Antagonists & dose response curves (L4) Flashcards
what is an antagonist?
a drug which blocks the response to an agonist
pure antagonists do not by themselves cause any action by binding to the receptor
what are the 3 general classes of antagonists?
chemical
physiological
pharmacological
what are chemical antagonists?
binding of 2 agents trendier active drug, inactive
commonly called chelating agents (binding agents)
what are physiological antagonists?
2 agents with opposite effects cancel each other out
what are pharmacological antagonists?
bind to receptor and block the normal action of an agonist on receptors
what are non-receptor antagonists?
either chemical or physiological antagonists
what are receptor antagonists?
can have different sites for binding
• orthosteric
• allosteric
can act in a reversible or irreversible way
what are reversible antagonists?
competitive
what are competitive antagonists?
reversible
share a structural similarity to the agonist
what are non-competitive active site antagonists?
stronger chemical interaction with the binding site - covalent bond
cannot dissociate the antagonist from the binding site
what is a non-competitive antagonist?
allosteric binding - has a different structure and doesn’t bind to the active site
binding to the allosteric site stops the agonist binding
either reversible or irreversible
do antagonists have efficacy?
no
AR* doesn’t exist
what are the 3 types of pharmacological antagonism?
competitive
irreversible
non-competitive
what is competitive antagonism?
binds and prevents agonist action but can be overcome with increased agonist concentration
causes parallel shift to the right of the agonist-repose curve
what is irreversible antagonism?
binds and forms irreversible covalent bonds with receptor
causes parallel shift to right of agonist-repose curve and reduced maximal asymptote
what is non-competitive antagonism?
signal transduction rather than receptor effects
downstream responses are blocked
reduced slope and maximum of agonist-response curve
what is the dose ratio?
agonist plus increasing concentration of competitive antagonist
measures the shift to the right
dose ratio = agonist + (antagonist EC50 (x) / agonist EC50 (y))
what is the Schild plot?
for competitive antagonists
mathmatical model for identifying and comparing the strength of antagonists
only works if we know the drug is working competitively and at the active site
what is the Schild equation?
r - 1 = [B] / Kb
r = dose ratio [B] = antagonist conc Kb = antagonist dislocation constant
what are pA2 values?
describe the activity of a receptor antagonist in simple numbers
pA2 = -logKb
only works if relationship is linear and slope of Schild plot = 1
what is the irreversible competitive antagonist?
non-competitive active site antagonist
reduced maximal response
binds irreversible with the receptor
antagonism cannot be overcome by increased agonist concentration
what happens in irreversible antagonism?
increased EC50
parallel shift to the right
looks similar to a partial agonist
how can you tell if a drug is a partial agonist or an irreversible antagonist?
you know what you put in the system
what is non-competitive antagonism?
blocks signal transduction events
allosteric binding site
reduces slope and maximal effect
looks same as irreversible antagonists
what is the therapeutic index (TI) ?
risk to benefit ration
= TD50/ED50 or LD50/ED50
helps to distinguish whether we could give the drug the title of being relatively safe or relatively dangerous
uses quantal dose curves
what does TD and LD stand for?
toxic dose or lethal dose
what does a large therapeutic window indicate?
a safer drug
bigger concentration range between desired and toxic effect
unlikely for patient to be near the toxic range
what does a small therapeutic window indicate?
a more dangerous drug
higher risk to benefit decision
more likely to get adverse side effects
