Clearance

Question 1

What is clearance? What is it expressed as?

Answer 1

◦ Volume of plasma which contains the total amount of drug that is removed from the body in unit time
- Expressed as volume per unit time

Question 2

What is clearance values usually used for? What is renal clearance?

Answer 2

• Clearance can assess the excretory capacity of an organ (kidney)

• Renal clearance (Clrenal): the volume of plama containing the amount of drug that is
removed from the body by the kidneys in unit time

Question 3

What is the formula for total body clearance?

Answer 3

• total clearance = sum of hepatic + renal + other

Question 4

What are the most important types of clearance? What is the overall clearance of a body called? What is the definition?

Answer 4

Usually renal and hepatic clearance are the most important • The overall clearance of a drug or total body clearance (CLtotal ) is the sum
of clearance rates for each mechanism involved in eliminating the drug

Question 5

What is clearance used to determine? What does it not determine?

Answer 5

• Determines rate of drug elimination.
• proportionality factor To determine the rate of drug elimination
Clearance does not describe the amount of drug being eliminated.
• Clearance is high, rate of elimination will be high as well.
• Clearance is volume of blood that is clear.

Question 6

What is the rate of drug elimination? What is the formula?

Answer 6

Rate of drug elimination is the amount of drug being eliminated per unit time
Rate of drug elimination: Cp x CL total

Question 7

How can overall clearance be determined after a single IV bolus? What is the formula?

Answer 7

The overall clearance CL total
can also be estimated by measuring plasma concentrations at intervals following a single intravenous bolus dose (Q mg

Formula attached:

Explainations for formula:

Where AUC 0 −∞
is the area under the full curve relating Cp to time following a bolus
dose given at time t = 0 • AUC 0 −∞ provides an integrated measure of tissue exposure to the drug in units of
time multiplied by drug concentration

Question 8

How can overall clearance be determined after a CRI? What is the formula?

Answer 8

Drug clearance can also be determined in an individual subject by measuring the plasma concentration of the drug ( mg/L) at intervals during a constant-rate intravenous infusion (X mg of drug per hour)
Formula attached:

Formula explaination: Where Css is the plama drug concentration at steady state

Question 9

What happens to the plasma drug concentration over time in each of these scenarios?

CRI administration?

Single Bolus dose?

Answer 9

During a constant intravenous infusion at rate X mg/h, the plasma concentration increases from zero to a steady-state value (C
ss
); when the infusion is stopped, C declines to zero.
Following an intravenous bolus dose (Q mg), the plasma concentration rises abruptly and then declines towards zero.

Concentration declines exponentially.

Question 10

What is the elimination half life?

Answer 10

Elimination T½ refers to the disapearance of drug from plasma
• Is clinically relevant and the most often reported pharmacokinetic parameter
• It is defined as the time necessary for plasma or blood concentrations to decline by 50%

Question 11

Fill in the blank:

The more ______ a drug is cleared by an organ, the shorter
the drug half-life

• The longer the half-life, the ______ the drug will_____ in the
body

Answer 11

The more rapidly a drug is cleared by an organ, the shorter
the drug half-life

• The longer the half-life, the longer the drug will persist in the
body

Question 12

How many half lives must occur for 97 % of the drug to be eliminated?

Answer 12

For example, at one drug half-life, 50% of the dose has been
eliminated; after five T ½s (half-lives) 97% of the drug has
been eliminated

Question 13

If Vd is low plasma concentration is ________

Answer 13

If Vd is low plasma concentration is high.

Question 14

What will affect a half life? How does that affect the duration of the drug?

Answer 14

• Any factor that changes VD of a drug will affect its half life
• An increases of Vd can increase the half-life and extend the duration of action of the drug

Question 15

What does elimination half life, and dosing interval help practicioners determine?

Answer 15

• Elimination half-life along with the dosing interval also determines the amount of drug that accumulates with each dose as steady-state equilibrium is reached

Question 16

What 2 things should be considered when determining an appropriate dosing interval?

Answer 16

• Along with the therapeutic range, the half-life should be the basis for an appropiate dosing interval

Question 17

What situations will increase a drugs half life?

Answer 17

◦ Decreased renal or hepatic blood flow: Hemorrhage, heart failure, cardiogenic shock
◦ Decreased renal function
◦ Decreased metabolism: Another drug inhibits its biotransformation, hepatic insufficiency

Question 18

What situations will decrease a drugs half life?

Answer 18

◦ Increased hepatic blood flow
◦ Decreased protein binding - if drug is bound to proteins its not being metabolized. So decreased binding = more rapid elimination.
◦ Increased metabolism
• anything changing volume of distribution

Question 19

What is first order elimination?

