L3 Pharmacodynamics II Flashcards
What is the difference between a full and partial agonist?
Full agonist can generate the maximal observed effect (Emax)
Partial agonist can generate a fractional effect
_________ means that a substance/drug binds to a receptor and influences its activity.
Usually depicted as a “concentration-response” curve
Agonism means that a substance/drug binds to a receptor and influences its activity.
Usually depicted as a “concentration-response” curve
How is agonism usually depicted?
As a concentration-response curve
_______ means that a substance/drug binds to a receptor and influences its response to an agonist
Antagonism means that a substance/drug binds to a receptor and influences its response to an agonist
What are the two extreme methods of antagonism?
- Competitive antagonist
- non-competitive antagonist
__________: a higher concentration of agonist is required to generate a given response, but efficacy is not changed
Competitive Antagonist: a higher concentration of agonist is required to generate a given response, but efficacy is not changed
What effect does a competitive antagonist have on the agonist?
When competitive antagonist is present, a higher concentration of agonist is required to generate a given response.
Effects agonist concentration (potency) but NOT efficacy
_______: Reduce agonist efficacy but has no effect on potency
Non-competitive antagonist: Reduce agonist efficacy but has no effect on potency
What effect does a non-competitive antagonist have on the agonist?
Non-competitive antagonists reduce agonist efficacy but have NO effect on potency
Define competitive antogonist
A compound that occupies the same binding site as the agonist but does not elicit a biological response
I = competitive antagonist
A = Agonist
Why might it be difficult to measure how competitive antagonists interact with a receptor?
What can be used to overcome this?
Because antagonists do not generate a biological effect on their own.
Can measure competitive antagonism by generating a schild plot based on dose ratio (or concentration ratio)
What is a schild plot?
Graph based on the dose ratio (or concentration ratio) that allows to measure how competitive antagonists interact with a receptor
dose ratio: ratio of agonist EC50 in the presence vs absence of atagonist
- done for multiple concentrations of antagonist
How do you calculate dose ratio?
Dose ratio = [EC50 (in presence of antagonist)] / [EC50 (control)]
The x-intercept of a Schild plot is sometimes called the _____ or _____ and reflects the ________
The x-intercept of a Schild plot is sometimes called the pA2 or pKi and reflects the potency of the antagonist
Competitive antagonists shift the ________ of an agonist, but do not change the ________
Competitive antagonists shift the apparent potency of an agonist, but do not change the efficacy (maximal response)
Provide an important example of a competitive antagonist (think opioid overdose)
Naloxone (‘Narcan’) is a competitive non-specific opioid receptor antagonist used as an antidote for opioid overdoses
Why might more than one naloxone administration be required to rescue an opioid overdose victim?
A single dose might not be sufficient if the overdosing patient has a large concentration of opioids
ie you would need a higher concentration of Naxolone to compete with the opioid
How can partial agonists act as antagonists?
By competing for binding with the full agonist - lead to decreased overall response
What is irreversible competitive antagonism?
Where the antagonist binds irreversibly to the drug binding site (cannot be displaced by increasing [agonist]) and reduces the apparent efficacy of the agonist
aka “non-competitive antagonism”
A pure Non-competitive Antagonist will have what effect?
Non-competitive antagonist will reduce agonist efficacy but NOT potency (ie will not shift EC50); no matter how much agonist is administered, a full effect cannot be observed.
Does not compete for drug binding site but instead binds to a different location on the receptor and alters agonist effect
What is an allosteric potentiator?
Drugs that, when bound to allosteric site, enhance the receptor response to agonist binding
Can enhance efficacy or potency or both
What causes non-competitive inhibition?
Antagonist binding at a distinct site from the agonist (called the allosteric site)
What effects might occur from the binding of the antagonist to an allosteric site?
- might prevent activation of the agonist bound receptor (pure non-competitive antagonism)
- binding of the antagonist might alter the properties of the agonist binding site leading to a combination of effects on potency and efficacy
Describe the equations shown in the image:
E:
Emax:
EC50:
B
Bmax
Kd
Describe the equations shown in the image:
E: Biological Effect
Emax: Efficacy Maximum Effect
EC50: [Drug] that gives you 50% of the maximal effect (Emax)
B: Binding
Bmax: maximal # of receptors that can be bound (usually 1)
Kd: Dissociation constant = chemical constant where you have 50% binding of receptors
Why can there be a mismatch between binding and effect?
Provide an example using GPCR
Often there are more receptors present than are required for activation of a full biological effect
eg
activation of a single GPCR can lead to generation of many cAMP molecules and activation of many effector proteins. Because of this amplifying effect, there is not a direct relationship btwn agonist binding and biological effect
What is receptor reserve?
The difference between binding and effect
- measure biological effect in the presence of increasing concentrations of an irreversible antagonist
- prevents receptors from being activated (A, B, C)
- full biological effect is observed
- In C, D, E all the receptors are involved in generating the biological effect, so the Kd and EC50 are similar
