Div: Outline alterations to drug response due to critical illness

Absorption

PO

Delayed Absorption

  • Delayed gastric emptying/ileus
    • Multifactorial drugs, Sx
    • ↓gut blood flow
    • Intestinal wall oedema

Impaired Absorption

  • Accelerated transit time 2° diarrhoea/drugs
  • Bacterial overgrowth
  • Brush border loss 2° ischaemia
  • ↓gut SA 2° ischaemia/Sx

Impaired 1st Pass Metabolism

  • ↓1st pass = ↑OBA

IM/SC

  • Unreliable
    • ↓peripheral perfusion
    • Delayed absorption i.e. IM SUXAMETHONIUM

Inhaled

  • ↓FRC, ↓V/Q MATCHING
    • Commonly, drugs which affect PVR given via inhaled route in critically ill → direct delivery to effect site

Distribution

PPB

  • ↓[protein] = ↑free drug (should be matched by ↑clearance, but not if concurrent renal F)

Vd

  • Usually ↑due to fluid overload
  • May ↓with hypervolaemic shock
  • Significantly affecting loading dose, esp. for RSI i.e. PPF

Metabolism

Hepatic Metabolism

  • ↑ = ↓t ½
    • Fever → ↑metabolic rate
    • Enzyme induction by other drugs
  • ↓ = ↑t ½
    • ↓hepatic BF
    • Hepatic injury
    • Hypothermia → ↓metabolic rate

Plasma Esterases

  • ↓plasma esterases =↓metabolism sux, remifentanil

Hoffman Degradation

  • ↓with hypothermia

Tissue Metabolism

  • ↓2° ↓tissue BF

Elimination

Renal Clearance

  • ↓renal clearance
    • ↓RBF
    • ↓GFR
    • ↓ nephrons
    • ↓active & passive transport
    • ATN

NB: some ↑ clearance → young, multi-trauma

Biliary Clearance

  • ↓biliary clearance
    • Biliary stasis
    • ↓gut transit & recirculation

Dynamics

  • CVS – susceptible to cardiotoxicity; altered circulation time → delayed onset
  • Renal – susceptible to impairment due to dehydration & ↓RBF
  • Nervous system – susceptible to CNS toxicity due to encephalopathy
  • Haem – susceptible to anticoagulation due to sepsis DIC, extracorporeal circuits