Pharmacologic Antagonists
Antagonists
- Antagonists do not reduce the overall effect, like inverse agonists do, but rather block the potential binding of a drug.
- We call this neutral antagonism because the antagonist, alone, produces no effect: it’s inert. It is only in the setting of an agonist that we see a change in the overall response.
Competitive antagonists
- We show that when introducing a competitive antagonist in with a full agonist, Emax is unchanged but the EC50, the concentration of drug required to reach 50% of Emax, is increased.
- In other words, Emax is unchanged but the potency is reduced (remember that potency is inversely related to the EC50).
- We show a closed system wherein an antagonist binds and releases from the receptor. And then an agonist beats out the antagonist and binds to the receptor and activates it; they are in competition.
Competitive antagonists
- We show that when introducing a noncompetitive antagonist in with a full agonist, the Emax, the maximal efficacy achievable, is reduced.
- As we add more drug, the effect does not change; we cannot reach the prior maximal effect.
- The reduction in Emax signifies that this is noncompetitive antagonism.
- On the contrary, we show that the EC50 does NOT change; the drug achieves 50% of the new maximal effect at the same concentration (however, the effect, itself, is reduced).
- We show a closed system wherein an antagonist binds to the receptor and does not release from it: this binding is irreversible. The agonist cannot bind to the receptor: the receptor site is inaccessible.
- The agonist and antagonist are not in competition because the receptor site is unavailable.
- We see that irreversible binding of an antagonist makes it, by definition, a noncompetitive antagonist.
- We can imagine that the duration of action of the antagonist is not dependent upon its rate of elimination but rather the rate of turnover of the receptor, itself.
Competitive vs Noncompetitive Anatgonism
Overcoming Emax or not
It’s easy to get confused about the semantics of antagonism when we think about the various mechanisms, so let’s follow a simple heuristic:
- In competitive antagonism, increasing the concentration of the agonist can overcome the antagonist’s effect on Emax; whereas, in noncompetitive antagonism, increasing the concentration of the agonist will NOT overcome the antagonist’s effect on Emax.
Chemical & Physiologic Antagonists
- Antagonism does not have to occur at the receptor site at all. It can occur via interactions between the drug and another drug, called chemical antagonism (for instance, the way that protamine binds up heparin to render it ineffective).
- Or it can occur in the opposition of physiologic responses induced by different drugs, called physiologic antagonism (for instance, steroids increase blood glucose levels whereas insulin reduces them).
Schild equation for competitive antagonists
Schild Equation
- C1/C2 = 1 + [I]/Ki
- C represents the drug concentration required to achieve a specific response: C1 is the drug concentration response prior to the addition of the antagonist and C2 is the drug concentration required to the same response after the addition of the antagonist.
- [I] is the concentration of the antagonist.
- Ki is the dissociation constant of the antagonist (its binding affinity).
- We can determine how well an antagonist binds to a receptor (its Ki), when we measure the concentration of the antagonist [I] and we determine the concentration of a drug required to achieve a specific response both without the presence of an antagonist (meaning, C1) and with it (meaning, C2).