Content Reviewers:Antonella Melani, MD, Lisa Miklush, PhD, RNC, CNS, Gabrielle Proper, RN, BScN, MN, Kelsey LaFayette DNP, RN
Contributors:Zachary Kevorkian, MSMI, Alaina Mueller, Rachel Yancey, Antonia Syrnioti, MD, Mary Roberts MSN, RN
Pharmacodynamics refers to the mechanisms and effects of a medication within the body. Or more simply, it’s what medications do to the body and how they do it. All right, in order to have an effect, most medications have to reach their target cells and bind to a receptor. Receptors are specialized proteins found inside the cell or on its surface. When receptors are bound by a signal molecule, called a ligand, they can alter their shape, or alter their activity, which ultimately results in some change in the cell’s activity or behavior.
Starting with cell surface receptors, these are embedded into the plasma membrane and based on their structure and properties, cell surface receptors fall into three main types: ligand-gated ion channels, G-protein coupled receptors or GPCRs, and enzyme- coupled receptors.
First are ligand-gated ion channels, which form channels or pores that are generally closed, but then open up once they bind a specific ligand. This allows ions like chloride, calcium, sodium, and potassium to flow into the cell, and trigger the signaling pathway.
Next 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.
The 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 go on to stimulate or inhibit different sets of enzymes and molecular pathways within the cell.
Finally, enzyme-coupled receptors are usually single-pass transmembrane proteins. The extracellular end of these receptors binds to ligands, and their intracellular end has enzyme activity. When a ligand binds, the intracellular end gets triggered, activating other proteins in the signal pathway.
In contrast, intracellular receptors are typically located in the cytoplasm or nucleus of the cell. Once bound to their ligand, the receptor-ligand complex attaches to specific DNA sequences that activate or inhibit specific genes.
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.
Agonists can be divided into full agonists, which can produce a maximal response; and partial agonists, which can only produce a submaximal or weaker response. In other words, a full agonist is like a really well made spare key that’s just as effective as the ligand, while a partial agonist is a poorly made spare key that could open the lock, but it takes longer.
An example of a full agonist is morphine, which binds to the mu opioid receptors, as well as the delta and kappa opioid receptors, to produce an analgesic effect; in contrast, pentazocine is a partial agonist to the mu opioid receptors, so it produces a less powerful analgesic effect.
On the other end of the spectrum, an antagonist is a medication that typically binds to a receptor without activating them, but instead, blocks the receptor so that it can’t be bound to and activated by agonist ligands. An example is naloxone, which is an opioid antagonist that binds to opioid receptors, blocking their effects.
Now, the way a medication and receptor interact with each other is ruled by two main principles: affinity and intrinsic activity. Affinity is how strongly a medication binds to its receptor. This is mainly determined by the strength of the chemical bond between the two. The higher the affinity, the higher the potency, which determines the amount of medication needed to elicit an effect. So, medications with high affinity can produce an effect at a lower dose.
Okay, after the medication binds to its receptor, it must also be able to have an effect on that receptor. This is known as intrinsic activity. Ultimately, the intensity of response to the medication depends on both the number of receptors bound to the medication, as well as its intrinsic activity. The maximal effect the medication can produce is called the efficacy.
All right, now, let’s plot all this into a nice graph to show the relationship between 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 dose is too low, so not enough receptors bind to the medication to cause a significant response. As the dose 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.
Now, the point where all receptors are occupied is where the maximum response or effect, abbreviated as Emax, is achieved, which is a measure of the medication’s efficacy. Now, if we move to the point where 50% of the maximum effect is produced, the effective dose of the medication producing this effect, known as ED50, marks its potency. So, the smaller the ED50, the less it takes to get halfway of the maximum effect, so the more potent that medication is. Okay, but if the dose gets too high, it can result in toxic effects or even death of the client.
So, the TD50 is defined as the average dose that causes a toxic response in 50% of the population. In animal studies, LD50 is defined as the average lethal dose or the dose of a medication that causes death in 50% of tested animals.
Now, if the ED50 gets divided by its TD50, or its LD50, we get the therapeutic index, or TI for short, of a medication. The closer to 1 this ratio is, the narrower the therapeutic index, which means there’s a greater danger of toxicity, so doses should be tightly regulated.
Medications with a wide therapeutic index are safer, since their toxic dose is much higher than their effective dose. On the flip side, medications with a narrow therapeutic index are more dangerous, since they have close toxic and effective doses. Two examples of medications with a narrow therapeutic index are lithium, which is a mood stabilizer, and theophylline, which is a bronchodilator.
Lets go ahead and create a new graph. This time with medicine concentration on the y axis, and time on the x axis. Now, the minimum concentration of a medication needed to achieve a therapeutic effect is known as the minimum effective concentration, or MEC for short. On the flip side, the minimum concentration of a medication that has a toxic effect is defined as the minimum toxic concentration, or MTC for short.