Pharmacodynamics: Mechanisms of Drug Action

Professor Dave again, let’s check out some mechanisms. We just learned about pharmacokinetics, which helped us understand how a drug moves through the body. Through absorption and then distribution, a drug will travel through the bloodstream and eventually arrive at its target cells, where it can elicit its intended effect, prior to being metabolized and excreted.

But what is this intended effect? Once a drug reaches its target, what exactly does it do, and how does this produce a cellular response? The study of this process is called pharmacodynamics.

So essentially, pharmacokinetics is the study of how our bodies affect a drug, while pharmacodynamics is the study of how a drug affects our bodies. Pharmacodynamics is quite complex, dealing with many advanced concepts in biochemistry, but we will do our best to go through the basics here, so that we will be ready to look at specific drugs and their mechanisms of action. Far and away, the vast majority of drugs elicit a physiological response because of the way that they interact with a particular protein.

Most often this will be a receptor protein, which may be embedded in the cell membrane, or it may be found inside the cell, whether in the cytoplasm or the nucleus. As we recall from the biochemistry series, any receptor will have a ligand, which is a molecule that fits into the active site of the receptor, and in essence turns the receptor on, evoking a conformational change that then propagates the signal in one of several ways. When drugs interact with receptors, there are two main ways that this could go.

A drug could be an agonist for a particular receptor, meaning that it fits into the active site and mimics the native ligand, eliciting the typical physiological response. We can call these facilitators. Or, a drug could be an antagonist for this receptor, meaning that it binds to the active site, but does not activate the receptor, thereby locking it in an inactive state.

We can call these inhibitors, or sometimes blockers. Whichever the case may be, we can represent binding with this very simple equilibrium, which depicts some ligand, L, referring to the drug, and R, referring to the receptor, in equilibrium with LR, which is the receptor-ligand complex, with the ligand bound to the active site. With that understood, we must now define two terms, potency and efficacy.

Potency refers to the strength of a drug at a particular concentration or dosage, or the amount of a drug that is required to produce a particular effect. And to get more technical, it refers to the concentration or dosage required to produce 50% of the maximal effect that drug can achieve. This can be examined on something called a dose-response curve.

As we can see, drugs of different potencies will require different doses, or different amounts of the drug being administered, to elicit the drug response it is capable of achieving. So if a drug is extremely potent, only a very small amount of it will need to be administered in order to achieve its maximum effect. By contrast, efficacy deals with the maximum effect that can be achieved by a drug, such that after this is reached, no higher dose will produce any further effect.

Two different drugs may have similar potencies, meaning that the response increases over the same increase in dosage, but one will achieve a more significant response than the other, or a more significant effect, due to its higher efficacy. And similarly, two drugs can have the same efficacy, but differ in their potency, since one requires a smaller dosage to achieve its maximum effect than the other. So we can clearly see that potency correlates with the X-axis, while efficacy correlates with the Y-axis.

So what is it that determines the efficacy of a drug? To understand this we have to look at how the drug interacts with its target. If the purpose of the drug is to bind to the active site of a receptor or enzyme, how well does it bind?

What is its binding affinity? If describing binding using this equilibrium from before, how heavily is the forward reaction favored, the one that produces the LR complex? Well in order to answer this question, we have to ask a few more.

How well does the drug fit into the active site? How many electrostatic interactions are being made, and of what variety? Are there hydrogen bonds?

Perhaps even covalent interactions? If the drug is acting as an inhibitor, then a high binding affinity will be crucial in order to have reasonable efficacy, because if the binding affinity is low, then when the native ligand comes along, which is the molecule that is supposed to go in the active site, it will most likely have a higher binding affinity than the drug, and will displace it, thus no inhibition can be achieved. Sometimes inhibitors will bind irreversibly, meaning that once they’re in, they’re stuck there, which is often the case if covalent bonds are formed between the drug and the protein, although covalent bonds are not necessarily required for binding to be irreversible.

On the other hand, if the drug is acting as an agonist, again binding affinity will be relevant, and it will also have to have the right functional groups necessary to promote the same conformational change in the protein as the native ligand, so that the protein will produce the same cellular response. Now that we understand affinity, we can conceptualize potency and efficacy in a slightly different way, using receptors as an example. Potency is the affinity of a drug for a particular receptor.

If the affinity is very high, most of the drug will be bound at any given time, and thus very little of the drug will be needed to occupy all the receptors. Efficacy describes the effect the drug has on the receptor once it is bound, or the degree of its ability to act as an agonist or antagonist. So potency is related to affinity, wherease efficacy is related to the clinical effect of the drug.

So now that we know a little bit about pharmacokinetics and pharmacodynamics, we are ready to start looking at specific examples of drugs. With each drug, or each class of drugs, we will try to be as specific as possible regarding the target of the drug, its effect, and its precise mechanism of action in producing the effect, so the concepts that we’ve gone over so far will be reinforced quite a few times moving forward. If you need a little more clarity, watch these first few tutorials again, otherwise, let’s move forward and tackle as many drugs as we can.