Agonists & dose response curves (L3) Flashcards
what is an agonist?
a ligand that combines with receptors to elicit a cellular response
- receptor
- agonist-receptor complex
- action
- effect
what are the 2 types of dose response curves?
concentration-effect curves
semi-logarithmic plot of agonist concentration against response
why do we use a semi-logarithmic plot of agonist concentration against response curve
linear scale would need to be massive
we log the scale to see the full rage of concentrations
changes graph to a sigmoid shape
what are the 2 types of dose-response relationships?
graded
quantal
what is a graded response?
response of a particular system
• isolated tissue
• animal
• patient
measured against concentration
what is a quantal response?
required to produce a specified response determined in each member of a population
population based data
tend to form a bell shaped curve in log form
why plot a dose response curve?
allow estimation of Emax
allow estimation of EC50/ED50
allow efficacy to be determined
allow potency to be determined
what is Emax?
concentration when we get 100% response
what is EC50/ED50?
dose required to produce 50% of maximal response
what is the 2 state hypothesis?
1) agonist binds to receptor
2) agonist-receptor complex made
3) if complex is activated then theres a response
what is affinity?
the strength with which an agonist/drug binds to a receptor
affinity = K1 / K-1 K1 = rate of association of the agonist with receptor K-1 = rate of AR complex dissociation
what is Bmax?
the maximum number of binding sites - receptor saturation
what is Kd?
equilibrium dissociation constant
a physiochemical constant
concentration of ligand at which 50& of the available receptors are occupied
it is the same for a given receptor & drug combination in any tissue, in any species
what can Kd tell us?
- can be used to identify an unknown receptor
- can be used to qualitatively compare the affinity of different drugs on the same receptor
- a lower Kd indicates a tighter ligand-receptor interaction
- curve moves to the left when Kd is lower
- tells you more about potency
what is potency dependent on?
affinity of drug
efficacy of drug
receptor density
efficiency of stimulus-response mechanism used
what is potency?
the amount of drug needed to produce a given effect
what is efficacy?
describes the ability of an agonist to activate a receptor - to evoke an action at cellular level
what are full agonists?
high efficacy - AR* very likely
produce a maximum response while occupying only a small % if receptors available
maximum response corresponds to the maximum response of the tissue
what are partial agonists?
low efficacy - AR* less likely
unable to produce a maximum response even when occupying all available receptors
maximal response falls short of the maximal response that the system is capable of producing
drop in Emax
examples of partial agonists?
varenicline
tamoxifen
aripiprazole
what are inverse agonists?
have higher affinity for the AR state than the AR* state
~85% of competitive antagonists are actually inverse agonists
what are the types of allosteric modulators?
positive (PAM)
negative (NAM)
what are PAMs?
not active alone but increase affinity and/or efficacy of endogenous agonist
what are NAMs?
not active alone but decrease affinity and/or efficacy of endogenous agonists
what happens in the desensitisation of receptors?
effect of the drug reduces with continual/repeated administration
termed tachyphylaxis
what are contributing factors to the desensitisation of receptors?
- conformational changes in receptor
- internalisation of receptors
- depletion of mediators
- altered drug metabolism
- other physiological responses
