in this lesson we'll cover the concept of pharmacodynamics so while pharmacokinetics describes the actions of body on the drug pharmacodynamics describes the opposite in other words in the study of pharmacodynamics we look at what a drug does to a body so when a drug enters your body it then starts interacting with cell receptors which in turn leads to a formation of signal and this signal through series of different reactions ultimately results in some biological effect so for example the signal can tell DNA to stop replicating cells in our body have lots and lots of different
receptors which when stimulated can produce very unique responses the receptors that have the most therapeutic relevance can be divided into four types number one ligand-gated ion channels number two G protein-coupled receptors number three enzyme-linked receptors and number four intracellular receptors so now let's talk about them in more details let's start with ligand-gated ion channel which is probably the easiest one to describe out of the four and just a quick reminder ligand generally refers to some molecule or an ion so this channel has a ligand binding site and when the ligand binds to it the channel
opens very briefly which allows ions such as sodium potassium chloride calcium etc to pass through the membrane and that's all it is to it next we have G protein-coupled receptor also known as seven-transmembrane receptor and this is because it passes through the cell membrane seven times so these receptors are composed of three subunits alpha beta and gamma all together known as G protein in its inactive form the alpha subunit has GDP attached to it however when ligand binds to the receptor the affinity for GTP increases so then GTP replaces GDP this in turn causes the
alpha subunit to dissociate from beta-gamma complex and then both of these complexes go to interact with other enzymes or proteins which they can alter and regulate ultimately leading to some kind of response now there are three kinds of G proteins that are important to remember these are Gs Gi and Gq first Gs is a stimulative g-protein that activates enzyme called adenylyl cyclase which produces cyclic AMP from ATP cyclic AMP is a very important second messenger the second kind the Gi is an inhibitory G protein which inhibits adenylyl cyclase thus lowers levels of cAMP in the
cell the last one is Gq which activates class of enzymes called phospholipases C we will refer to them as PLC now PLC produces two second messengers first diacylglycerol which we will refer to as DAG and the second one inositol triphosphate which will refer to as IP3 now DAG just like cAMP leads to different responses through activation of protein kinases however IP3 produces various responses by mediating intracellular release of calcium it's also important to remember that G protein-coupled receptors as well as most enzyme-linked receptors have ability to amplify signals that they receive so for example just
one stimulated G protein receptor can activate many adenylyl cyclases which will result in more cyclic AMP molecules produced and ultimately amplified response now let's move on to enzyme-linked receptors these receptors just like G protein receptors have extracellular binding site where ligand typically hormone or growth factor can attach and thus stimulate enzymatic activity inside the cell most enzyme-linked receptors are of tyrosine kinase type which simply means that they display kinase activity and that there is a amino acid tyrosine involved in that so the way it works is that when ligand binds to two of these receptors
it causes conformational change that results in aggregation of both receptors once the dimer is formed the tyrosine regions get activated and cause ATP to become ADP which results in auto phosphorylation of the receptors now once each tyrosine picks up phosphate group different inactive intracellular proteins come up and attach themselves to phosphorylated tyrosine this in turn causes conformational change in the attached protein ultimately leading to cascade of activations that produces cellular response next and the last type of receptor that I want to talk about is intracellular receptor unlike the other three this receptor is located entirely
inside the cell rather than on cells membrane therefore the ligand has to first cross lipid membrane and then once it's inside it can then bind to the receptor now the activated ligand receptor complex can move into the nucleus bind to DNA and regulate gene expression ultimately leading to synthesis of specific proteins now let's briefly talk about life cycle of receptors so each cell's DNA contains code that's used to synthesize proteins from which different receptors are assembled once assembled the receptors get embedded into the cell membrane and can receive and respond to signaling molecules but now
let me ask you what happens if cells receive too much stimulation which can potentially damage the cell well fortunately for us cells have the ability to downregulate receptors meaning they can take them out of the membrane and recycle them which leads to fewer number of expressed receptors and thus decreased sensitivity to signaling molecules on the other hand let me ask you what happens if most of cell's receptors get blocked and cell receives very weak signals well in that case cells have the ability to upregulate their receptors which means that more receptors can get inserted into
the membrane thus increasing cell sensitivity to signaling molecules now let's look at the example where our signaling molecule is actually some kind of a drug so as the concentration of that drug increases its pharmacologic effect also increases until we reach the point at which all the receptors are occupied if we plot this we can determine EC50 from the graph EC50 is simply the concentration of a drug that produces 50% of the maximal effect and it tells us how potent the drug is so let's call this curve drug "A" now if we can graph dose response
for a different drug let's say drug "B" which yields different curve we can now easily tell that of the two drug "A" is more potent because it has lower EC50 simply less drug is needed to get half of the max response now what else can we see on this graph it looks like drug "B" doesn't even reach the same level of pharmacological effect as drug "A" and this is due to its efficacy so maximum efficacy of each drug is represented by Emax at which we assume that all the receptors are occupied by the drug and
higher concentrations of it don't produce larger effect so in this example drug "A" is not only more potent but also more efficacious now let's talk about intrinsic activity of drugs so intrinsic activity refers to ability of a drug to produce maximal effect so if a drug binds to a receptor and is able to produce maximum effect that is comparable to effect produced by our bodies own endogenous ligand we call it a full agonist now let's say about 15% of receptors show some kind of activity when there is no agonist around this is what we call
basal activity so again in presence of full agonist we would see maximal effect next if we have agonist that is unable to produce maximal effect even if it occupies all the receptors we call partial agonist lastly if we have an agent that binds to the receptors and instead of activating them it stabilizes receptors in their inactive form we call it inverse agonist and this is because it simply eliminates basal activity on the other side of the spectrum we have antagonist which refers to a ligand that can bind to receptor and block it thus reducing agonist
activity so if we have both agonist and antagonist that can bind to the same side on the receptor they will compete for that side therefore antagonist that binds and prevents agonist from binding it's called competitive antagonist the characteristic of competitive antagonist is that it shifts dose response curve of the agonist to the right so for example if agonist is some drug in the presence of competitive antagonists we need higher concentrations of that drug to get half of the max effect which is EC50 so potency is reduced now some antagonists can form covalent bonds with active
site on the receptor and thus irreversibly block it this is non-competitive process because irreversible antagonists can't be displaced by agonist which leads to reduction in maximal effect which is Emax and thus reduction in agonist efficacy another type of antagonist is called allosteric antagonist unlike the other ones these bind to the site different from agonist binding site and induce conformational change which prevents agonist from activating the receptor and just like with irreversible antagonist the allosteric ones also cause reduction in Emax but no change in EC50 the last important concept in pharmacodynamics that would like to talk
about is therapeutic index our bodies are very complex therefore not everyone will experience the same exact effect from the same dose of a drug this is why we came up with therapeutic index as it helps us to measure the relative safety of a drug for a particular treatment so therapeutic index is simply the ratio of the dose of a drug that produces toxicity in 50% of the population to the dose of a drug that produces effective response in 50% of the population so if we were to graph it we would need to determine the curve
that represents positive therapeutic response and the curve that represents negative toxic response so in this example after obtaining data from the population we can determine dose of a drug at which we observed effective response in half of the population which is our ED50 and we can also determine dose of a drug at which we observed toxic response in half of the population which is our TD50 now having all that on the graph we can easily determine therapeutic index which is this range of doses at which a drug provides benefits without causing major toxicity and with
that I wanted to thank you for watching and I hope you enjoyed this video
