antagonists and quantitative pharmacology

Question 1

in terms of efficacy and affinity describe antagonists ?

Answer 1

contains affinity as it holds the ability to bind to the receptor by obeying the law of mass action, however, it does not contain efficacy as no measurable response is seen.

Question 2

chemical antagnoist ?

Answer 2

A chemical antagonist works as one drug antagonises the action of another by chemically combining with it

Question 3

physiological antagonism ?

Answer 3

A physiological antagonist is when two drugs counteract each other by producing opposing effects on different receptors. For example, a potassium blocker could increase the amplitude of a twitch in skeletal muscles, while a nicotinic receptor antagonist would decrease the twitch.

Question 4

pharmacological antagonism ?

Answer 4

Pharmacological antagonism: when drugs counteract each other by acting on the SAME receptor type.

Question 5

high beta rate ?

Answer 5

If a drug has a high beta rate then this is a full agonist

Question 6

alpha rate high ?

Answer 6

alpha rate is high then this is probably a partial agonist as it drives the receptor from the active state into the non active state.

Question 7

receptor occupation and agonism ?

Answer 7

In addition to not producing a response, the occupation of the receptor by the antagonist reduces the ability of the agonist to interact with the receptor. Thus antagonists reduce the responses produced by agonists , as they will have a higher binding affinity for the receptor preventing the agonists binding to produce a response.

Question 8

how can the effects of an antagonist be reversed ?

Answer 8

The effects the antagonists have on the agonists can be reversed by increasing the agonist concentration which will restore the response that is blunted by the antagonist.

Question 9

CRC for competitive antagonism ?

Answer 9

Note that the control curve is shifted to the right and in a parallel fashion by increasing concentrations of the antagonist. As you increase the antagonist concentration the curve shifts to the right and doesn’t affect the Max. This is competitive antagonism

Question 10

how did Gaddum find a way to derive the dissocation constant for the antagonist ?

Answer 10

Gaddum in 1937 found a way to derive the dissociation constant for the antagonist from the rightward shift in the agonist concentration curve. He did this by extending the Hill-Langmuir equation to describe the reaction involving two or more competing drugs binding to a single site on a receptor. Applying the rules from law of mass action, the occupancy equation becomes in the presence of a competitive antagonist.

Question 11

Ka

Answer 11

dissocation constant (Kd) for agonist

Question 12

Kb?

Answer 12

dissociation constant (Kd) for antagonist

Question 13

XA

Answer 13

agonist concentration

Question 14

Xb

Answer 14

antagonist concentration

Question 15

R?

Answer 15

Gaddum quantified the rightwards shifts of curves in the presence of the antagonist, assuming that equal responses (e.g. 50% maximum) are produced by an equal proportional occupation of the receptor population. Rightward shift of an agonist concentration response curve are quantified by the ratio (r) of agonist concentrations required to produce the same response in the presence and absence of the antagonist

Question 16

what do you plot ?

Answer 16

You plot the control response in the absence and presence of an antagonist this means a rightward shift. You then calculate the Ec50 and ratio.

Question 17

r=2 mean ?

Answer 17

When r =2 this means that twice as much agonist is required to produce the same response with the antagonist present.

Question 18

Kb equation ?

Answer 18

the gaddum equation can be rearrnaged that’s the concentration of the blocker divided by r the dose of agonist to get responses.

Question 19

limitation of Kb ?

Answer 19

for the equation below only one data point has been used to calculate the antagonist dissociation and it is assumed that the antagonist is competitive.

Question 20

logarithim form of schild or Gaddum Schild equation ?

Answer 20

Schild took this analysis a stage further to experimentally determine the nature of the antagonism with no underlying assumptions. The Schild or Gaddum-Schild equation can be expressed logarithmically in the form:

Question 21

what is the most accurate way of determing the Kb of antagoist ?

Answer 21

A plot of Log (r-1) against Log XB is commonly called a Schild plot and is the most accurate way of determining the KB of an antagonist.

Question 22

what did plotting log(r-1) against Log(Xb) yeild ?

Answer 22

Arunlakshana & Schild showed that plotting log (R-1) against log [XB] for increasing concentrations of antagonist yielded a straight line and that for competitive antagonism the slope of the line should be 1.

Question 23

on the graoh where can Kb be calculated ?

Answer 23

By setting the left hand side of equation to zero

0=log XB – log KB).

KB can be estimated as the point at which the line crosses the X axis. This also corresponds to the antagonist concentration which produces a dose ratio of r=2. Better way of determing Kb of antagonist as doesn’t assume any assumptions.

Question 24

what is Pa2 value ?

Answer 24

The KB can be converted into a numerically simpler term the pA2 by expressing the value as a –log

pA2 = - log (KB).

Question 25

if a PA2 value is 6 and 8 what is the fold difference ?

Answer 25

Remember that pA2 values are on a log scale, thus pA2 values of 6 and 8 indicate a 100-fold difference in the potencies of the antagonists.

Question 26

higher Pa2 value indicate ?

Answer 26

pA2 values the higher the value, the less antagonist has been required to produce the effect, i.e. the more potent is the antagonist.

Question 27

irreversible competitive antagonist ?

Answer 27

An irreversible competitive antagonist is when the bond between the antagonist and the receptor is so strong, that even increasing concentrations of agonists cannot displace the antagonist. This is often due to covalent bonding, e.g. by the a-adrenoceptor blocking drug phenoxybenzamine. Leads to reduction in amplitude of the maximum response and curves not parallel.

Question 28

in this what proportition are the control curve ?

Answer 28

Control curve only a very small proportion (2 %) of the receptors are required to produce a maximal response “Spare receptors”. 98% of the receptors can be occupied by the antagonist.

Question 29

non competitive antagonist ?

Answer 29

A non competitive antagonist is when antagonists act at sites other (allosteric site) than the agonist binding site. They interfere with the agonists ability to produce a response. These drugs, like irreversible competitive antagonists, produce non-parallel rightwards shifts of agonist concentration-response curves. Graphically it’s difficult to differentiate between non competitive and competitive antagonism , to differentiate between them an experiment will need to be conducted.