Drugs In Liver Disease

11.5.07

Liver disease
• Common.
-ALD >20,000 deaths per annum.
• May need treatment.
-For liver disease and complications.
-For concomitant conditions.
• Liver is major site of drug metabolism.
-Can have major effects on drug handling.

Functions of the liver
• Processing digested foods from the intestine.
• Controlling levels of fats, amino acids and glucose.

Clinical signs of liver disease
• Jaundice.
• Ascites.

Drug handling in the body and effect of liver and kidney disease
Lipophilic drugs Hydrophilic drugs
↓ ↓
Liver Kidneys
Phase I metabolism Excretory processes
Phase II metabolism
Phase III metabolism
↓
Reduced hepatic clearance Reduced renal clearance

How are drugs metabolised?
• Phase I (oxidation, reduction, hydrolysis).
-Small chemical changes.
-FUNCTIONALISE molecule for phase II.
• Phase II (glucoronidation, sulphation, acetylation, amino acid conjugation, glutathione conjugation).
-Conjugation reactions.
-Increased water solubility.
-Increased excretion.

Functionalisation
• Addition of reactive group.
• Unmasking of reactive group.

Conjugation
• Addition of large group.
• Often charged.

Phase III: membrane transporters.
P-glycoprotein: an efflux transporter.

Effect of liver disease on drug disposition
• Severity of liver disease.
-Enormous reserve in liver.
-Affected in severe disease.
• Enzymes responsible.
-Phase II affected less than Phase I.
• Type of liver disease.
-Cholestasis (increases in alkaline phosphatase and GGT) - transporters.
-Acute hepatic inflammation (increase in transaminases) - p450 enzymes.

Effect of pharmacokinetic changes on drug effects
Liver disease
↓
Pharmacokinetic changes
↓
Clinical effect of drug
↓
Increased No change Reduced

Other effects of liver disease
• Changes in drug absorption.
-Changes in gut motility.
-Delay in gastric emptying and orocaecal transit.
• Changes in protein binding.
-Hypoproteinaemia.
-Affects drugs with high protein binding.
• Changes in liver blood flow.
-May be decreased/bypass liver.
-Increased bioavailability of certain drugs.
• Changes in renal excretion.
-Affected in severe liver impairment.
-Etc.

Effect of pharmacodynamics changes in liver disease
Liver disease
↓
Pharmacodynamic effects
↓
Exaggerated response Reduced response Increased toxicity
↑ ↑ ↑
Sedation with Decreased diuresis with Nephrotoxicity
benzodiazepines loop diuretics with aminoglycosides

Use of potentially hepatotoxic drugs
• Not an increased risk of further liver damage when administered hepatotoxic drugs.
• Decreased hepatic reserve therefore, more severe clinical consequences of any damage.
• Judicious use.

Using drugs in liver disease
• Careful clinical assessment always important.
• Questions to ask:
-How serious is the condition, and what if the treatment was withheld?
-What drug treatments are available?
-Are efficacies of different treatments equivalent?
-What are the adverse effects of different treatments?
-Is the drug metabolised by the liver?
-Is the drug potentially hepatotoxic?

Simple rules in liver disease
• Determine whether dose needs to be decreased (see appendix in BNF).
• Start at low doses and increase dose slowly, depending on response and adverse effects.
• Carefully monitor patients and review regularly.
• Avoid interacting drugs.
• Provide information for patients.
• Contact in case of problems.
• Consider drugs in differential diagnosis if new symptoms.

Practice points
• Liver disease affects both pharmacokinetics and pharmacodynamics parameters, both of which increase risk of drug toxicity.
• Doses of lipophilic drugs should be decreased, particularly for those with narrow therapeutic index.
• First-pass metabolism of drugs with high hepatic extraction decreased, necessitating decrease in dose of oral formulations.
• Choose hydrophilic drug over lipophilic compound when available.