Receptor Theory 3

Question 1

What are the mechanisms of antagonism

Answer 1

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

Question 2

Describe reversible competitive antagonism

Answer 2

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.

Question 3

What effect does raising the agonist concentration have on reversible competitive antagonism

Answer 3

1. Raising the agonist concentration will restore occupancy and tissue response.
2. Antagonist rate of dissociation is high, (can come off receptor easily) and so equilibrium rapidly established with addition of agonist.
3. The agonist is able to displace the antagonist from the receptor.
4. Displacement occurs because by occupying a proportion of the vacant receptors, the agonist reduces the rate of association of the antagonist. So the rate of antagonist dissociation exceeds association and so antagonist occupancy falls.

Question 4

Describe Irreversible Competitive Antagonist

Answer 4

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.
4. e.g. omeprazole, aspirin, monoamine oxidase inhibitors.
5. Reduces the maximal response of agonist
6. 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.
7. Thus low antagonist concentrations will only cause a parallel shift in the DR curve, like reversible competitive antagonists.

Question 5

Describe non-competitive antagonism

Answer 5

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 6

Describe chemical antagonism

Answer 6

1. Two drugs combine in solution so that the effect of the active drug is lost.
2. e.g. chelating drugs which bind to heavy metals, neutralising antibodies vs protein mediators (cytokines).

Question 7

What is Pharmacokinetic antagonism

Answer 7

1. Where one drug reduces the concentration of an active drug at its site of action.
2. Variety of mechanisms
   - Change in rate metabolism
   - Change in absorption
   - Change in renal excretion

Question 8

What is Physiological Antagonism

Answer 8

1. Interaction of two drugs whose opposing actions cancel each other.
2. e.g. ACh vs NA on heart rate, histamine-induced acid secretion vs omeprazole inhibition of proton pump.

Question 9

Describe Potency of Reversible Competitive Receptor Antagonists

Answer 9

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.

Question 10

What is the dose ratio

Answer 10

1. The dose ratio = the ratio by which the agonist concentration is increased in the presence of the antagonist to restore the given response.
2. Theory predicts that the dose ratio increases linearly with the concentration of antagonist

Question 11

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

Answer 11

1. Kb= dissociation constant of antagonist,
2. B is conc of antagonist,
3. R is conc of freely available receptor,
4. BR is drug receptor complex conc.
5. [B][R]/[BR]=KB

Question 12

What is an equation for dose ratio

Answer 12

1. 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], respectively
2. then the dose ratio for the [agonist] in absence and presence of antagonist is
   [XA]/[X]=1+[B]/[KB]
3. 6. Where [B] = antagonist and KB is the antagonist dissociation constant.

Question 13

What is the Schild equation

Answer 13

1. log(DR-1)=log[B]-Log(Kb)

Question 14

What happens when DR=2

Answer 14

1. When DR=2
2. then log [B] = log KB = dissociation constant for antagonist (M concentration).

Question 15

How can you draw a Schild Plot

Answer 15

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 16

What can you do with a Schild Plot

Answer 16

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

Question 17

What does the extrapolation value from a Schild Plot tell you

Answer 17

1. 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.
2. This is a system-independent and molecular quantification of the antagonist affinity and is the concentration of antagonist at 50% occupancy.

Question 18

What is pA2

Answer 18

1. The pA2 value of an antagonist is the negative log of [antagonist] - when DR=2
2. pA2 expresses antagonist potency in simple positive terms.
3. Not always selective- so may block other systems e.g. atropine blocks ach and at high concentraions histamine
4. If the slope of the Schild plot is 1, then antagonist is competitive.
5. Similar pA2 values in different tissues indicate identical receptors.

Question 19

What do different pA2 values indicate

Answer 19

1. pA2 of 9 or greater indicates a potent antagonist
2. pA2 of 5-6 indicates a weak antagonist

Question 20

What is agonist equivalent of PA2

Answer 20

1. pA2 = log [DR-1] – log [B] =antagonist potency whereas PEC50 is agonist
2. Pa2 is of antagonist against an agonist v important

Question 21

What is equation for PA2

Answer 21

1. pA2 = log [DR-1] – log [B]