serum protein levels and pH which accompany critical illness may result weird protein binding and compartment trapping effects. As far as literature sources go, Boucher's 2006 article ("Pharmacokinetic changes in critical illness") is going to be enough for most people. The various factors which influence pharmacokinetics in the ICU are discussed to a much greater depth in the Pharmacokinetics section dedicated to the CICM Primary Exam. For instance, the chapter on bioavailability and bioequivalence has a massive table listing all the various ways in which shock influences bioavailability of drugs. A more detailed and specific discussion of pharmacokinetics in critical illness is also available. For the purposes of rapid revision before the Part II exam, this chapter offers only a short point-form summary: 

Effect of critical illness on  drug absorption:

• Delayed absorption:
  • poor stomach emptying rate
  • slowed gut transit time
  • altered pH of the stomach
  • decreased blood flow to the gut
  • decreased venous fow from the gut
  • intestinal wall oedema
• Impaired absorption:
  • Increased gut transit due to diarrhoea or prokinetics
  • Poor gut function due to bacterial overgrowth or ischaemia
  • Brush border loss due to ischaemia
  • Continuous feeds instead of intermittent meals results in poor absorption of drugs like thyroxine

Effects of critical illness on drug clearance:

• decreased spontaneous degradation
  • hypothermia
• decreased tissue metabolism
  • decreased tissue blood flow
  • hypothermia
• decreased plasma metabolism
  • due to poor hepatic synthetic function, many serum enzymes responsible for drug removal are not synthetised in appropriate quantities
• decreased metabolism in the liver
  • decreased hepatic blood flow
  • cytokine-induced decrease in hepatic metabolism
  • hepatic injury
  • hypothermia leading to diminished enzyme function
  • hepatic enzyme inhibition by other drugs
• increased metabolism in the liver
  • pyrexia leading to increased metabolic rate
  • enzyme activation by other drugs
• decreased clearance in the urine
  • decreased renal blood flow
  • decreased glomerular filtration rate
  • poor tubular function, decreased active transport
  • acute renal injury eg. ATN
• decreased clearance in the bile
  • biliary stasis
  • decreased gut transit leading to recirculation
• increased clearance due to decreased protein binding
  • thus, increased free fraction, which is exposed to clearance mechanisms