Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

Drug Disposition > Clearance & Hepatic Elimination > Flashcards

Clearance & Hepatic Elimination Flashcards

(49 cards)

Start Studying
1
Q

Where can excretion of drugs occur?

A

renally, hepatic (biliary excretion), pulmonary

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Significance of clearance of drugs?

A

It is the primary pharmacokinetic parameter describing drug elimination

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is the concept of clearance?

A

parameter than relates the rate of drug elimination to its concentration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the definition of clearance?

A

The apparent volume of plasma (or blood, or plasma water) completely cleared of drug per unit of time

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

In what situation is clearance constant irrespective of dose?

A

If drug PK is linear

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

When may drug PK not be linear?

A

Situations where you get enzyme/transporter saturation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

How can you describe clearance?

A

By organ (hepatic, renal, pulmonary) and by site of measurement (plasma, blood, plasma water)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Why does clearance vary between drugs?

A
  • inefficient extraction through the elimination organ - only a fraction removed
  • additivity of clearance
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What assumption do you make when determining rate of elimination in an organ?

A

That there is a quick distribution equilibrium - all change in concentration when passing through the organ is due to elimination

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is the extraction ratio?

A

How much of the drug is removed from the blood when passing through an organ (value 0 - 1)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

How does extraction ratio relate to fraction escaping metabolism?

A

1-E = F for the given organ

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Examples of drugs with a low hepatic extraction ratio?

A

Diazepam, warfarin, tolbutamide, phenytoin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Examples of drugs with a medium hepatic extraction ratio?

A

Quinidine, codeine, cyclosporine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Examples of drugs with high hepatic extraction ratio?

A

Alprenolol, propranolol, verapamil, lidocaine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Typical blood flow to the liver?

A

1300-1500mL/min

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Typical blood flow to the kidney?

A

1100mL/min

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Typical cardiac output?

A

6000mL/min

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What is additivity of clearance?

A

liver and kidney are both major organs of elimination, so occurs in both and has a combined overall clearance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are the major routes of hepatic elimination?

A

Metabolism and biliary excretion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Why is the liver so highly perfused?

Study These Flashcards
A

Dual blood supply - hepatic artery and portal vein

21
Q

What does the portal vein supply to the liver?

Study These Flashcards
A

Brings venous blood from the GI tract

22
Q

What does the hepatic artery supply to the liver?

Study These Flashcards
A

Carries oxygenated blood to the liver

23
Q

What are the different fates for a drug molecule relating to hepatocytes?

Study These Flashcards
A
  • binding to blood cells or plasma proteins
  • active transport into hepatocytes
  • passive diffusion into or out of hepatocytes
  • metabolism (once inside hepatocyte)
  • biliary excretion (from hepatocyte)
24
Q

What factors influence hepatic clearance?

Study These Flashcards
A
  • Hepatic blood flow
  • Plasma protein binding
  • Enzyme activity
  • Disease status
  • Transporter activity - uptake or reflux
25
What types of drugs have clearance that is largely influenced by hepatic blood flow?
Those with a high excretion fraction (>0.7)
26
What types of drugs have clearance that is largely influenced by plasma protein binding?
Those with a low excretion fraction (<0.3)
27
What can increase hepatic blood flow?
Bed rest, thyrotoxicosis, isoprenaline
28
What can decrease hepatic blood flow?
Exercise, heart failure, propranolol
29
What can increase plasma protein binding (lower fu)?
alpha1-acid glycoprotein - stress, cancer, arthritis, Crohns, myocardial infarction albumin - myalgia
30
What can decrease plasma protein binding (higher fu)?
alpha1-acid glycoprotein - neonates, nephrosis albumin - heart failure, burns, pregnancy
31
What can increase enzyme activity to increase clearance?
enzyme induction - rifampicin (many enzymes) smoking (CYP1A2)
32
Relevance of CYP1A2 induction clinically?
clozapine is metabolised by Cyp1A2 so smoking increases metabolism - patients require higher dose. narrow therapeutic index
33
Which emzyme does smoking induce?
CYP1A2
34
What can reversibly decrease enzyme activity to reduce clearance?
Ketoconazole
35
What can irreversibly decrease enzyme activity to reduce clearance?
mibefradil
36
What other factors can influence emzyme activity and affect clearance?
Genetic polymorphism e.g. in CYP3A5 - affects metabolism of tacrolimus disease e.g. liver cirrhosis
37
General principles of liver cirrhosis?
- commonly caused by excessive alcohol, Heptatitis B and C - decreased liver volume and portal hypertension - generally reduced activity of metabolic enzymes (some enzymes affected more than others) - GFR often impaired in cirrhotic patients - generally irreversible and transplant is the only option once advanced
38
Effects of liver cirrhosis on drug elimination?
reduced clearance usually, can be very significant
39
Why can plasma protein binding of drugs change in liver cirrhosis?
impaired albumin synthesis - affect distribution and elimination
40
What determines whether changes need to be made to the dosage regimen of a drug in cirrhotic patients?
- relevance of hepatic elimination for the drug | - severity of the liver cirrhosis
41
Role of uptake transporters in hepatic clearance?
active uptake of drugs intothe hepatocyte - via e.g. OATP1B1 - often coupled with subsequent metabolism
42
Role of efflux transporters in hepatic clearance?
Exretion of drug or conjugates into the bile - e.g. excretion of rosuvastatin by BCRP - biliary excretion of glucuronnide metabolites
43
What can reduce efflux or uptake transporter action in hepatic clearance?
Genetic polymorphism or inhibition
44
What are the mechanical and structural requirements for biliary excretion?
- active facilitated transport (as it must be moved by transporters) - polar (e.g. glucuronide metabolites) - large mW >350
45
Average bile flow rate?
0.5-0.8mL/min
46
What is the enterohepatic circulation circuit?
- eliminated from liver into the bile - bile drains into small intestine (here it can be eliminated in faeces) - can get absorbed again into the superior mesenteric vein which feeds hepatic vein, and back to the liver
47
Physiologial purpose of enterohepatic circulation?
Recycle bile salts
48
Which drugs are susceptible to enterohepatic circulation?
``` Rosuvastatin Mycophenolic acid (via glucuronide) ```
49
What impact does enterohepatic circulation have on plasma concentrations over time?
Can cause spikes/fluctuations in plasma conc as it is removed into the bile then reabsorbed from the intestine

Drug Disposition (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions