Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

The Medicine Y3 Semester 1 - Drug disposition > Clearance and hepatic elimination > Flashcards

Clearance and hepatic elimination Flashcards

1
Q

What is elimination?

A

irreversible removal or loss of a drug from the body

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

What is metabolism?

A
  • Major sites are liver and intestine
  • Is still a dominant mechanism of drug elimination (may be coupled with transporters)
  • Involves enzymatic conversion of a drug to metabolites
  • Metabolites are more polar and hydrophilic than the parent drug and are renally excreted
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is excretion?

A
  • Elimination of unchanged drug or its metabolites from the body
  • Occurs mostly in the kidney
  • Occurs also at other sites
  • -> Liver (biliary excretion)
  • -> Lungs (pulmonary)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the primary pharmacokinetic parameter describing drug elimination?

A

Clearance

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

Concept of clearance:

A

CLEARANCE is the parameter that relates rate of drug elimination to its plasma concentration:

CL = Rate of Elimination / C plasma

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

Clearance as a PK parameter:

A

CL is the apparent volume of plasma (or blood) completely cleared of drug per unit of time L/h or L/min

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

Rate of elimination =

A

CL·C = CLb·Cb = CLu·Cu plasma* blood plasma water

  • Value of clearance depends on the site of measurement
  • Clearance is CONSTANT irrespective of the dose, if the drug PK is LINEAR
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Description of clearance.

By Organ:

A

Hepatic –> CLH
Renal –> CL
Pulmonary –> CLpulm

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Description of clearance.

By Site of Measurement:

A

Plasma–> CL
Blood –> CLb
Plasma water (unbound) –> CLu

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

Elimination rate constant:

A

k (min-1), defined as fractional rate of drug loss:

k = Rate of elimination/amount = CL x c / V x c = CL/v

CL = K x v

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

What is t1/2?

A

t1/2 - time taken for the plasma concentration to fall by half, once distribution equilibrium has been achieved

t1/2 = ln2/K

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

PK parameters relevant for dosage regimen design:

A

Loading dose = V Css

Maintenance dose
F D/t = CL Css

t - dosing interval
Css – steady-state concentrations

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

Why do CL values vary among the drugs?

A
  1. Inefficient extraction through the elimination organ (e.g., liver) - only a fraction removed passing through the organ
  2. Additivity of clearance
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Extraction ratio:

A

CLb = Q x E

E 0–> 1

EH – hepatic extraction ratio

1- EH = FH - Fraction escaping hepatic metabolism

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

Typical blood flow values:

A

Liver - 1300-1500 ml/min
Kidney - 1100 ml/min
Cardiac output - 6000ml/min

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

First-pass metabolism:

A
  • Loss of a drug as it passes through intestine and liver during absorption (presystemic metabolism)

F = Fa FG FH
= Fa (1- EG) (1- EH)

Fa – fraction absorbed
FG – fraction escaping intestinal metabolism
FH - fraction escaping hepatic metabolism

17
Q

Clearance may be a composite of the contribution of different organs:

A
  • Clearance can be additive – liver and kidney
    –> when eliminating organs are arranged in parallel
    Not applicable when organs are in series (liver – lungs)

CL x C = CLR x C + CLH x C

18
Q

Hepatic elimination and liver blood supply:

A

Major routes of hepatic elimination:

  1. Metabolism
  2. Biliary excretion

Highly perfused organ!

19
Q

Dual blood supply:

A
  • Portal vein (1.1 L/min) – brings venous blood from the GI tract
  • Hepatic artery (0.4 L/min) - carries oxygenated blood to the liver
20
Q

Factors influencing hepatic clearance:

A
  1. Hepatic blood flow
  2. Plasma protein binding
  3. Enzyme activity
  4. Disease status
  5. Transporter activity – uptake or efflux
21
Q

Hepatic blood flow and hepatic clearance:

A

Affects only drugs with high EH (>0.7)

  • Increase QH - bed rest, thyrotoxicosis, isoprenaline
  • Decreased QH – exercise, heart failure, propranolol
22
Q

Factors influencing hepatic clearance:

A
  • Enzyme activity (CLint)
  • Increased Enzyme induction –> rifampicin, smoking (clozapine)
  • Decreased enzyme inhibition –> reversible (e.g., ketoconazole) or irreversible (e.g., mibefradil)
  • Decreased genetic polymorphism - CYP3A53/3 (tacrolimus)
  • Liver cirrhosis
23
Q

What is liver cirrhosis

A
  • Commonly caused by excessive alcohol intake, Hepatitis B and C
  • Decreased liver volume in liver cirrhosis and portal hypertension
  • Generally reduced activity of metabolic enzymes
  • Renal function (GFR) often impaired in patients with liver cirrhosis
  • Generally irreversible, in advanced stages liver transplant is the only option
24
Q

Impact of liver cirrhosis on drug elimination:

A
  • Hepatic clearance of many drugs significantly reduced in liver cirrhosis!
  • Plasma protein binding of drugs may change
  • Modifications of the dosage regimens depends on
  • Relevance of hepatic elimination for a drug
  • Severity of liver cirrhosis
25
Q

Role of uptake and efflux transporters in hepatic clearance:

A

A. Active uptake of drugs into the hepatocyte (e.g., via OATP1B1)*
- often coupled with subsequent metabolism

B. Efflux - excretion of drug or drug conjugates into the bile

  • e.g. excretion of rosuvastatin by BCRP
  • biliary excretion of glucuronide metabolites
  • Decreased transporter activity - inhibition or genetic polymorphism*
26
Q

Biliary excretion:

A
  1. Mechanism and structural requirements
    a. Active facilitated transport
    b. Polar; MW > 350
  2. Biliary clearance
    CLbile = bile flow x drug conc in bile/ Drug conc in plasma
27
Q

Enterohepatic circulation:

A

Liver –> Common bile duct –> Small intestine –> Superior mesenteric vein –> Portal vein –> Liver

28
Q

Factors influencing hepatic clearance – summary

A
  1. Hepatic blood flow – affects drugs with high EH
  2. Plasma protein binding – affects drugs with low EH
    e. g., decreased albumin in pregnancy - results in increased fu
  3. Enzyme activity – inhibition or induction
    - Increased Enzyme induction - Decreased Enzyme inhibition - Decreased Genetic polymorphism of some metabolic enzymes
  4. Liver cirrhosis - CL is generally decreased
  5. Transporter activity
    - Decreased Inhibition of uptake transporters or genetic polymorphism (OATP1B1)

The Medicine Y3 Semester 1 - Drug disposition (14 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions