Question 1

College Answer

The effects of critical illness on the physiological factors that influence drug pharmacokinetics was used to analyse the candidates understanding of this core pharmacological principle. Better responses were able to identify the key elements perturbed by critical illness as well as outlining outline the potential cause and effect on the specific PK aspect being discussed. Stronger answers also included specific drug examples. The failure to utilise a structure (absorption, distribution, metabolism, and elimination) with very superficial detail and limited examples limited marks and was common in poorly scoring answers.

Discussion

This question is identical to Question 13 from the first paper of 2013. The college comments in 2013 were a bit less vague. Apart from examples and ADME structure, it appears they were also looking for a direction of change, which they did not mention this time. 

Absorption

• Delayed gastric empying = decreased drug absorption (paracetamol)
• Gastric pH is higher = decreased drug absorption (clopidogrel)
• Increased GIT permeability = increased drug absorption (electrolyte replacement)
• Decreased mesenteric perfusion = decreased drug absorption (paracetamol)
• Increased preabsorptive interactions = decreased drug absorption (NG feeds and phenytoin)
• Decreased active efflux = increased drug absorption (tacrolimus)
• Decreased skin/muscle perfusion tissue = decreased absorption from subcutaneous or intramuscular injectoins (heparin) 

Distribution

• Decreased protein = increased free drug levels of highly protein-bound drugs (phenytoin)
• Altered protein binding due to changes in pH = altered free drug levels (calcium)
• Increased volume of distribution = decreased clearance of drugs, decreased plasma concentration (aminoglycosides)
• Microvascular haemodynamic dysfunction = decreased tissue penetration (piperacillin)
• Impaired barrier functions = increased tissue penetration (benzylpenicillin into the CNS)

Metabolism

• Decreased hepatic blood flow = decreased clearance of high extraction ratio drugs (propofol)
• Hypothermia = decreased hepatic clearance (midazolam)
• Hyperthermia = increased clearance due to increased enzyme activity (suxamethonium)
• Downregulation of hepatic enzymes = decreased clearance (theophylline)
• Decreased hepatic syntheic function = decreased levels of soluble enzymes, decreased clearance of drugs in the plasma (suxamethonium)

Elimination

• Decreased renal blood flow and function = decreased clearance of unchanged drugs or metabolytes (everything! pick any example)
• Increased glomerular filtration in hyperdynamic circulatory states = increased clearance of drugs (vancomycin)

Boucher, Bradley A., G. Christopher Wood, and Joseph M. Swanson. "Pharmacokinetic changes in critical illness." Critical care clinics 22.2 (2006): 255-271.

Roberts, Derek J., and Richard I. Hall. "Drug absorption, distribution, metabolism and excretion considerations in critically ill adults." Expert opinion on drug metabolism & toxicology 9.9 (2013): 1067-1084.

Smith, Brian S., et al. "Introduction to drug pharmacokinetics in the critically ill patient." CHEST Journal 141.5 (2012): 1327-1336.