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0:07
what's up ninja nerds in this video today we are going to be talking about pharmacodynamics if you guys really want to understand this i truly strongly urge you guys go down in the description box below we have a link to our website on our website we'll have some awesome notes but even better some illustrations that you guys can follow along with me as we go through this lecture so go check that out also please if you guys like this video if you benefit from it it makes sense it helps you please support us in the best way you can do this by hitting that like button commenting down the comment section and please also subscribe now let's talk about pharmacodynamics when we talk about pharmacodynamics it's basically a very interesting concept that we're going to pick up from pharmacokinetics so if you guys remember from pharmacokinetics really basic the adme the absorption of the drug the distribution of the drug the metabolism of the drug and the excretion of the
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drug were all a part of the pharmacokinetics where you take a drug and we said in a perfect world let's say that we take it orally po moves through the gastrointestinal tract has to be absorbed so it has to cross cell membranes when it crosses cell membranes to get into the blood it goes into the hepatic portal system the hepatic portal system will then take this medication to the liver the liver will always if it goes via the oral route will get some piece of that drug where it can activate or you know break down some of the actual drugs so it'll have what's called first pass effect or first pass metabolism so then what it'll do is some of that drug it may metabolize and then the other remaining portions it'll put into the systemic circulation from there we know once the drug goes it'll actually distribute throughout the actual vasculature and into the tissues where it can go and exert its effect this here is where we're going to see
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the pharmacodynamic effect but if you guys remember finishing off the pharmacokinetics after a drug is done performing its particular function or it's moving through the circulation it can be taken to the kidneys where it can be excreted or it can be taken to the liver where it can be metabolized and also excreted and these are the primary organs of clearance of the drug now whenever the drug gets to the actual tissues what we can see is what the drug does to the actual body whereas pharmacokinetics is like you know what the body is actually doing to the drug if you will so now we have to see what does this drug actually do to the body particularly the cellular component of our tissues or organs subsequently so if we take and we actually look and zoom in at this drug interaction here we're going to look at one of these particular cells so here's our drug in order for a drug to be able to bind to a cell and produce a particular cellular response
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it needs to be able to act on a receptor right so there needs to be a receptor that the drug can actually bind to once it binds to that receptor it'll then produce a particular cascade of events intracellularly that activate the cell or inhibit the cell and cause it to produce the appropriate cellular response so some drugs are working to inhibit the cells some drugs are working to stimulate the cell either way that is the cellular response in order for the drug to do that it has to bind either 2a extracellular receptor we'll put ec receptor and then via second messenger systems work to be able to stimulate second messages to produce the cellular response or the drug has to be able to move into the cell and bind onto a intracellular receptor where it will then again produce a cellular response via a specific cascade of events what we have to understand now is if we take this drug and have it bind onto extracellular receptors what are
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the different types of extracellular receptors and why are they different what are some examples of drugs that act with different types of receptors and then we talk about the intracellular receptors and what kind of drugs particularly interact that way we're not going to go down the crazy rabbit hole of signal transduction and intracellular receptor pathways we talk about that in cellular biology but it's just enough for us to understand the basic concept here and the last thing we'll do is we'll talk about something called desensitization also known as tachyphylaxis intolerance with respect to drug receptor interactions all right so let's come and now talk about when we have a drug interacting with a receptor let's say an extracellular receptor what happens all right so we have different types of extracellular receptors first one that i want you guys to remember is drugs can actually bind onto extracellular receptors that are poor what's called a ligand ligand-gated
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ion channel it's actually pretty straightforward let's say here i have a neuron on this neuron i have these particular channels if you will that are supposed to allow for maybe particular ions maybe positive ions to flow in maybe negative ions to flow in maybe positive ions to flow either way it's some kind of concept like that there's a little gate if you will that's basically controlling the entry of drugs so there's these ions are not going to be able to allow for these this gate is blocking these ions from moving into the actual cell but if i give a particular drug that wants to bind into this little pocket here that's a part of the ligand-gated ion channel and once it binds onto that pocket it lifts the gate open and now this gate that was completely closed is open and there's an opportunity for the particular ions to easily flow in or out of this neuron and now this is actually a really cool concept for example let me tell you an example of a particular drug here let's
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say i have a drug such as lorazepam so lorazepam is really interesting because lorazepam acts on what's called gaba a receptors so it'll work on what's called gaba a receptors now gaba a receptors are ligand-gated ion channels so let's pretend this black dot here is gaba when gaba binds on to these channels these channels are generally closed we don't want them to be open but when gaba binds to it what it'll do is it'll open up the channel and allow for negatively charged chloride ions to easily flow into the actual neuron and as these chloride ions inflow into the neuron it makes the cell super negative and it basically hyper polarizes it and decreases action potentials you want to know why this is interesting we can give lorazepam in situations where you want to decrease the activity of neurons you know where that would be a very important situation seizures so it may be able to work to inhibit or decrease seizure activity so that's kind of one example
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of how drugs can work at the receptor and produce a cellular response is they bind onto a ligand-gated ion channel either open that channel close that channel and then depending upon what kind of channel they bind onto will determine which kind of ion flows in or out and then the associated cellular response so you get you see how that happens there all right so the next situation here that we have to talk about where a drug can bind to an extracellular receptor and produce the cellular response is not the ally and data but it can be via what's called g-protein-coupled receptors this is also pretty cool so g-protein-coupled receptors are what's called seven pass receptors or serpentine receptors and basically it has a little receptor domain where the drug combines so this is the receptor domain so where a drug would actually bind into that pocket and then there's these like you see how it actually moves through the actual membrane seven times one two three four five six seven that's
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why they call it a seven pass transmembrane receptor what happens is drugs can actually bind onto these particular receptor domain when it binds on to the receptor domain of each one of these little pockets here of this g protein coupled receptor what it does is it changes the shape of the actual receptor it changes the shape of this intracellular domain if you will now this intracellular domain is connected to something called a g protein so it's connected to something called a g protein and there's different types of g proteins if you will so here i'm going to have a g protein for each one one of the g proteins may be what's called gq so gq and what gq is it's a very interesting type of g protein so let's say that we have a drug binds to this receptor domain changes the shape of the receptor and then what it does is it stimulates a particular g protein now g proteins normally they're bound to something called gdp but what we're going to do is we
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want to activate this even more so what we do is we have them pop out gdp and have them bind what's called gtp and this really stimulates this gq protein what gq will do then is it'll move along the cell membrane and stimulate this enzyme okay that's embedded into the cell membrane you know what this enzyme is called it's a very important one for you guys to remember especially for this it's called phospholipase c and what phospholipase c will do is is it'll break down different components of the cell membrane a molecule called pip2 it'll break it down into two components one is called diacylglycerol and the other one is called ionocytotriphosphate and what these things do is is this will activate something called a protein kinase particularly a protein kinase c and this will work to increase calcium ions inside of the cell what this may do is you might be like okay zach i have no idea what the significance of this is protein kinases you know what's really
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interesting about these is they phosphorylate things so if there's let's say channels that are on the cell membrane that currently currently they're inactivated currently they're inactivated but i have this drug bind to this receptor activate this gq protein it then activates this enzyme which activates these second messengers like diacetyl glycerol or inositol triphosphate what do they do well this will increase calcium let me explain why this could be cool protein kinase c can then go and phosphorylate all of these channels if it adds a phosphate group to these channels it may activate them or inactivate them let's say it activates them if it activates them it opens them up so allow for maybe positive ions to easily flow into the cell bringing positive ions into the cell could potentially stimulate this cell let's give an example let's say i have a drug here like norepinephrine here's norepinephrine and i want norepinephrine to act on the heart cells the heart muscle
