Antagonists Flashcards
What is the definition of an antagonist?
Any drug which reduces the response to another drug
What types of antagonists exist?
Competitive
Non-competitive
Physiological
Pharmacokinetic
Chemical
Describe how competitive antagonists work
They compete with naturally occurring chemicals mediators and agonist drugs to bind to the same receptors, but will not evoke a cellular response
What is the intrinsic efficacy of competitive antagonists?
They are neutral so 0
But they may still have a high affinity
What are the two types of competitive antagonists?
Reversible
Irreversible
How do reversible antagonists work?
The can associate and dissociate again, the effects are overcome by adding more agonist as higher chances of agonist binding
Ionic bonds can be broken
How is a log concentration response curve altered by a reversible competitive antagonist?
The curve is shifted further to the right
As more antagonist is added, more receptors will be occupied by antagonists, higher numbers of agonist are needed to overcome this
How is agonist affinity affected by the presence of antagonists?
Agonist affinity appears to reduce
Is the max response changed by reversible antagonists?
No, the max response can still be achieved but will require much greater numbers of agonist
What is the equation for dose ratio (DR)?
DR = apparent EC50 / EC50
How is the EC50 changed when in the presence of reversible antagonists?
It appears to be greater due to the right ward shift
Can reversible antagonist affect inverse agonists as well?
Yes, they will also move inverse agonist graphs to the right
What is the definition of pA2?
It is a measure of how potent a competitive reversible antagonist is
Defined as -log10 molar concentration of antagonist at which the agonist concentration needs to be doubled to elicit the same level of response as in the absence of the antagonist
Or when DR =2
What does the pA2 say about the antagonist?
Typically between 4 and 12
pA2 of 8 means a very potent antagonist, strong bonds and effective competitor
pA2 of 4 means a very weak antagonist, weak bonds and ineffective competitor
How do calculate pA2?
Plot results generated from log10 concentration response curves of agonist with various antagonist concentration
(Schild plot)
What is the schild equation?
Log10 (DR-1) = Log10 [A] + pA2
What point of a schild plot is used to determine pA2?
-pA2 is where y=0
Therefore this value must be minused to get pA2
How do irreversible competitive antagonists work?
They associate and remain associated with the receptor indefinitely - they receptor is now permanently blocked
Increasing the agonist concentration will have no impact on the response
Usually dependent on covalent bonds
What effect do irreversible competitive antagonists have on log concentration response curves?
There is a progressive reduction in maximum response to agonist without any rightward parallel shift in agonist log concentration response curve
How do non- competitive antagonists work?
Affects the action of agonists at some point in the chain leading to the response
Do not compete with the agonist for the same receptor site
Can be reversible or irreversible
Normally reduce the max response
What is an allosteric site?
A receptor site for a non-competitive antagonist on an unoccupied receptor.
When bound will cause a conformational shape change that alters agonist binding and or signal transduction
How do local anaesthetics work as non competitive antagonists?
They interfere with signal transduction downstream of nicotinic receptors for acetylcholine in nerve fibres
How do physiological (functional) antagonists work?
Acts on separate cells or tissues or on a different population of receptors on the same cell
Two systems are involved
Are really agonists acting on receptors coupled to opposing actions
What is the intrinsic efficacy of physiological antagonists?
Since they’re actually agonists of different cells they have an efficacy value of +1
How do pharmacokinetic antagonists work?
By decreasing the concentration of the agonist by interfering with its absorption, distribution, metabolism, or excretion
Reduces the concentration of it in the vicinity of its molecular target
