Drug Antagonism

Question 1

What are antagonists ?

Answer 1

Drugs that work to oppose the action of other chemical substances (e.g. agonists)

Most frequently, antagonists work by binding to the same receptor macromolecule as the agonist

Question 2

What is PA2?

Answer 2

A measure of the potency of an agonist

Question 3

What can PA2 be used for?

Answer 3

To compare different types of antagonist

Question 4

Describe the 2 key stages in the production of an active agonist-receptor complex?

Answer 4

1. Agonist binding: A + R <—> AR
2. Agonist efficacy: AR <—> AR*

AR - the inactive agonist-receptor complex
AR* - the active conformation of receptor (due to interactions between agonist and the receptor)

Question 5

How does reversible competitive antagonism work?

Answer 5

1. Antagonist competes with agonist and (reversibly) binds to receptor: B + R <—> BR
2. However, the antagonist doesn’t interact with the receptor so no active conformation is formed (i.e. BR*) - no activation of receptor

Question 6

Why is reversible competitive antagonism surmountable?

Answer 6

Because both agonist and antagonist bind reversibly

Question 7

How can reversible competitive antagonism be overcome?

Answer 7

By increasing [agonist]

Due to the law of mass of action: the rate of formation of complex is directly proportional to [reactants]

Question 8

When does competitive antagonism occur?

Answer 8

When the binding of the agonist and antagonist is ‘mutually exclusive’

Question 9

What are the 3 ways the binding of agonist and antagonist can be mutually exclusive?

Answer 9

1. Agonist & antagonist bind compete for same binding site
2. Or combine with adjacent sites, which overlap
3. Or different sites are involved but they influence the receptor macromolecule in such a way that agonist & antagonist molecules cannot be bound at the same time

Question 10

What is the Gaddum equation?

Answer 10

pAR = [A] / KA (1+ [B]/KB) + [A]

Question 11

How should you label the axes of a graph that shows how pAR changes with changes in [antagonist]?

Answer 11

Y-axis - pAR
X-axis - agonist concentration (log scale)

Question 12

What happens to the shape of the graph when [antagonist] is increased?

(Graph of pAR against agonist conc)

Answer 12

Graph should include a control (agonist only) where [B] = 0 (Hill-Langmuir equation: pAR = [A] / KA + [A])

Adding / increasing [antagonist] ([B])
- same sigmoidal curve
- curve shifts to the RHS on the x-axis in a parallel fashion
- because KA term is being multiplied by ([B]/KB)
- therefore, the greater the [B], the greater the shift

Question 13

What are the 3 key points about reversible competitive antagonism?

Answer 13

1. The action of the antagonist can be overcome by a sufficient increase in the concentration of agonist (i.e. the antagonism is surmountable)
2. In the presence of an antagonist, the curve relating the log of the agonist concentration to the size of the response is shifted to the right in a parallel fashion
3. The quantitative relationship between the magnitude of the shift (as expressed by the concentration ratio) and the antagonist concentration obeys the Schild equation

Question 14

How can the action of a reversible competitive antagonist be overcome?

Answer 14

By a sufficient increase in [agonist] (i.e. antagonism is surmountable)

Question 15

In the presence of an antagonist, the curve relating the log of the [agonist] to the size of the response (pA2) is…

Answer 15

Shifted to the right in a parallel fashion

(Sigmoidal shape of the curve remains the same)

Question 16

The magnitude of the shift in the graph is expressed by…

Answer 16

The concentration ratio

Question 17

The quantitative relationship between the magnitude of the shift (as expressed by the conc ratio) and the [antagonist] obeys which equation?

Answer 17

The Schild equation

Question 18

What is chemical antagonism?
Give an example

Answer 18

The antagonist combines directly with the substance being antagonised. Receptors are not involved.

E.g. the chelating agent EDTA is used to treat inorganic lead poisoning (a less toxic chelate is formed and excreted)

Question 19

What is functional / physiological antagonism?
Give an example.

Answer 19

The ‘antagonist’ is actually an agonist which produces an opposite biological effect to the substance being antagonised. Each substance acts through its own receptors.

E.g. adrenaline relaxes bronchial smooth muscle and can therefore reduce bronchoconstriction caused by histamine & the leukotrienes.

Question 20

What is pharmacokinetic antagonism?
Give an example.

Answer 20

The ‘antagonist’ effectively reduces the concentration of the active drug at its site of action.

E.g. repeated administration of phenobarbitone (anti-epileptic drug) induces an increase in the activity of hepatic enzymes that inactivate the anticoagulant drug warfarin. Hence if phenobarbitone and warfarin are given together, the plasma concentration of warfarin is reduced, so that it becomes less active, at a given dose.

Question 21

What are the 2 ways of indirect antagonism?
Give examples.

Answer 21

1. The antagonist acts as a second ‘downstream’ receptor which links the action of the agonist to the final response observed.
   E.g. beta-adrenoceptor blockers (e.g. propanolol) reduce the increase in HR caused by indirectly-acting sympathomimetic amines (e.g. tyramine). This is because tyramine acts by releasing noradrenaline from noradrenergic nerve endings, and the released noradrenaline acts on beta-adrenoceptors to increase heart rate
2. The antagonist interferes with other post-receptor events which contribute to the tissue response
   E.g. calcium antagonists / calcium channel blockers (e.g. Verapamil), block the influx of calcium needed for smooth muscle contraction, hence reducing the contractile response to ACh