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what norepinephrine will do is it'll bind onto this receptor activate the gq protein activate this enzyme diacetyl glycerol phospho protein kinases will go phosphorylate particular channels to increase calcium ion influx or sodium ion influx and anesthetic triphosphate will activate what's called your smooth er or in this case the rough endoplasm i'm sorry the particular endoplasmic reticulum to activate or the sarcoplasmic reticulum to release calcium into the actual muscle cell the whole concept is that i increase ions inside the muscle cell particularly calcium i'm going to increase the contraction of the heart muscle cell so you guys see the clinical response if this was norepinephrine working on the heart muscle cell it would increase the amount of ions rushing into the cell stimulating its ability to contract that's the whole concept of its cellular response so the cellular response for this if this was a heart muscle
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would be that it would increase contraction do you guys get the whole point here right so the same concept exists for these other two components so there was a gq protein guess what we can actually make our lives a little bit easier for these two there's a g stimulatory protein and a g inhibitory protein so what i'm going to do is i'm going to explain this one and this one is the g inhibitor is the exact opposite so let's say i have another drug this drug binds to this receptor when it binds to this receptor the receptor changes its shape it then activates the g-stimulatory protein in order for this protein to be truly activated needs to get rid of gdp and bind on to gtp then when it's super activated it then will go move along the cell membrane and stimulate this particular enzyme embedded in the cell membrane which is called adenylate cyclase adenylate cyclase adenylate cyclase is a really interesting enzyme once it's activated it takes atp
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and converts it into cyclic amp and cyclic amp will activate a molecule called protein kinase a what do we say protein kinase a does it phosphorylates things so if there's particular channels that are on this particular cell membrane it may go and phosphorylate this cell membrane and if it phosphorylates these proteins on the cell membrane it can either open up the ion channel or close the ion channel either way ions will move in or out of the cell it'll potentially cause some cellular response this could be norepinephrine as well acting on a heart muscle cell it can do both of these concepts here but you get the point it's going to be causing some type of a cellular response now with that being said g inhibitory is just the opposite you have a drug it binds to this g protein coupled receptor changes its shape activates a g inhibitory protein the g inhibitory protein will then release a gdp and bind a gtp this g inhibitory protein will then go and inhibit
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it'll inhibit this enzyme the same enzyme here which is adenylate cyclase the adenylate cyclase is supposed to convert atp into cyclic amp and then supposed to activate protein kinase a which is then supposed to do what maybe go and phosphorylate specific types of proteins this could be structural proteins these could be enzymatic proteins or functional proteins any kind of protein you can think of it can go and phosphorylate which could either inactivate or activate the particular protein or enzyme in this situation with g-inhibitory protein you inhibit adenylate cyclase you inhibit the ability to convert atp into cyclic amp you decrease protein kinase a you decrease the phosphorylation of these particular proteins and again depending upon what you're looking for this could produce a particular cellular response so when a drug interacts with a receptor to produce a cellular response it either can act on a ligand-gated ion channel binding to a spot opening up the channel
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closing the channel one of the two which produces a cellular response or it can bind to a protein that is connected on the outside of it changes the shape of the protein the morphology of the protein that activates second messenger systems to produce a cellular response what's the last one the last one for extracellular receptors is what's called a tyrosine kinase receptor it's the same concept here i have a receptor on the out outside here and i'm going to have a particular drug let's just say for example i pick something like insulin insulin will bind to this receptor now because insulin will bind to this receptor domain what happened is in g-protein it changed its morphology right when you bind to this what it does is it activates these like enzymes that are a part of the receptor you see these blue components here these are called your tyrosine kinases and so on this kind of receptor there's these little residues called tyrosine residues they're little amino acids
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when insulin binds on to this receptor the receptor kinases become activated and what they do is they cross phosphorylate so this tyrosine kinase will phosphorylate these tyrosine residues and this tyrosine kinase will phosphorylate these tyrosine residues once you phosphorylate these it causes them to have a change in their structure once you change the structure it then makes it easier for these guys to be able to bind to specific types of proteins or second messengers and when that happens these second messengers that you're going to activate will go down and do the same thing that the protein kinases or the ionosol tile for triphosphate or all of these other molecules cyclic amp it's going to act like a second messenger which will produce the cellular response so this is an important concept so we can have three extracellular receptor pathways that i want you guys to remember that a drug can work on the cell to produce a cellular response through one
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ligand-gated ion channels two g-protein coupled receptors three tyrosine kinase receptors now this is particularly important that i want you guys to remember for ligand-gated g-protein coupled receptors and tyrosine kinase receptors this is for what kind of drugs here's what i really want you to remember this is specifically for hydrophilic
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large drugs i want you to remember that these drugs that are hydrophilic they're large they're not going to be able to move through the cell membrane and act on different types of receptors in the cell they're also polar they're charged they're not going to be able to crash through the phospholipid bilayer but if i talk about intracellular receptors my friend those are hydrophobic those are small molecules those are non-polar they can easily pass across the cell membrane and bind to intracellular receptors don't forget that let's talk about that now all right so when we talk about intracellular receptors what did i tell you remember for intracellular receptors this is for what kind of drugs this is for drugs that are hydrophobic or lipid soluble non-polar and small drugs because of that these drugs such as steroids nitric oxide things of that nature so examples of this would be something like maybe like a corticosteroid so if someone's taking
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some type of steroid of some kind corticosteroid mineral mineral corticoid one of those some type of steroid drug or maybe even they contain something like a nitric oxide molecule these drugs are small enough or hydrophobic enough that they can cross right through the cell membrane because they can cross right through the cell membrane they can bind onto an intracellular receptor when they bind onto the intracellular receptor that receptor can then translocate into the nucleus where it'll bind to you see these like little turquoise proteins here that are connected with the dna these are called transcription factors transcription factors obviously regulate the degree of transcription of dna converting dna into rna because rna is important to be able to make proteins so if i give a particular drug that activates this receptor intracellular receptor then goes and translocates and works to stimulate a transcription factor i can then increase the
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transcription process of making more rna making more proteins to produce a cellular response so this is an important thing to think about also this pathway of intracellular receptors takes time it may take some time to be able to produce this response in comparison to extracellular that's a lot faster and more amplified so there's a lot of amplification one drug can activate multiple second messenger system producing a massive clinical response this you have one drug interacting with one receptor which will take some time for it to trigger this transcription process protein synthesis process and kick into high gear so that's an important thing to remember this is a little bit quicker but it can stay around a lot stay around for a very very long time this takes some time to be able to produce a very good clinical effect all right so that's your intracellular receptor pathways between drugs and receptor interaction all right so when we talk about this next concept is a
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very interesting concept called tachyphylaxis intolerance it's really important when drug receptor interactions so when a drug works on a receptor whether it's an extracellular receptor intracellular receptor and produces a cellular response what can happen is is when a patient is exposed to maybe a particular dose of a drug maybe a lot of it let's say that you give a very large dose of a particular drug and what happens is that drug will bind on to many different receptors and keep trying to stimulate the living crap out of this cell producing a massive cellular response what happens is when you produce this massive cellular response and again here's the key term i need you to remember that it could come up on the exam for tachyphylaxis is it is a rapid type of response so a rapid response to maybe a initial dose maybe you gave a very a large initial dose of a drug and it caused a very intense stimulation of the cell because these drugs are binding on to
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many many different receptors the cell's like whoa bro you're stimulating way too intensely i got to protect myself here so what i'm going to do is is i'm going to desensitize myself to how much drug is actually out there right now and so the way it does this is very very interesting has a couple of different mechanisms one is it can say okay what i'm going to do is i'm making these receptors right so what i'm going to do is is since i have to make these receptors to plug them into the actual cell membrane what i'm going to do is i'm going to decrease the synthesis of these receptors so this pathway is decreased or inhibited so there's less receptors that are actually available for the drug to bind to so one of the ways that i can do this is i can decrease the number of receptors so there could be drug out here trying to be able to produce this clinical effect but there's no receptor for it to bind to the second thing that it can do which is
