Session 10.2: Pharmacodynamics 2 Flashcards
what are the types of agonists
full and partial - may or may not ellicit maximal response
what are full agonists generally
endogenous ligand
what are some features of full agonists
EC50 less than or equal to Kd
what are some features of partial agonists
EC50 = Kd as no spare receptors….no response with increasing drug conc…intrinsic efficacy insufficient for maximal response
same magnitude of response
same intrinsic activity, but may not be same efficacy (need to look at binding curves)
why do partial agonists have lower intrinsic activity
lower efficacy than full agonists
what does increasing receptor number cause for a full agonist binding
no change - same maximal response, with spare receptors
what does increasing receptor number cause for a partial agonist binding
larger response…same as response from full agonist so becomes a full agonist
what are partial agonists
ligands that evoke responses that are lower than the maximal response of a full agonist = lower Emax values and lower intrinsic activity
why are partial agonists useful as drugs
can allow a more controlled teponse - work in absense/low level of ligand but can act as antagonist if high levels of full agonist
what are examples of drugs that are full agonists
opioids such as heroin - pain relief, recreational but also respiratory depreesion which can lead to death. act via u upioid receptor
how can partial agonists be used for the treatment of opioid addiction
buprenorphine - high affinity, occupies receptors and limits response as prevents heroin binding
partial agonists also referred to as
mixed agonist or antagonist
higher potency
low EC50 value and furthest to the left
lower efficacy
lower intrinsic activity, not reach full response
what are antagonists
block the effects of agonists - prevent receptor activation by agonists
what are the three types of antagonists
reversible competitive
irreversible competitive
non competitive/allosteric
what is reversible competitive antagonism
relies on dynamic equilibrium between ligands and receptors
compete for binding of receptor, when add more antagonist outcompete agonist for binding
greater conc = great inhibition - reverse sigmoidal curve
what is irreversible competitive antagonism
antagonist binds and slowly disociates or not at all
with increasing agonist conc..no effect as more receptors are blcoked by antagonist so non-surmountable. spare receptors filled by antagonists - parallel shift to right and can at high concentration surpress the maximal response as there are insufficient receptors bound to agonists to cause a full response
what is IC50
the concentration of antagonist giving 50% of inhibition
- indication of antagonist affinity but determined by affinity and concentration/strength of agonist
competitive inhibition is
surmountable..increasing concentration of agonist combats its effects…all receptors bound to agonists. this causes a parallel shift to right of agonist concentration-response curve as require more and more agonist
what is an example of reversible competitive antagonist
naloxone - of u opioid receptors..has high afffinity so outcompete other opioids such as heroin for receptor
reverses respiratory depression
what is an example of irreversible competitive antagonist
to treat pheochromocytoma (hypertensive episodes)
lots of adrenaline due to tumour of chromaffin cells which causes vasoconstriction (alpha 1 adrenoreceptors)
eg: phenoxybenzamine binds irreversibly with covalent bonds to alpha 1 adrenoreceptor, so if increase conc of adrenaline - no effect
or
clopidogrel - thrombosis
what is non competitive antagonism/negative allosteric modulation
bind to allosteric sites…enhance or reduce effects on agonists…reduces orthosteric ligand affinity and/or efficacy…no competition for binding site
where do natural ligands bind
orthosteric site
what is an example of a negative allosteric modulator
maraviroc binds to chemokine receptor 5
used by HIV to enter cells so stops this binding as reduced affinity of receptor for virus
how else are allosteric compounds used
ion channels, enzymes - positive and negative effects
