Pharmacodynamics: Agonist, partial agonist and antagonist

Definitions & Key takeaways

Depending on their effect on receptors in the body, drugs can be grouped into receptor agonists, partial agonists, and antagonists. An agonist is a drug that binds to a receptor and activates it, mimicking the effects of the body's natural ligands. It can have a full or high efficacy on the receptor. A partial agonist also binds to a receptor but only partially activates it. It has lower efficacy than a full agonist. An antagonist binds to a receptor but does not activate it. Instead, it blocks or interferes with the action of other ligands and drugs.

Chapters:

Watch video only

Introduction0:00–1:08

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.

Full and Partial Agonists1:08–2:51

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.

Competitive Antagonists2:51–3:43

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.On the other hand, non-competitive antagonists don’t bind to the same site as an agonist.

Noncompetitive antagonist3:43–4:40

They bind to a spot called an “allosteric site”. When they bind, it causes the shape of the receptor to alter in such a way that the ligand can no longer recognize it as a binding site.
And even if it does manage to bind, it won’t be able to produce the agonist effect. Now, binding of a noncompetitive antagonist to the receptor is either irreversible or it dissociates very slowly.
This means that the receptor will not activate, no matter how many agonists are around. In other words, this type of antagonism is not surmountable.
What we see on a graph is that the dose-response curve won’t shift, so the ED50 won’t change, but the slope and peak, and thus the maximal effect Emax that can be achieved by any dose of an agonist would be reduced.
In other words, non-competitive antagonists reduce agonist efficacy without affecting agonist potency. All right, as a quick recap, agonists activate receptors and can be divided into full agonists, which can produce a maximal response, and partial agonists, which can only produce a submaximal response.

Review4:40–5:12

Antagonists prevent receptor activation and can be competitive, meaning they bind reversibly to the same agonist binding site; and noncompetitive, meaning they bind irreversibly to the same agonist binding site or to a different allosteric site.
Competitive antagonism can be overcome by adding more of the agonist, while