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also pretty cool here is they can also work particularly to have specific enzymes if you will maybe there are specific types of enzymes and what these enzymes will do is maybe they're like kinases of some type they'll add phosphate residues onto this particular receptor and what it does is it inhibits or inactivates the receptor because you know what happens is certain kinases what these kinases could do is they could phosphorylate these particular receptors right and when they phosphorylate them what it does is it actually tags them and then a protein called arrestin so a protein called arrested if you just wanted to think about it let's say i have a protein here and purple once these receptors get phosphorylated this protein called arrestin will bind with that and basically say hey these receptors no good inactivate them don't let them respond to a particular drug and then eventually they get internalized but again we're inhibiting it so even if
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the drug is present it's not going to be able to work on the receptor because the receptor is arrested in the phase of inactivation pretty cool right the third thing that this actual receptor and drug interaction can do is we can say okay bro way too much stimulation what i'm going to do is is i'm going to take this receptor and i'm going to internalize the receptor via an endocytosis mechanism i'm going to bring this receptor into the actual cell and if i bring this receptor into the cell you won't be able to stimulate him so therefore i down regulate my number of receptors so i can do three things via this process of tachyphylaxis one is i can internalize my receptors two i can inactivate the receptors by phosphorylating them and then having a rest and protein bind to them the third way is i can decrease the synthesis of these actual receptors and the whole purpose is trying to have a less significant cellular response in response to a rapid
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dose a rapid response to a very high dose of a drug very very quickly so that's a very important thing to be able to remember now with tachyphylaxis the other thing that's important to remember that sometimes they'll ask you is between tachyphylaxis and tolerance if i increase the concentration of the drug will it change the actual cellular response it's important to remember that it won't so the reason why is because i'm getting rid of particular receptors i'm decreasing the synthesis of the receptors or i'm inactivating the receptors tolerance is a little bit different tolerance is usually more of a chronic response so usually just a chronic response it's over you know weeks for let's say just say for example weeks or let's even be a little bit more you know less intense here let's say hours days weeks whatever we can go hours to weeks so it's way more delayed it's not the initial dose so it's a chronic response it's over time okay so it's important to remember that this is
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usually just repeated exposure to a drug so repeated exposure to a particular drug it's not like a one-time initial rapid response this is chronic exposure you're being exposed to a drug constantly every single day for a long period of time this response develops over a decent amount of time this doesn't happen rapidly or initially it's usually over time what happens is the same concept here you have a drug that you're exposed to it's basically binding on to these particular receptors and trying to cause this excessive stimulation of the receptors your cell says yo bro can't handle all this we need to be able to change this up a little bit it does all the same kinds of things it says okay what i'm going to do is i'm not going to make as many of these particular proteins i'm going to internalize these actual receptor proteins so it's going to do two things just like we did up here above it's going to internalize and it's also going to reduce the
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synthesis of these particular proteins right so this process is inhibited and this process is actually going to be also occurring the other thing that happens is it doesn't do this arrestin type of process where it phosphorylates it do something else you know that drugs sometimes they need to be metabolized by particular enzymes so sometimes drugs are metabolized especially think about alcohol in that sense sometimes drugs need to be metabolized by particular enzymes so here's this enzyme here what happens is if what if i'm exposed to a drug and i increase the number of enzymes so i'm going to increase the number of metabolic enzymes that basically works to break down that drug and patients who have tolerance what happens is when they're exposed to this drug over a long period of time chronic exposure repeated doses what we do is we increase the number of metabolic enzymes and what these metabolic enzymes will do is it'll continue to keep breaking down
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the drug so it'll keep breaking down the drug all right and that'll reduce the actual efficacy of the drug that'll reduce the response that the actual drug can produce on the body and so that's the whole point is trying to be able to have a compensation mechanism what's important to remember though is is i can overcome the activity of this enzyme if i over saturate the enzyme so if i increase the number of metabolic enzymes theoretically if i increase the drug dosage super super high eventually causes this enzyme to be so saturated where they'll still be drug left over that it won't be able to break down and metabolize and so one of the big things with tolerance is that if you increase the actual dose you can overcome the decreased response slash effect and that is an important concept the reason why is tolerance is an example of something like opioid over opioid abuse so if a patient is taking opioids they're exposed to opioids chronically what
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happens is that continuous opioid kind of working on the particular cells will cause this excessive activity of the cells to again a diminished pain response what will happen is particular cells will try to develop a particular way of metabolizing that drug a little bit easier quickly and because of that maybe what you have to do is because you're metabolizing or your receptors are becoming less sensitive is you need to increase the number of drug to be able to work on these receptors or overcome the metabolic enzymes to produce the same clinical effect and this is a very important concept with things like opioid overdose or alcohol opioid abuse alcohol abuse cocaine methamphetamines things of that nature all right that covers tachyphylaxis intolerance now what i need to do is we need to say okay we take a drug it interacts with the particular receptor when it binds with that receptor what's the affinity that the receptor has between the drug so
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what's the the bondage the actual connection between them how strong is the actual connection between the receptor and the drug and the next thing is what's the maximum clinical effect that that drug receptor interaction can produce and then we'll talk about some other things called therapeutic index all right my friend so now we're going to talk about what's called the dose response relationship so this is actually a pretty cool concept and it's going to be something that you'll definitely be tested on so you have to know this for your exam especially for the step one so when we talk about this we're going to have two curves here that are going to compare two particular components one thing is we're going to talk about the potency of the drug and the other things we're going to talk about is the efficacy of the drug and we'll have some quick kind of clinical points in there and the big pearls to take out of this so on this type of graph here on the
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x-axis what i want you to remember is whenever you see these types of graphs on your questions or on your exam on the x-axis we're taking the concentration of the drug or the dosage of the drug particularly but you know on a logarithmic scale and then on the y-axis you're looking at the response of the actual drug dosages therefore it's the dose response curve or relationship now what's really important is when we're talking about these curves let's actually say that we have the same concept here so we're going to have in black here we're going to have we give a drug we give a particular dosage of a drug what happens is when you start off with the low dosage of the drug only small amounts of drug are going to bind on to a very little of these receptors okay so what happens is if you only have a little bit of drug only binding onto a few out of the tons of receptors that you have the clinical response that you're going to see is pretty minimal
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and so what we'll see here is we'll see like a pretty like flattish curve but then what happens is as you start to have more drug binding onto more receptor you start seeing what you start seeing an increase in the response now what's really really interesting is that as i have more and more and more drug that's actually increasing based upon an increase in the drug dosage eventually all of these receptors are going to become saturated with drug and no matter how much more drug i give there's not going to be enough receptors for that drug to bind to to produce a cellular response so therefore it'll plateau or remain constant that cellular response because all of my receptors are saturated and activated and so because of that what we'll see is we'll see this kind of trail off and become flat that's a very important concept so we kind of say this kind of looks like an s-shaped curve or a sigmoidal curve and again the first component here is where
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it's initially flat that again is whenever there's very little drug binding on to not very many receptors so we're not producing a massive clinical response phase two of it is when we're actually seeing tons of drug binding to tons of receptors producing a good cellular response and the third part here is where we have all the drugs saturating all of the complete number of receptors that we have and this point here is the e-max that's the max amount of drug that you can give to produce the maximum response or effect that you're looking for and so this is an important concept now another thing that we have to talk about here so we're going to say let's say that this is a hundred percent effect or response and then somewhere in the middle here we're going to say is about a 50 response and then here is going to be about a zero percent response we'll see the same thing over here on this curve i'm just comparing potency and efficacy
