Hepatic Disease Flashcards
List the different types of liver disease?
- Alcoholic cirrhosis
- Chronic infection (Hep B and C)
- Least common Hep D and E
- Primary biliary cirrhosis
- A-1 antitrypsin deficiency
- Drug induced hepatoxicity (DILI)
What do hepatic disease alter?
- ADME and PD responses (efficacy and safety)
- Drug accumulation
- Failure to form active or inactive metabolites
- Increased F
- Alterations in drug protein binding
- Kidney function
How does liver disease affect protein binding?
- Affects the synthesis of albumin, globulins, and others
- Affects unbound drug fraction and Vd
What is a liver function test?
- ONLY indicate that the liver has been damaged
- Doesn’t assess the function of CYP450 or CLint by the liver
What are types of phase 2 metabolism?
Glucoronide, sulfation, GSH
How does liver disease affect phase 2 metabolism?
Depleted
What happens when the drug is more potent than the metabolite of a hepatic impaired patient?
- Increased toxicity and pharm activity
- Parent drug concentration is higher
What happens when the drug is less potent than the metabolite (prodrug) of a hepatic impaired patient?
- Decreased pharm activity
- Reduced production of more active metabolite
What parameters are changed from hepatic disease?
Qh and CLint
How is Qh affected by hepatic disease?
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
How can hepatic disease increase resistance in Qh?
Liver tissue damage and fibrosis -> hepatic CLint to decrease
Why is it difficult to estimate CLh in disease states?
Complexity and stratification of the live enzyme systems
Are there test to assess total liver function?
No
What are some test to assess liver impairment?
- Clinical lab tests detect damage but not function
- Ability of the liver to eliminate following drugs
- Endogenous substrates used for the evaluation of liver impairment
What kind of chemicals test for liver impariment?
- Antipyrine
- Indocyanine green
- Monoethylglycine-xylidide
- Galactose
What kind of endogenous substrates evaluate liver impairment?
Albumin, bilirubin, and prothrombin time
What is the child-pugh classification score?
- Widely used classification of hepatic function
- Assess overall hepatic impairment: mild (5-6), moderate (7-9), severe (10-15)
What are the clinical measures child-pugh scores employ?
- Total bilirubin
- Serum albumin
- Prothrombin time
- Ascites
- Hepatic encephalopathy
What are the dosing strategies for hepatic disease?
- Based on remaining hepatic function
- Impariment may not sufficiently alter PK of some drugs requiring adjustment
What kind of drug that are less likely to need hepatic dosage adjustment?
- Drugs that are only excreted renally
- Drugs metabolized in liver by a small extent (<20%, low ER drugs) with wide therapeutic range, and modest impairment
- Drugs and their active metabolites that are gaseous and eliminated by lungs
How do you calculate appropriate dose if there’s no readily available measure of hepatic function?
- Drugs that are dependent on enzymatic elimination are administered in half-life or less standard dose
- Therapeutic response or plasma concentrations is monitored and based on which dosage is adjusted
- Drugs with low fe values are more affected by a change in liver function due to hepatic disease.
- Since low fe indicates high fm (as fm = 1 – fe)
Which should High ER drugs be avoided?
- Drug is dependent on blood flow
- Oral doses of these drugs may need to be reduced to as low as one-tenth of the standard dose
