Agonist And Antagonist Interactions Flashcards
Antagonist
Antagonists are a type of receptor, ligand or drug that does not bind to a receptor, but blocks or dampens agonist mediated responses.
They are drugs which have affinity but NO efficacy
For their receptors and binding will disrupt the interaction and inhibit the function of an agonist
Most important antagonisms
Physiologically and pharmacologically, most important antagonisms are:
1. Physiological antagonism
2. Competitive antagonism
3. Non-competitive antagonism.
There are other types:
*Chemical antagonism; two drugs, interact in a solution *Pharmacokinetic antagonism; one drug modifies ADME of another drug
Physiological Antagonism:
~ Substances which have opposing physiological actions but act at different receptors
-the 2 drugs are both agonists and aid in regulating organ function in the body.
-eg. histamine lowers arterial presture through vasodilation
At the histamine H1 receptor, While adrenaline raise arterial pressure through vasoconstriction mediated by B-adrenergic receptor activation
Competitive antagonism:
the antagonist reversible binds to receptors at the same binding site as the endogenous ligand or agonist, but without activating the receptor.
~Agonist and antagonist compete for the same binding site and once bound an antagonist will block agonist binding
Characteristics of competitive antagonism:
1.)Concentration response curve to an agonist remains parallel with original (control) curve
2.)Concentration response curve to agonist to an agonist will be shifted to the right
3.)The maximum response will still be obtained
4.) The effects of a competitive antagonist by may be overcome by increasing the concentration of agonist
5.)Often (not always) these antagonists possess a very similar chemical structure to that of the agonist
Response curve to an agonist by a competitive agonist and what it depends on:
Extend of the right shift of concentration, response curve to an agonist by a competitive antagonist depends on
1. Concentration of the antagonist used.
2. Affinity of the antagonist for a particular Receptor
Find sample to antagonist with equal concentration, antagonist with high affinity water cause a big shift to the right
Concentration Ratio:
The concentration of agonist producing a defined response in the presence of an antagonist, divided by the concentration producing the same response in absence of antagonist.
Concentration ratio= Ec50 for curve B (d2) / Ec50 for curve A (D1)
Affinity of antagonist:
Determined using Schild plot
Schild plot equation -> (concentration ratio-1) = (antagonist
concentration)/ KB
Concentration ratio- concentration ratio for the agonist KB= dissociation equilibrium constant for the antagonist; the concentration which would occupy 50% of the receptors at equilibrium. The reciprocal (1/Kb) is called affinity constant or the association constant
When slope= 1 then PA2= pKB
Range of antagonist concentration:
A plot is made of the log (dose ratio-1) vs the log concentration of antagonist for a range of antagonist concentrations.
~The intercept on the x axis is called pA2 and the slope gives info about nature of antagonism
Slope= 1, indicates of competitive antagonism
PKB:
it’s a measure of the potency of a competitive antagonist
~it’s the negative log of the molar concentration of antagonist which at equilibrium would occupy 50% of the receptors in absence of agonist
~In a experiment in which a single concentration of antagonist has caused a parallel shift of the agonist concentration response curve, the pKB value can be calculated using the Gaddum equation
Gaddum equation:
Gaddum equation: pKB= log (concentration ratio- 1) - log (agonist concentration)
For a competitive antagonist (one where the slope of the schild plot =1) the pKB is theoretically = pA2 value. In practice there may be some discrepancy. pKB value should also= pKi value for compound determined in a binding assay although there may again be a discrepancy caused by the use of different media etc.
Schild plot:
The slope of a Schild plot should equal 1 for a competitive antagonist.
• A slope which is significantly greater than 1 may indicate nonspecific binding (e.g. to glassware or partitioning into lipid), or lack of antagonist equilibrium,
• A slope which is significantly less than 1 may indicate removal of agonist by a saturable uptake process, or it may arise because the agonist is acting at a second receptor type (this can also cause curved Schild plots).
• If the slope of a Schild plot is greater than 1, the calculated pA2 value will be an underestimate of the pK value (i.e. the antagonist is less potent than expected).
Conversely, if the slope is less than 1, the calculated pA2 value will overestimate the pKB value.
Non competitive antagonism:
in this antagonism no amount of agonist can completely overcome the inhibition once it has been established
~non competitive antagonist may bind:
1. Covalently to the agonist binding site
2. To site adjacent to agonist receptor and modify conformation of the receptor preventing the agonist binding (allosteric)
3. To a site involved in mediating the cellular responses, e.g blocking ca2+ of binding to contractile protein= cell can not respond to an agonist
Antagonist affinity use:
To classify receptors
To investigate agonist specificity
Example of competitive antagonism:
A good example of competitive
antagonism is the effect of tubocurarine on the responses to acetylcholine at motor end plates in skeletal muscle.
• Kg values for Tubocurarine vs Ach:
• Intestine
Heart
Skeletal muscle
• 10-4 М
10-4M
10-8 M
• Kg values for Atropine vs Ach:
• Intestine
Heart
Skeletal muscle
• 10-8M
10-8M
10-4
