Hepatic Insufficiency on Drug Clearance

Question 1

What pharmacokinetic changes come with liver disease?

Answer 1

• Bioavailability
• Protein binding and therefore distribution
• Hepatic drug clearance

Question 2

What are the two types of drug clearance in the liver?

Answer 2

Flow depedent clearance and enzyme dependent clearance

Question 3

Describe what is meant by flow dependent clearance?

Answer 3

Clearance from the liver is so rapid that it is effectively dependent on the rate of blood flow through the liver.

Hepatic clearance of >800mL/min

Question 4

If a drug has high first pass hepatic clearance, does it have high or low bioavailability?

Answer 4

Low oral bioavailability.

Question 5

How does chronic liver disease impact flow dependent drug clearance?

Give examples of drugs that are affected

Answer 5

Chronic liver disease results in damage to blood vessels, causing shunting and obstruction.

This causes drugs in portal/arterial blood to bypass hepatocytes:

• Increased bioavailability
• Decreased clearance

Examples: Beta-blockers, calcium channel blockers, opiates, lignocaine

Question 6

Define enzyme dependent drug clearance.

Answer 6

<300mL.min celarance, limited due to hepatic enzyme activity being capped out.

Enzyme dependent clearance is open to enzyme induction or inhibition of CYP450.

Question 7

What are some examples of drugs that undergo enzyme-dependent clearance.

Answer 7

• Warfarin
• NSAIDs
• Benzodiazepines

Question 8

Do hepatic function tests give a good indicators of the impact of hepatic disease on drug clearance?

Answer 8

No. Effect on drugs depends on the degree of hepatic damage, which is not always predictable from hepatic function tests.

Question 9

What causes hypoalbuminaemia, and how does it impact drug clearance?

Answer 9

Liver failure results in decreased production of albumin.

Decreased albumin means that there is a smaller fraction of drugs in the blood bound by albumin, and more float free to cause effect.

Decreased albumin also results in increased extravascular water vol and decreased intravascular water vol - this alters the distribution volume for highly water-soluble drugs.

Vdist is increased for water soluble drugs, decreasing clearance and thus prolongs the effect of the drug.

Question 10

Give two examples of drug impacted by altered volume of distribution in hypoalbuminaemia and the toxic effects they can cause.

Answer 10

Aminoglycoside - renal damage and deafness

Methotrexate - bone marrow toxicity

Question 11

How can liver disease increase the effect of anticoagulants?

Answer 11

Liver disease causes decreased clotting factor synthesis.

This increases the effectiveness of drugs such as warfarin, heparin and dabigatrin.

Question 12

How can liver disesae increase sensitivity to sedatives?

Answer 12

It just does lol

Examples: Benzodiazepines, opiates

Question 13

How can liver disease impact the effect of diuretics?

Answer 13

Liver disease decreases plasma albumin and plasma osmotic pressure, causing increased tissue fluid and decreased plasma volume.

This causes decreased renal flow

Through the renin-angiotensin system, decreased JGA flow = renin released = increases angiotensin II = increases aldosterone = Na+ and H2O retention and K+ loss

Therefore, we should avoid K+ depleting diuretics as this + liver disease = profound K+ loss.

Question 14

What is the solution to using diuretics in a patient with liver disease?

Answer 14

Use an aldosterone antagonist - spironolactone: A K+ sparing diuretic.