Pharmacodynamics -> lecture 3 Flashcards
What is pharmacodynamics?
How the body deals with drugs
What are the two main modes of drug action?
Receptor activators => agonists.
Receptor blockers => antagonists.
What are receptors?
Proteins in membrane that bind neurotransmitters + cause cell response.
What are the different types of receptors?
- Ligand gated ion channels.
- GPCRs.
- Kinase-linked.
- Gene transcription.
What are agonists?
Receptor activators
What are the steps by which agonists activate receptors?
- Agonist binds to receptor.
- Agonist bound to receptor forms AR complex.
- Receptor is conformationally changed.
- Causes a response e.g. muscle contractions.
What will make agonists bind to receptors better?
- Higher affinity = easier binding.
What would cause an agonist to switch on a receptor better?
- Higher efficacy = better activator.
What would cause an agonist to produce a higher response?
- Higher potency = larger response.
What does a log (conc)-response curve of an agonist show?
- Shows maximum response via sigmoidal curve (top of peak).
- Can calculate the EC50.
What is the EC50?
- The conc of agonist that produces 50% of maximum response.
What is the maximum response?
- The response when all receptors are occupied (also called saturated response).
Affinity vs Efficacy vs Response how is the max response and EC50 affected?
- High efficacy = close to high max response.
- Low efficacy = lower response.
- Same affinity = same EC50 => but efficacy can change max response.
What is Kd?
The conc of drug that is required to occupy 50% of receptors.
How does Kd link with affinity?
Lower the Kd = Higher affinity.
(lower conc needed to occupy 50% so higher affinity).
How to measure affinity?
- Use a ligand binding assay:
–> cannot measure response as is affinity + efficacy.
What are the steps for a ligand binding assay?
Radio label drug (H, C, I) to make it hot, outcompete hot drug w cold ligand.
What are the issues with Kd?
- Doesn’t take into account non-specific binding.
How to take into account the non-specific binding?
- Make [radio drug] high enough so can’t be outcompeted.
- Measure non-specific binding + subtract from total to get specific.
Can receptors be desensitised?
Yes
How can receptors be desensitised?
- If agonist + receptor bound for too long.
What is the difference between desensitisation and tachyphylaxis?
Tachyphylaxis = whole tissue stops responding due to desensitisation.
What does it mean if a max response isn’t produced?
- Partial agonists present.
What are partial agonists?
- Reduced effects of the agonists => doesn’t fully block basal activity.
When are partial agonists useful?
- Useful when want lower adverse effects.
What are inverse agonists?
- Produces a response that is opposite to an agonist.
- Switches off receptor activity after binding.
What are competitive antagonists?
- Compounds that bind to a receptor without any activity.
- These block the receptors from being able to accept an agonist or inverse agonist.
What is the efficacy of a competitive antagonist?
0% efficacy.
What do competitive antagonists do to EC50?
- Increase the EC50, (more agonist is needed to produce same response).
How to measure the potency of a competitive antagonist?
- How good are they at blocking agonist effects.
- pA2 => bigger = better antagonist.
How to calculate pA2 of antagonist?
pA2 = negative log of [antagonist] reduces effect of [agonist] to half its original conc.
What are non-competitive antagonists?
- Antagonists that cannot ever reach max response.
- Cannot be outcompeted by [agonist]
- Bond covalently to receptors (why they can’t be outcompeted).
What are spare receptors?
- To get full response => not always 100% saturation of receptors.
- Sometimes only need 80% so 20% = spare.
How to measure how many spare receptors?
- Measure via the addition of irreversible antagonists.
Will Kd always = EC50 if there are spare receptors?
No, if there are spare receptors = don’t need to occupy 50% for full response.
What are the theoretical reasons for there being spare receptors?
- Increases system sensitivity.
- Additional receptors mop up excess agonist to stop over the top response.
What are use-dependent drugs?
Activity-dependent drugs i.e. compounds whose effectiveness increases w activity or use.
What do use-dependent drugs target commonly?
- Bind to ion channels or receptors.
What happens as the receptor is used more to the drug if it is activity-dependent?
- The more the receptor is used = more drug is active and binds.
