Drug Receptor Interactions Flashcards
What are receptors ?
Receptors are specialised, localised proteins whose role it is to recognise stimulants and translate this event into an activation of the cell.
Describe the interaction between drug and receptor
Interaction is loose & freely reversible and does not involve strong chemical bonds.
Agonist
Recognise the active site of the receptor as its chemical structure has a similarity to the binding site
Once it binds to the receptor, the agonist can cause a response.
Antagonist
Recognises the active site of the receptor.
Once it is bound to the receptor it does not cause a response.
Difference between agonists and antagonists
Agonists bind and cause a response, whereas antagonists just bind, and do not have a response.
State the 4 receptors (regulatory protein families - commonly drug targets)
Enzymes
Carrier molecules (transporters)
Ion channels
Neurotransmitter, hormone or local hormone receptors
How can drug receptor relationship be compared to ?
Lock and Key relationship
- Drug unlocks the response
- specificity of the lock is relative
- Lock may be jammed
Describe the rules of drug receptor theory
Agonists and Antagonists :
Both bind same receptor and so must have chemical similarities.
One activates the receptor, the other does not : must also have chemical differences.
Law of Mass Action
The rate of a chemical reaction is proportional to the product of the concentration of the reactants.
Equation for Law of Mass action (applied to pharmacology)
[D] + [R] <=> [DR]
[D]
Concentration of drug
[R]
Concentration of receptors
[DR]
Concentration of occupied receptors
K1
Rate constant for associations
K2
Rate constant for dissociations
What happens as you add drug to the law of mass action ?
There will be a rate of associations (K1 x [D] x [R])
Also a rate of dissociations (K2 x [DR])
Affinity of binding
How tightly a compound is bound, how difficult it is to dissociate.
Non-Specific binding
As more drugs are added and the tissue is saturated, most of the drug will bind to the active site, but some drug will also bind to the receptor or to the tissue in a random fashion.
Won’t bind to the active site, will bind randomly.
How can you measure non-specific binding ?
Bound drug to receptor.
Flush the system with unbound drug.
Unbound drug will displace the bound drug at the active site (as it recognises the active site).
Freely reversible
As the labelled drug comes off, and as you add more and more of unbound drug the probability of the unbound drug to bind to the active site becomes greater and displaces the labelled drug.
Only displaces the labelled drug at the active site.
Non-specific sites are not displaced, as they are random binding.
Probability of the unbound drug binding at the same site is very low.
How to calculate specific binding ?
Calculate how much labelled drug is still left when saturated with a unlabelled drug.
Subtract non-specific binding from the total binding, this gives us the specific binding
What is equilibrium dissociation constant ?
Equilibrium when the rate of associations = the rate of dissociations
Kd
Equilibrium dissociation constant
What does Kd represent ?
The concentration of drug required to occupy 50% of receptors at equilibrium.
Describe the Kd relationship with drugs
Kd :
Different for every drug.
A measure of the affinity of any one drug for a receptor.
High Affinity drug
You don’t need a lot of the drug to occupy the receptors.
Will be in a low concentration (nm)
Low affinity drug
You need a lot of it to occupy the receptors.
Will be in a high concentration (mm)
What is meant by the pD2 for an agonist ?
It is conventional to express the equilibrium dissociation constant (Kd) as -log10 of the Kd.
pD2
-log10 of [D] that occupies 50% of the receptors at equilibrium
pD2 equation
pD2 = -log10(Kd)
Efficacy
Ability to elicit a response
Describe efficacy
The maximum response of a tissue can be obtained by occupying less than 100% of the receptors.
(HIGH EFFICACY DRUG)
How is max response achieved ?
When a particular stimulus is generated by receptor occupation.
Receptor theory
Biological responses to drugs are graded.
Response is proportional to the fraction of receptors occupied
What type of relationship exists between drug concentration and the magnitude of response obtained ?
Systematic response
Occupancy theory
Equation
Response = [DR] / [RT]
[DR] = number of occupied receptors
[RT] = total number of receptors
State the efficacy relationship
Equation
. beta
[D] + [R] <=> [DR] <=> [DR]*
alpha
Alpha
Rate constant of receptor inactivation
Beta
Rate constant of receptor activation
Stimulus equation
Stimulus = [DR] / [RT]
Response
Response = f [DR] / [RT]
Spare receptor theory
If <100% of receptors are required to evoke a maximum response then these extra receptors are referred to as spare receptors.
Describe the relationship between very efficacious drugs and receptors
Very efficacious drugs will require to occupy fewer receptors to give a response than less efficacious ones.
Describe powerful drugs
Powerful drugs will produce a large stimulus upon receptor occupation, which summates until a max response is reached.
