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1.
a) Write brief notes about the differences between competitive reversible, competitive
irreversible and non-competitive antagonism, giving drug examples where appropriate.
(6 marks)
Both competitive antagonists (reversible and irreversible) bind to the same site on the receptor as an
agonist (orthosteric site), however irreversible antagonists bind with greater affinity. These bonds are
often covalent and mean the antagonism cannot be overcome by increasing the agonist
concentration. The concentration-response curve in the presence of CIA will be non-parallel with
depression of the maximum response, in contrast to a CRA which would produce a parallel shift with
no depression.
[Note: Vague talk of spare receptors and therefore parallel shift with no depression did not earn
marks]
Non-competitive antagonists differ from the other two types of antagonist in that they do not bind to
the orthosteric site (may be on the receptor or part of the signalling pathway; drug example needed
to match so allosteric site on the receptor and verapamil did not score full marks). Agonist binding
not affected so increasing agonist concentration does not restore maximum response, the same as
with CIA.
C o n t r a c t ile r e s p o n s e ( g )
Examples correctly used included atropine and propranolol (CRA), phenoxybenzamine (CIA) and
verapamil (NCA).
10
D r u g A A lo n e
8
D ru g A + D ru g B
( 1 x 1 0 -7 M )
6
4
2
0
-8
-6
-4
-2
lo g [ A g o n is t] , M
Above is a concentration-response curve obtained from an organ bath experiment similar to the one
conducted in Lab 2 – Potency of Agonists and Antagonists.
MEDSCI 303
b) Based on the data, what type of drug (i.e. type of agonist or antagonist) does Drug B appear
most likely to be? Explain your answer and provide an example of this type of drug.
(3 marks)
Full marks could be achieved with either CRA or NCA, depending on how data was interpreted –
either was fine, but these two are the most likely. Shifts in the curve needed to be identified and
explained.
CIA did not achieve full marks because using a method like the one used in this course would not
work with a CIA. The only exception to this was if it was specified that he equilibration time was
reduced to a point that still allowed a contractile response in the presence of antagonist.
{Note: marks were only awarded for a drug example if it hadn’t already been done in part a)
c) What other types of agonist or antagonist could it be? Explain your answer(s).
(4 marks)
Because the data were so inconclusive this answer was open to several options. Best answers were
CRA, NCA (2.5 each) and inverse agonist (1.5) as long as explanations were provided. Partial agonist
fittingly scored partial marks (1-1.5), as did physiological antagonist (1) and CIA scored a maximum
of a half mark. Marks were also awarded for explanation of why CIA was unlikely.
d) If possible and appropriate for Drug B, calculate:
i. pA2
ii. pD2’
If either of these calculations are not possible or relevant, explain why not.
(4 marks)
Both were possible and should have been calculated given the lack of clarity in the data for 2 marks
each.
The pD2 should have been estimated from the response at 3.4 g (the maximum response is given as
6.8 g in the next part of the question), giving a pA2 of approximately 7.6.
pD2’ should have been calculated with maximums of 6.8 and 6 g in the absence and presence of
antagonist, giving a pD2’ of 6.12.
“Not relevant” was awarded a half mark as long as the corresponding antagonist was not mentioned
in the answer to part b or c
e) When the concentration of Drug A alone was increased from 1x10-5 M to 1x10-4 M the
response decreased from 6.8 g to 6.15 g. What is the most likely explanation for this
decrease? Briefly explain how this occurs?
(3 marks)
Given the timeframe of the experiment, the most likely explanation was desensitisation in response
to continued, but short-term, exposure to high agonist concentrations. This usually involves a
phosphorylation of the receptor which uncouples the receptor from the signalling pathway.
Partial marks were awarded for receptor internalisation and exhaustion of mediators.