2. Drug-Receptor Interaction - Antagonists (1) Flashcards
What is a receptor?
Protein target with which a naturally occurring chemical mediator binds specifically to initiate a cellular response
What are the two classes of chemical mediator?
Molecules that are too big to pass membrane and rely on CSM receptors
Molecules that are small enough to pass through and directly activated by intracellular receptor proteins
What will the binding of a chemical mediator result in?
Causes a shape change which stabilises active form of receptor, enhances interaction with signal transduction mechanisms
What are the two stages of interaction for drug action?
Binding
Activation
What are the two stages of interaction for drug action?
Binding
Activation
What are the two categories of drug interaction?
Category 1 agonist bind and activate mimics action of chemical mediator will be a response
Category 2
receptor antagonist- binding of chemical mediator or agonist drug blocked
bind but do not activate
no response
What are the 5 factors that affect size of response to a receptor agonist?
- Concentration of drug in vicinity of receptor at a given time
- Affinity - tendency to bind, strength of attraction between agonist and receptor
- Intrinsic efficacy- ability to activiate a shape change leading to repsonse
- Nature of receptor-response coupling “signal transduction mechansm”
- Total number of receptors present
How does the size of response from the agonist-receptor complex?
Proportion of receptors occupied by agonist
How does the size of response from the agonist-receptor complex?
Proportion of receptors occupied by agonist
When does the maximum response to agonist occur?
When all receptors for that agonist that are present in that tissue are occupied by agonist
What does the proportion of the total receptors available which are occupied depend on?
Agonist conc
Strength of bonds formed
What is Ka?
Equibibrium constant- sometimes called the dissociation constant - for agonist drug A
Characteristic of the drug-receptor complex and has dimensions of conc
What is the eqn of occupancy?
[Xa]/[Xa] + Ka
What happens when Ka is a very small value?
The occupancy at a given agonist drug conc tends towards 100%
What happens as the numerical value of Ka increases?
Proportion of occupied receptors at a given agonist conc decreases
What is meant when Ka=Xa?
and why?
Ka is numerically equal to the conc of agonist when half od the total receptors present are occupied
increase in Ka means a decrease in affinity of agonist for receptor
How does actual response vary with agonist conc?
Biological response to agonist is usually measured downstream in a cell or tissue
muscle set up under controlled conditions in a bath and agonist is added and response is recorded on a computer screen
What is EC50?
a practical, indirect, measure of Drug A’s potency, measured downstream of receptor – relates agonist drug A’s concentration to biological effect produced as a consequence of occupancy
The effective conc to produce 50% maximum response
What is the effect of an increase in EC50?
A decrease in potency
What are the properties of agonist receptor complex?
The ability of an agonist when binding to a receptor to activate a change in shape to the receptor
conformational changes reuired to couple to occupied signal transduction mechanism
Why do full agonists have an intrinsic efficacy of 1 (100%)
They are efficiently coupled to initiation of signal transduction mechanism
They evoke the maximum shape change response with which the receptor protein is capable.
Why do partial agonists have an intrinsic efficacy value between 0 and 1?
Less efficiently coupled to initiation of signal transduction mechanism
evoke less than the max shape change response of which the receptor is capable
What are inverse agonists?
Can
What are inverse agonists?
Can couple to and casue some activation of signal transduction even when not occupied by agonist
