Drug antagonism Flashcards
Why are antagonists useful ?
- As experimental tools to block the action of natural hormones or neurotransmitters
- To identify receptors
- To identify enzymes or other molecules involved in signal transduction pathways
What are the 2 mechanisms by which an antagonist can work ?
- Mechanisms not involving the receptor macromolecule through which the agonist acts
- Mechanisms involving the receptor
What is an example of antagonism not involving the receptor ?
Functional or physiological antagonism : the ‘antagonist’ is actually an agonist that produces an opposite biological effect to the substance being antagonised. Each substance acts through its own receptors.
Example: adrenaline relaxes bronchial smooth muscle, and so can reduce the bronchoconstriction caused by histamine and the leukotrienes
What examples of antagonism involving the receptor ?
- reversible competitive antagonism : binding of agonist and antagonist is mutually exclusive
Example: atropine competitively blocks the action of ACh on muscarinic receptors - noncompetitive antagonism : agonist and antagonist can be bound at the same time, to different regions of the receptor molecule
Example: ketamine reversibly blocks NMDA receptors in the brain by blocking the NMDA receptor ion channel
What is the Gaddum equation ?
In what context can it be applied ?
Why is this equation linked the the H-L equation ?
pAR = [A] / Ka(1+([B]/Kb)) + [A]
This can be used to study the effect of a RCA.
Note : if [B] = 0, we get the H-L equation
If we assume that an equal response corresponds to equal amount of agonist occupancy, what is the consequence of adding a RCA on the dose response curve ?
What can we say about the RCA ?
Adding a RCA causes a parallel shift to the right of the dose-response curve.
How ever, with increasing concentrations of agonist, we can still illicit a maximal response. Thus, we can say that the RCA is surmountable w/ increasing concentrations of agonist.
What is the Schild equation ?
What is the Schild plot ?
Schild equation : r - 1 = [B]/Kb
Schild plot : log(r - 1) = log[B] - logKb
Why is the Schild plot useful when studying RCAs ?
- The action of the antagonist can be overcome by a sufficient increase in the concentration of agonist (i.e., the antagonism is surmountable)
- In the presence of the antagonist, the curve relating the log of the agonist concentration to the size of the response is shifted to the right in a parallel fashion.
- The relationship between the magnitude of the shift (as expressed by the concentration ratio) and the antagonist concentration obeys the Schild equation
What are common practical application of RCA ?
- The characterization and classification of receptors
- The assessment of new competitive
antagonists - The classification of agonists –> the dose-ratio is independent of the nature of the agonist, we will always have r - 1 = [B]/Kb
The dissociation equilibrium constant Kb of the antagonist depends on :
- the nature of the agonist
- the receptor
Antagonist Kb is independent of the nature of the agonist.
Antagonist Kb is dependent on the receptor subtype.
What is the special feature of non-competitive antagonists ?
In general, antagonist binding is independant of aginst.
What is the effect of adding NCA on the dose-response curve ?
Adding increasing amounts of NCA causes a shift towards the bottom.
Using the del Kastillo-Katz mechanism, what is pAR* ?
pAR* = E[A] / (Ka+ (1+E)[A])
Give 2 examples of NCA.
Block of ion channel receptors :
- ketamine or Mg2+ block of NMDA receptors
- hexamethonium block of ganglion nAChRs
What is open channel block ?
What does it exemplify ?
- Block of the ion channel can only occur when the channel is open
- When the ion channel is open, the blocking site is exposed
- If a drug binds to that site, flow of ions through the channel is blocked
- Suppose that the drug has to un-block before the channel can close normally
Open channel block is a sepcial case of NCA :
B + A + R –> AR –> AR* + B –> BAR
Ka E Kb
