l14 pharm

what is the main focus of the agonism and antagonism lecture?

how drugs behave after binding receptors, including efficacy, potency, agonists, partial agonists, inverse agonists, antagonists, receptor reserve, and response curves

what is efficacy?

efficacy is the ability of a drug to activate a receptor and produce a response

what is efficacy measured by?

Emax, the maximum response a drug can produce

what is potency?

potency is the concentration of drug required to produce a response

what is potency measured by?

EC50 in vitro or ED50 in vivo

what is EC50?

EC50 is the concentration of drug required to produce 50% of the maximal response

what is ED50?

ED50 is the dose required to produce 50% of the maximal response in vivo

what is Emax?

Emax is the maximum possible response produced by a drug

what is affinity?

affinity is how strongly a drug binds to a receptor

what is affinity measured by?

Kd

what is Kd?

Kd is the concentration of drug required to occupy 50% of receptors

what is the difference between affinity and potency?

affinity is about receptor binding, while potency is about the concentration needed to produce a response

what is the difference between potency and efficacy?

potency is how much drug is needed, while efficacy is the maximum response the drug can produce

what is an agonist?

an agonist is a drug that binds to and activates a receptor

what is a full agonist?

a full agonist binds to a receptor and produces a maximal response

what is a partial agonist?

a partial agonist binds and activates a receptor but produces less than the maximal response, even at full receptor occupancy

what is an antagonist?

an antagonist binds to a receptor but does not activate it

what does an antagonist do?

it blocks an agonist or endogenous messenger from activating the receptor

what is an inverse agonist?

an inverse agonist binds to a receptor and reduces constitutive/basal receptor activity

what is constitutive activity?

constitutive activity is receptor activity that occurs even without an agonist bound

what does positive efficacy mean?

positive efficacy means the drug activates the receptor and increases response

what does no efficacy mean?

no efficacy means the drug binds but does not activate the receptor

what does negative efficacy mean?

negative efficacy means the drug reduces basal/constitutive receptor activity

what type of efficacy does an agonist have?

positive efficacy

what type of efficacy does an antagonist have?

no efficacy

what type of efficacy does an inverse agonist have?

negative efficacy

what type of efficacy does a partial agonist have?

positive efficacy, but less than a full agonist

what is the orthosteric binding site?

the orthosteric binding site is the normal site where the endogenous agonist binds

what is 2-AG?

2-AG is an endogenous cannabinoid ligand that binds CB1

where does THC bind on CB1?

THC binds at the orthosteric binding site, the same site as 2-AG

how many drugs can occupy the orthosteric site at a time?

only one drug/ligand can occupy the orthosteric site at a time

why can agonists and antagonists compete?

because they can bind to the same orthosteric binding site

does affinity tell you what a drug does after binding?

no, affinity only tells you about binding, not activation or response

what does biological response measure?

it measures what happens after a drug binds, such as receptor activation or tissue response

give examples of biological responses

a rise in blood pressure, smooth muscle contraction, receptor activation, cAMP change, or pERK activation

what is a concentration-response curve?

a graph showing how response changes as drug concentration increases

what is a dose-response curve?

a graph showing how response changes as dose increases, usually in vivo

what does in vitro mean?

in vitro means in cells, tissues, or lab systems outside a living organism

what does in vivo mean?

in vivo means in a living organism

what happens to response as agonist concentration increases?

response increases until it reaches a maximum/plateau

why does the response curve plateau?

the system reaches maximum response, so more drug cannot produce more effect

what does the x-axis show on a concentration-response curve?

drug concentration

what does the y-axis show on a concentration-response curve?

effect or response

why are log concentration-response curves used?

they spread out concentration values so EC50 and curve differences are easier to see

what does a curve further left mean?

the drug is more potent because less drug is needed

what does a curve further right mean?

the drug is less potent because more drug is needed

what does a higher plateau mean?

higher efficacy

what does a lower plateau mean?

lower efficacy

what is logEC50?

the log10 of the EC50 concentration in molar units

if EC50 = 10 nM, what is logEC50?

10 nM = 10⁻⁸ M, so logEC50 = -8

what is pEC50?

pEC50 is the negative log of EC50

if logEC50 = -8, what is pEC50?

pEC50 = 8

what does higher pEC50 mean?

higher potency

what was AMB-FUBINACA’s EC50 in the pERK example?

