Receptors 4

Question 1

What is reversible competitive antagonism?

Answer 1

1. When the antagonist binds to the same receptor site as the agonist.
2. The blockade of the antagonist can be overcome by increasing the concentration of the agonist and the maximum efficacy can still be reached.
3. produces parallel shift in log conc-effect curve

Question 2

What is irreversible competitive antagonism?

Answer 2

1. The dissociation of antagonists is very slow and there is little to no displacement.
2. Covalent bonds are formed to the receptor.
3. The size of the maximal response is decreased with increasing concentration of antagonist.
4. no change in antagonist occupancy when agonist applied

Question 3

What is non-competitive antagonism?

Answer 3

1. When the antagonist blocks the events that lead to the response.
2. It has a similar graph to the irreversible competitive antagonist graph.
3. The antagonist binds to a different receptor site.

Question 4

What are allosteric moderators?

Answer 4

1. Drugs that work in the same way as non-competitive antagonism and bind to an allosteric site.
2. They can change the shape of an agonist binding site and can increase or decrease affinity.

Question 5

What is chemical antagonism?

Answer 5

Two drugs combine in solution so that the effect of the active drug is lost.

Question 6

What is pharmacokinetic antagonism?

Answer 6

1. When one drug reduces the concentrations of an active drug at its site of action
2. for example changing the rate of metabolism can alter how quickly the drug is removed from the body and changing the rate of absorption can result in more or less drug at the target site.

Question 7

What is physiological antagonism?

Answer 7

1. The interaction of two drugs whose opposing actions cancel each other.

Question 8

how does reversible competitive antagonism work

Answer 8

1. antagonism rate of dissociation high- equilibrium rapidly established by addition of agonist.
2. Can displace antagonist because by occupying vacant receptors, agonist reduces rate of association of antagonist
3. so rate of antagonist dissociation>association, so antagonist occupancy falls

Question 9

allosteric modulation

Answer 9

1. receptors have other allosteric binding sites in addition to site where agonists/antagonists bind (orthosteric)
   through this binding site drugs can influence receptor function
2. eg changing affinity for agonists or produce a response themselves

Question 10

What is the Two-state model receptor activism

Answer 10

1. Binding of inverse agonist or agonist changes position of equilibrium
2. Agonist has preferential affinity to activated state so binds more to activated state. So, equilibrium moves to right so larger response.
3. Inverse agonist has preferential affinity to receptor in resting state which shifts equilibrium in other direction. 4. Brings receptors in activated state to left to resting state. Reduces response.
4. Antagonist blocks both receptors.

Question 11

What are 5 different models of drug antagonism

Answer 11

1. Antagonism by receptor block
   a) reversible competitive block
   b) irreversible competitive block
2. Non-competitive antagonism
3. Chemical antagonism
4. Pharmacokinetic antagonism
5. Physiological antagonism

Question 12

Describe reversible competitive antagonism

Answer 12

1. Parallel shift in response curve.
2. No reduction in maximal response
3. At a given agonist concentration, the agonist occupancy is reduced in the presence of the antagonist. Raising the agonist concentration will restore occupancy and tissue response.
4. Antagonist rate of dissociation is high, and so equilibrium rapidly established with addition of agonist.
5. The agonist is able to displace the antagonist from the receptor.
6. Displacement occurs because by occupying a proportion of the vacant receptors, the agonist reduces the rate of association of the antagonist.
7. So the rate of antagonist dissociation exceeds association and so antagonist occupancy falls.

Question 13

Describe Irreversible competitive Antagonism

Answer 13

1. Antagonists dissociates very slowly from the receptor.
2. No change in antagonist occupancy occurs when agonist applied.
3. Occurs with drugs with reactive groups which form covalent bonds with receptor.
   a) e.g. omeprazole, aspirin, monoamine oxidase inhibitors.
4. If agonist occupancy for max response is low (e.g. <5%) then over 95% of the receptors must be blocked before the maximal response is reduced.
5. Thus low antagonist concentrations will only cause a parallel shift in the DR curve, like reversible competitive antagonists.

Question 14

Describe non-competitive antagonism/negative allosteric efficacy modulation

Answer 14

1. Antagonist blocks the chain of events that lead to the evoked response.
2. e.g. verapamil and nifedipine prevent calcium ion influx through cell membranes producing a non-specific block of smooth muscle contraction induced by other drugs (e.g. ACh).

