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Flashcards in SESSION 6 Deck (37):

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



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?

- have intrinsic efficacy- activate the receptors
- have efficacy- cause a measurable response

- 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

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?

Small difference in affinity but large difference in efficacy so doesn't activate b1

- 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?

- 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

- negative allosteric modulator of chemokine receptor 5
- used in AIDs treatment
- usually used by HIV to enter the cells