How drugs and receptors interact to change biological responses Flashcards
An agonist has both affinity and efficacy
what determines AR affinity?
what is Ec50?
what is efficacy?
Ka determines AR affinity
activity of a drug bound receptor to produce a biological response is governed by efficacy (Ec50 which is effective conc to produce 50% max response)
Binding of agonists to receptors
how does it bind?
Most agonists bind reversibly to their receptors
Agonist binds to receptor - then dissociates
This is a continuous process
Why is binding reversible?
what is a strong stable bond? effect of this?
Hydrogen bonding
Ionic bonding
Van der Waal’s forces
Have Relatively weak -> Reversible binding hence Good dissociation
Covalent binding has Stable strong bonds -> Irreversible binding hence Poor dissociation
What is the rate of reversible binding of agonist to receptor governed by?
Rate of reversible binding of agonist to receptor is governed by
Law of Mass Action :
Dependent on concentration of the reactants involved
A + R ->
What determines drug affinity?
what if Low A?
what if you increase A?
if A increase but limited R?
Law of mass action predicts :
(1) Low [A] - lots of Rfree – low rate of AR interactions
(2) Increase [A] – increasing rate of AR interactions - reaction driven greatly to right
(3) Continue increasing [A] – few Rfree, low rate of AR interaction,
maximal number of AR interactions
What is Ka?
When 50% of receptors are free and 50% are bound by agonist = the equilibrium constant (KA)
Importance of Ka
what does smaller KA mean?
KA is the [A] at equilibrium, e.g. KA of 50 nM means that at this concentration half the agonist will be bound to receptors
Each drug has it own KA value
Smaller KA means agonist has a greater AFFINITY for receptor
(it binds more) than a drug with a higher KA value
Outcome of affinity if you keep increasing concentration
shape of graphs on linear and log scale
There is a maximal number of AR interactions
due to finite number of receptors
rectangular hyperbola for linear scale once plateau reached
Sigmoid curve for log scale
What determines efficacy?
what does affinity look at?
what does efficacy look at?
3 levels when looking at drug efficacy?
Similar principles to affinity but different measurement
Affinity – occupancy, binding of drug to receptor
Efficacy – biological effect, e.g. increase in heart rate
a) Threshold concentration - certain amount of drug needed for a biological response
b) EC50 = effective concentration giving 50% biological response
Used to compare drug potency (determined by affinity and efficacy)
c) Maximal concentration
Important: Affinity (KA) and Efficacy (EC50) of a drug are not equal
why?
Interpretation : You do not need full occupancy
to give a maximum response
Remember: receptors amplify signals, so only a small number of drug-receptor interactions produce biological effects
- Why drugs can work at such low concentrations -
Partial Agonists
example of this?
affinity and efficacy?
why is this drug used?
example of an anatagonist?
effect of drug?
what is a full agonist?
Partial agonists - e.g. Buprenorphine for opioid addiction
Present at receptors – high affinity, but less efficacy
Reduces withdrawal effects and additive ‘highs’
Heroin-induced highs are reduced in presence of partial agonist
therefore can use a higher conc to make sure all receptors are bound with a lesser response and reduce the effects of other drugs
Antagonist – e.g. Naloxone
Reverse/block effects of morphine
Useful to reduce morphine-induced symptoms after overdose
full agonist -> full efficacy
Competitive Antagonism
what may receptors do?
what do A and Ant do? how do they bind? significance of this?
what if KAnt < KA?
Receptors may either bind Agonist (A) or Antagonist (Ant)
A and Ant compete for the same binding site
A and Ant both bind reversibly
Reaction now dependent on two equilibrium constants, KA and Kant
If KAnt < KA, then Ant has greater affinity for receptors than A
[A] must increase to overcome Ant binding to Receptors
‘Surmountable’ antagonism
what will happen to the curve?
maximal response?
example of this?
In the presence of the Ant concentration - curve to A is shifted to right
Shift to right is linearly related to [Ant]
Same maximal response – increase [A] will ‘out-compete’ antagonist
e.g.
B-adrenceptor antagonist atenolol on adrenaline-increase in heart rate
Atenolol will reduce heart rate
Reduce effect of endogenous adrenaline on heart
Principle of many clinical therapies
Non-Surmountable’ Antagonism
what will the graph have? (2)
Non-competitive antagonism? effect? example?
Irreversible antagonism? effect? example?
what do both of these do? reduce what?
Graph curve has:
Reduce slope
Depress maximum
Non-competitive antagonism
Ant binds to a different site from the agonist
e.g. Ketamine blocks glutamine receptors by acting at a different site
in the receptor structure compared to glutamate
Irreversible antagonism
Ant binds irreversibly to either agonist- or non-agonist binding sites
on the receptor through covalent bonds
e.g. aspirin – acetylates (covalent changes) COX enzyme
Both non-competitive/irreversible antagonists reduce
number of receptors the agonist can bind to – reduce max response
