Drug handling in hepatology

Question 1

Child Pugh score

Answer 1

Assess

• encephalopathy
• ascites
• bilirubin
• albumin
• INR

Question 2

Assessment of liver function

Answer 2

Albumin

Clotting screen - PT, INR

Bilirubin

Gamma- glutamyl transferase

Alkaline phosphatase

Transaminases

Question 3

INR, albumin and drug handling

Answer 3

Generally

• low albumin and/or high INR indicate reduced synthetic function
• significance will depend on the drug and is difficult to predict
• lower dose with close monitoring may be required

INR/PT
- dose adjustment if PT>130% normal

Albumin
- low albumin = low protein binding

Question 4

Bilirubin and drug handling

Answer 4

Drug absorption for highly lipophilic drugs- possible reduced absorption

Biliary clearance- possible reduced clearance

Competition for protein binding sites- potential to displace drug, enhancing clinical effect

Question 5

Transaminases and drug handling

Answer 5

Transaminase enzymes ? drug induced

Alkaline phosphatase and GGT

• certain drugs can cause cholestasis
• cholestasis may reduce drug absorption
• certain drugs (enzyme inducers) can cause elevations in GGT

Question 6

Hepatic disease

Answer 6

Increase of hepatic enzymes e.g. ALT and AST
- indicate liver damage

Decrease concentration of protein and albumin
- indicate a reduction in the synthetic capacity

None directly reflects the metabolic function of the liver

Question 7

Absorption (bioavailability)

Answer 7

Extent of drug absorption

Bioavailability of 20%
- means that an oral dose of 100mg would achieve an exposure equivalent to that of an IV dose of 20mg

Cholestasis

• decreased absorption
• may be less well absorbed in patient with cholestasis

Question 8

Changes in distribution: ascites

Answer 8

Increased distribution

Water soluble medicines may distribute into the ascetic fluid which may reduce concentrations e.g. gentamycin

Question 9

Changes in distribution: low albumin

Answer 9

Decreased distribution

Highly protein bound medicines may be affected by low albumin

Hypoalbuminaemia will result in higher ‘free’ concentrations of highly protein bound drugs

Question 10

Changes in distribution: raised bilirubin

Answer 10

Decreased distribution

Highly protein bound medicines may be affected by raised bilirubin levels

Bilirubin can dispalce highly protein bound drugs from their binding sites, increase ‘free’ concentrations of these drugs

e.g. phenytoin

Question 11

Elimination

Answer 11

Drugs cleared principally by renal excretion
- kidney function determines the efficacy of elimination

Drugs that are mainly cleared by hepatic metabolism

• liver blood flow
• access to hepatic enzymes
• enzyme factors

Question 12

Metabolism in hepatic elimination phase 1

Answer 12

Functionalisation reactions

• converted into more hydrophilic compounds
• three main types: hydrolysis, oxidation and reduction
• involve CP450 system

Question 13

Metabolism in hepatic elimination phase 2

Answer 13

Conjugation reactions

• usually the true detoxification pathway
• involve conjugation: glucuronidation, acetylation