MCBoM Intervention in Homoeostasis, Element 5

Drug-Receptor Interactions: Pharmacology Tutorial 1 (Feb 2014)

The purpose of this tutorial is to help you with quantitative aspects of drug receptor interactions
and help ensure that you understand the basic principles, including:

- affinity
- efficacy
- potency
- receptor reserve/partial agonists
- drug antagonism/ inverse agonism
- the differences between a receptor and an enzyme for drug action

If you need further information on the topic, before the tutorials, please consult MCBoM Course
Materials section on Blackboard, or see Rang & Dales Pharmacology.



1. What do you understand by the terms potency and efficacy of a drug? How could you
compare the potencies of a number of drugs which produce qualitatively the same
pharmacological effect?








2. A radiolabelled drug, at a concentration of 2 x 10
-8
M is found to occupy 40% of the total
receptor population. What is the K
D
of the drug? If the drug concentration was doubled,
what would be its occupancy? Under what conditions would this estimate be reliable?











Potency relates to the amount of drug that is needed to produce a particular response.
The potencies of a number of drugs could be tested by plotting a graph and see at what concentrations
the drugs produced a response. The higher the drug concentration, the lower the potency of the drug.
P = [D]/([D] + KD)
KD = [D]/P - [D]
KD = [2x10^-8]/0.4 - 2x10^-8
KD = 3x10^-8
If the drug concentration was doubled:
[D] = 4x10^-8
P = (4x10^-8)/(4x10^-8 + 3x10^-8)
P = 4/7 = 0.57 ->57%
Under what conditions is this reliable?
- Equlibrium is reached
- Drug concentration at receptors is the same
as that applied to system
- 1 drug molecule combines with one receptor
molecule
- A negligible amount of the drug added is
bound
- Binding of one drug molecule does not
influence the binding of another
(no cooperativity)
P = occupancy
3. An agonist produces a maximum response by occupying 15% of the total receptors
present. What is the receptor reserve? What proportion of receptors would have to be lost
in order to observe a decrease in maximum response?








4. In the above example, if 80% of the total receptor population was inactivated, how would
this be reflected in the dose-response curve?








5. In a tissue, an agonist was found to have a K
D
of 1 x 10
-8
M, while the EC
50
was 1 x 10
-9
M.
What percentage of the binding sites are occupied when the drug concentration added is
1 x 10
-9
M? Why should the K
D
and EC
50
be different?








6. When an agonist was tested in the presence of a single concentration of antagonist A, a
dose ratio of 10 was obtained. The same concentration of drug B gave a dose ratio of 100.
What can you conclude from this? If the concentration of A was 1 x 10
-8
M, what is its K
B

(K
D
for antagonist)? Will the K
B
for antagonist B be greater or smaller than that for A?













Receptor reserve = 100 - 15 = 85%
Therefore, more than 85% of receptors would have to be lost in order to observe a decrease in maximum
response
More drug would be needed to produce the same response, so there would be a rightward shift
of the curve
Dose ratio, r, (the ratio by which the agonist concentration has to be increased in the presence of
the antagonist in order to restore a given level of response)
-> Drug B is a stronger antagonist than Drug A (ten times), as more agonist is needed for drug B to
restore a given level of response
Gaddum-Schild Equation:
[A] =1x10^-8 M
Dose ratio = 1 + [B]/Kb
10 = 1 + (1x10^-8)/Kb
Kb = 1 + (1x10^-8)/Dose ratio
Kb = 1 + (1x10^-8)/10 = 1
P = [D]/([D] + KD)
P = (1x10^-9)/(1x10^-9 + 1x10^-8)
P = 0.0909 = 9.1%
EC50 does not equal KD
The Kb for antagonist B should me smaller, as
it is stronger than antagonist A.
7. Concentrations of an antagonist of respectively 1 x 10
-8
M, 1 x 10
-7
M and 1 x 10
-6
M, in the
presence of a range of concentrations of agonist, gave dose ratios of 10.5, 100 and 1100.
Determine the K
B
of the antagonist. How can you tell that this is a competitive antagonist?








8. What is meant by constitutive activity when applied to a receptor. How has this
discovery modified our perception of drug-receptor interactions? How might you identify
whether a drug was acting as an antagonist or an inverse agonist, when the receptor is
being activated by an agonist?






1. 10.5 = 1 + (1x10^-8)/KB
Kb = 1 + (1x10^-8)/10.5 = 1.000000000952381
2. Kb = 1 + (1x10^-8)/100 = 1.0000000001
3. Kb = 1 + (1x10^-8)/1100 = 1.0000000000090909
The Kb of the antagonist = 1
Constitutive activity =
A receptor which is capable of producing its biological response in the absence of a bound ligand is said
to display "constitutive activity".The constitutive activity of a receptor may be blocked by an inverse agonist.
- this can be blocked by inverse agonist (blocks the constitutive receptor, i.e. switching of the receptor
between being active and inactive without a bound ligand