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so let's say same thing here i draw this curve here just to kind of make it representative this was a little bit too much of a slope here so let's bring that less of a slope okay so here's our sigmoidal curve same concept here here's one so that's whenever little of the drug is binding to very little receptors as we increase the concentration of the drug we start to see again more drug binding to more receptors and then eventually we saturate all of those particular receptors so that's our concept there this should be this dose response curve what it should look like sigmoidal now here's what i want you to think about with respect to potency of the drug what i want you to remember terminology wise is potency is correlational with affinity so in other words so i want you to think potency correlational with affinity so as i increase the affinity i increase the potency of the drug and this is basically the strength so this is the strength of drug receptor
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interaction so the stronger the bond is between the drug and the receptor the more affinity the more potent the drug is now if i have an actual drug and it's binding onto this receptor and the strength of this actual bond is very very powerful that doesn't necessarily produce the same efficacy okay so you can have a drug that has a very high potency but what is the significance of having a drug with a very high affinity or a high potency let me explain let's say here that as i what do i know then if i have a very high affinity that that that that drug has for the particular receptor okay so this drug has a very high affinity for this receptor meaning it's very very potent what i can do is very very cool here is when we look at this we actually can take into consideration something called the ec 50 which is a measure of potency and so the ec 50 is the concentration of the drug so it's the concentration of the drug that will reach 50 percent of the max response or effect so what is
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this called this is called your ec50 that is a measure of potency or affinity so what i want you to remember is the ec 50 is basically kind of a measure of potency now why is this important because when you guys get a graph you have to be able to consider this okay watch as the ec 50 increases meaning you go towards the right the concentration of drug that you have to give to reach 50 of the mass effect as that increases what am i saying that i have to give more drug to produ produce 50 of the max effect that means the potency is doing what it's decreasing i don't have a strong of a drug receptor interaction so what i want you to remember is is that as you increase your ec 50 you decrease the potency meaning that these are inversely proportional if i decrease my ec 50 meaning i don't require as much of a drug concentration to be able to produce 50 percent of the max effect what does that mean for my potency that means this potential so because of
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that we have a very very good situation here now watch what would this curve look like if i actually took this into consideration where i had one situation where i want to change the potency so let's say i want to have a decreased potency that means that this curve would go which way it means it would go this way right because now look at where my ec50 is my ec 50 is all the way over here so what i see is as i see that whenever the potency is actually decreasing what happens to the sigmoidal curve where does it shift shifts to the right if i want to increase the potency let's say that i do this in a different color here then i would have this go this way and look where my ec50 is so my ec50 is shifted to the left and if it's a decrease ec50 that means a higher potency of the drug so it's important to be able to remember that so whenever you see these particular curves here and they say which one of these if i were to say this is medication a medication b
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medication c which one of these has the d the lowest potency you'd say a b c which one has the highest potency it would be a so it's important to be able to remember that concept all right we have to now take into consideration something called efficacy so efficacy is actually a very interesting concept and it's actually dependent upon two things it's dependent upon the drug receptor interaction right so basically how many receptors the actual drug is occupying so if i give a drug and this drug is occupying 100 of the receptors that means it's probably going to have an increased efficacy if i give a drug and it's only occupying some of those receptors the efficacy is going to be decreased that's one component the other component is the intrinsic activity intrinsic activity of the drug meaning if this drug binds to this receptor if this drug binds to this receptor will produce a 100 clinical response will it produce a 70 clinical response will it
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produce a 50 of a clinical response that's dependent upon the intrinsic activity of the drug so some drugs are what's called full agonists meaning that when they bind to the receptor the effect that they have is 100 some are partial agonists meaning that when they bind to the drug even if they occupy all the receptors the effect that they will give you is never going to be maxed it's not going to be 100 and so that's another important concept so when i think about efficacy it's really determined by what what we set up here the point when all of the receptors are stimulated so drug receptor interaction you have to have at least you'd like to 100 of the receptors that are occupied but it's also dependent upon the intrinsic activity so even if you had let's say i had a cell where 100 of the receptors are occupied if i had 100 of their cells uh all the receptors occupied and the intrinsic activity of that drug was very high a full agonist
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it would give me this type of emax then it would give me this where my hundred percent or my emacs the point where all my receptors are occupied doesn't matter if i increase the drug anymore the maximal effect that i have will be at this point all the receptors are occupied if i take a drug that has a decreased efficacy meaning that maybe it has less receptors that it's bound to or meaning it has less intrinsic activity what would it look like while i'd expect the e-max to come down it wouldn't shift to the right or shift to the left they should they could actually keep the potency about the same so what would i see with this curve if i were to compare here i would actually see something like this you see how it trails off like that so this would be the emax and this here the difference between these two is the difference in efficacy so this here is the difference in efficacy this here between each one of these between this component here
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and this component here is the difference in potency so remember that if my curve is shifting down i'm changing the efficacy if my curve is shifting to the right or the left i'm shifting potency but again the same concept here exists so again if i take this difference here between on the y-axis this tells me my response to the actual drug right so the max effect and again same thing this drug a would have the highest efficacy this drug would have the lowest efficacy but if i even wanted to make it even more intense i keep the same potency but again trail off here so my emacs is even lower so if they were to say okay in a question you have drug a which is black drug blee which is pink drug c which is going to be green which one of these has the highest efficacy you would say would be the top one a which one has the lowest it'd be the green the bottom one and so this is an important concept to be able to understand all right now sometimes the question may come up
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and say okay if i have a particular situation where let's say i have a drug for example a commonly utilized one bumetanide and furosemide those are diuretics when you think about these the efficacy so let's actually just put here bumetanide and furosemide be metanide and furosemide when you think about this bumetanide i can actually give a very low dose to be able to produce 50 of the max effect so because of that if i give a very low dose what's the potency of that drug it's very very good it's very high potency so in that situation bumetanide can be more potent than furosemide because i can give a low dose to be able to produce 50 of the mass effect max effect whereas with furosemide i'd have to give a little bit of a higher dose so we can say that the potency of these are different but the literature has actually shown that just because the potency is different doesn't mean that the efficacy is different so if i actually take bumet nine
41:44
ferocity and compared them around the same like level of actual dose comparison with their potency i could actually see that these do have an equal efficacy so just because a drug has a different potency does not mean that it doesn't have the same efficacy so just make sure you remember that as well all right my friends so we talked about efficacy we talked about potency the last thing that we got to talk about here for this section of dose response is something called the therapeutic index alright guys so now let's talk about the therapeutic index so therapeutics is actually a really important thing is in terms like the safety of the drug if you will so what i want us to think about is same kind of concept here we're still going to have like this dose response curve if you will it's just on the x-axis it's logarithmic concentration of the dose but instead of it being a response or effect on the y-axis with the dose response curve for therapeutic index we
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determine a patient population so the percentage of patient population if you will but it's still going to be the same dose response curve so i'm going to start here move up like this that's my dose response curve same thing over here i'm going to move up and there's my dose response curve okay so same concept here now we use that terminology where we said okay here's 100 that's emax right and then somewhere in the middle here we're going to be about 50 that was the ec 50 for the dose response curve well now we're talking about something different okay we're talking about the percentage of patient population so remember here at about 50 percent of the patient population just like 50 percent of the max effect that you can produce at this drug concentration that was called ec50 all we're doing is we're saying this is now the ed50 for therapeutic index same thing over here here's i'm going to bring this response curve up just a little bit higher okay so here if we look at this
