Competitive Antagonists and Irreversible Antagonists
Antagonists are drugs which bind to receptors without activating them.
There are a few varieties of antagonism…
Both the agonist and the antagonist compete for the same receptor, hence competitive. The antagonist drug, when bound to the receptor, does not activate the receptor, and thus has no pharmacodynamic effect.
The need to compete for receptors increases the dose of agonist required to achieve EC50. However, the Emax will still be achieved, provided you flood the receptors with enough of the agonist.
One drug might bind to the receptor or target molecule in a manner which makes it impossible to reverse the binding (eg. with a covalent bond). No amount of agonist will overcome this sort of bond. One example is the way phenoxybenzamine binds to the α-receptors.
In short, irreversible antagonists decrease the maximum possible effect, whereas competitive antagonists merely make it more difficult to achieve.
One drug simply BINDING TO THE OTHER DRUG and making it unavailable for binding to the receptor site. One example is the way protamine disables heparin molecules.
The effect of one drug happens to cause a physiological effect which is opposite to the action of another drug, but totally unrelated to their functions. EG. glucocorticoids increase blood sugar, and insulin lowers it, but the two drugs act by completely different pathways.
This is when a drug binds to the receptor at a completely separate site, and modifies the extent to which this receptor responds to the agonist. This doesn’t have to be an antagonistic effect. The benzodiazepines, for example, are allosteric modulators of the GABA receptor, which increase its affinity for GABA.
These can be overcome with a high enough concentration of agonist.
With competitive antagonism, the amount of agonist needed to get the same response is greater, and the EC50 is shifted to the right. The potential for a maximum effect remains the same (there is, after all, the same number of receptors to bind to- its just that some of them have an antagonist latched onto them, and with a high enough concentration you will displace them all and get a maximum effect)
These drugs take some receptors completely out of the game. The favourite way of doing this is to bind to the receptor in a covalent fashion.
This may mean that the remaining number of free receptors is uselessly low.
The maximum possible response is thus DECREASED. … UNLESS! There are "Spare receptors".
Say there are 100 receptors and 50 effectors. So maybe you manage to irreversibly antagonize 50 of the receptors. So what? The redundant 50 receptors are still enough to activate 50 effectors, so if you then give an agonist drug it will still achieve the maximum effect. The dose-response curve will look as if no antagonist was given.
A drug doesn’t need to bind to a Kd degree (i.e it doesn’t need to bind 50% of the receptors)- a maximum response is achieved with a mere 10% binding, and a Kd response is achieved with only 5% receptor occupancy. So you need a much smaller concentration of the drug.
If that cell only had 4 receptors to begin with, and you increased the number of receptors to 40, you have effectively sensitized the cell and reduced the necessary concentration of the drug.