By Duy Thai: www.geocities.com/d.

thai Pharmacology Semester 1 page 1 of 5

PHARMACODYNAMICS 1

Receptor occupancy - mass action

• The interaction of a drug with a receptor is reversible due to interactions via weak bonds (not covalent).
k1
• [A] + [R] [AR]
k-1

• [A] = Agonist concentration

• [R] = Receptor concentration
• [AR] = Agonst - receptor complex
• There is a limited number of receptors on a cell surface.
• [RT] = [R] + [AR]
• [RT] = Total concentration of receptors
• [R] = Concentration of unbound receptors
• [AR] = Concentration of bound receptors with agonist
• At equilibrium, the forward rate = backward rate, so that:
• k1.[A][R] = k-1.[AR]
• Combining this with the number of receptors equation, we get an equation relating the concentration of
drug to its occupancy (how much of the drug is bound to receptor).
[ AR] = [ A]
[ R T ]  k −1 + [ A]
 k1 
• [AR]/[RT] is the drug occupancy.
• It is the fraction of bound receptors over the total number of receptors
• k-1/k1 is known as the equilibrium dissociation constant.
• It is given the symbol KA
• It corresponds to the concentration of drug at which half the receptors are occupied.
• A low value of KA means that the forward rate (formation of [AR] complexes) is greater than the
backward rate (dissociation of drug from the receptor). i.e. k1 > k-1
• Hence, KA can also be considered as a measure of a drug’s affinity for its receptor.
• Low KA means there is high affinity because the drug “likes” to be bound to a receptor.
A low KA signifies that a lower concentration of drug is required to occupy half the
receptors than another drug with a higher KA.
• A graph of the occupancy vs drug concentration looks like this:

Occupancy
[AR]/[RT] KA = concentration of
drug at which half the
receptors are bound

Concentration of drug [A]

• With an increasing concentration of drug, there is an increase in the fraction of receptor binding (occupancy), until
we get to a point of maximum occupancy at which all the receptors are occupied.
• At this point, it is important to note that no response has been mentioned yet, only occupancy. Whether or not
there is a response is determined by other factors. Binding of drug to receptor alone is not sufficient to say that it
will cause a response!
By Duy Thai: www.geocities.com/d.thai Pharmacology Semester 1 page 2 of 5

• To make analysis of this curve easier, we do a mathematical trick of making the x scale a logarithmic scale. By
doing this, the curve is converted to a sigmoid curve. Advantages of this curve:
• It is linear over 20-80% of the occupancy range
• It is more easier to quantitative values looking off the curve
• It can show a much larger range of concentrations. At low concentrations, we are able to see the rapid
changes that occur, while at the higher concentrations, where things are much more boring, we don’t see
much.
• Figure 1: sigmoid curve of occupancy vs concentration

Occupancy
[AR]/[RT]

logKA

log[A]

• As you can see from the graphs, when the concentration of drug is at KA, half the receptors are occupied.
• The KA remains constant for a given drug receptor combination.
• If you change the drug, the new drug will have a new KA value. Depending on the chemical
structure of the new drug, the KA may be less (the drug has a higher affinity to the receptor) or
greater (the drug has a lower affinity) than the original drug. Similarly, a change in receptor,
with the drug remaining constant will alter the KA.
• Potency of a drug is related to the affinity.
• If we compare 2 different drugs acting on the same receptor, we can see that one drug has a higher affinity
(lower KA) to the receptor than the other drug.

Drug 1 Drug 2
Drug 1 has higher
affinity to the receptor
than drug 2

KA1 KA2

• The drug with the higher affinity also has a higher potency.
• Potency is actually concerned with the response of a drug, rather than its occupancy. When we
say that a drug has high affinity, it means that more of the drug can bind to receptors at low drug
concentrations. When we say that a drug has high potency, we mean that at low concentrations,
the drug with higher potency will have a larger response/effect than a drug with low potency.
• Potency is related to EC50 rather than KA (see later).
• A high potency does not necessarily mean it is better therapeutically. Why?
• It is harder to control the dosage. Sometimes we want to regulate the dosage of a drug by
deliberately trying to make it act more slowly. This is important for drugs with a small
therapeutic window.
By Duy Thai: www.geocities.com/d.thai Pharmacology Semester 1 page 3 of 5

• What we have considered so far is the binding of drug to receptor. This is only the very first part of the stimulus -
response interaction.

The response
• [A] + [R] [AR] + Transducer [AR]-Transducer Response
• In order for the drug receptor interaction to produce a response, it must interact with a transducer.
• The response is all dependent on the transducer.
• A weak transducer will result in a weaker response
• A strong transducer results in a stronger response
• What does the drug - response curve look like?
• The drug - response curve looks sigmoidal (if graphed against the log[A]), and it can mirror the drug -
occupancy curve. However, this may not always be the case.