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this would be our max effect or 100 percent and somewhere here in the middle of about 50. so again here is going to be 50 of the patient population i'm giving this concentration or dose of the drug now this is also called the ed50 now let's compare ec50 was the concentration of drug that i would give to produce 50 of the max effect the ed50 is the dose of drug that i would give to 50 of the population to produce the clinically desired effect okay so let's put desired effect this is good good stuff right so this is clinically desired effect within 50 of the population if i give this dose of the drug now what i'm gonna do is is i'm gonna be a little evil and i'm gonna give a toxic dose but on one situation the the actual toxic dose that i can give to 50 of the population that actually produces that toxic effect is not very large so what i can say is like let's say it's like right here so that's my toxic dose so this is a toxic effect so if that's the toxic effect then right here
44:44
at giving 50 of the population this dose of drug that is my toxic dose so td50 same thing over here i'm going to give it but now what i'm going to do is it takes a very large dose of that drug to give to 50 of the population to produce the toxic effect if you will so now this is the toxic effect and the td50 the dose that i got to give to 50 of the population is right here there's my td50 now the therapeutic index is the difference between these two that is the therapeutic index so this is a therapeutic index which is small and small therapeutic index that's a scary situation that's not a good thing ones with a large therapeutic index is a good thing it's very hard to be able to you know make a mistake with these types of drugs giving a particular dosage you won't kill the patient or cause a very toxic effect so it's important to remember that so how do we determine therapeutic index therapeutic index is dependent upon the td50 divided by the ed50 so
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td50 divided by ed50 so think about this in this situation here the td50 is relatively low it's decreased so the therapeutic index if we think low low they're directly proportional so a decreased td-50 and i don't have a very i don't have to give a very large dose to produce the toxic effect of 50 of the population this very low td50 will give me a very small or narrow therapeutic index and this is scary because they have high risk of side effects or toxicity if you will meaning let's say i take for example you know i remember the drugs in this category remember a guy a guy right warning these drugs are lethal all right so it goes guy warning these drugs are lethal and if you like this and it helps you remember it great it just makes me laugh but it goes gentamicin gentamicin warfarin which is a really big one it's theothen which we probably don't use too much anymore nowadays for copd digoxin good one for afib and heart failure
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aeds and i think one of the big ones to remember is phenytoin and the last last one is lithium okay which we use for bipolar so what's important to remember about these is that you could give a dosage of this drug that produces a clinically desired effect and increasing the dose just a little bit is a very risky situation to put you in a toxic effect of the dose that's why it's important whenever drugs have a very small therapeutic index you monitor these drugs through particular like serum levels or labs so one of the best ones to give an example about is warfarin i determine it by its inr right the other ones i can check their levels i can check the level of an aminoglycoside or i can check the level of digoxin i can check the level of phenytoin and lithium because i want to make sure that the concentration i have in the blood is not too high but it with risk of toxic effect so the margin of error for a therapeutic index when it's small is very very
47:59
very tiny and there's a high risk of side effects and the opposite you probably already know now that this is a large therapeutic index you have to give a very high td50 so you increase the td50 you increase the therapeutic index and so this is a large therapeutic index and so because of that there's less risk of side effects so i could give a pretty heavy dosage you know what a good example of this one is uh steroids and penicillin so good examples of this one is penicillin g i can give like massive amounts of penicillin g and small amounts of penicillin g and i would have a very difficult time being able to get to the toxic effect of it corticosteroids so steroids are another one as well you can get pretty like large doses of steroids as well and again less risk of a toxic side effect so i think this is an important really really important concept to remember especially for clinicals and as well as your exams all right now let's talk about intrinsic
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activity so agonist and antagonists alright guys so now let's talk about intrinsic activity between drug receptor interactions this is actually a pretty cool concept very high yield so we should know this as well so whenever you have a drug that binds to a particular receptor we want to try to in some way compare it to our endogenous system and so i think one of the really cool examples to think about is let's say that um let's say a very common one is you have a blood vessel and on that blood vessel you have what's called alpha-1 receptors so here's an alpha-1 receptor what we know is that norepinephrine and epinephrine are basically molecules that will bind onto this receptor stimulate it and trigger vasoconstriction that's the response or the effect if you will of the drug binding onto that receptor now let's assume that there's 100 receptor binding by norepinephrine we know that its effect is vasoconstriction if i give a drug that also can act like
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norepinephrine whenever it binds on to 100 percent of the receptors are completely saturated with this drug and it produces the same intensity or maximal effect 100 vasoconstriction just like norepinephrine it's a full agonist if i give another drug drug b and i have it bind on to 100 of the receptors are saturated by this other type of agonist drug b but it doesn't produce the same maximal effect or efficacy as drug a did we call that a partial agonist and then when you have another drug drug c and this binds on to the alpha-1 receptor and all it does is it keeps the actual receptor completely inactivated then you significantly reduce the actual efficacy and the maximal effect of that drug to below the basal activity of the receptor because normally receptors have some degree of basal activity that degree of basal activity is about 12 percent so no matter what if i give a particular drug all we're doing is we're increasing the efficacy of that drug above its
50:56
basal activity 12 percent about most textbooks will say so say i say a full agonist with the first case so full agonist so for example norepinephrine i can give a drug just like norepinephrine norepinephrine i can just give it exogenously so levofed norepinephrine another agonist would be phenylephrine or epinephrine they both can bind onto the alpha receptors and produce the same type of you know maximal effect so that would be an example of a full agonist so if i were to give let's say these are all alpha one receptors i could give a drug like norepinephrine epinephrine or i can give something called phenylephrine okay and these will all produce the same type of clinical response when they bind to so 100 percent of the receptors are bound by a drug and they produce the clinical response the clinical effect that they have will be the max effect that you can produce the e max okay so if we were to drop that off on the curve here log mere the
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concentration of the drug on the x-axis response on the y-axis just like the dose response curve what we're going to see is is that there's 12 basal activity i'm going to increase it from that point that would be the curve at 100 max efficacy if i give a full agonist so remember this is a full agonist it will produce the same it'll mimic the basic endogenous system okay a partial agonist will be something a little bit different so i think a really interesting example about a partial agonist could be something for example you know there's a opioid receptors so let's say that this is what's called a mu receptor a mu receptor is a type of opioid receptor and it loves to bind onto something called morphine and so what happens is if you give something uh like a partial agonist this is really interesting partial agonists they'll bind on to these receptors these mu receptors let's just say an example of this could be something called buprenorphine buprenorphine
53:03
and what happens is this will actually bind onto these new receptors if it saturates 100 of the mu receptors it'll produce a clinical effect that is below the max effect it's sub-par sub max effect maybe like if we were to say this is 100 this is like 70 or 60 percent but it's below the max effect that's a partial agonist it will not produce the max effect but there's something really interesting about partial agonist that i'm going to talk about in just a second but let's say that we graph this out in a pink so now we have another one where we're going to start this off beyond the basal activity of the receptor i'll see that as i increase the concentration of the drug i will do what i'm going to drop off my efficacy because no matter what i'll never reach max effect so this one i'm going to even i'm going to make it a little bit more drastic so we're going to drop this one off even a little bit more than that so this is going to be a partial
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agonist now here's something that's really interesting about partial agonist partial agonists if you keep giving higher concentrations of a partial agonist and you give it in combination with an agonist so for example what did we say would bind on to the mu receptors let's say that you give buprenorphine and you're giving it with morphine and let's make sure morphine is like in a different color here let's make him in this red color here so here's morphine in red and then buprenorphine is going to be in black here if you give buprenorphine what it'll do is it'll bind to all of these mu receptors and basically as you increase the concentration of it it's going to block the actual morphine from being able to bind into that receptors because it's kind of in the same active site as the buprenorphine and so that's blocking that morpheme from being able to bind to that actual receptor so what's really interesting is that when you give an agonist and a partial agonist together
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so this is an agonist
55:00
