ICPP 15 - Pharmacodynamics 2 Flashcards
What determines the potency of a pharmacological compound?
- Both the affinity (Kd) and the intrinsic efficacy (EC50).
Explain the functional antagonism that occurs in asthma.
Describe why therapeutic targets for asthma must be selective?
- Asthma leads to contraction of airways, however endogenous activation of B2 adrenoreceptors cause relaxation (functional antagonism).
- If we target B-adrenoreceptors others in the body will also we affected, e.g.: B1-Adr’s in the heart which will increase rate and force of contraction - therefore they must be B2 receptor specific.
What properties make drugs have enhanced selectivity
Either:
1) Increased efficacy at a particular receptor (e.g.: salbutamol at the B2 receptor) - even though it has poor selectivity.
OR
2) Increased affinity for the receptor (e.g.: salmeterol at the B2 receptor)
What can we infer about a receptor population if less than 100% occupancy of those receptors produces a maximal (100%) response?
That there are “spare” receptors - not all receptors are required to be bound in order for the maximum response to be produced.
Example: 10% occupancy of muscarinic receptor leads to maximal contraction - therefore 90% of receptors are “spare”.
Why is it possible to have “Spare” receptors and a maximal response?
What kind of receptor populations is this often seen in?
- Due to amplification of signal in transduction pathway.
- Tyrosine kinase or GPCR’s (as they undergo amplification)
Why is it useful for a receptor population to have “spare” receptors?
As it increases the sensitivity/potency of the agonist - i.e.: allows responses at low concentrations of agonist.
If 10,000 receptors are required for a maximal cell response, what happens to the potency of an agonist at
- 100,000 receptors?
- 10,000 receptors?
- 5,000 receptors
- 10% occupancy produces full response, therefore potency of agonist is increased, curve shifts to left.
- 100% occupancy produces full response, potency of agonist is reduced compared to 100,000 receptors
- 100% occupancy cannot produce maximum response, as there are insufficient receptors.
When do receptor populations upregulate and downregulate?
- Upregulate when activity is low (to increase sensitivity)
- Down-regulate when activity is high (to decrease sensitivity) - this can contribute to drug tolerance/withdrawal symptoms.
What is the difference between a partial and full agonist?
- A partial agonist cannot elicit a maximum response even when all receptors are bound
- A full agonist can produce a maximum response and may also have “spare” receptors.
Is it possible to convert a partial agonist into a full agonist?
Yes - if we increase receptor population such that they now have “spare” receptors.
Why is the partial agonist buprenorphine used to treat opioid addiction and heroin overdose?
Partial agonist can have mixed agonist/antagonist activity. Buprenorphine binds to the same receptor as heroin with a higher affinity, however its intrinsic efficacy is lower, so limits the response and antagonises heroin.
What are the 3 main kind of antagonists?
1) Reversible competitive antagonists
2) Irreversible competitive antagonists
3) Non-competitive antagonists
How do reversible competitive antagonists work and what pharmacodynamic effects do they have on agonist responses? (include effects on concentration response curve)
- They bind reversibly to the active site and compete for the active site with the agonist.
- Their response is surmountable, i.e.: they increase the EC50 for the agonist, and thus reduce its potency, however the effect can be overcome by adding more agonist. (Emax unaffected).
- They cause a parallel shift to the right of concentration-response curve.
Give a clinical example of reversible competitive antagonism.
Naloxone - high affinity competing with heroin/opioid respiratory depression causing drugs at U-opioid receptors.
How do irreversible competitive antagonists work and what pharmacodynamic effects do they have on agonist responses (include effects on concentration response curve).
- They bind covalently/irreversible to active site and compete with agonist.
- Their response is Non-surmountable, they increase EC50 for agonist, and thus reduce its potency - effect can not. be overcome by adding more agonist.
- Cause a parallel right shift to the concentration response curve AND suppress Emax/maximum response as insufficient receptors are available to elicit it.
