College Answer

a) Outline the effect of critical illness on enteral drug absorption

•    Multiple   factors   may  alter  gastrointestinal   mucosal   absorption   including   mucosal oedema, disordered gastrointestinal motility and disordered mucosal blood flow
•    Gastric  emptying  / gut motility  affected  by drugs  (opioids.  Anticholinergics,  antacids, inotropes), enteral nutrition, brain or spinal injury, diabetes
•    Incomplete oral medication disintegration or dissolution
•    Changes in pH
 

b) List the reasons for altered drug clearance in the critically ill.

Liver function
Reduced clearance
With hepatic dysfunction present in more than half the critically ill patients, drug clearance may be reduced because of :
a.   Lower hepatic blood flow
b.   Decreased hepatocellular enzyme activity c.   Lower bile flow
d.   Administration of other drugs competing for enzymes
Increased clearance
Hepatic enzyme induction by certain drugs may increase clearance of others

Renal function
Reduced clearance
Compromised  kidney function  may be secondary  to reduced  perfusion,  intrinsic  damage secondary to ischaemia or drug toxicity and immunologic injury
A decrease in GFR would increase the half-life of medications that are renally cleared and may result in drug or metabolite accumulation
Increased clearance
Increased cardiac output in early sepsis increases GFR and increased drug clearance Burns, use of diuretics and hypertonic saline also result in increased GFR and potentially increase clearance

Protein binding changes
Three major proteins affecting drug protein binding – albumin, alpha 1 acid glycoprotein and lipoproteins
Reduced clearance
Some proteins (eg alpha 1-acid glycoprotein binding morphine) are increased in critically ill resulting in reduced clearance
Increased clearance
Albumin is reduced so there will be a higher concentration of free drug for drugs normally bound to albumin resulting in increased clearance
Protein  binding  affected  by other  factors  including  accumulation  of endogenous  binding
inhibitors, qualitative changes on binding sites, competition for binding by other substances, pH changes

Discussion

a) in short, critical illness decreases drug absorption by the following mechanisms:

• poor stomach emptying rate
• poorer gut transit time
• altered pH of the stomach
• decreased blood flow to the gut
• decreased venous fow from the gut
• intestinal wall oedema

b) critical illness may reduce drug clearance by the following mechanisms:

• 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 portein binding
  • thus, increased free fraction, which is exposed to clearance mechanisms