this is a partial agonist again full agonist partial agonist when you give these together what you see is is you see something called competitive inhibition where this buprenorphine is going to compete with morphine for the actual mu receptor blocking it and the only way that you're going to be able to see the morphine produce max effect meaning that whenever this guy binds to the receptor it produces the max effect is if i keep trying to increase and increase and increase the concentration of my morphine to eventually displace the buprenorphine out of that active site that's a really interesting concept to remember so partial agonist can also act like antagonists so remember that okay sometimes partial agonists if you increase the concentration of them they can act like antagonists specifically competitive antagonists all right off my soapbox with that one the next one that i want you guys to think about is called inverse agonist
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now inverse agonists are a little funky they're weird ones so what happens is these drugs will bind to the receptor and when they bind to the receptor they will significantly decrease the effect of this drug like less than 12 which is the basal activity of the drug you're like what the heck so what would i see that i would see this thing do something like this that's that's my inverse agonist so for my inverse agonist i'm going to see this particular drug reduce the actual effect of the um it's going to reduce the actual maximal effects significantly to the point where it's less than the basal activity how the heck do you decrease the drug receptor interaction where you go below the basal activity you inactivate the receptor that's what this thing does so basically what it does is you have receptors that can exist in two forms so let's say here's one receptor here's another receptor and if i want to go back and forth
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between these two forms here so let's say i want to go back and forth so this is going to be r which let's say that this is the active form and then we're going to make this one so make this r let's make this one r prime this is the in active form what we do here is that when an inverse agonist interacts it tries to be able to push the reaction and keep it in this inactive form so what it does it tries to be able to keep this receptor in the inactive form it shifts this reaction to keep it inactivated so now no other agonist will be able to bind to it so it completely reduces the drug receptor interaction below the basal activity that's an important thing to think about inverse agonists there's not too many drugs that you can think about for this one one of them could be something like antihistamines can act like this on the h1h2 receptors but don't get too bogged down in the details focus more on full and partial now the next thing is that sometimes we
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have to talk about antagonists and what antagonists do which we're going to talk about next is they work to be able to oppose the agonists and what they try to do is they try to be able to act like a neutral component here and so they'll basically kind of like inhibit any type of agonist being able to bind to the receptor but at least allow for the receptor to maintain basal activity and so this will be the antagonist and that's what we're going to talk about next we're going to talk about competitive and non-competitive antagonists let's talk about that now all right so now we're going to talk about the same concept we talked about agonists full agonist partial agonist inverse agonist with antagonists these are basically going to be working in the opposite function of an agonist so they're completely opposite so take for example um let's use this example here we had up above we have a blood vessel has a alpha 1 alpha 1 receptor norepinephrine will
58:44
bind to that and cause vasoconstriction an antagonist to that drug would be something that is an alpha one blocker so i would give something like an alpha one blocker and that would basically bind on to this little receptor site inhibiting or preventing norepinephrine from being able to exert its effect on it therefore there would be no vasoconstriction that is what an antagonist does is it opposes the action of the agonist in this case we're using norepinephrine as an example so how does it do this well what happens is let's say here we have our cell and here's the receptor let's say we have in general our agonist and we're going to represent agonist here in black okay so here's our agonist and what we're going to do is we're going to give what's called a competitive antagonist and we'll just use this example here here's our neuroepinephrine which is going to bind onto these alpha-1 receptors and then over here i have my alpha i'm going to
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put alpha blocker all right so one of the alpha blockers you can have tons of these dang things but an alpha blocker of some kind right we could use phentolamine whatever we'll just say phentolamine it's just an example of one of these so phentolamine
1:00:06
what phentolamine will do is is it'll come and basically norepinephrine is supposed to bind to these receptors the phentolamine will plug into these receptors and basically block the norepinephrine from being able to bind here so if we were to look at the normal curve let's say that we have the normal dose response curve when norepinephrine binds to these receptors we know that it produces a nice sigmoidal curve so same thing effect you can say response it's the same concept this is the dose response curve i'm going to see something like this right that's my dose response curve this is a 100 max effect and this right here will be somewhere around 50 max effect right now what i know is is that this would be what would happen if neuroepinephrine was to bind to the actual alpha and receptor now what i'm going to do is is i'm going to give phentolamine and when i give so this is actually going to be my agonist if you will so this is my agonist whenever it's
1:01:05
supposed to bind so norepinephrine what i'm going to do is i'm going to give it a competitive antagonist like phantolamine it's going to work to block these receptors now if there is any receptors that are available norepinephrine will still bind so if there is any receptors that are actually available norepinephrine will bind to these and still produce some type of response but if i still want it to be able to produce the maximum response what do i have to do what i need to do is is i need to increase the concentration of my norepinephrine or my agonist to overcome and displace the antagonist out of the active site i want to pop those out of the active site so that i have the ability to beat that guy out and bind onto these receptors and produce the same type of clinical response that i want but in order for me to do that in the presence of this antagonist i need to increase the concentration heavily so let's say now i have a new curve and this new curve what am i going to
1:02:13
have to do if i need to be able to produce the same clinical effect the same response as an agonist would by itself i'm going to have to increase the concentration of the drugs significantly to be able to produce the same type of clinical response and so this would be a combination of my agonist and antagonist and specifically which one competitive antagonist so what i'm seeing is is in order for me to be able to produce the same kind of maximal effect i'm going to have to do what to my dosage increase the dosage so i have to increase the dosage do you guys remember off of that curve what that looks like so remember this is our e max the maximal effect that this actual drug receptor interaction can perform and then at 50 percent this was our ec 50 and then this was our ec 50. what was happening if i increased or i shifted the actual curve to the right what did that do that increased my ec 50 what does that do to the potency then it decreased the potency so competitive
1:03:29
antagonists do what to your potency they decrease your potency but what do they do to the emacs nothing so here's what i want you to remember no change in emacs but what do they do to the ec 50 they decrease your ec 50 which is going to do what it's going to require if i'm sorry if you're actually increasing your ec50 i apologize if you're increasing the ec50 what is that doing to the potency it's decreasing the potency because these are inversely proportional so we're shifting it to the right increasing our ec 50 which means i have to give more of the drug to be able to have the same type of potent effect that's what i want you to remember so for one thing for competitive no change in e-max but it does decrease the potency so you have to give more of the drug to displace the competitive inhibitor out of that spot so that you can produce the same type of maximal effect or clinical response all right i hope that made sense for non-competitive antagonists it's a
1:04:22
teensy bit different so let's use the same example here that we talked about this blood vessel let's say here this actually kind of worked out well i didn't even think about this but here you have an alpha-1 receptor again norepinephrine's supposed to bind so i'm going to give an alpha blocker that's going to work to basically block prevent work against the activity of the agonist right so we know normally if we were to give norepinephrine by itself it would look something like this right same kind of curve there that's our dose response curve this is the agonist by itself okay just the agonist now here is my norepinephrine and then down here same color here in blue i'm going to have my antagonist but this is a non-competitive i didn't plan this but this actually worked out perfectly so another alpha blocker so this is actually noroepinephrine there's another alpha blocker that acts as a non-competitive antagonist and it's called phenoxybenzamine benza
1:05:22
mean now the difference here is that phentol mean bound to the actual active site so you see a little pocket there that's called the active site the same site where the actual agonist binds to now phenoxybenzamine does not bind to the active site so when you have a non-competitive inhibitor like phenoxybenzamine it binds to another site besides the active site so let's say that it binds to like right here binds to like right here binds to here binds to here it's not the active site this site here if we were to kind of like let's say that we zoomed in on this theoretically let's say here's the receptor i'm going to put a little kind of like divot here so here's the receptor when we really zoom in on it here's the active site that right there is called the allosteric site so it's a site on the actual protein or receptor other than the active site when this phenoxybenzemian or non-competitive antagonist binds to this it changes the shape of the actual receptor to where now
1:06:28
it changes it in such a way where maybe it's not even the same shape here or maybe maybe it looks like this now maybe it's like
1:06:38
