Neuropharmacology: drug antagonism (Dr. Moss)

Question 1

Why is the pairing of a receptor w/ a drug often transient ?

Answer 1

Because the bonds that hold the receptor/drug complex together are often are comparatively weak.

Question 2

How can the agonist-receptor or antagonist-receptor occupancy be shifted ?

Answer 2

Be increasing the concentration of one or the other (Law of mass action): the greater the concentration of a drug, the greater the chance of a collision occurring between the drug and a vacant receptor and therefore the greater the chance that a complex will form

Question 3

How does a rev reversible competitive antagonist (RCA) (e.g. atropine) alter the concentration-response relationship for the action of an agonist (e.g. ACh) ?
What can we say about the antagonism ?

Answer 3

The presence of the RCA causes the agonist log concentration-response curve to be shifted to the right, without any change in slope or maximal response.
The antagonism is surmountable over a wide range of concentrations.

Question 4

What is the concentration ration r ?

Answer 4

r = factor by which the agonist concentration must be increased to restore a given response in the presence of the antagonist
Detail: In the absence of antagonist, a response is elicited by a concentration [A] of agonist. When the antagonist is present, to achieve the same level of response, the agonist concentration has to be increased to a new value [A’]. This concentration [A’] > [A] and so it is possible to find a number r > 1, such that [A’]=r[A]

Question 5

What is the Gaddum equation ?
What does it express ?
What happens if [B] = 0 ?

Answer 5

pAR = [A] / (KA (1 + [B]/KB) + [A])
It expresses how pAR depends on the concentration of [A] and [B], w/ B = RCA
If [B] = 0, we get the Hill-Langmuir equation.

Question 6

To address the practical problem of how a RCA will affect the response to an agonist, what crucial assumption did JH Gaddum and HO Schild make about the relationship that exists between the response and the proportion of receptors occupied by agonist ?

Answer 6

They assumed that the same response (e.g. 30% of the maximum attainable) corresponded to the same receptor occupancy by agonist whether the agonist was acting alone, or in the presence of the competitive antagonist. This assumption makes made it unnecessary to know the exact form of the relationship between occupancy and response.

Question 7

What is the Schild equation (first applied in 1949) ?

Answer 7

r-1 = [B] / KB

Question 8

What does the Schild equation predict ?

Why ?

Answer 8

That a RCA should cause a parallel shift in the log agonist concentration response curve.
This is because for a given value of [B] and of KB, the concentration ratio, r, should also be constant, regardless of the concentration and even the identity of the agonist

Question 9

What is the most important application of the Schild equation ?

Answer 9

It provides a way of estimating the dissociation equilibrium constant for the combination of an antagonist with its binding sites. A series of agonist concentration-response curves is established, first without and then with increasing concentrations of antagonist, and tested for parallelism. If this condition is met, the value of (r - 1) is plotted against the [B]. This should give a straight line of slope equal to the reciprocal of KB.

Question 10

What is the Schild plot ?

Answer 10

log(r-1) = log[B] - logKB

Should give slope = 1 and x-intercept = logKB

Question 11

What is pAx ?

Answer 11

pAx = the negative logarithm of the concentration of antagonist which causes a concentration ratio of x.
This term was introduced by H.O. Schild as an empirical measure of the activity of an antagonist. The value most often quoted is pA2: pA2 = pKB = -logKB
Hence, pA2 = the value of [B] that forces us to double [A] to get the same response

Question 12

What are the 5 major assumptions for the Schild equation to function ?

Answer 12

1. Equilibrium
2. Equal response = equal proportion of receptors activated
3. A and B are mutually exclusive
4. B is a “pure” RCA
5. B must have the same affinity at all binding sites

Question 13

What are the 3 main characteristics of RCAs ?

Answer 13

1. The action of the RCA can be overcome by a sufficient increase in the concentration of agonist (i.e., the antagonism is surmountable)
2. In the presence of the 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

What are other mechanisms of drug antagonism (different from RCAs) ?

Answer 14

• chemical antagonsim
• fctal or physiological antagonism
• pharamacokinetic antagonism
• indirect antagonism

Question 15

What is chemical antagonism ?

Answer 15

The antagonist combines directly with the substance being antagonised. Receptors are not involved.
E.g. the chelating agent EDTA (ethylenediaminetetraacetic acid) is used to treat inorganic lead (Pb) poisoning (a less toxic chelate (a compound containing a ligand (typically organic) bonded to a central metal atom at two or more points) is formed and excreted).

Question 16

What is fct/physiological antagonism ?

Answer 16

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. AD relaxes bronchial smooth muscle and can thereby reduce the bronchoconstriction caused by histamine and the leukotrienes.

Question 17

What is pharmacokinetic antagonism ?

Answer 17

The “antagonist” effectively reduces the concentration of the active drug at its site of action.
E.g. repeated administration of the anti-epileptic drug phenobarbitone 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 18

What is indirect antagonism ?

Answer 18

The antagonist interferes with other post-receptor events which contribute to the tissue response.
E.g. 1: β-adrenoceptor blockers such as propranolol reduce the increase in heart rate caused by indirectly-acting sympathomimetic amines such as tyramine. This is because tyramine acts by releasing NA from noradrenergic nerve endings, and the released NA acts on β adrenoceptors to increase heart rate
E.g. 2: Ca2+ channel blockers ( “calcium antagonist”) such as verapamil block the influx of Ca2+ needed for smooth muscle contraction, and hence they reduce the contractile response to acetylcholine.
Some pharmacologists prefer to describe this as a variant of functional antagonism.