W19&21 Agonists and Antagonists Flashcards
What is an agonist?
A substance which initiates a physiological response when combined with a receptor.
How is Propanalol an antagonist?
- Is a beta blocker
- Binds to beta 1 receptor so adrenaline cannot bind
Drug affinity:
Receptor (inactive) = Free, inactive
Receptor (active) = Bound, inactive
Receptor (active) = Bound, active
What do agonists need to have? (2)
Affinity and Efficacy to produce a physiological response
What do antagonists have?
ONLY affinity (not efficacy)
Can only bind to receptor but will not conformationally change it from inactive to active
Does not produce a response, will block the ability of an agonist’s response
- Efficacy= capacity to bind to a receptor to produce an effect.
What is the Law of mass action?
Association= Disassociation
D + R = DR
What is the definition of
Affinity?
Efficacy?
Affinity- The ability of drug binding to receptor
Efficacy- The ability of a drug to activate the receptor
What is kD?
(Dissociation constant)
The concentration required to occupy 50% of receptor
= Measure of drug affinity
What is EC50/Potency?
EC50 - Effective Concentration of agonist for 50 % of a response
It is an empirical measure of agonist potency
A lower kD value means..
A higher affinity as the drug is associated to the receptor
- inversely proportional
Plotting drug concentration and receptor occupancy:
Better to plot a log concentration/dose vs Receptor occupancy/affinity
- as a sigmoid curve is produced and is easier to read
What is meant by ‘Efficacy’ of drug?
Where do you find the Efficacy of a drug?
Once drug bound to receptor complex, how well it can covert drug from inactive to active
By looking at RMax (at top of curve)
What is meant by Full Agonist/ Receptor reserves?
Produces 100 % response with 50% occupation (Full Agonist); Receptor reserves
e.g. only 2/4 receptors bound but leads to an 100% receptors
What is a Partial agonist?
Produces less than 100 % max response with maximal receptor occupation
e.g. all receptors filled but only a 40% response
Acts as an antagonist in the presence of a full agonist.
e.g Tolazoline effect on Phenylephrine
What does potency mean?
Response
Examples of full agonists (for info)
Morphine, Heroin, Oxycodone
Examples of partial agonists (for info)
Codeine, Acebutolol
What is an antagonist?
A substance which interferes with or inhibits the physiological action of another.
What is antagonism?
Drug/ligand that reduces/blocks the agonist response
Types of antagonism?
- Receptor antagonism
- Pharmacokinetic
- Reversible/Irreversible competitive
- Chemical
Define:
Orthosteric (Competitive binding)
Allosteric (Non-competitive)
- Same binding site of the endogenous hormone
- Different binding site of the endogenous hormone
Non-competitive antagonism?
- Non-competitive antagonist blocks agonist response by binding different binding site from the agonist
- Non-competitive antagonists doesn’t need to have identical chemical signatures (look at the structure of glutamic acid and memantine)
What are Reversible antagonists?
Can bind and then dissociate from the receptor
Dissociation of a reversible competitive antagonist from the receptor enables either agonist or antagonist molecules to re-occupy the binding site
Reversible competitive antagonists
Most common
- Competition between antagonist and agonist about which will bind to the receptor. If agonist conc increases it will replace the agonist. e.g. Naloxone
By adding more agonists, the agonist maximal response can still be achieved, if the antagonist drug/ligand is reversible and competitive,
(surmountable antagonism)
Increasing agonist concentration could reverse and regain agonist maximal response (surmountable antagonism)
What is Irreversible Competitive antagonism?
Inc conc of agonist has no effect on antagonist. This is because antagonist binds irreversibly to receptor.
- Still competitive as both molecules compete for the same receptor
What is Allosteric non-competitive antagonism?
Binds to an allosteric site near receptor, modifying its shape so agonist can no longer bind.
- Reduces affinity of agonist
e.g. Ticargrelor (anti-platelet)
What is chemical antagonism
Only chemical interactions, no drug targets (receptors) involved.
examples:
Heavy metal chelators/ chelating agents- binds to heavy metal and reduces their toxicity
Neutralising antibody/Antibody therapy= Avastin (bevacizumab) or Infliximab
What is pharmacokinetic antagonism?
(ADME)
An antagonist that effectively reduces the concentration of the active drug at its site of action.
e.g. Phenytoin inc hepatic metabolism of warfarin which decreases the conc of warfarin
PK antagonism is also found in:
1. Decreased absorption / altered distribution
-Anti-diarrhoeal drugs inhibit gut absorption of other drugs from the GI tract
-Vasoconstriction by adrenaline restricts the distribution of local anaesthetics
- Increased metabolism
-phenobarbital increases liver enzyme activity and
stimulates the metabolism of many drugs, including warfarin
-Increases renal excretion
These lead to decrease in concentration at site of action
What are the 4 phases of Pharmacokinetics?
Absorption
Distribution
Metabolism
Excretion
Why is adrenaline injected along with local anaesthetic during tooth extraction
Adrenaline is a vasoconstrictor and so it will ensure there is no spreading of the local anaesthetic except in that specific area
Why is adrenaline injected along with local anaesthetic during tooth extraction
Adrenaline is a vasoconstrictor and so it will ensure there is no spreading of the local anaesthetic except in that specific area
What is physiological antagonism?
Antagonist binds to completely different receptor. Physiological response resulting from this will antagonise the effect of the agonist.
Different physiological mechanism
-Blood pressure regulation by DIURETICS
- Diuretics increase the urine output and by which it reduces the sympathetic control of blood pressure (by adrenaline)
Match the most appropriate enzyme with its major function:
1.Synthesis of cAMP
2.Synthesis of vasodilator NO
3.Breakdown of phospholipids
4.Prostaglandin synthesis
5.cAMP/cGMP breakdown
6.Synthesis of cGMP
7.Acetylcholine breakdown
- Adenylyl cyclase
- Endothelial nitric acid synthase
- Phospholipase C
- Endothelial nitric acid synthase
- Cyclooxygenase
- Phosphodiesterase
- Guanylyl cyclase
- Acetylcholine estrase
What is surmountable antagonism?
