Pharmacodynamics II Flashcards
Spare receptors exist when
It is possible to elicit a maximum
biological response without occupying all of the available receptors.
When spare receptors exist, what happens to the concentration-response curve (EC50)?
EC50 is shifted to smaller concentrations (left)
When spare receptors exists, how is Kd effected?
Kd remains the same
If EC50 is lower than Kd then there are
Spare receptors
In the case of spare receptors, is the maximal response still produced?
Yes, the maximal response is still produced due to amplification of the cell signaling mechanism
What is the clinical implication of spare receptors?
Use a lower dose
How do competitive antagonists effect ED50 and Emax?
ED50 of agonist increases Emax does not change
How do non-competitive antagonists effect ED50 and Emax?
ED50 may/maynot change
Emax decreases
Do competitive antagonists bind to the same or different receptor site as agonist?
Bind to same receptor site as agonist
How do competitive antagonist effect affinity of an agonist for its receptor?
Decrease affinity (increase Kd) of an agonist for its receptor
What is the relationship between competitive antagonist and potency of agonist?
As antagonist concentration increases, potency of agonist decreases (increase EC50)
With the addition of a competitive antagonists would the curve for agonist shift to the left or right?
Right
Do competitive antagonists have an effect on maximal response?
No
Can the effects of a competitive antagonist be overcome?
Yes, effects can be overcome by increasing dose of agonist
What are the two mechanisms for non-competitive antagonists
- Inhibit agonist binding at active site by binding to a secondary site on the receptor (allosteric)
- Irreversibly (covalent) bind to the same site as an agonist
How do non-competitive antagonist effect affinity and potency of an agonist for its receptor?
Affinity (Kd) and potency (EC50) may or may not change
How do non-competitive antagonist effect Emax and Bmax?
Decreases Emax and Bmax
Can the effects of a non-competitive antagonist be overcome?
No
Explain physiologcial/functional antagonism and give an example
Two drugs that act on different receptors or by different mechanisms, to counteract effects of agonist
Ex: Reversing a fall in blood pressure produced by histamine with epinephrine
Explain chemical antagonism
Directly interacts with agonist and inactivates it
Partial agonists have higher/lower efficacy than full agonist?
Lower efficacy (α); cannot produce the same maximal response as full agonists
The dose response curve for a partial agonist will have higher/lower Emax and Bmax?
Lower Emax and Bmax
What are the effects of a single concentration of full agonist and increasing concentrations of partial agonist?
Response caused by full agonist decreases
Response caused by partial agonist
increases
Total response gradually decreases
Partial agonists can act as competitive antagonists in the presence of ____?
Full agonist
The particular agonist binds to the receptor, displacing the agonist, and the overall effect is lower.
What is an example of molecule that binds to intracellular receptors and how do they work?
Lipid soluble ligands (hormones, steroids)
Modify gene transcription
Are the effects of intracellular receptors
a) immediate or slow
b) short-term or long-lasting
a) Effects are not immediate
b) Effects are long lasting
What is a common transmembrane receptor?
Tyrosine kinase receptors
How do transmembrane receptors work?
Self phosphorylation
Tyrosine kinase receptors activate what pathway?
What are examples?
Activate the Ras/Raf signaling pathway
- Insulin
- Epidermal and nerve growth factor
- Platelet-derived growth factor
Cytokine receptors activate what pathway?
What are examples?
Activate JAK/STAT
- Growth hormone
- Erythropoietin
- Interferons and interleukins
What are 2 examples of ligand ion channels?
Acetylcholine binding to nicotinic receptors
GABA (benzodiazepines, barbiturates, ethanol)
Do ion channels have a slow or rapid response?
Very rapid response
How do G-protein coupled receptors work?
Signal amplification
Gs (stimulatory) increases cAMP
Gi (inhibitory) decreases cAMP
Gq activates PLC
Ca2+ release
DAG activates PKCAre βeta receptors activated by Gs, Gi, or Gq?
Gs
Are α2 receptors activated by Gs, Gi, or Gq?
Gi
Is desensitization reversible or irreversible?
Reversible, a second exposure to agonist will produce the response again
Stimulation of G-protein receptors either stimulate or inhibit the formation of
cAMP
Polyphosphoinositide signaling uses ___ proteins to activate ___
Gq
PLC
Polyphosphoinositide signaling and Gq proteins have what effect on Ca and kinases?
Increase Ca
DAG activates protein kinase C (PKC)
Are α1 receptors activated by Gs, Gi, or Gq?
Gq
Cyclic GMP uses nitric oxide (NO) because
it is diffusible and can be synthesized in one cell and exert its effect in another cell
If a system has spare receptors then
- The dose response curve shifts to the right
- The dose response curve does not change
- The dose/response curve shifts to the left
- The maximal binding (Emax) decreases
- The EC50 and Kd are the same
The dose/response curve shifts to the left
An agonist has:
- High efficacy but low affinity
- Intrinsic activity of zero
- Both efficacy and affinity
- High affinity but no efficacy
- Both efficacy and affinity
A drug is a competitive antagonist. Therefore:
- It has low affinity for the receptor
- It binds irreversibly to the receptor
- It has higher efficacy than a partial agonist
- It can be displaced by a large enough concentration of agonist
- It can be displaced by a large enough concentration of agonist
In the presence of a partial agonist, why doesn’t the dose response curve start at zero?
Because the partial agonist itself causes some stimulation of the receptor
Desensitization is generally mediated by what?
Phosphorylation
What does it mean if a biological effect is amplified?
The biological response is greater than the degree of receptor occupancy (g proteins)
What does cGMP cause?
Relaxation of smooth muscle
