Lec-1 Pharmacodynamics Flashcards
what is Pharmacodynamics?
the mechanism of drug action
what do drugs act on that results in chemical change in the system?
Receptors (usually proteins- high affinity but low capacity
what are Effectors
molecules that translate the receptor-drug interaction into a change in cellular activity.
- drugs do not bind to an effector
Instead of thinking of the lock and key model, what is the correct way?
Think as receptors fluctuating between favored and disfavored energy states
- R=favored low energy state
- R*= disfavored, active, high-energy state
- there are no perfect keys/ locks- just only ratios between how well your drug binds to your preferred targets vs. other targets
___ lowers the free energy of the activated state, making it more favorable than the baseline state.
Agonists
finish the thought -Binding of a ligand can cause induced fit:
Conformational shift of the receptor that can cause effector signaling.
Do receptors require a specific agonist?
No, receptors do not require a specific agonist.
T or F: Receptors are completely inactive until an agonist comes along.
False. Receptors are not completely inactive until the agonist comes along.
-they are never completely “on” or “off”, & that some imperfect agonist can still stimulate the receptor given enough concentration.
What is the Key method for measuring the binding of drugs to receptors?
-radioligand binding
- sometimes it’s more effective to use competition radioligand binding to test new drug binding.
Radioligand binding Basics:
A known amount of radiolabeled, established drug is competed off a receptor by a non-radiolabeled drug with an unknown affinity.
Bmax:
Kd:
IC50:
Ki:
-> total number of binding sites (fmol/mg)
->Binding constant (affinity) of the drug (in nM)
-> Concentration at 50% inhibition
-> Binding constant (affinity) of the experimental, unlabeled drug (in nM)
Assumptions of the experiment
- Bound concentration is negligible compared to free
- No binding cooperativity
- At equilibrium
- Binding is reversible and follows laws of Mass action
what are the problems with competition binding experiment?
Allosteric sites
what do most drugs binding receptors involve?
Non-covalent interactions w/ key amino acids(Ionic bonds, hydrogen bonds, Van der Waals)
Affinity is
Affinity: how well a drug binds to a target & the amount - basically fixed/ independent
why don’t we test all drugs with saturation binding?
The expense & the difficulty of radioactivity
Partial Agonist
- don’t stimulate the receptor as much as a full agonist
-can’t shift as well - ” there is something off w/ interactions of target”
Potency (EC50 , ED50 )
How much is needed to achieve w/ affect
Efficacy (EMax)
the max activation
Antagonist
- don’t change the receptor
- can’t turn off or on the receptor
- does not change its shape/ conformational shift -. baseline activity is still the same
-will not 100% prevent agonist binding, it will leave or be over competed eventually
- IT does prevent agonist from binding and having an effect
“The annoying neighbor that sits there” - one can only see the effects of an antagonist when agonist is present
How are affinity and potency different?
Affinity is basically fixed/ independent
Potency and Efficacy can vary strongly by the tissue, signaling pathway, etc.
Reversible antagonist vs Irreversible
Reversible antagonist - competitive/ reversible
irreversible- they bind -> covalent bonds-> stuck permently -> reducing the total amount of receptors available to bind agonists)
Inverse agonists
Bind the receptor but shift the energy landscape so that the Baseline is lower and / or the active state is higher, so the receptor spends less time in the active state than before.
Drug selectivity
deals w/ how well your drug binds to your preferred target vs other targets
