SESSION 6 Flashcards
Define a ligand
A molecule that binds to another molecules
Define affinity
The degree to which a substance tends to combine with another
To bind to a receptor a ligand must have affinity for the receptor
Higher affinity -> stronger binding
Define partial agonist
Drugs that bind to/ and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist
All receptors occupied- insufficient efficacy fro maximal response
Low intrinsic efficacy
Define intrinsic activity/ efficacy
The ability of a ligand to cause a response (receptor activation)
Efficacy is governed by intrinsic efficacy
The number of receptors, influence the response
Define functional antagonist
An antagonist may act as a completely separate receptor, initiating effects that are functionally the opposite of the agonist
Define reversible competitive antagonism
a receptor antagonist that binds to a receptor but does not activate the receptor.
The antagonist will compete with available agonist for receptor binding sites on the same receptor
- the inhibition is surmountable
Relies on dynamic equilibrium between ligands and receptors
Cause a parallel shift to the right of the agonist concentration- response curve
Define irreversible competitive antagonism
A type of antagonist that binds permanently to a receptor, either by forming a covalent bond to the active site that does not dissociate or dissociates too slowly
Non surmountable
- with increased antagonist or increased time more receptors are blocked
Cause a parallel shift to the gist of the agonist concentration- response curve
And at high concentrations suppress the maximal response
Define non- competitive antagonism
Non- competitive antagonism is when the antagonist binds to an allosteric site of the receptor
No competition for binding site- reduce orthosteric ligand affinity and/ or efficacy
Define agonist
A substance which initiates a physiological response when combined with a receptor
Define antagonist
A substance which interferes with or inhibits the physiological action of another
What is drug action determined by?
The concentration of drug molecules around receptors
What is the significance of molarity?
An international unit of measure- allowing easy comparison
LEARN MOLE CONCENTRATION TABLE
What is drug- receptor interactions governed by?
Binding governed by association and dissociation
What is the difference between agonists and antagonists in terms of efficacy?
Agonists:
- have intrinsic efficacy- activate the receptors
- have efficacy- cause a measurable response
Antagonists:
- only have affinity
- no efficacy as the receptor is not activated
How do we measure drug -receptor interactions by binding?
- bind radioactively labelled ligands to cells
- these radio ligands enable us to track and measure the drug- receptor interactions
Define Bmax
Bmax is the maximum binding capacity- all the receptors are saturated, adding more ligand will have no further effect
Define Kd
Kd is the dissociation constant
Kd is the concentration of ligand required to occupy 50% of the available receptors
Indicated the strength of interaction
Kd- index of affinity
Lower value = higher affinity
Is affinity important for ligand?
High affinity allows binding at low concentrations
As a result sensible seized tablet can be given
Define Emax
Emax is the effective maximum response achievable from an applied or dosed agent
Define EC50
Effective concentration giving 50% of the maximal response
This is a measure of agonist potency
It depends on both affinity and intrinsic efficacy
Define potency
The generation of a measurable response to efficacy and affinity
Affinity + efficacy = potency
Same potency could occur with different combinations of affinity and efficacy
What is required for a ligand o have potency (generate a measurable response)?
1) ligand binding to the receptor- affinity
2) receptor activation - intrinsic efficacy
3) things to happen to generate measurable response
2&3 are efficacy
Define concentration
Known concentration of drug at site of action
E.g. In the cells or tissues
Define dose
Concentration at site of action unknown
E.g. Dose to a patient in mg
Using asthma as an example explain the clinical relevance of receptor selectivity
Asthma results in the airways contracting
It is treated by adrenaline- attaches to B2- adrenoreceptors (GPCR)- causing the airways to relax
Problem:
It is hard to create a drug that is specific to B2 - adrenoreceptors
As B1 receptors are very similar and result in increased contraction of the heart
How do we achieve selectivity in treating asthma?
Salbutamol
Small difference in affinity but large difference in efficacy so doesn’t activate b1
Salmeterol:
- No selective efficacy
- Selectively based on affinity
- B2 affinity is a lot higher
Salbutamol cannot be given to people with heart problems as it isn’t;t selective enough
May result in angina- sipped up of the heart
Define spare receptors
The situation in which maximum tissue response occurs when not al the receptors of the tissue are occupied by the drug
What factors other than the number of receptors limit response?
- a muscle can only contract so much
- a gland can only secrete so much
Why are spare receptors important?
Spare receptors increase sensitivity
- allow response at low concentrations of agonist
10% occupancy of muscarinic receptors –> 90% of receptors are spare
What is the relevance of altered receptor number ?
Changing receptor number changes agonist potency
- and can affect the maximal response
Tend to increase with low activity (increase regulation)
Tend to decrease with high activity (down regulation - result in tolerance with reference to drugs)
Define full agonist
Full agonists have affinity for/ and activate a receptor, producing full efficacy at that receptor
Often endogenous ligands
What is the relevance of partial agonists?
- allow a more controlled response
- work in the absence of low levels of endogenous ligands
- act as antagonist if high levels of full agonist
Give an example of a partial agonist
Buprenorphine- higher affinity but lower efficacy than morphine
Advantageous to morphine in some clinical settings:
- pain control
- less respiratory depression
If a heroin addict is placed on buprenorphine they may become ill as a result of withdrawal symptoms
Buprenorphine will inhibit the effect of heroin, ie. partial agonist
Are partial agonists always partial agonists?
NO:
- increasing receptor number can change partial agonists to full agonists
- partial agonist still has low intrinsic efficacy at each receptor
- BUT sufficient receptors to generate a full response
Define IC50
IC50- index of antagonist potency
Determined by strength of stimulus (ie. agonist)
Give an example of an irreversible competitive antagonist that is used clinically
Phenoxybenzamine- non- selective irreversible a1- adrenoceptor blocker used in hypertension episodes
Pheochromocytoma - tumour of adrenal chromaffin cells
Resulting in excessive adrenaline
Phenoxybenzamine prevents vasoconstriction by a1- adrenoreceptors
Give an example of a non- competitive antagonist that is used clinically
Maraviroc:
- negative allosteric modulator of chemokine receptor 5
- used in AIDs treatment
- usually used by HIV to enter the cells
