Hepatic Disease Pharmacokinetics

Question 1

What lab value may indicate liver dysfunction?

Answer 1

ALT, AST

ALT is more specific to liver dysfunction

Question 2

What lab values may provide information to indicate the livers functional capacity?

Answer 2

albumin, bilirubin, INR

Question 3

How is hepatic drug clearance characterized and quantified?

Answer 3

1. hepatic blood flow (Q)
2. intrinsic clearance
3. fraction of drug unbound (fu)

alterations in these parameters can impact the clearance of the drug

Question 4

How does the extraction ratio (ER) relate to the liver?

Answer 4

ER refers to the efficiency of the liver to remove drug during one pass through the organ and provides a direct measurement of drug removal from the liver after oral administration

Question 5

What is liver cirrhosis?

Answer 5

degeneration of cells, inflammation, and irreversible fibrosis that leads to a conversion of normal liver structure to abnormal nodules

Question 6

What are the pathophysiologic and Clinical Manifestations of cirrhosis?

Answer 6

• capillarization of sinusoids
• reduced liver blood flow
• portal-systemic shunting
• hepatic encephalopathy
• reduction in intrinsic clearance
• altered expression of drug transporters and enzymes
• esophageal varices
• edema and/or ascites
• portal hypertension
• severe impairment of parenchymal function
• decreased plasma proteins

Question 7

What are the considerations of drug absorption in a patient with cirrhosis?

Answer 7

-increased gut wall permeability
-portosystemic shunting of blood from liver -> decreased hepatic blood flow
-decreased drug-metabolizing enzymes -> decreased intrinsic hepatic function

Question 8

What is the effect on the bioavaliability (F) of high ER drugs with patients with cirrhosis?

Answer 8

increased bioavaliability (F)

Question 9

What is the effect on the half-life (t1/2) of high ER drugs with patients with cirrhosis?

Answer 9

increased t1/2

Question 10

What is the effect on the area under the curve (AUC) of high ER drugs with patients with cirrhosis?

Answer 10

increased AUC

Question 11

How is the volume of distribution (Vd) affected by cirrhosis?

Answer 11

ascites is a common complication of cirrhosis which is when water accumulates in the peritonem= increase Vd of water soluble drugs

increased doses may be needed for water soluble drugs

Question 12

What drugs may require increased dosing in a patient with hepatic disease?

Answer 12

highly water soluble drugs

Question 13

What does the intrinsic hepatic clearance represent?

Answer 13

the ability of the liver to clear free/unbound drugs when there is no limitations on flow

Question 14

How may liver disease effect the metabolism of drugs?

Answer 14

impaired/reduced metabolism due to:
- a reduction of hepatocytes and/or the alteration of the function of remaining hepatocytes
- a reduction in drug uptake by drug transporters into hepatocytes

Question 15

Are phase I or phase II are more alterated by cirrhosis?

Answer 15

phase I CYP450 isoenzymes

Question 16

How does liver disease effect the excretion of compounds via biliary excretion?

Answer 16

there is a reduction in formation or secretion of bile into the duodenum will lead to a decrease in clearance of substances both endogenous and exogenous

Question 17

What other complication may arise in advanced liver disease?

Answer 17

impaired renal function, known as hepatorenal syndrome

Question 18

What kind of dosing adjustments can be made in hepatic disease?

Answer 18

• decrease the dose
• increase the interval
• combination of both

Question 19

What drug properties would cause increased oral bioavaliability in patients with hepatic disease?

Answer 19

high ER drugs

Question 20

What drug properties would cause reduced intrinsic clearance?

Answer 20

• drugs with low ER, high PB
• drugs with low ER, low PB

Question 21

What drug properties would cause reduced fu?

Answer 21

drugs with low ER, high PB