Pharmacodynamics 2 - Partial Agonists & Antagonists Flashcards
What is the difference between full and partial agonists?
Full agonist
- EC50 < or = to Kd
- +/- spare receptors
- higher intrinsic activity
Partial agonist
- EC50 about Kd
- no spare receptors (all receptors occupied but insufficient intrinsic activity for maximal response)
- lower intrinsic activity
What is intrinsic activity?
Measure of maximal response.
Why do partial agonists have a lower intrinsic activity than full agonists?
They have lower efficacy - usually lower intrinsic efficacy (don’t quite stimulate correct conformational change).
May still have high potency due to high affinity.
How can a partial agonist be changed into a full agonist?
- By increasing receptor number - still has low intrinsic efficacy at each receptor but sufficient receptors to generate a full response.
- Partial agonism is compound and system dependent.
What are the different types of antagonism?
- Reversible competitive antagonism (most common)
- Reversible non-competitive antagonism
- Irreversible antagonism
What is reversible competitive antagonism?
- Antagonist competes with agonist for binding site.
- Greater [antagonist] = greater inhibition.
- Inhibition is surmountable by increasing [agonist].
What is IC50?
- Concentration of antagonist giving 50% inhibition (50% agonist response).
- Index of antagonist potency.
What is the effect of a reversible competitive antagonist on [agonist]-response curve?
Parallel shift to the right
Give a clinical example of a reversible competitive antagonist.
- Naloxone = high affinity, competitive antagonist at u-opioid receptors.
- Can be used clinically in reversal of opioid-mediated respiratory depression (e.g. In heroin overdose).
What is irreversible competitive antagonism?
- When the antagonist dissociates slowly or not at all from the receptor.
- Non-surmountable
What is the effect of a irreversible competitive antagonist on [agonist]-response curve?
- Causes a parallel shift to the right
- At higher concentrations, suppresses the maximal response (as insufficient receptors)
Give a clinical example of an irreversible competitive antagonist.
- Phenoxybenzamine = non-selective irreversible alpha1-adrenoreceptor blocker used in hypertension episodes in pheochromocytoma (tumour of adrenal chromaffin cells).
- Inhibits the vasoconstriction stimulated by excessive adrenaline/NA binding to alpha1 adrenoRs.
What is non-competitive antagonism?
- Generally allosteric, sometimes post-receptor.
- Binding to allosteric site reduces orthosteric ligand affinity and/or efficacy.
Give a clinical example of a non-competitive antagonist.
Maraviroc used in AIDS: negative allosteric modulator of chemokine receptor 5 (CCR5) - blocks HIV entry into cells.
What is the effect of opioids?
Act primarily through u-opioid receptor (GPCR) in:
- pain relief
- euphoria
- BUT respiratory depression - can lead to death