Importance of the liver for pharmacology and toxicology

This chapter is not based on any specific Section from the 2017 CICM Primary Syllabus, but there are certainly plenty of questions in the papers which ask about the role of the liver in the metabolism of xenobiotics. Most of the questions in the CICM First Part exam that deal with this fall into two categories: the broad and generic, and the weirdly specific. Observe:

  • Question 15 from the second paper of 2019 (role in drug clearance)
  • Question 20 from the first paper of 2016 (role in drug clearance)
  • Question 5 from the first paper of 2014 (toxicology of paracetamol)
  • Question 5 from the second paper of 2012 (liver failure)
  • Question 12 from the second paper of 2011 (toxicology of paracetamol)
  • Question 1 from the first paper of 2008 (toxicology of paracetamol)

So, really, it's half paracetamol, and half vague "role" and "list the functions". 

Unfortunately, the liver's role is so far-reaching that it had to be scattered over multiple pages. The interested reader is directed to these other sections for more detail:

In order to avoid duplicating a lot of this content, while also wanting to have something here as a quick revision instrument, what follows is a brief summary of the various ways the liver is involved in drug metabolism, as well as what might happen if it fails (in keeping with what has been expected in some past CICM First Part Exam SAQs).

Role of the liver in drug clearance

The liver is conveniently placed to metabolise drugs. It is central to the enteric circulation, insofar as all of the splanchnic blood flow ends up being funnelled through it on the way to the systemic bloodstream. It also receives a rather generous systemic blood supply. It's rather safe to assume that any moleculse in the systemic circulation will eventually find its way to the liver one way or another. The degree to which they will be captured there is described as the hepatic extraction ratio, defined the fraction of the drug entering the liver in the blood which is irreversibly removed (extracted) during one pass of the blood through the liver.

To summarise: 

  • Hepatic extraction ratio is determined by the free (unbound) fraction of the drug and by the intrinsic clearance rate, which is the intrinsic ability of the liver to remove (metabolise) the drug in absence of restrictions imposed on drug delivery to the liver cell by blood flow or protein binding.
  • The effect of liver blood flow on hepatic clearance depends on the hepatic extraction ratio of the drug.
  • With increasing hepatic blood flow, hepatic extration ratio will decrease for all drugs.
  • For drugs with low intrinsic clearance:
    • Hepatic extraction ratio will drop more rapidly with increasing hepatic blood flow
    • Hepatic clearance will not increase significantly with increasing blood flow
  • For drugs with high intrinsic clearance:
    • Hepatic clearance will increase in a fairly linear fashion, in proportion to hepatic blood flow
    • Increasing the intrinsic clearance will have diminishing effect on total hepatic clearance 

First pass metabolism

First pass clearance is not only due to the effects of hepatic metabolism, but is a combination of metabolism by gut bacteria, metabolism by intestinal brush border enzymes, and metabolism in the portal blood. Still, metabolism by liver enzymes is a major part of first pass metabolism.

  • For drugs with low hepatic extraction ratio:
    • First pass clearance will be low
    • A change in liver enzyme activity will lead to a proportional change in first pass metabolism, which may not change the bioavailability by a clinically significant degree.
  • For drugs with high hepatic extraction ratio:
    • First pass clearance will be high
    • A small change in liver enzyme activity will lead to only a small change in first pass metabolism, but a large clinically significant change in bioavailability

Biotransformation reactions in the liver

By weirdly persistent convention, the metabolic effects of the liver on drugs are divided into Phase I and Phase II reactions. Supposedly Phase II conjugation reactions are always "deactivating" (i.e. resulting in a relatively inert and readily excreted metabolite) whereas Phase I reactions can either "activate" or "deactivate" a compound, potentially rendering it even more toxic

  • Examples of Phase I reactions:
    • Hydrolysis
    • Reduction
    • Oxidation.
  • Characteristics of Phase I reactions:
    • these reactions expose or introduce a functional group (–OH, –NH2, – SH or –COOH)
    • They usually result in a small increase in hydrophilicity.
  • Examples of Phase II reactions:
    • Glucouronidation
    • Sulfation
    • Acetylation
    • Methylation
    • Conjugation with glutathione
    • Conjugation with amino acids eg. taurine, glutamine, glycine
  • Characteristics of Phase II reactions:
    • The products are supposed to be significantly more hydrophilic than the original substrate

Effects of liver failure on the pharmacology of drugs

Question 5 from the second paper of 2012 asked the candidates to describe the ways in which liver failure affects pharmacology. The examiners' comments suggested to structure the answer using pharmacokinetics and pharmacodynamics as headings, but on closer inspection one might find this results in a clustering of most of the points under "pharmacokinetics" because that is where most of the effects would be. Instead, it may be better to separate it into synthetic, metabolic and secretory headings, and find somewhere to explain how portosystemic shunting influences drug clearance.

Morgan & McLean (1995) are probably the best specific reference for this topic.

  • 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)

References

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