Hepatic Disease

Question 1

List the different types of liver disease?

Answer 1

1. Alcoholic cirrhosis
2. Chronic infection (Hep B and C)
3. Least common Hep D and E
4. Primary biliary cirrhosis
5. A-1 antitrypsin deficiency
6. Drug induced hepatoxicity (DILI)

Question 2

What do hepatic disease alter?

Answer 2

1. ADME and PD responses (efficacy and safety)
2. Drug accumulation
3. Failure to form active or inactive metabolites
4. Increased F
5. Alterations in drug protein binding
6. Kidney function

Question 3

How does liver disease affect protein binding?

Answer 3

1. Affects the synthesis of albumin, globulins, and others
2. Affects unbound drug fraction and Vd

Question 4

What is a liver function test?

Answer 4

1. ONLY indicate that the liver has been damaged
2. Doesn’t assess the function of CYP450 or CLint by the liver

Question 5

What are types of phase 2 metabolism?

Answer 5

Glucoronide, sulfation, GSH

Question 6

How does liver disease affect phase 2 metabolism?

Answer 6

Depleted

Question 7

What happens when the drug is more potent than the metabolite of a hepatic impaired patient?

Answer 7

1. Increased toxicity and pharm activity
2. Parent drug concentration is higher

Question 8

What happens when the drug is less potent than the metabolite (prodrug) of a hepatic impaired patient?

Answer 8

1. Decreased pharm activity
2. Reduced production of more active metabolite

Question 9

What parameters are changed from hepatic disease?

Answer 9

Qh and CLint

Question 10

How is Qh affected by hepatic disease?

Answer 10

Fibrosis of liver tissues occurs -> intrahepatic or extrahepatic shunt, a cappilarization of sinusoids and a reduction in the number and in the activity of the hepatocytes -> may lead to decreased of drug extracted and eventually F will increase

Question 11

How can hepatic disease increase resistance in Qh?

Answer 11

Liver tissue damage and fibrosis -> hepatic CLint to decrease

Question 12

Why is it difficult to estimate CLh in disease states?

Answer 12

Complexity and stratification of the live enzyme systems

Question 13

Are there test to assess total liver function?

Answer 13

No

Question 14

What are some test to assess liver impairment?

Answer 14

1. Clinical lab tests detect damage but not function
2. Ability of the liver to eliminate following drugs
3. Endogenous substrates used for the evaluation of liver impairment

Question 15

What kind of chemicals test for liver impariment?

Answer 15

1. Antipyrine
2. Indocyanine green
3. Monoethylglycine-xylidide
4. Galactose

Question 16

What kind of endogenous substrates evaluate liver impairment?

Answer 16

Albumin, bilirubin, and prothrombin time

Question 17

What is the child-pugh classification score?

Answer 17

1. Widely used classification of hepatic function
2. Assess overall hepatic impairment: mild (5-6), moderate (7-9), severe (10-15)

Question 18

What are the clinical measures child-pugh scores employ?

Answer 18

1. Total bilirubin
2. Serum albumin
3. Prothrombin time
4. Ascites
5. Hepatic encephalopathy

Question 19

What are the dosing strategies for hepatic disease?

Answer 19

1. Based on remaining hepatic function
2. Impariment may not sufficiently alter PK of some drugs requiring adjustment

Question 20

What kind of drug that are less likely to need hepatic dosage adjustment?

Answer 20

1. Drugs that are only excreted renally
2. Drugs metabolized in liver by a small extent (<20%, low ER drugs) with wide therapeutic range, and modest impairment
3. Drugs and their active metabolites that are gaseous and eliminated by lungs

Question 21

How do you calculate appropriate dose if there’s no readily available measure of hepatic function?

Answer 21

1. Drugs that are dependent on enzymatic elimination are administered in half-life or less standard dose
2. Therapeutic response or plasma concentrations is monitored and based on which dosage is adjusted
3. Drugs with low fe values are more affected by a change in liver function due to hepatic disease.
4. Since low fe indicates high fm (as fm = 1 – fe)

Question 22

Which should High ER drugs be avoided?

Answer 22

1. Drug is dependent on blood flow
2. Oral doses of these drugs may need to be reduced to as low as one-tenth of the standard dose