Question 5

College Answer

Good answers were structured using pharmacokinetic and pharmacodynamics headings.  They included some mention of changes in absorption, volume of distribution (an increase in Vd in liver failure), altered protein binding, altered metabolism and thus change in clearance, and changes in excretion (decreased biliary excretion of drugs). In respect to pharmacodynamics candidates could have mentioned increased sensitivity and prolonged action of sedative drugs, oral anticoagulants, etc. Good candidates also differentiated for acute (often hepatocellular dysfunction) and chronic liver failure (cirrhosis and changes in liver blood flow). Common problems were not using a logical structure to answer the question and stating an effect but not describing how this affected pharmacology. For example stating decreased albumin production but then not stating the consequence of this on drug distribution. Primary examination questions may often require candidates to integrate knowledge from across different sections of the syllabus or apply basic physiological or pharmacological principles.

Discussion

Morgan & McLean (1995) are probably the best specific reference for this answer. The college examiners were generous with their explanations, making it easier to reconstruct a model answer. 

• The effects of changes in metabolic function:
  • Decreased clearance of drugs which depend on hepatic metabolism
  • Thus, longer half-lives for these drugs
• The effects of changes in synthetic function
  • The liver synthesises plasma proteins; plasma protein binding influences the volume of distribution
  • Low plasma protein levels lead to raised free drug levels (the free fraction increases)
  • This process is therefore synergistic with the concurrent decrease in liver blood flow and hepatic extraction ratio
  • The liver synthesises plasma esterases and peptidases; these metabolise certain drugs
  • Significant liver disease can result in prolonged clearance of drugs which are susceptible to these enzymes (eg. suxamethonium)
• The effect of changes in secretory function
  • Drugs and metabolites which rely on biliary excretion will be retained, and may require dose adjustment
  • Drugs which enjoy enterohepatic recirculation may have decreased halflives due to failure of recirculation
  • High bilirubin levels may result in the displacement of drugs from albumin as it competes for binding sites 
  • Decreased secretion of bile may result in malabsorption of drugs 
• The effects of portal hypertension on pharmacokinetics
  • Portal venous hypertension leads to shunting of portal venous blood into the systemic circulation
  • This has the effect of decreasing first pass metabolism
• Effects of liver failure on pharmacodynamics
  • Increased sensitivity to sedatives due to the loss of blood brain barrier integrity and baseline encephalopathy
  • Increased sensitivity to drugs which target hepatic storage or synthesis (eg. anticoagulants that interfere with vitamin K metabolism)
  • Decreased sensitivity to drugs which rely on proteins synthesised by the liver to exert their effect, eg. reduced effects of heparin in the absence of sufficient antithrombin-III
  • Decreased sensitivity to furosemide (mainly because of reduced albumin  binding on which its delivery to the tubule is dependent)
  • Decreased sensitivity to β-blockers because of downregulation of receptors (due to chronic sympathetic activation in cirrhosis)

Morgan, Denis J., and Allan J. McLean. "Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease." Clinical pharmacokinetics 29.5 (1995): 370-391.