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
Name an example of an agonist and a partial agonist of u-opioid receptors. Which has the higher affinity and efficacy?
- Agonist = morphine
- Partial agonist = buprenorphine
Buprenorphine has lower Kd so higher affinity, but lower efficacy (inability to produce full response).
Why can buprenorphine be used in the treatment of opioid addiction?
- Enables gradual withdrawal.
- Prevents use of other illicit opioids as can provide antagonism: has higher affinity than heroin so occupies receptors and limits response.
Which receptors are targeted by agonists used in asthma treatment?
- Stimulation of beta2-adrenoreceptors in lungs to promote bronchodilation (smooth muscle relaxation).
- But may also act on other beta-receptors, e.g. Beta1 in heart - increases inotropy and chronotropy.
Name 2 drugs used in the treatment of asthma.
- Salbutamol
- Salmeterol
Which problems are associated with the use of salbutamol?
- Has a Kd of 20uM for Beta1 Rs, and of 1uM for Beta2 = only 20-fold more beta2 selective.
How is the utility of salbutamol enhanced despite poor beta2 selectivity?
- Has beta2-selective efficacy (less drug required to activate beta2 than beta1).
- Route of administration (preferentially target airways).
Describe the selectivity of salmeterol for beta adrenoRs. What is it based on?
- Has Kd of 1900 nM for Beta1, and of 0.55 nm for Beta2 - 3455-fold more Beta2-selective.
- Has no selective efficacy (once bound will bind to anything) - selectivity is based on affinity.