and now it's going to be harder for that to be able to bind to the agonist norepinephrine so because of that norepinephrine wants to be able to bind here but it can't even know that there's a site available these non-competitive antagonists bind to the allosteric site changing its shape that no matter what even if i try to increase and increase and increase the concentration of norepinephrine it's not going to matter because it's going to have tons of active sites available that's not going to make a difference and if i increase the concentration it'll still have a difficult time being able to bind to the active sites but what i know is that no matter what i do to the concentration if i can increase it increase and increase it it's not going to be able to produce any improvement in the overall response or cellular effect and that's a really important concept so the response i can't spell a response for the life of me the response or the clinical effect
1:07:36
is going to plummet it's going to plummet even if i increase the concentration of this dang drug or agonist it's not going to matter because this not non competitive inhibitor phenoxy benzamine is binding to the allosteric site changing its shape to no matter what it's not going to be able to bind properly to the agonist so what would the graph look like here well i know that if with respect to concentration or potency that's not going to change it's going to stay the same so if i were to look here it would should look just like this i shouldn't shift the curve i'm going to do it just a little so you guys can see the difference here but what i'm going to notice here is that this is son of a gun this is my max effect this is my emacs so that's at a hundred percent response or effect here i'm going to come right in the middle about 50 so i know that this right here is my ec 50. they're about exactly the same and that should make sense because
1:08:35
even if i increase the concentration of my monopoly it's not going to make any difference in the response there's no effect on potency with respect to non-competitive inhibitors but what i am going to see is that the response the effect that it's going to have is going to decrease significantly because the agonists can't bind to the dang active site and produce the response it wants to because the non-competitive inhibitor changed its shape by binding to the allosteric site so what will i see i'll see this thing drop off before reaching maximal response or effect so it'll drop off like this and here will be its emacs this is the agonist and the non-competitive
1:09:15
antagonist and what do i see with respect to the e-max i see a decrease in the e-max if i see a decrease in the e-max what do i know then i know that non-competitive inhibitors do what they decrease the efficacy of the drugs so what would they do to the ec 50 the ec-50 will be the same no effect no change that's one thing but the e-max that will change you'll decrease the e-max with respect to non-competitive inhibitors the only way you can actually prevent this and improve the efficacy is getting rid of the non-competitive inhibitor you increase the drug concentration trying to decrease the potency is not going to affect it so that's an important thing to remember all right initiatives we covered pharmacodynamics now let's do a couple practice problems see if we can test you guys knowledge and review or your understanding now let's get to it all right engineer so we finished our pharmacodynamic video but now we got to really put everything that we talked
1:10:13
about on the whiteboard to practice to see if you guys really understand this okay so first question here which of the following best describes how a drug that acts as a agonist on the gaba a receptor affects signal transduction in a neuron i went through this example very specifically so a gaba a receptor is an example of what kind of receptor is it a ligand-gated type of ion channel that it will act as right whenever gaba-a receptors are particularly is it a ligand-gated is it a g-protein g-protein-coupled receptor or is it some type of tyrosine kinase receptor or is it an intracellular receptor i use this one as a very specific example as a ligand-gated ion channel and so whenever you give a agonist of the gaba a receptor it'll bind onto that little pocket open up the channel to allow for chloride ions to flow into the cell decreasing the chance of generating a action potential so would it be activating the intracellular receptor process so no
1:11:15
would it be opening up ion channels that allow sodium no would it be activation of this receptor subtype that opens up ion channels that allow chloride to enter in yes that's likely the one or does it activate the receptor the g protein remember i told you it was not a g protein it's not an intracellular receptor it does act as a ligand-gated ion channel so it is opening up for sodium or chloride it's particularly for chloride remember that example i showed you on the whiteboard this was the one and we used this kind of way of being able to treat anxiety and seizures etc all right next question after one milligram if one milligram of lorazepam produces the same anxiolytic response as 10 milligrams of diazepam which is correct think about your dose response curve so remember as we increase the dosage going towards the right what happens to the potency of the drug remember i have one drug here it's going to be towards the left i can give a very low dose of that drug to produce the
1:12:12
same efficacious response if i have to give a higher dosage to produce the same efficacious anxiolytic response what is happening to the potency of that drug that means the potency of diazepam is decreased that means i have to give a higher con a higher dose of that drug to be able to produce the same effect so what i say lorazepam is more potent than in this case i would i would say that one milligram is definitely that lorazepam is more efficacious no because remember doses were producing the same anxiolytic response so the efficacy is the same it's just the dosage that i have to give to change that to reach that efficacious response is different so it's not b lorazepam is a full agonist and diazepam as a partial agonist don't worry about that that has nothing to do with this lorazepam is a better drug to take for anxiety than diazepam again has nothing to do with this so it's either efficacy or potency and in this case lorazepam is more
1:13:06
potent than diazepam again remember that as you have to increase the concentration of your drug so the ec50 so that was the actual concentration to reach 50 of the max effect as that goes more towards the right or increases the potency of the drug decreases so that's an important concept all right next one here so we have 10 milligrams of oxycodone produces a greater analgesic response than does aspirin at any dose which is correct so now we're looking at the response so the response is actually a degree of efficacy of 10 milligrams of oxycodone will produce a higher efficacious response than compared to aspirin at any dose that means that oxycodone is more efficacious than aspirin is because again we're looking at the response not the dose that we need to attain the same response so in this case it's more efficacious for oxycodone okay all right in the presence of propanol a higher concentration of epinephrine is required to elicit full anti-asthmatic
1:14:14
activity propanol has no effect on asthma symptoms which is correct regarding these medications so what you're trying to look at is you're trying to look at particularly here again for presence of propranolol a higher concentration of epinephrine is required to elicit a full anti-asthmatic activity propanol has no effect on asthma symptoms which is correct regarding these medications so when you look at this we're looking at now agonist and partial agonists etc so if i get propanol i need to increase the concentration of my epinephrine to be able to reach the full antismatic activity well epinephrine will act in this case is kind of like wanting to be able to act as a full agonist in this situation that's what epinephrine wants to be able to do it wants to be able to produce bronchodilation if you give her panel off her panel law is going to try to be able to block that in a particular way because of that propanol since it has no effect on asthma symptoms it's not
1:15:12
really going to act as like you know in this situation here it's not really going to work as an agonist because it has no effect on asthma symptoms so therefore it can't act as an agonist if that's the case then i have to increase the concentration of my epinephrine to be able to reach the full activity that means the propanol is acting as a beta blocker so i'm going to have to increase the concentration of epinephrine to block to push him out of that beta receptor site to produce the same effect if you remember this diagram here this was competitive antagonist non-competitive antagonist so if you look here for competitive antagonists what do we need to do to produce the same efficacious response so imagine here is just going to be epinephrine okay here's its efficacious response this is the dose that we can give if we give propanol propanol is actually going to take up some of those receptors and block epinephrine so then what i'm going to have to do is increase the
1:16:08
concentration of my epinephrine even more so my ec50 is going to increase so the potency of my drug is less and so because of that i'm going to have to increase the concentration of epinephrine to push some of the perpendicular out to get the same efficacy so in this situation i would say epinephrine is definitely a full agonist propanol is a partial agonist no because it has it says here propanol has no effect on asthma symptoms so usually that means that it's an antagonist so epinephrine is an agonist that is true and propanol is a non-competitive antagonist no because if you look at this situation even if i increase the concentration here of my actual epinephrine again it's not going to be able to reach the max effect so again usually with non-competitive antagonists there's no change in actual potency potency changes with only competitive antagonists efficacy changes with non-competitive antagonists we're still trying to elicit the full
1:17:03
antisemitic activity so in this situation i would say epinephrine is the agonist trying to produce the bronchodilation per panel is the competitive antagonist trying to produce no actual benefit on asthma symptoms but if i increase the concentration of my epinephrine i can beat some of the upper panel out of the beta receptor site and increase the actual efficacy of its effect but it's going to have to be at higher dosages so with this being said i would say that epinephrine is an agonist and propanol is a competitive antagonist the key thing here is here is the antagonist and you can tell it's an antagonist because when it says perpendicular has no effect on asthma symptoms that meaning it can't be as an it can't be an agonist if you give a drug and you're trying to look at the actual effect of that drug in this situation because it has no effect we're going to say it's more of an antagonist it definitely won't have agonistic effects so it automatically gets rid of
