UMP2003 drug receptor interactions: agonists and antagonists Flashcards
give some examples of drug targets
- DNA
- receptors
- enzymes
- carriers/transporters
- mediators of inflammation
what are the 4 main types of receptors?
- GPCRs
- ligand-gated ion channels
- kinase-linked receptors
- nuclear receptors
what does an agonist drug do to receptors?
- directly activate the receptor
- promotes the normal action
what do antagonist drugs do to receptors?
- directly blocks/prevents the action of the receptors
what do modulator drugs do to receptors?
- they can alter the effect that the agonist has on the receptor
what is k+1 and k-1 in the agonist receptor equation?
- k+1 = association constant
- k-1 = dissociation constant
what is the 2 state theory of agonists and receptors?
- A + R =(K1)= AR =(E)= AR*
- A = agonist
- R = receptor
- AR = agonist bound to receptors but inactive
- AR* = agonist bound to receptor and active
- K1 = affinity
- E = efficacy
- if A is an agonist, the bound complex AR can activate becoming AR*
- the 2nd reaction is ‘gating’ and it os described by another equilibrium constant E (how well it activates the receptor)
- ## the position of equilibrium is now described by both reactions, binding and gating
what is a full agonist in terms of the 2 state theory?
- it binds and fully activates the receptor
- favours AR*
- channel/receptor is open almost always
What is a partial agonist in terms of the 2 state theory?
- it binds to but only partially activates the receptor
- favours AR
- channel/receptor is open less frqeuntly
what is a modulator in terms of drugs and receptors?
- modulators aren’t agonists or antagonists but they can increase or decrease the response when the agonist binds
- modulators do not bind to the same site as an agonist/antagonist
- 2 types, positive allosteric modulators (PAMs) which increase the effect of agonists and negative allosteric modulators (NAMs) which decrease the effect of agonists
what are positive allosteric modulators?
- substances that increase the effect of agonists
what are negative allosteric modulators?
- substances that decrease the effect of agonists
describe how benzodiazepines are positive allosteric modulators at the GABA A receptor
- they bind to GABA receptor and increase the effect of the neurotransmitter GABA on this channel
what are the 2 ways that modulators can work?
-they can either shift the dose response curve
- it affect the maximum response to the agonist
describe antagonists in the A+R=AR 2 step equation
- antagonists have an efficacy of 0
- so often no gating reaction occurs after binding, so it is stuck in the inactive bound form
describe how reversible competitive antagonists work
- they cant activate the receptor once bound and, if bound, they prevent the agonist from binding and activating the receptor
- they bind to the same receptor as the agonist
-increasing the concentration of agonist can overcome the action of the reversible competitive antagonist
what is the effect of a reversible competitive antagonist on the dose-response curve?
- they are shifted to the right in the presence of a competitive antagonist ( increased conc of agonist needed to overcome antagonist for same response)
- the extent of the shift depends on 2 things: the concentration of antagonist and the affinity of the antagonist for the receptor
what 2 things does the extent of the shift of an agonsit on a dose-response curve depend on?
- concentration of the antagonist
- affinity of the antagonist for the receptor
describe what the Schild analysis/plot is
- measure and plot a graph for agonist and antagonist dose-response curve
- then calculate logKb (antagonist dissociation constant) and pA2 (a numerical representation of the affinity of an antagonist for its receptor)
- the higher the pA2, the higher the affinity of the antagonist for the receptor
- dose ratio = EC50 in presence of antagonist/EC50 in absence of antagonist
- plot : log (antagonist conc) on x axis against log (dose ratio - 1) on y axis (straight line graph)
- where the line touches x axis = logKb
- pA2 = -logKb
what is logKb?
- antagonist dissociation constant
- where Schild plot line touches X axis
- pA2 = -logKb
what is pA2?
- numerical representation of the affinity of an antagonist for its receptor
- pA2 = -logKb
what is the dose ratio?
dose ratio = EC50 in presence of antagonist/EC50 in absence of antagonist
what is on the x and y axes of a Schild plot?
- x axis = log (antagonist conc)
- y axis = log ( dose ratio - 1)
how do irreversible competitive antagonists work?
- bind to the agonist binding site, don’t activate the receptor but prevent the agonist binding
- however these bind covalently to the agonist binding site, so you cannot out-compete it by increasing the agonist concentration
- requires the synthesis of new receptor to overcome effect
what effect does an irreversible competitive antagonist have on a dose-response curve?
- shifts curve down
- so maximum response is decreased
how do non-competitive antagonists work?
- prevent receptor activity but fo not bind to agonist binding site, binds elsewhere at the allosteric site
what effect does a non-competitive antagonist have on a dose-response curve?
- shifts curve down
- so maximum response is decreased
what is a therapeutic index?
- ratio between the effective dose in 50% of the population and the toxic dose in 50% of the population
- wider the therapeutic index the better
what is the margin of safety?
- ratio between the amount of drug that is toxic in 1% of the population and the amount of drug that is effective in 99% of the population
