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Pharmacodynamics: Agonist, partial agonist and antagonist

Transcript

Content Reviewers:

Antonia Syrnioti, MD

Pharmacodynamics refers to the mechanisms and effects of medications within the body. Or more simply, it’s what medications do to the body and how they do it.

Alright, so, in order to have an effect, many medications have to reach their target cells and bind to a receptor. Receptors are specialized proteins found inside the cell or on its membrane. When they bind to a signal molecule called a “ligand”, they can alter their shape or activity, which ultimately results in some change in the cell’s activity or behavior. You can imagine the ligand as the key that fits into the lock, which is the receptor, causing it to open or activate. Now, depending on the effect a medication has on its receptor, they are often divided into two major categories: agonists and antagonists. An agonist is a medication that mimics the action of the signal ligand by binding to and activating a receptor. On the other hand, an antagonist is a medication that typically binds to a receptor without activating them, but instead, decreases the receptor's ability to be activated by another agonist.

Okay, now the maximal effect or response an agonist can produce, abbreviated as Emax, is determined both by the number of receptors bound to the agonist, which depends mainly on the amount of the agonist given, also known as dose, as well as its intrinsic activity, which is the ability of the agonist to fully or partially activate its receptors. Let’s plot all this into a nice graph to show the relationship between the dose given, on the x axis, usually on a logarithmic scale, and the response produced, on the y axis. So full agonists, upon binding to the receptor at high doses, are capable of producing a maximal response of 100% Emax on the y axis. This represents the point where all available receptors are bound to an agonist. In contrast, partial agonists, even at very high doses, when they occupy all of the receptors, result in a smaller response, so their Emax will be lower. For example, a 70% response would shift the curve downwards.

Now, let’s say a partial agonist is used at the same time with a full agonist and they compete for the same receptors. If we increase the dose of the full agonist, it will displace the partial agonist from the receptor, and the maximal response will still be achieved. So, the dose-response curve will shift to the right, without affecting Emax, but the dose required to achieve 50% of the maximum effect, also known as effective dose ED50, will be increased. In other words, when a partial antagonist and a full agonist of the same receptor are present together, then the full agonist’s potency, which is the dose of agonist needed to elicit a maximal response, will be decreased, but the full agonist’s efficacy, which is the maximal effect that an agonist can produce, will stay the same.

Alright, at the other end of the spectrum, antagonists can be divided into competitive antagonists, and non-competitive antagonists. Now, a competitive antagonist is a medication that reversibly binds to the same receptor site where an agonist binds, but it does not activate it. Competitive antagonists usually bind to the receptor in a reversible way, meaning that they bind and dissociate from it pretty fast. So when they unbind, it’s more likely for one of the ligands to bind. So the inhibition caused can be overcome when there are more ligands floating around. This is sometimes referred to as surmountability. Now, on the graph, competitive antagonists typically shift the curve to the right without affecting Emax, but increase the effective dose ED50. So, competitive antagonists decrease the agonist potency, but do not affect the agonist efficacy.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "First Aid for the USMLE Step 1 2021, Thirty First Edition (31st ed.)" McGraw-Hill Education / Medical (2021)