6.2 Pharmacodynamics 2 Flashcards
What do we see on the [Drug] Log10 (M) vs response graph for the following things:
- Binding (occupancy)
- Response (affinity + efficacy)
Why?
Both are sigmoidal curves
- Binding usually further to the right
- Response usually further to the left
- because <100% occupancy = 100% response
(Not all receptors need to be occupied to get the full effect)
What are spare receptors? Their significance?
- Not all receptors need to be occupied to get full response effect. The receptors that are extra are called spare receptors.
- they increase sensitivity to a ligand and allow responses at low concentrations of agonist
- common in amplification in signal transduction pathway
Give a clinical example associated to spare receptors.
Parasympathetic nerves release ACh Acts upon M3 GPCRs Contraction of airway smooth muscle (lung) 10% occupancy = maximal contraction 90% spare!
What is up-regulation and down-regulation? Why does it make drug giving difficult?
Up regulation - increase of number of receptors requiring occupancy for max response (happens with low activity)
Down regulation - decrease of number of receptors requiring occupancy for max response (happens with high activity)
Drug giving difficult as can contribute to tolerance/tachyphylaxis
On the [Drug] (log10M) vs Response (%) curve, where would the curve be for following:
- 10% occupancy = full response
- 50% occupancy = full response
- 100% occupancy = full response
- 100% occupancy but insufficient receptors for full response
Sigmoidal curves
- Furthest left
- Kd in the middle of 1 and 3
- To the right
- Furthest right and lower in height curves as full response not reached
Note - height of sigmoidal curve indicates increasing intrinsic activity. Curve further to left indicates higher potency
What is a full agonist?
What is a partial agonist?
1. Agonist induces 100% response EC50 < Kd 2. Same conc of agonist but max response 50% EC50 =approx Kd I.e. Low intrinsic efficacy
Why are partial agonists useful? Give an example. A
Allow a more controlled response
Can act as an antagonist if high levels of full agonist
E.g.
Morphine and buprenorphine
Buprenorphine doesn’t give max response (low efficacy) but kd is very low so high affinity
Advantage is that can control pain with less risk of respiratory depression
How can partial agonist create 100% response?
If enough receptors are stimulated partially, may equate to 100% response
- inc receptor number can change partial agonist to full
- note they still have low intrinsic efficacy, but sufficient receptors activated to get full response
Three types of Antagonism?
- Reversible competitive antagonism
- Irreversible competitive antagonism
- Non-competitive antagonism
What is reversible competitive antagonism?
Shape of curve on [Antagonist] Log10 M vs response?
What value can be extrapolated off of the graph?
Adding [antagonist] has what effect on [agonist] vs response graph?
- Competition between agonist and antagonist
- Putting more antagonist, out compete agonist, greater [antagonist], greater inhibition and vice versa
- Backward sigmoidal
- IC50 - conc of antagonist giving 50% INHIBITION
- index of antagonist potency - Moves sigmoidal curve to right as potency for agonist decreasing!
What is irreversible competitive antagonism?
Adding [antagonist] has what effect on [agonist] vs response graph?
- Competition between agonist and antagonist but when antagonist binds, cannot come away again (high affinity for receptor)
- doesn’t matter how much agonist added, antagonist will not be surmounted - Causes a parallel shift to the right, and then at higher concentration suppresses maximal response (goes to right and dec in height)
What is non-competitive antagonism?
How does this provide opportunity for novel drugs?
- Ligand binds to allosteric sites (not active site!)
- no competition but reduces affinity and efficacy - B1 and B2 receptors have similar active sites, but allosteric sites are different and can design a drug targeting that region instead!
