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Agonists & Antagonists

Notes

Agonists & Antagonists

Sections





Overview

Here, we'll learn about agonists and antagonists.

  • Start a table.

Remind ourselves that:

  • Pharmacodynamics is the study of the actions of drugs on the body.

Denote the following key terms:

Agonist

  • An agonist binds to a receptor and activates it.
  • We'll specifically address: full agonists, partial agonists, and inverse agonists.

Antagonist

  • On the contrary, an antagonist binds to a receptor but does NOT activate it; they block agonists from binding.
  • We'll specifically address: competitive and noncompetitive antagonists.

Allosteric Modulators

Lastly, we'll address allosteric modulators.

  • Denote that allosteric modulators bind to a site other than the agonist's binding site (the orthosteric site) to deliver a positive or negative modulatory effect.

Agonists

Overview

  • Now, let's draw our various agonist/receptor interactions and graph their effect.
  • Indicate columns for: Drug, Receptor, and Effect.
  • Draw a receptor and show its binding site.
  • Then, draw the X and Y axes of a graph.
  • Label the Y axis as Effect
  • Label the X axis as Log dose

Constitutive Activity

  • Show that at baseline, the receptor exhibits constitutive activity, which means that it naturally flips between its active and inactive states to produce a basal level of effect (a low level of activity).

Full Agonist

Full Agonist Curve

  • Then, show a full agonist bind to the receptor binding site and activate it.
  • Indicate that it follows our standard sigmoidal-shaped log dose curve.
    • The full agonist produces the maximal effect possible; full activation of the receptors it binds to.

Full Agonist Example: Dopamine Agonists (eg, Pramipexole & Ropinirole)

Consider Parkinson's disease, in which our goal is to increase dopamine levels within the brain.

  • We can administer levodopa, which acts as replacement therapy for the loss of naturally occurring dopamine.
  • Or we can administer a full dopamine agonist, such as pramipexole or ropinirole. These drugs mimic the molecular structure of dopamine, which allows them to bind to various dopamine receptors and activate them.
    • They are considered direct-acting because they act directly at the dopamine receptor binding site.
    • Alternatively, we can administer an indirect-agonist, such a monoamine oxidase inhibitor (eg, selegiline or rasgiline), which does not directly act at the binding site but rather acts indirectly; it increases levels of dopamine by preventing its breakdown.

Partial Agonist

Partial Agonist Curve

  • Next, indicate that we can administer a partial agonist, which also acts directly at the receptor but it only produces a partial response.

Partial Agonists as Competitive Antagonists

  • Consider that in the presence of a full agonist, a partial agonist can actually reduce the overall response.

To understand why, draw a closed system, which will contain our full agonist, only.

  • Include a small pool of receptors.
  • Indicate that the system is filled with the full agonist and all of the receptor sites are bound by them, which generates a maximal response: 100%.
  • Next, redraw the system but here we'll include both our full agonist and partial agonist.
  • Draw the pool of receptors.
  • Show the full agonist molecules but show them amidst a flood of a partial agonist.
    • The partial agonist competes for the receptor sites.
  • Show that a minority of the sites are bound with the full agonist and the majority is bound with the partial agonist.
  • Thus, the response is less than the 100% response that we saw with the full agonist, even though there is more agonist present within the system.
    • This example helps reinforce that if there's a finite number of receptors available, the full and partial agonist competing for binding sites.

Partial Agonist Example: Buprenorphine

  • A great example of this is buprenorphine, which is a partial agonist at the mu receptor (an opioid receptor): it produces less of a response than other opioids, like morphine.
  • Buprenorphine is used to prevent morphine abuse because it is far more potent than morphine for the mu receptor. So even if a patient takes morphine, the receptors are already bound up by the less efficacious buprenorphine.

Inverse Agonist

Inverse Agonist Cuve

  • Now, show that we can bind the receptor with an inverse agonist, which reduces the activity to less than the constitutive level; it reduces its the effect below the unbound state of the receptor.