Answer 19

First order elimination: A constant fraction is eliminated per unit time. 50% of drug per hour. The half-life (T½) of a drug will be constant regardless of drug concentration

• volume cleared per unit of time by an organ is independent of PDC.
  • The same volume of blood will be irreversibly cleared of drug by an organ regardless of how much drug is in the blood

This is that there is an constant

Question 20

What happens if elimination mechanism becomes saturated?

Answer 20

If elimination mechanisms become saturated, elimination
becomes zero-order

Question 21

What is zero order of elimination?

Answer 21

Less common
• Occurs only if so much drug is present in the blood that the organ of clearance becomes
saturated

• There is limited amount of enzyme and too much of the drug

• The rate of elimination of a drug from the plasma is constant regardless of the plasma
concentration of the drug
• The half-live is not meaningful. It is not constant and varies with the amount of the drug
concentration

Question 22

What is an example of first order elimination? Why is half life important in these scenarios?

Answer 22

Assume a dog has ingested several aspirin to the point that the plasma drug concentration has surpassed the therapeutic range of 100 to 500 mg/mL and has achieved the toxic concentration of 2000 mg/mL. The half-life of aspirin in the dog is about 9 hours

First order: First-order elimination results in a concentration of 1000 mg/mL by 9 hours and 500 mg/mL at 18 hours. By 18 hours, the drug is back into the therapeutic range and by 36 hours, it approximates the low therapeutic range.

1st order -> half life is important because it is constant. Not so much in zero order.

Question 23

What is an example of zero order elimination?

Answer 23

Assume a dog has ingested several aspirin to the point that the plasma drug concentration has surpassed the therapeutic range of 100 to 500 mg/mL and has achieved the toxic concentration of 2000 mg/mL. The half-life of aspirin in the dog is about 9 hours

For zero-order elimination a constant amount is eliminated per unit time. For example, if 100 mg/mL of aspirin is eliminated every 9 hours. By the time 36 hours has passed, concentrations will have declined to only 1600 mg/ml

Question 24

In zero order, how does plasma concentration effect rate of elimination?

Answer 24

Zero order Rate of elimination will always be constant regardless of the plasma concentration/ dose.
Whether you have 1200 mg or 30,000 mg it will always decrease by a certain amount. Unlike 1st order which will decrease by 50% concentration each half-life.

Question 25

Drug eliminated slowly _______ require more frequent dosing.

Answer 25

Drug eliminated slowly does not require more frequent dosing.

Question 26

Why is Pharmacokinetics important?

Answer 26

• To interpret drug concentration • To adjust dose regimens rationally • To identify evaluate possible drug interactions • To individualise the dose regimen in particular when dealing with a
severely ill patient

Question 27

What is pharmokenetics?

Answer 27

Pharmacokinetics provides a framework for understanding what happens to a drug when given to an animal or human, where it goes in the body, and how quickly, that enables one to understand the effects that it produces
• What happens to a drug, where it goes, and how quickly. This will help us understand the effect it produces.

Question 28

How are plasma concentrations used in clinical practice? What is the individual patient approach known as>

Answer 28

• Clinics focus on concentration of drug in plasma. Plasma concentrations are used to individualize dosages
• To achieve the desired therapeutic effect while minimizing adverse effects in each individual patient- an approach known as therapeutic drug monitoring, TDM

Question 29

What does the pk model help to do?

Answer 29

• PK model used to product behavior of drug in the body
◦ Generally given as single dose, samples collected for 3 elimination half lives, to monitor drug movement.
◦ Bioavailability studies -> drug given iv and compared to administration by route of interprets

Question 30

What is the single compartment model?

Answer 30

The body is considered as consisting of a single homogenous compartment.
That is, the entire dose X of drug is assumend to move out of the body at a single rate
• This model is applicable if the plasma concentration falls exponentially after
drug administration • This is a useful way to illustrate some basic principles but is clearly a
phisiological oversimplification
• The characteristics of different part of the body, such as brain, body fat,
and muscle, are quite different in terms of their blood supply

Question 31

What is the two compartment model?

Answer 31

◦ Introduces peripheral model to represent tissues/ in communication with central plasma compartment
◦ More realistic
◦ Used a lot
◦ Drugs can enter/ leave peripheral compartment via central compartment.
◦ Distribution rate is constant out of central compartment
◦ Redistribution rate constant from peripheral back into central compartment.

Question 32

What is the multicompartment model? What is the goal of this model?

Answer 32

Multicompartment model: generally used when experiments are conducted over long time frames.
• goal is to describe the tissue residue of drug in food producing animal

Question 33

What is pharmacokenetics?

Answer 33

• Pharmacokinetics: study of 4 key physiologic processes that govern the time course of drug fate in body. What the body does to drugs
◦ ADME