GP 15 - Clinical Pharmacokinetics 1

Question 1

List and define the three most important pharmacokinetic parameters.

Answer 1

• Volume of distribution - a measure of the apparent space in the body available to contain the drug. Specifically, it is the volume that would be required to contain all of the drug in the body at the sam concentration as it is in the blood.
• Clearance - a measure of the body’s ability to eliminate the drug
• Bioavailability - the fraction of drug absorbed into the system circulation

Question 2

Give the volume of distribution equation.

Answer 2

Question 3

What kinds of drugs have high and low Vd?

Answer 3

• Drugs that are completely retained within the vascular compartment have a minimum Vd equal to the vascular compartment
• Drugs that have much higher concentrations in the extravascular tissues than in the vascular compartment(i.e. - they distrubute easily) have a very high Vd

Question 4

What factors are the Vd of a drug dependent upon?

Answer 4

How that drug is absorbed, distributed, and eliminated

The patient’s body volume

Question 5

What is an α phase and a ß phase?

Answer 5

When a dose of a drug is injected IV and the plasma [drug] is plotted vs time, the plot usualy shows two phases.

• An initial rapid fall which is the drug distributing into the tissues, this segment is called the distribution phase or α phase
• A slower, more gradual fall to zero which is the drug being eliminated from the body, this segment is called the elimination phase or ß phase

Refer to image

Question 6

How is the C₀ of a drug determined?

Answer 6

The plasma [drug] vs time plot of the drug given IV is linearized by instead plotting the log plasma [drug] vs time. The extrapolation of the elimination line (ß phase) to the y axis then yields the C₀. This can then be used to find Vd

Question 7

What is the primary use of Vd?

Answer 7

It allows us to determine the loading dose that should be used to quickly achieve a desired target plasma concentration.

Dose = Vd*TC

TC - target plasma [drug]

Question 8

What is clearance? Give the equation for it.

Answer 8

Clearance is the volume of blood cleared of drug per unit time.

Refer to image for equation

Question 9

In pharmacokinetics, what does the term “first order kinetics” refer to.

Answer 9

For most drugs, CL correlates directly with the plasma [drug]. This called first order elimination or first order kinetics

Question 10

Use the rate of elimination equation to describe why most drugs follow first order kinetics

Answer 10

The dependence of the rate of drug elimination on plasma [drug} is:

• Rate of Elimination = (V_max*C)/(K_m+C), K_m is C at 1/2 V_max

For the majority of drugs, the therapeutic plasma [drug] is well below the K_m so equation simplifies to:

• Rate of Elimination - V_max*C/K_m

Since V_max and K_m are constants for a particular drug, rate of elimination is directly related to C and clearance is:

• CL = V_max/K_m

Question 11

What is the variable k_e? How is it found? What equations utilize it?

Answer 11

k_e is the elimination rate constant of a drug. It is the slope of the elimination (β) phase of the log plasma [drug] vs time graph of a drug. It represent the fraction of drug eliminated per unit time (e.g. - a k_e of 0.25h^-1 means 25% of the drug is eliminated per hour). It can also be determined if the drugs CL & Vd are known or if its half-life is known:

• k_e = CL/Vd and k_e = 0.693/t_1/2

It can be used to determine plasma [drug] after a certain period of time:

• C_t = C₀e^-k_et

Question 12

How is drug half-life determined if only Vd and CL are known?

Answer 12

t_1/2 = (0.693*V_d)/CL

Question 13

How does the half-life of a drug change as its plasma concentration increases or decreases?

Answer 13

If the drug is eliminated by first-order kinetics, its half-life is constant no matter its plasma concentration

Question 14

What is C_ss?

Answer 14

During a continuous IV infusion, eventually the plasma [drug] will reach steady state. This concentration value is referred to as the C_ss for a drug at a given infusion rate.

Question 15

T/F - the rate of IV infusion is what determines the time it takes to reach C_ss

Answer 15

False
Half-life is what determines time to C_ss

Question 16

During constant IV infusion, how does plasma [drug] change over time?

Answer 16

Every half-life, the plasma [drug] increases 50% of the difference between C_ss and the current C

Question 17

During constant IV infusion, after how much time is it assumed that C_ss has been reached?

Answer 17

4 half-lives

Question 18

How does increasing or decreasing the infusion rate affect the C_ss and the time it takes to reach the C_ss?

Answer 18

Doubling the infusion rate doubles the C_ss

It has no affect on the time to C_ss

Question 19

How do the following affect Vd, CL, and t_1/2:

• Obesity
• Pathologic fluid
• Ageing
• CYP induction
• CYP inhibition
• Cardiac failure
• Liver failure
• Renal failure

Answer 19

• Obesity - increases V_d and t_1/2, no affect on CL
• Pathologic fluid - increases V_d and t_1/2, no affect on CL
• Ageing, CYP inhibition, Cardiac/Liver/Renal Failure - decreases CL, increases t_1/2, no affect on V_d
• CYP induction - increases CL, decreases t_1/2, no affect on V_d

Question 20

What do we need to know about saturation kinetics?

Answer 20

When drug concentrations exceed K_m, they no longer follow first order kinetics, instead they follow zero order kinetics. This means that their rate of elimination is constant no matter how high the plasma [drug] gets. However, since CL is rate of elimination/C, CL is not constant.

CL = V_max/(K_m + C)

Drugs that follow this are: aspirin (at high doses), ethanol, and phenytoin