Scenario one NB: The response curve is superimposed on the

occupancy curve

Occupancy Response curve

Response
100% Occupancy Maximum
curve possible response

Log[A]

• In this case, the response curve is identical to the occupancy curve.

• If we have half of the receptors occupied, we would get half a response.
• The concentration of drug at which we see half a response is called the EC50 (the effective concentration that gives
50% response)
• In this case, EC50 = KA
• What this means is that when 100% of the receptors are occupied, we get 100% response (maximum response)
• In real life, we find that this is not often the case.
• Normally, we do not need to occupy all the receptors in order to get a maximal response.

Scenario two
Occupancy Response
Response curve
100% Maximum
possible response
Occupancy
curve

½ max response

EC50

Log[A]

• In this situation, we can get a maximum response when only ½ the receptors are occupied.
• EC50 < KA
• This occurs because the transducer is very effective at converting the drug-receptor signal into a response.
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 4 of 6

• Since we can have a maximum response when not all of the receptors are occupied, we have the concept of receptor
reserve. Therefore, we can lose some receptors (in this case up to 50%) and still get a maximum response.

Scenario three:
Occupancy Occupancy curve
Response
100% Maximum
possible response

Response curve
Submaximal response

Log [A]
• If the transducer is weak, we will find that even when all the receptors are occupied, we still cannot get a maximum
response.
• It is not really the transducers fault.
• All the transducer is doing is responding to the interaction between drug and receptor. If the binding of the
drug to the receptor is not very good, the effectiveness of the transducer is thus diminished.
• We see this effect with the use of partial agonists.
• EC50 > KA

• The response ≠ receptor occupancy unless under special circumstances. i.e. EC50 does not always = KA

Different types of agonist

Drug A

Drug B
Response

Drug C

Log[A]

• Drug A is a full agonist because it can produce a maximum response

• Drugs B is a partial agonist because it has a range of response which is sub-maximal. They can never get a
maximum response, no matter how many receptors are present.
• Drug C has got no response, so it termed a silent agonist.
• However, it may still have full occupancy of the receptors.
• Efficacy is a term used to describe the maximum response of a drug.
• Drug A has a better efficacy than drugs B and C
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 5 of 6

• Intrinsic activity is a mathematical value which determines the efficacy of a drug. It acknowledges the fact that not
all agonists to a receptor produce a maximum response.
α × E max × [A]
E=
EC50 + [A]
• E stands for response
• α stands for intrinsic activity
• When α = 1 Full agonist
0 < α < 1 Partial agonist
α = 0 Silent agonist (an antagonist)

• The way the agonist pertubates (changes the receptor shape) the receptor affects the activity of the transducer.
This can lead to a good or bad response.

The transducer and its role in the response to agonist

• What happens if you want to stimulate a receptor in the heart to cause increased contractility but there is exactly the
same receptor in the blood vessel which causes vasodilation (hence a decrease in BP). We can’t stimulate both
because the vasodilation would cause a reduced perfusion to a heart which is pumping harder than ever. This would
cause an infarct of heart muscle due to insufficient blood supply.
• We can find a drug which is only specific to the heart, but this is hard because the receptors are exactly the same.
• In times like these, mother nature has given us a helping hand.
• It turns out that with the same drug, acting on the same receptor, but in different tissues, we find that the efficacy of
the drug differs.
Response of drug Remember:
acting on the heart
Same drug +
Same receptor +
Response of drug
Different tissue =
Response Different response
acting on blood
vessel compared with:
Different drug +
Same receptor +
Same tissue =
Different response

• In this example, the drug acting on the heart acts as a full agonist whereas the drug acting on the blood vessel is
acting as a partial agonist. Because the drug and receptor are the same, only the transducer is left to blame.
• This is an important concept: in different tissues, there may be different transducers, and so the efficacy of the drug
will be altered at different tissues.
• Efficiency (not efficacy) explains the drug-receptor interaction with the transducer.
• A good example of a drug with this property is glibenclamide (a hypoglycemic). See lecture “Ion channels 1”.
• Glibenclamine is designed to work on the β cells of the pancreas to cause insulin secretion. It also acts on
vessels to cause vasoconstriction.
• The potency of glibenclamide on β cells is greater than it is on vessels. Hence, at low drug concentrations,
glibenclamide is able to cause a response on the β cells but cannot cause a response in vessels. The vessels
require a higher concentration of glibenclamide to have a response.

• The response to agonist depends on:

• The chemical property of the drug and its interaction with receptor.
• The affinity of the drug to the receptor may change
• The efficacy of the drug will change
• Efficacy is a measure of the maximum possible response
• In tissues:
• Variations in receptor density
• Does not pose as much a problem if there is receptor reserve
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 6 of 6

• Efficiency of the coupling

• Efficiency is the drug - receptor interaction with the transducer