Drug Response Variability: Critical Illness

Master answer

Absorption

• IV
  • Unchanged
• Oral
  • If GI inflammation → increased GI absorption (aminoglycosides)
  • Concomittant drug administration may inhibit intestinal transporters (amiodarone inhibits p-glycoprotein) or hepatic enzymes (valproate inhibits P450 enzymes) à Variable effect on bioavailability
  • If hepatic failure (i.e. ischaemic hepatopathy) → Decreased hepatic first pass effect → Increased oral bioavailability (aspirin)
  • Decreased splanchnic bloodflow (due to vasopressor agents, shock) → Decreased drug absorption → Decreased bioavailability
• IM/Subcut
  • Decreased peripheral blood flow due to shock, vasopressors → Delayed absorption (IM suxamethonium will delay onset)

Distribution

• Protein binding → albumin decreases as an acute phase reactant → Increased free drug fraction of protein bound drugs (propofol)
• pKa
  • Acids are ionized when pH >pKa, bases ionized when pH < pKa → acid base disturbances will alter drug ionization → permeability through cell membranes (Na channel blockers are less effective in acid environments)
• Volume of distribution
  • Renal failure, hepatic failure, heart failure + overzealous fluid resuscitation → increased total body water → Increased volume of distribution of drugs distributed to extracellular compartment

Metabolism

• Hepatic phase I (zone III) susceptible to ischaemia
  • Decreased phase I metabolism in shock (fentanyl metabolized by CYP450 3A4)
  • More global reduction of hepatic function in global hepatic failure
• Butylcholinesterase produced by liver → decreased levels in hepatic failure → decreased metabolism (suxamethonium → more drug delivery to NMJ)

Excretion

• Renal
  • Shock → decreased renal perfusion pressure (although renal blood flow may actually increase in distributive shock) → decreased glomerular filtration of drugs → Decreased clearance
  • Decreased plasma protein will promote glomerular filtration and filtration of free drug
  • Acute tubular necrosis → decreased tubular secretion of drugs → Decreased clearance
• Biliary
  • Hepatic failure → decreased biliary secretion

Mooney 2016

Answer by Mooney