Pharmacology- agonists and antagonists Flashcards
Learning Outcomes
- Define the terms receptor agonist and antagonist
- Explain how fractional occupancy is influenced by a drug’s concentration and its affinity for its receptor
- Define the potency of an agonist drug in terms of its EC50 value and be able to determine this value from an agonist log concentration response curve
- Distinguish between full and partial agonists in terms of intrinsic efficacy and its influence on the agonist log concentration response curve
- List the 5 factors which influence the size of response to an agonist drug
- Define, with appropriate examples, the following types of antagonism: competitive, non-competitive, pharmacokinetic, physiological, chemical
- Explain how competitive reversible and competitive irreversible antagonists affect the agonist log concentration response relationship differently
What are the 2 classes of chemical mediator?
1 .Molecules too large or too hydrophilic to cross the cell membrane rely on cell surface receptors
2. Molecules that are small enough and hydrophobic pass through the membrane and directly activate intracellular receptor proteins
How do receptors act as targets for drug action?
require linkage
/to a signal transduction process for effect of the chemical mediator to be apparent
chemical mediator, on binding causes a shape change which stabilises active form of receptor, enhances interaction with signaltransduction mechanism
occupation of a receptor by a drug doesn’t necessarily result in receptor activation
2 stages of interaction:-binding - activation
Agonist drugs bind and cause shape change (activator)
Receptor antagonist fit into binding site, but cannot bring about shape change for activation
What factors affect the size of response to a receptor agonist?
•concentration of drug in vicinityof receptor at a given time
influenced by dose given, route of administration,distribution throughout the body, rate of elimination(metabolism, excretion) –pharmacokinetics
- characteristics of tissue-nature of receptor-response coupling‘signal transduction mechanism’ -total number of receptors present
- characteristics of agonist-receptor complex ‘affinity’-tendency to bind, strength of attraction between agonist and receptor (number/type of bonds)‘intrinsic efficacy’-ability to activate a response
What are the properties of agonist- receptor complexes?
Receptor Binding (Occupancy) •agonist interacts reversibly with receptor •proportion of total receptors available which are occupied depends on:–agonist concentration–strength of bonds formed (affinity)
What is the fractional occupancy equation?
Fractional Occupancy= Na/Ntot =[XA]/[XA] + KA
(Xa is agonist concentration)
•KA is the drug’s equilibrium constant = k-1/k+1
•KA is numerically equal to the concentration of agonist when half of the receptors are occupied i.e. KA= XA when 50% receptors are occupied
•↑KA value ↓ affinity (weaker bonds) of agonist for receptor
What is the difference between Ka and EC50?
KAis a theoretical measure of affinity of agonist-receptor complexes as anisolated entity –relates agonist drug concentration to fractional occupancy
EC50 is a practical, indirect, measure of drug potency, measured downstream of receptor –relates agonist drug concentration to biological response produced
Increasing EC50 conc = decreasing potency
*EC50: effective concentration to produce 50% of maximum response possible on stimulationof that receptor population: know definition
What is intrinsic efficacy?
•ability of an agonist on binding to a receptor to activate a change in shape or folding of that receptor •such conformational changes are required to couple the occupied receptor to initiation of the signal transduction mechanism
Full agonist vs partial agonist = efficacy or 1 or 100%, pa is less than 1% efficacy
less efficient at bringing about shape change than a fa
What are the different types of antagonist?
•competitive (receptor) antagonists
- competitive reversible
- competitive irreversible
- non-competitive antagonists
- physiological antagonists
- pharmacokinetic antagonists
- chemical antagonists
What are competitive antagonists?
compete with naturally occurring chemical mediator or agonistdrug for same binding site on receptor but without initiating acellular response; reduce probability that receptors will be occupied by the chemical mediator or agonist drug
Competitive antagonists: intrinsic efficacy = 0
(but can possess high affinity for receptor, can occupy a large proportionof the receptor population and be potent inhibitors of the action of an agonist drug or chemical mediator)
Example- atenolol, a beta blocker which competes with agonists on b1 adrenoreceptors.
It cannot cause shape change leading to muscle contraction, and through attenuating binding, it attenuates noradernaline/ adrenaline on heart.
Their ability to increase cardiac work/ oxygen demand blunted, angina prevented
What is a reversible antagonist?
Antagonist effect can be reversed ( ionic bonds can be broken)- e.g atenolol
associate but can then dissociate again so effects can be overcome by adding more agonist as this increases chance that receptor will be occupied by an agonist rather than antagonist molecule when antagonist dissociates to leave a free receptor
Occupancy influenced by drug conc and affinity, true for agonists/ antagonists in competition
What is an irreversible antagonist?
Often involve covalent bonds, effect of antagonist cannot be reversed unless new receptor proteins made
associate and remain associated with receptor indefinitely; receptors are permanently blocked and increasing agonistconcentration will have no effect since the receptors remainblocked and agonist molecules cannot get in to the binding site to replace antagonist molecules
Example: clopidogrel (active metabolite is an irreversible antagonist at ADP P2Y12 receptors) anti-platelet drug to inhibit thrombus formation)
How does a reversible antagonist affect the log concentration response relationship versus an irreversible antagonist?
-rightward parallel shift without reduction in maximum response to agonist
Agonist EC50 value ‘appears to be ’larger’ in the presence of a fixed concentration of the competitive reversible antagonist
Progressive reduction in maximum response to agonist without rightward parallel shift in agonist log concentration response curve
What is a non- competitive antagonist?
- affects action of agonist at some point in chain leading to response but does not compete with agonist for same site on receptors themselves
- can be reversible or irreversible
- normally ↓ maximum response
- can involve binding to an allosteric site on anunoccupied receptor to cause conformationalchange which opposes agonist binding and/orinitiation of signal transduction: e.g palonosetron
- can involve interference with a component of the signal transduction pathway downstream from the receptor binding site : e.g local anaesthetic that interfere with signal transduction downstream of (nicotinic) receptors for ach in nerve fibres
What is physiological/ functional antagonism?
- has an opposite effect to the agonist but achieves its result by acting on separate cells or tissues or on different population of receptors on the same cell i.e. two systems are involved e.g. parasympathetic and sympathetic nerves supplying heart
noradrenaline (neurotransmitter released from sympathetic nerves) is an agonist ↑ rate and force of contraction
acetylcholine (neurotransmitter released from parasympathetic nerves)is a functional antagonist of noradrenaline and ↓rate andforce of contraction
