S1: Drug-Receptor Interactions Flashcards
How does a agonist act at an receptor?
It has affinity (will occupy receptor) and efficacy (will activate receptor)
Why is it important we know how to measure and compare the affinities and efficacies of drugs?
So we have an understanding of how a correct dose is determined
Are agonists reversible?
Yes
Most agonists will bind reversibly to their receptors (which are very selective). The agonist will associate and then dissociate
How is binding irreversible or reversible?
it depends on the type of binding that occurs between receptor and agonist
Hydrogen bonds, Ionic bonds, Van der Waals forces = Are relatively weak –> Will reversibly bind
Covalent bonds= Stable, strong bonds –> Will irreversible binds and have poor dissociation
What determines drug affinity?
Reversible binding of an agonist to a receptor is governed by ‘Law of Mass Action’
What is ‘Law of Mass Action’?
It is dependent on the concentration of reactants involved so essentially, drug affinity is dependent on the concentration of reactant.
Agonist + Receptor Agonist-Receptor Complex
(A) + (Rfree) (AR)
What does the ‘Law of mas action’ predict?
Low (A) = Lots of (Rfree) = Therefore few AR interactions
Increase (A) = More AR interactions = Reaction driven to the right
Continue to increase (A) = Few Rfree = Reaction begins to reach max
What is the equilibrium constant (KA)?
When 50% of the receptors are free and 50% of the receptors are bound to agonist
Explain how KA is the (A) at equilibrium
e.g. KA of 50nM means that at this concentration, half the agonist will be bound to receptors
Does each drug have its own KA value?
Yes
What does a smaller KA mean?
It means that the agonist have a greater affinity for a receptor (binds more than drug with higher receptor)
e.g. Drug Y has KA of 5nm
Drug X has KA of 50nm
This means that drug Y has a higher affinity for its receptor as a lower concentration is needed to occupy 50% of its receptor
Why is there a maximum number of AR?
There is a finite number of receptors
Increasing the concentration any further than maximum affinity will have no effect on efficacy (may even induce more side effects).
Describe the linear and logarithmic graph of AR against concentration of agonist
Initially, on linear scale there are many free receptors so upon increasing concentration of agonist, the agonist-receptor complexes increases very rapidly. However as we increase it to much higher values, it slows down as there are fewer receptors - shape is a rectangular hyperbola
On the sigmoid curve, there are as a proportion very few agonist present initially so it increases slowly, however once it reaches threshold, the affinity is much higher so the number of AR interactions increases rapidly, until it reaches a maximum value, where all receptors are filled.
What determines efficacy?
A + R AR AR*
1 = Binding (affinity) 2= Response (efficacy)
As agonist concentration is increased, more receptors will be bound to, so there is a greater biological response (efficacy).
It reaches a maximum bio response where an increase in concentration of agonist doesn’t make a difference
What is a threshold concentration value?
What is maximum concentration?
Once breached, the biological response will start to be seen and increase as (A) increases
Maximum concentration is when any further increase of (A) does not increase biological response
What is EC50?
It is values to measure efficacy
- This is the effective concentration (of agonist) giving a 50% biological response
Why are EC50 values important?
They tell us both about affinity and efficacy
(an agonist has to bind to receptor first to activate it and cause an biological response)
- It is therefore useful in determining drug potency
Why are KA and EC50 values not equal?
Full occupancy of a drug is not needed to give an maximum response because receptors AMPLIFY signals e.g. 50% occupancy can produce 100% biological response.
What is a full agonist?
A full agonist will give 100% response/efficacy
What is an antagonist?
It has not efficacy and does not produce any response
What is a partial agonist?
It produces a biological response but has less efficacy that doesn’t reach 100%
What is an inverse agonist?
It reduces the basal receptor activity so it reduces biological response
(it is not an antagonist because it has an action)
What is competitive antagonism?
- Receptors only bind to either agonist (A) or antagonsit (Ant)
- A and Ant will compete for the same binding site and both will bind reversibly
- Reaction dependent on KA and KAnt (relative affinities)
- If KAnt < KA then antagonist has greater affinity for receptor than agonist and will outcompete the agonist (if this is by a high margin there may be little or no bio response)
- To overcome this, the concentration of A must increase to outcompete Ant binding to R
Compare the graph of response and (A) [with agonist alone] and response and (A) [with agonist and antagonist]
- The curve is shifted to the right in the presence of an Ant
- The linear part of the curve is parallel
- The same maximal response is obtained as long as (A) is increased so that is outcompetes the antagonist
