Lecture 14; Pharmacodynamic principles and the time course of immediate drug effect

Question 1

What does the time course of drug action combine?

Answer 1

Pharmacokinetics and pharmacodynamics

Question 2

What are the three ways to think about time course effects?

Answer 2

1) Drug effects are immediately related to observed drug concentration (i.e plasma)
2) Drug effects are delayed in relation to observed drug concentration
3) Drug effects are determined by the cumulative action of the drug

Question 3

What are the main two pharmacokinetics properties?

Answer 3

Clearance and volume of distribution

Question 4

What are the main two pharmacodynamic properties?

Answer 4

Emac

EC50 or C50

Question 5

Describe the concentration and effect relationship of drugs in relation to the law of mass action:

Answer 5

Based on the law of mass action principle the binding of a drug to a receptor should follow a hyperbolic curve

It is assumed that the effect is directly proportional to the binding then C50 will be the same as Kd.

NB: Emax can never be directly observed. It is the asymptomatic effect of the drug at infinite concentration. Even 10 times the C50 only reaches 90% of Emax.

Question 6

What is Kd?

Answer 6

The Kd is the equilibrium binding constant

Question 7

On a log scale Conc . Effect scale what is seen between 20 and 80%? and why use a log scale?

Answer 7

Between 20-80% of Emax is approximately a straight line.

Log scale is used as can described a wide range of concentrations

Question 8

Describe the Emax model?

Answer 8

E = (Emax.Conc) / (C50 + Conc)

E = Drug effect
Conc = Conc. at the receptor
Emax = is the maximum drug effect
C50 = Is the conc. at 50% of Emax

Question 9

Explain the Emax model?

Answer 9

The Emax model is the most fundamental description of the concentration effect relationship.

All biological responses must reach a maximum and this is an important prediction of the Emax model

Question 10

Describe how C20, C50 and C80 all related:

Answer 10

C20 is 1/4 the concentration of C50

C80 is 4x the concentration of C50

I.e the Emax model predicts a 16x change in concentration between C20 and C80

Question 11

Describe the equation for the sigmoid Emax model:

Answer 11

E = Emax . Conc(Hill) / C50(Hill) + Conc(Hill)

E = Drug effect
Conc = Conc at the receptor
Hill = Hill determines steepness

Question 12

Describe how the Hill co-efficient changes the Emax model: (forming the sigmoid emax model)

Answer 12

Hill = 1, curve is same Emax model
Hill 1< = Steeper
Hill <1 = Shallower

I.e hill co-efficient is used to describe drugs where the relationship is steeper/or not that the Emax model

Question 13

What is theophylline used for?

Answer 13

Theophylline is used to treat severe asthma. It is a bronchodilator.

Theophylline can increase the peak flow rate and as an C50 of about 10mg/L.

Emax of theophylline is to increase peak flow by 100% above the baseline peak flow.

Question 14

What does the time course of immediate drug effects depend on?

Answer 14

Initial concentration

Pharmacokinetics of the drug

Question 15

Describe the concentration effect when 1x C50 is given:

Answer 15

C50 dose will only produce 50% Emax. At these lower concentrations the time course of effect is almost parallel to the time course of concentration?

Question 16

Describe the concentration effect when 10x C50 is given:

Answer 16

Concentration can fall by 50% but the effect only redues by 10% (ON A BOLUS) As concentration falls the effect disappears more quickly.

Question 17

Describe the concentration effect when 100x C50 is given:

Answer 17

100% Emax is achieved

The effect changes very little despite big changes in drug concentration. After 5 half lifes nearly all the initial dose will have been eliminated from the body the effect is still 70% of Emax.

i.e this shows how drugs which have short have lives can have big effects even if the dosing internal is many half lives.

Question 18

What is the implication of the 100x C50 dose and effect graph

Answer 18

i. e this shows how drugs which have short have lives can have big effects even if the dosing internal is many half lives.
i. e Beta blockers and ACE inhibitors

Question 19

What are the three regions of the timecourse of effect?

Answer 19

Flat (Conc>C80) (very little change in effect desp. big change in conc.)

Linear (C80>Conc>C20)

Exponential (Conc

Question 20

What is the principle of duration of response:

Answer 20

If the dose of a drug is doubled then the duration of response will increase by one half life

i.e The duration of response means that the drug effect is above a pre-defined critical value. e.g the time above EC50. A low dose (C50) the duration of a dose is around 20hrs (in this example) Doubling the dose will have a duration of 30hrs.

= The increase in duration of response from doubling the dose is independent of the size of effect that is chosen to mark the end of the response.

Question 21

What is the application of the of emax model? and a relevant equation

Answer 21

Prediction of the target concentration from the target effect

Conc = C50 . Effect / Emax-Effect

Question 22

What does selecting the dosing interval depend on?

Answer 22

Selection of an appropriate dosing interval depends on more than the half-life - the target concentration and its relation to C50 must be considered too.

i. e Half life of hours but effectively daily dosing
- > Beta blockers
- > Ace inhibitors
- > Prednisone

Question 23

Describe what happens to doubling the dose does:

Answer 23

• > Doubling the dose usually does NOT lead to doubling the effect
• > Doubling the dose WILL increase the duration of effect by 1 half-life