Antagonists

Next, let's address antagonists.

Neutral Anatgonism

  • Show an antagonist bind to the receptor.
  • Indicate that there is no change in effect from the baseline constitutive activity; this is why we place it in between the partial and inverse agonists in our illustration.
  • 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.
  • Let's focus on two key types of antagonism competitive and noncompetitive.

Competitive antagonists

Reduction of EC50

  • First, let's address competitive antagonism.
    • We're well prepared for this discussion because we've already seen how partial agonists compete with full agonists for binding sites. In fact, partial agonists are actually competitive antagonists in the setting of full agonists.
  • Draw the X and Y axes of a graph.
    • Label the Y axis as Effect
    • Label the X axis as Log dose
  • Now hash out the sigmoidal curve for our full agonist and label the EC50.
  • Next, to the right of this curve, redraw a similar curve to represent the full agonist in combination with a competitive antagonist.
  • Show that it reaches the same Emax as the full agonist, alone.
  • But show that EC50, the concentration of drug required to reach 50% of Emax, is increased; in other words, the potency is reduced: remember that potency is inversely related to the EC50.

Competitive Antagonism Mechanics

  • Let's illustrate competitive antagonism.
  • Draw a closed system.
  • Then, draw a single receptor.
  • Next, show an antagonist bind and release from the receptor.
  • Now, show a pool of agonist start to fill the system.
  • Show that an agonist beats out the antagonist and binds to the receptor and activates it; they are in competition.¬

NonCompetitive antagonists

Reduction of Emax

Now, let's shift to a graph of noncompetitive antagonism.

  • Label the Y axis as Effect
  • Label the X axis as Log dose
  • Hash out the same sigmoidal curve for our full agonist and label the EC50.
  • Next, beneath the current curve, draw a curve for the full agonist in the presence of a noncompetitive antagonist.
  • Indicate that 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, 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).

Noncompetitive Antagonism Mechanics

  • Let's illustrate noncompetitive antagonism.
  • Draw a closed system.
  • Then, draw a receptor.
  • Now, show an antagonist bind to the receptor and not release from it: this binding is irreversible.
  • Add the agonist but show that 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

Does increasing the concentration of the agonist overcome the reduction of Emax?

It's easy to get confused about the semantics of antagonism when we think about the various mechanisms, so let's provide ourselves with a simple heuristic:

  • Write out that 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.

Allosteric Modulators

Allosteric Site

  • Thus far, we have focused on the effects of receptor binding at the orthosteric receptor site; the site where the agonist binds to produce its effect.
  • Now, let's focus on an allosteric receptor site, a site where the agonist does not bind.
  • Show that allosteric modulators can bind to this site.

Postitive Allosteric Modulators

  • Indicate that we refer to them as positive modulators, if they potentiate the effect of the receptor.

Negative Allosteric Modulators

  • We refer to them as negative modulators, if they inhibit the effect of the receptor.

Negative Allosteric Modulators as Noncompetitive Antagonists

  • As we can imagine, if a drug binds to the allosteric site and produces a conformational change in the receptor that makes it unavailable for the agonist to bind to, a negative allosteric modulator, we can call this a noncompetitive antagonist, as well, because we cannot overcome the effect of the antagonist by increasing the concentration of the agonist.

Additional Topics

Chemical & Physiologic Antagonists

Chemical Antagonists

  • Finally, 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).

Physiologic Antagonists

  • 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

Variables

  • Before we conclude, for reference, let's include the Schild equation for competitive antagonists:
  • Indicate that C represents the drug concentration required to achieve a specific response.
  • Indicate that [I] is the concentration of the antagonist.
  • Indicate that Ki is the dissociation constant of the antagonist (its binding affinity).

Schild Equation

Write out the equation as follows:

  • C1/C2 = 1 + [I]/Ki
    • C1 is the drug concentration response prior to the addition of the antagonist.
    • C2 is the drug concentration required to the same response after the addition of the antagonist.

Meaning

  • 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).

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