Drug-Receptor Interactions Flashcards
What is the importance of receptors?
- Pharmaceutical industry and drug development
- Physiology of endogenous transmitters
- chemical toxicity
- Viral toxicity
How do agonists bind to their receptors?
Mostly reversibly, agonists bind to receptors and then dissociate
What are the 2 major types of receptors involved in drug interactions?
- Ligand Gated Ion Channels LIGC (ionotropic)
2. G-Protein Coupled Receptors GPCR (metabotropic)
Name an irreversible antagonist
Aspirin - acetylates COX enzyme
What is the role of the thalamus in the brain?
Thalamus modulates pain
How does receptor transduction occur via LIGC?
An influx of ions causes hyper/depolarisation causing a cellular effect
- occurs in milliseconds
e. g. nAChR
What is drug efficacy determined by ?
- Threshold concentration
- EC₅₀
- maximal concentration
What is irreversible antagonism?
When an antagonist binds irreversibly either to agonist/non-agonist binding sites on the receptor
via covalent bonds
Reduces the number of free receptors
Why is the agonist-receptor binding weak?
Relatively weak and reversible binding due to Hydrogen and Ionic bonding
Van der waals forces allow dissociation
How do receptors limit the need for a large [drug]?
Receptors amplify signals so only a small number of drug-receptor interactions can produce a biological response
Where can partial agonists be found?
Present at receptors with high affinity but less efficacy
Using the agonist-receptor mechanism explain why opioids are so addictive to humans?
Thalamus in the brain contains many opioid receptors
There is therefore high opioid binding
Outline a drug receptor mechanism
Drug A (agonist) + Receptor AR AR+ --> response
(Ka occupation)(EC₅₀ activation)
Ka occupation governed by affinity
EC₅₀ activation governed by efficacy
- an agonist has both efficacy and affinity
What does a smaller Ka value mean?
Agonist has a greater affinity for receptors so binds more
Give an example of non competitive antagonism
Ketamine blocks glutamine receptors by acting at a different (allosteric) site in the receptor to glutamate (agonist)
How do G protein coupled receptors cause transduction?
An excitability change occurs, caused by ions or a secondary messengers causing cellular effects
via Ca2+ release or protein phosphorylation
- takes longer (seconds)
e.g. Muscarinic AcHR
What is the relationship between EC₅₀ and Ka for a maximum biological response?
Affinity (Ka) and Efficacy (EC₅₀) are not equal
- full occupancy isn’t required for a maximum response
What is an Agonist?
A drug that binds to a receptor causing a biological response
What is non competitive antagonism?
When the antagonist binds to a differing site from the agonist
What is the law of mass action?
A + Rfree AR
A = [agonist] Rfree = [free receptors] AR = [agonist-receptor complexes]
How does a non surmountable graph look?
Curve slope is reduced and the maximum is depressed
How is drug affinity regulated?
Reversible binding of an agonist to its receptor is governed by the law of mass action
What is the effect of partial agonists?
Reduce withdrawal effects
Reduce additive ‘highs’
What is Bmax value?
Maximum number of receptors which can be bound by the drug
What does the term drug affinity mean?
The ability of a drug molecule to bind to a receptor site
What is meant by the term surmountable antagonism?
When the same maximal response is obtained via increasing [A] as you can out-compete the antagonist
What is the threshold?
Maximum amount of drug required for a biological response?
What is the relationship between Ant. and concentration curve?
In the presence of Ant., the concentration curve shifts to right as its linearly related
What is Drug Efficacy?
The ability of a drug to elicit a biological response from a drug-receptor interaction
What is the consequence of competitive antagonism?
If Kant < Ka, then Ant has a greater affinity for receptors than A
[A] must increase to overcome Ant binding to receptors
What is EC₅₀?
The effective concentration giving a 50% biological response
Explain what is meant by a partial agonist
An agonist drug producing a biological effect that is always less than the maximum capacity of the tissue
Give an example of a partial agonist used for opioid addiction
Brupernorphine used for opioid addiction
- heroin induced highs are reduced in the presence of
partial agonists
What is the law of mass action affected by?
Dependent on [reactants] (agonist and free receptor concentrations)
Why is there a maximum no. of AR complexes that can form?
There is a maximal no. of AR interactions due to a finite number of receptors
How does competitive antagonism arise?
A and Ant compete for the same receptor binding site
Reaction is then dependent on 2 equilibrium constants (Ka and Kant)
What is Ka?
The amount of drug required to occupy 1/2 max no. of receptors
the [A] at equilibrium
e.g. Ka at 50nM means at this conc. 1/2 the max no. of receptors are bound by the drug
What is the Ka value for drugs?
Each drug has its own individual Ka value
Which drug molecules do receptors bind to?
Reversibly bind to both Agonists or antagonists only
How is EC₅₀ used?
Used to compare drug potency (determined by drug efficacy and affinity)
What is an Antagonist?
A drug blocking the effect of an agonist commonly by binding to its receptor antagonist binding to receptor inhibits biological responses
What does the law of mass action predict?
Low [A] means lots of free receptors so few AR interactions
If [A] increases, more AR complexes form, reaction driven to right, so more [A], few receptors left
free => reaction reaches maximum
