Pharmacodynamics: Drug-receptor interactions

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.In order to have an effect, most medications have to reach their target cells and bind to a receptor.

Receptors are specialized proteins both inside the cell and on the cell membrane that can bind to a ligand and get triggered to alter their shape or activity.

This gives rise to a signal cascade of intracellular molecules, known as the second messengers, which, ultimately, results in some change in the cell’s function.

Intracellular receptors are typically located in the cytoplasm or nucleus of the cell and recognize small, hydrophobic, meaning water- hating, ligands.

These include molecules like steroids, which are happy to diffuse across the phospholipid membrane. Once bound to their ligand, the receptor- ligand complex attaches to specific DNA sequences that activate or inhibit specific genes.

On the cell membrane are cell-surface receptors, which are embedded into the plasma membrane and bind to ligands too large or hydrophilic to pass through.

Based on their structure and properties, cell- surface receptors fall into three main types: ligand-gated ion channels, enzyme coupled receptors, and G-protein coupled receptors.Starting with ligand-gated ion channels, also known as the ionotropic receptors, these form channels or pores that are generally closed.

Once they bind a specific ligand, they open up and allow ions like chloride, calcium, sodium, and potassium to passively flow through the membrane, down their gradient, and trigger the signaling pathway.Next are enzyme-coupled receptors, which are usually single-pass transmembrane proteins, meaning that they have only one transmembrane segment.

The extracellular end of these receptors binds to medications, and their intracellular end has enzyme activity. The enzymatic domain is usually a protein kinase known as the tyrosine kinase, which phosphorylates other molecules.

When a ligand binds, it triggers a conformational change in the enzymatic domain to form high-affinity binding sites for the second messengers.

These second messengers get phosphorylated by the tyrosine kinases before heading off to activate other proteins in the signal pathway.Finally, there are the G-protein coupled receptors, also known as seven-pass transmembrane receptors, which means they are really long proteins that have one end that sits outside the cell, and then the snake-like protein dips in and out of the cell membrane seven times, and finally ends on the inside of the cell.

A ligand binds to the end sitting outside the cell, and the end of the protein that’s within the cell activates guanine nucleotide-binding proteins or G proteins, which contain an alpha, beta, and gamma subunit.

Normally, the alpha subunit binds to a guanosine diphosphate or GDP molecule and the G protein is inactive. When a ligand binds to the receptor, the G protein changes shape, causing the alpha subunit to release the GDP and allowing a guanosine triphosphate or GTP, to bind.

This causes the alpha subunit to detach and trigger other proteins in the signalling pathway.Now, there are three types of G proteins: Gq, Gi, and Gs.

Each type has its own kind of alpha subunit. The Gq protein activates the enzyme phospholipase C, which cleaves a phospholipid called phosphatidylinositol 4,5-bisphosphate, or PIP2, into inositol trisphosphate, or IP3, and diacylglycerol, or DAG.

On the other hand, Gs and Gi proteins stimulate or inhibit, respectively, the enzyme adenylate cyclase, which takes adenosine triphosphate or ATP, and removes two phosphate molecules and transforms it into cyclic adenosine monophosphate or cAMP.

IP3, DAG and cAMP are second messengers, which go on to stimulate or inhibit different sets of enzymes and molecular pathways.

For example, DAG activates protein kinase C, while cAMP activates protein kinase A.Okay, the way a medication and receptor interact with each other is ruled by three important principles: affinity, potency, and efficacy.

Affinity is how strongly a medication binds to its receptor. This is mainly determined by the strength of the chemical bond between the two.

Next is potency, which refers to the amount of medication needed to elicit an effect. This means that the higher the potency, the less medication is needed for a given effect.

When we compare these principles with each other, we can see that affinity is directly proportional to potency. So, medications with high affinity can produce an effect at a lower dose.

Finally, there is efficacy, which is the maximal effect a medication can produce. Alright, now, let’s plot all this into a nice graph to show the relationship between the concentration of a medication in the body, which depends on the amount of a medication given, also known as dose- on the x axis, usually on a logarithmic scale, with the response produced- on the y axis.

What we get is an S- shaped curve, called dose- response curve. At first, the curve is more or less flat; that’s because the concentration is too low, so not enough receptors bind to the medication to cause a significant response.

As the concentration increases, more receptor- medication complexes form, so the response to the medication climbs upward.

This is described as a graded dose- response relationship. Eventually, we reach a point where all the receptors get occupied, so the curve starts to flatten out.

This is where the maximum response or effect, abbreviated as Emax, is achieved. And that’s a measure of the medication’s efficacy.

Now, if we move to the point where 50% of the maximum effect is produced, the median effective concentration of the medication producing this effect, known as EC50, is inversely proportional to its potency.

So, the smaller the EC50, the less it takes to get halfway of the maximum effect, so the more potent that medication is.

To illustrate this, let’s plot the dose- response curves of two medications- medication A and medication B, on the same graph.

Notice both reach the same maximum effect Emax on the y axis, so the same efficacy. However, on the x axis, the EC50 required to produce 50% of that effect is much lower for medication A than B, meaning medication A is a lot more potent than B.

In other words, the closer the curve is to the left, the higher the potency is. Now, let’s look at two other medications- C and D.

Medication C achieves a higher maximum effect Emax on the y axis, meaning that it’s more efficacious than D. In other words, the higher the curve, the higher the efficacy.

At the same time, though, on the x axis, the EC50 for 50% of that effect is the same for both, so they are equally potent.All right, as a quick recap, medications produce their effects by interacting with receptors, either intracellular, or extracellular ones, including ligand- gated ion channels, enzyme- linked receptors, and G- Protein linked receptors.

These interactions are characterized by the medication’s affinity, or strong binding with the receptor, which, in turn, determines its potency, or the dose needed to produce an effect.

Efficacy, on the other hand, represents the maximum effect the medication can produce. medication A is a lot more potent than B In other words the closer the curve is to the left the higher the potency is now let's look at two other medications C and D medication C achieves a higher maximum effect on the Y axis meaning that it's more efficacious than D In other words in the in the higher the curve the higher the efficacy at the same time though on the X axis the dose ed 50 for 50% of that effect is the same for both So they're equally potent All right as a quick recap medications produce their effects by interacting with receptors either intracellular or extracellular ones including ligand gated ion channels G protein linked receptors and enzyme linked receptors These interactions are characterized by the medication's specificity for the receptor affinity or strong binding with the receptor and intrinsic activity or ability to activate it which in turn determine its potency or the dose needed to produce an effect and efficacy or the maximum effect the medication can