Question 13

College Answer

Most candidates answered the question under the subheadings absorption, distribution,
metabolism and elimination. However, they didn’t give any details of the direction or 
mechanism of change, often used vague statements without specifically addressing the 
question and failed to give examples. The impact of the shock state on different kinetic 
parameters including absorption from skin, tissue, muscles, enteral absorption and 
inhalational was often overlooked. Similarly, the consequences of changes in volume of 
distribution, protein binding (e.g. albumin and globulin, ionisation) was poorly understood
as was alteration in liver and kidney function. Although this topic is very broad candidates 
were asked to only outline the details of this topic

Discussion

This question is very similar to Question 5 from the first Fellowship paper of 2011. An attempt is made to answer the question and incorporate all the comments made by the college. Some mechanisms are listed, their pharmacokinetic effects are briefly outlined, and an example is offered. As the official college textbooks are useless for this topic, one should read Roberts and Hall (2013) to prepare for this question. It's paywalled, but because of the high quality of this article it would not be unreasonable for the time-poor candidate to resort to prostitution or piracy. 

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.