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b then you come down to the point here where you're trying to look at is it a competitive and non-competitive antagonist well the way that we tell is based upon the way they write this we know in the presence of perpendicular a higher concentration of epinephrine is required to produce the same efficacy so efficacy is staying the same look efficacy changes here but i require a larger dosage of the drug meaning that the curve shifts to the right i have to increase the concentration of my epinephrine my agonist in the presence of a competitive antagonist and that's why this answer is the correct answer c all right let's see if we can actually test your knowledge again here we go in the presence of picker toxin diazepam is less efficacious at causing sedation regardless of the dose you see the way the word of that picker toxin has no sedative effect meaning it's not an agonist even at the highest dose which of the following is correct regarding these
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agents so think about this guys in the presence of picker toxin diazepam which is going to be in this situation providing sedation so it's an agonist if you give picrotoxin diazepam is less efficacious meaning that this is not going to shift to the right it shifts down efficacy is decreasing in this situation here where you have your agonist and then the presence of an agonist and some type of antagonist in this situation picrotoxin is a non-competitive antagonist and it's decreasing the efficacy of diazepam so in this situation picker toxin is a competitive no picker toxin a non-competitive yes diazepam is less efficacious than has nothing to do with it because again we're looking at in the situation here diazepam is less efficacious in the presence of picker toxin not in comparison to this because picker toxin has no effect on sedation diazepam is less potent than pickertox and again not a comparison that we're making in this situation
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picrotoxin is a non-competitive antagonist all right let's move on to another question here so it says here in this question which of the following up regulates post-synaptic alpha-1 adrenergic receptors all right so daily use of amphetamine that causes release of neural epinephrine okay so it's just saying if you use amphetamine basically the amphetamines will potentially continue to cause the release of norepinephrine and maybe that'll act on those alpha-1 adrenergic receptors and potentially help to upregulate them because of repeated exposure that doesn't actually completely kind of go in line with this and the reason why is that if a patient is using amphetamines daily and that causes the release of norepinephrine it'll act on those alpha-1 adrenergic receptors pretty consistently and they'll get kind of like over-stimulated and a way to protect themselves is to regulate so i don't think that's the correct answer and being a
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a disease that causes an increase in the activity of norepinephrine neurons so in this situation here we're saying some disease that causes an increase in the activity of these norepinephrine neurons so it's saying that these neurons are releasing more norepinephrine consistently meaning that it's acting on the alpha one and or adrenergic receptors over stimulating them if they're over stimulating them they wouldn't up regulate they would potentially develop a response to down regulate in response to all of that so that again can't be the right answer saying that a and b are the same thing daily use of phenylephrine an alpha one receptor agonist so again this is another way of saying okay you have daily use of phenylephrine it's going to act on the alpha-1 receptor overstimulate it cause it to again cause an increase in vasoconstriction and again over time the cell will say this is too much of this type of response can't tolerate it don't like it i'm
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going to decrease the number of receptors that you can't bind to me so again it's the same as a b and c so that leaves d so d has got to be the right answer then right well how would it be that answer daily use of prasasin is an alpha 1 receptor antagonist so it's going to bind to the alpha 1 adrenergic receptor and block any other drug from being able to bind to it now that's kind of a problem and the reason why is is what in certain situations we maybe want to stimulate that alpha-1 adrenergic receptor you're not going to be able to because you have a practicing bound to it and so if you need an agonist to come and stimulate it guess what it's blocked by praises in so in that situation where maybe you do need to stimulate that that receptor guess what i'm going to have to kind of up regulate more risk more receptors available for one of those agonists like phenylephrine or norepinephrine or epinephrine to bind to that's the only
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way i'm going to make more receptors so that because of practicing binding to the alpha-1 receptors right now if i make more receptors maybe i'll have more spots for the agonists like phenylephrine and norepinephrine or epinephrine to bind to so it's got to be d okay so up regulates because again it needs receptors that are available for it to bind to agonists because right now let's say that right here is your alpha 1 receptor and let's pretend that these were not here you only have two receptors and processing down here processing bound here well now you have no other receptor for epinephrine norepinephrine epinephrine to bind to so what's going to happen is you're going to try to make more and more receptors that'll be open for epinephrine norepinephrine or phenylephrine to bind to to be able to produce an agonistic response so that's a little concept there okay question number nine methylphenidate helps patients with attention deficit hyperactivity disorder
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maintain attention to perform better at school or at work with an ed50 and again that's the dose that you want to give to 50 percent of the population that would have an actual clinically desired effect that's 10 milligrams however methylfinity can also cause side effects so significant nausea at higher doses so td50 which is the dose that you would give to 50 of the population to cause a toxic effect that's 30 milligrams so what is the correct what is which one of the following is correct regarding methylphenidate so in this situation i would need to take what i would need to be able to take my in this situation here my td 50 and my ed50 and plug it into a particular equation and that equation is the therapeutic index the therapeutic index is the td50 so 30 milligrams divided by the ed50 which is 10 milligrams what does that give me 30 divided by 10 is 3. so my therapeutic index is 3. what that helps me to understand is is the range that i have
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to basically what's the window what's my margin of error that i have so if i give 10 milligrams i'll produce my desired effect and at 30 milligrams i'll produce a toxic effect the kind of window where i have a good degree of desired effect before i reach a toxic effect is my therapeutic index the narrower your therapeutic index the you know the risk of toxic adverse effects are higher because the margin of error is very very tiny with a very large therapeutic index there's a very low risk of toxic side effects because the margin of error is huge you could give a very large dose and still not produce that toxic effect so remember that relationship here but the basic answer to the question is that the therapeutic index of methylphenidate is three all right and again take that into consideration when you're talking about the safety of a drug all right guys let's move on to question number ten so again we're going to talk a little bit about safety here so which of the
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following is the correct answer concerning the safety of using warfarin small therapeutic index versus penicillin with a large therapeutic index so we know that with this being said here the higher your therapeutic index right the safer the actual drug is likely to be okay that's for most patients but it wouldn't be for like every single patient okay but i'd say for most patients so the smaller the therapeutic index more dangerous higher the therapeutic index more safe but again that's not for every single patient there's obviously contingencies in that situation here so let's go through this answer here orphan is a safer drug because it has a low therapeutic index now we already said low is dangerous um this is kind of the same situation the higher the therapeutic index the high therapeutic index makes penicillin a safer drug for all patients i'd say for most patients not for all patients okay again not absolutely the correct answer it's
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relatively close but it's not the best answer here warfarin treatment has a high chance of resulting in dangerous adverse effects if bioavailability is altered i'd say that's yeah it's likely the right answer the reason why is look at warfarin it's a small therapeutic index so because that has a high risk of dangerous adverse effects and if you alter his bioavailability so let's say for whatever reason i don't know you give this particular drug and in some way shape or form you know you are taking something with it that actually has the amount of the drug that usually it's supposed to be bioavailability a bioavailable uh bioavailability of that dosage is usually i'm just making it up 50 okay when you take it orally and then afterwards you have another medication that you're taking it with you have a problem with your absorption process something happens where you're taking another drug with it and the bioavailability of that drug the amount of drug that gets into
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the systemic circulation is increase from 50 to 80 percent now there's more of that drug in the bloodstream and therefore the actual toxic effect is going to be higher easier to reach so because of that i would say that this would be the right answer warfarin definitely has a very small therapeutic index so anything that alters its bioavailability which can actually cause higher amounts of the drug to be in the circulation can definitely produce dangerous adverse effects so i would say would be b okay and again you can remember this by the sad face again the drugs with a very small therapeutic index very very dangerous side effects if it's actually going to lead to higher concentrations of the drug with this one smiley face is a large therapeutic index you could give this and the bioavailability wouldn't actually be a big deal because again it's going to be really hard to cause adverse effects you could give it and even at high concentrations of the
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drug you're still not going to produce the toxic side effect you have a very larger you know range to be able to kind of give drug dosages without causing that nasty toxic effect so i'd say this would definitely be the right answer here b all right guys we went through a couple examples here we went through a lot in this video i hope it made sense i hope that you guys really did enjoy it and as always until next time
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