2. Drug - Receptor Interaction (Agonists) 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 mediators?
- Cell surface receptors as they are too big to pass through the cell surface membrane
- Intracellular receptors - molecules that are small enough and hydrophobic can pass through the membrane
How do receptors work?
They undergo a subtle change in shape which allows for the effect of the chemical mediator to be apparent. The chemical mediator on binding causes a shape change which stabilises the active form of receptor which enhances the interaction with signal transduction.
What are the two stages on interaction?
Binding and activation
What are Beta-1 adrenoreceptor, (Nor)adrenaline, Dobutamine and atenolol
Beta 1-adrenoreceptor is a receptor, it is what the agonist, antagonist and mediators act on, (Nor)adrenaline is a mediator, Dobutamine is an agonist, and atenolol is an antagonist.
What is the difference between, agonist, and antagonists?
Dobutamine - agonist - binds and activates
Atenolol - antagonist - binds but cannot activate
What are five factors that affect the size of a response to a receptor agonist?
- Concentration of drug in vicinity of receptor at a given time - which is influenced by dose, route, distribution
- Affinity - tendency to bind, i.e. the strength of attraction between receptor and agonist
- Intrinsic efficacy - ability to activate a shape change leading to a response
- Nature of receptor-response coupling, signal transduction mechanism
- Total number of receptors present
What is receptor occupancy?
The interaction between the agonist and the receptor, the size of the response will vary with the proportion of receptors occupied by agonist
What is the maximum response?
All receptors for that agonist that are present in the tissue are occupied by the agonist
What does the proportion of receptors available depend on?
The agonist concentration and the strength of the bonds formed
What is the rate of a reversible reaction proportional too?
The product of the concentration of the reactants.
What is the equation for occupancy?
Occupancy = [Xa] divided by [Xa] + Ka
What is the explanation of a big and small Ka?
When Ka is small the occupancy at a given agonist drug concentration tends towards 100%, a higher Ka means that the proportion of receptor-agonist complexes decreases
At 50% occupancy what does Ka equal?
Ka = Xa when half of the receptors are occupied
How do you know if the bonds between the receptor and agonist are strong?
Ka is very small i.e pico molar
Where will the curve shift when there is a larger Ka
To the right
What does occupancy depend on?
Ka and Xa where Xa = the concentration of agonist in vicinity of receptors and Ka is a theoretical measure of affinity of Drug receptors
How does actual response vary with agonist concentration
A muscle strip is set up in an organ bath containing suitable physiological medium, the agonist is added and response measured e.g. the force of contraction and a graph plotted
What is EC 50 ?
The effective concentration to produce 50% of maximum response.
What is the explanation of an increasing EC50?
An increased EC50 results in decreased potency.
What is the intrinsic efficacy of an agonist-receptor complex?
The ability of an agonist on binding to a receptor to activate a change in shape
What are full and partial agonists?
Full agonist - Produces the maximum response of which the tissue is capable on activation of all of that population of receptors
Partial agonist - Produces a smaller response even at very high concentrations
They can even have the same potency.
What is the intrinsic efficacy of full agonists?
+1 or 100% - they are efficiently coupled to initiation of signal transduction mechanism
What is a full agonist of Beta 1 adrenoreceptors?
Dobutamine
What is the intrinsic efficacy of partial agonists?
between 0 and +1, they are less efficiently coupled to initiation of a signal transduction mechanism
What is a partial agonist of Beta 1 adrenoreceptors?
Pindolol
What are inverse agonists?
They cause a negative shape change which stabilises inactive state of receptor and reduces the effect of basal activity
What is the intrinsic efficacy of inverse agonists?
Between -1 and 0
What is transduction?
Relay of molecules in a signal transduction pathway
What are the different types of coupling that can affect the extent of amplification?
- Chemical gated ion channels
- Activation of G-proteins linked to ion channels or enzymes
- Direct activation of enzymes
- Regulation of gene transcription
What is occupancy?
A proportion of the total number of receptors that are in an agonist-receptor complex
What is the equation for the size of a response to an agonist?
Look in notes
What can explain the reduction in the size of response of chronic exposure to an agonist drug?
- Increased metabolism
- Altered characteristics of agonist receptor complex
- Down-regulation of signal transduction
- Reduction in the number of receptors
- Reflex activation of opposing physiological pathways