2 nM

what was THC’s EC50 in the pERK example?

40 nM

which is more potent in the pERK example, AMB-FUBINACA or THC?

AMB-FUBINACA, because it has a lower EC50

how much more potent is AMB-FUBINACA than THC in the pERK example?

about 20-fold more potent

what was AMB-FUBINACA’s Emax in the pERK example?

100%

what was THC’s Emax in the pERK example?

about 30% or 32.8%

which is more efficacious in the pERK example, AMB-FUBINACA or THC?

AMB-FUBINACA, because it has a higher Emax

why is THC a partial agonist in the pERK pathway?

because it activates CB1 but produces less than maximal response

can a partial agonist have high affinity?

yes, a partial agonist can bind strongly but still have low efficacy

what is the key difference between binding and activation?

binding is affinity, while activation is efficacy

in the pathway Agonist + Receptor → AR → AR* → response, what is AR?

AR is the agonist-receptor complex

in the pathway Agonist + Receptor → AR → AR* → response, what is AR*?

AR* is the activated receptor complex

which step relates to affinity?

agonist binding to receptor to form AR

which step relates to efficacy?

conversion of AR to activated AR* and response

what is antagonist binding?

antagonist binding is when a drug binds the receptor but does not activate it

do antagonists have affinity?

yes, antagonists have affinity because they bind to receptors

do antagonists have efficacy?

no, antagonists have no efficacy

what is a competitive reversible antagonist?

a drug that reversibly binds the orthosteric site, competes with agonist, but does not activate the receptor

what does reversible mean in reversible competitive antagonism?

the drug binds non-covalently and can come off the receptor

what does competitive mean in reversible competitive antagonism?

the antagonist and agonist compete for the same orthosteric binding site

what does surmountable mean?

the antagonist effect can be overcome by increasing agonist concentration

why is reversible competitive antagonism surmountable?

because agonist and antagonist both bind reversibly, so enough agonist can outcompete antagonist

what does a competitive reversible antagonist do to an agonist concentration-response curve?

it shifts the curve to the right without decreasing Emax

what happens to EC50 in the presence of a competitive reversible antagonist?

EC50 increases because more agonist is needed

what happens to agonist potency in the presence of a competitive reversible antagonist?

apparent potency decreases

what happens to Emax with a competitive reversible antagonist?

Emax stays the same

what is the classic graph effect of reversible competitive antagonism?

parallel rightward shift with no change in Emax

what happens as competitive reversible antagonist concentration increases?

the agonist curve shifts further to the right

what response does an antagonist alone produce?

no response

why does an antagonist alone produce no response?

it binds the receptor but does not activate it

give an example of a clinical antagonist

naloxone, propranolol, or antihistamines

what is naloxone?

naloxone is an opioid antagonist used to treat opioid overdose

how does naloxone help in opioid overdose?

it blocks opioid agonists like heroin from activating opioid receptors

what is propranolol?

propranolol is a beta-blocker that non-selectively blocks beta1 and beta2 adrenergic receptors

what endogenous messengers does propranolol block?

adrenaline and noradrenaline at beta receptors

what are antihistamines?

H1 histamine receptor antagonists

give examples of H1 antihistamines

cetirizine and loratadine

what is an irreversible competitive antagonist?

a drug that binds covalently to the receptor’s orthosteric site and permanently blocks it

what does covalent binding mean?

a very strong bond that is essentially irreversible

is irreversible competitive antagonism surmountable?

no, it is not surmountable

why is irreversible antagonism not surmountable?

the antagonist permanently removes receptors from availability, so more agonist cannot fully overcome it

what does an irreversible antagonist do to receptor availability?

it reduces the number of receptors available to the agonist

what does an irreversible antagonist do to Emax?

it decreases Emax

what happens as irreversible antagonist concentration increases?

maximal response decreases further

what is the classic graph effect of irreversible antagonism?

a decrease in maximum response/Emax

how does irreversible antagonism differ from reversible competitive antagonism on a graph?

reversible competitive antagonism shifts the curve right with same Emax, while irreversible antagonism lowers Emax

are irreversible antagonists common clinically?

no, they are much less common than reversible antagonists