Question 15

What are 4 types of allosteric modulation of receptors

Answer 15

1. Negative affinity modulation
2. Positive affinity modulation
3. Negative efficacy modulation
4. Positive efficacy modulation

Question 16

Describe negative affinity modulation

Answer 16

1. Acts like a competitive antagonist- greater concentrations of agonist needed for response

Question 17

Describe positive affinity modulation

Answer 17

1. Presence of allosteric modulation increases efficacy of agonist- lower concentrations needed

Question 18

Describe effect of negative efficacy modulation

Answer 18

1. Maximal response decreases

Question 19

Describe effect of positive efficacy modulation

Answer 19

1. Increase in maximum response and so reduction in Ec50

Question 20

Describe chemical antagonism

Answer 20

1. Two drugs combine in solution so that the effect of the active drug is lost e.g.
   a) Chelating drugs which bind to heavy metals
   b) Neutralising antibodies vs protein mediators (cytokines).

Question 21

Describe Pharmacokinetic antagonism

Answer 21

1. where one drug reduces the concentration of an active drug at its site of action e.g.
   a) Change in metabolism
   b) Change in absorption
   c) Change in renal excretion of drug- appears as though reducing efficacy of drug

Question 22

Describe physiological antagonism

Answer 22

1. Interaction of two drugs whose opposing actions cancel each other.
   a) ACh vs NA on heart rate,
   b) Histamine-induced acid secretion vs omeprazole inhibition of proton pump.

Question 23

Describe what happens as potency of reversible competitive receptor antagonists changes

Answer 23

1. Increasing agonist concentration overcomes the block due to a reversible competitive antagonist. Antagonism is surmountable.
2. The antagonist-induced parallel shift in the response curve allows the dose ratio to be calculated.
3. The dose ratio = the ratio by which the agonist concentration is increased in the presence of the antagonist to restore the given response.
4. Theory predicts that the dose ratio increases linearly with the concentration of antagonist.

Question 24

How can the Law of Mass Action be applied to the dissociation of an antagonist from the complex.

Answer 24

KB= [B][R]/[BR]
B= Antagonist
KB= antagonist dissociation constant

Question 25

If the doses of an agonist to evoke the same magnitude of response (e.g. EC50) in the absence and presence of antagonist are [X] and [XA] what is the dose ratio

Answer 25

1. Then the dose ratio for the [agonist] in absence and presence of antagonist is
2. [XA]/[X]= 1 + [B]/KB= DR
3. So DR-1= + [B]/KB

Question 26

What is the Schild equation and how is it found

Answer 26

1. Take negative log of DR-1= + [B]/KB

2. log(DR-1)= log[B] - logKB

Question 27

What happens when DR= 2

Answer 27

Then log [B] = logKB= dissociation constant for antagonist (M) concentration

Question 28

How do you create a Schild Plot

Answer 28

1. From the log dose-response curves determine the EC50 values for the agonist in the presence of each concentration of antagonist.
2. Then calculate the dose ratio, and log (DR-1) at each antagonist concentration.
3. Now plot log10 (DR-1) y-axis against log10 [antagonist] x-axis`

Question 29

What can you find from a Schilds plot

Answer 29

1. Extrapolate line back to x-axis.
2. A value of zero for the ordinate (y-axis) will give an intercept on the x-axis where log [B] = log KB. i.e. the [antagonist] where the line bisects the x-axis is where log10 (DR-1) = 0.
3. Thus DR-1 = 1, so DR = 2
4. This is the [antagonist] where twice the [agonist] is required to elicit the same response as the agonist alone, and is equal to the equilibrium dissociation constant (KB) of the antagonist-receptor complex.
5. This is a system-independent and molecular quantification of the antagonist affinity and is the concentration of antagonist at 50% occupancy.

Question 30

What is pA2

Answer 30

1. pA2 value is the negative log of antagonist concentration found when DR=2
2. pA2 expresses antagonist potency in simple positive terms.

Question 31

What do different values of pA2s mean

Answer 31

1. pA2 of 9 or greater indicates a potent antagonist
2. pA2 of 5-6 indicates a weak antagonist
3. Similar pA2 values in different tissues indicate identical receptors.

Question 32

What is the equation linking pA2 to DR

Answer 32

1. pA2 = log [DR-1] – log [B]

2. Allows us to estimate pA2 value based on just one concentration of antagonist.