this is Dr busy and we're now going to go over the basics of pharmaccoinetics and uh pharmacodnamics specifically um and when we talk about pharmacocinetics we're really talking about the movement of drug throughout the body and that will be discussed a little bit more in detail under the lecture where we'll be going through the specifics of ADM absorption distribution metabolism and elimination but to lay some of the groundwork and some of the principles of that um discussion we need to look at some of the things that are happening and as we relates to measurement of drug and movement of drug in the body and so this is an example of the drug concentration here on the y-axis and time and when we administer a medication traditionally by mouth what we typically see is an absorptive phase and when absorption is occurring don't forget there is also some elimination but absorption is exceeding that of elimination and when you achieve the CAX or the peak concentration the absorption then equals the elimination whatever the elimination pathway is it is now equal and on the down slope we have elimination exceeding that of absorption but you can still be absorbing drug even though elimination is exceeding that of the absorption now at some interval before all of the drug concentration has left the body there is going to be a certain amount and that's what we call the cmen or the trough and that's the time point at which we administer another medication or a dose I'm sorry and when you administer that dose and you keep doing that dose at that dosing interval you will see that you begin to accumulate drug over a period of time to where you achieve what is called the steadystate concentration where we desire the that's where the traditional efficacy occurs occurs now obviously during the peaks and the in the minimum concentrations or the troughs we can have variations in the dose or pharmacologic and a biologic effect that's happening in the body and that is pharmacodnamics what is the drug doing the effect on the cells or the the cellular function in the body and certain drugs where peak concentrations can result in side effects as well as troughs can cause an insufficient control of whatever the symptoms might be and so what we traditionally want is a smooth we don't usually like peaks and troughs especially when they vary very wide from each other because that provides variability in the response so like for example in the management of hypertension we don't want drugs where the blood pressure is going up and down up and down we want consistent steady control of the blood pressure and that is why we tend to develop dosage formulations that are time release or extended release products so the dosage formulation and the way the product is manufactured can influence that C cmin and the C uh the C max or the peak concentrations and so we we have a smoothed out effect which is what we tend to desire um and we can adjust that by the dosage formulation or the frequency of administration as well because we if we lower the dose and give it more frequency frequently we can start to narrow in and reduce the peaks and the troughs that occur now there are some formulas that are important to recognize one is the maintenance dose uh formula that this is the dose that is needed at that interval to maintain the drug concentration in the body and that drug concentration in the body that we care about is the steadystate concentration where we usually get the majority of efficacy without too many side effects or toxicity and so there's a number of formulas that can be interchangeable those are very important especially on exams now there's also the the formula for how what would be the steadyst state concentration if I administer a particular dose at that dosing interval and that's going to be also influenced by the half-life of that drug as well as what's called the volume of distribution because we need to know where the drug con drug is going to go is it going into tissue or is it staying in the blood before we can determine that because when we measure drug concentrations in the body pharmacocinetically in studies we're measuring the plasma concentration generally um we're not measuring tissue concentrations in most part now that can happen that's some processes called micro diialysis that can do that to help understand what is the concentration of drug in a specific compartment but generally what speaking we're talking about the plasma concentration now there are scenarios where we don't have days or weeks to get to steady state concentration we may need it in minutes or within a couple hours and that is what is the purpose of a loading dose is to achieve the steadyst state concentration quicker than normal and so that loading dose equation that sometimes people need to know and that shows up on your board exams is listed here for you but is influenced by what is the desired initial concentration that you're looking for and the drugs volume of distribution and when you multiply those two together you you achieve what is going to be called the loading dose for that particular agent now drugs then as I said are being absorbed are also being eliminated and there's a number of processes by which the body handles and maneuvers the drug around or metabolizes it to be eliminated and we have two big categories of elimination that most drugs follow there's called first order and then there's zero order the majority of drugs follow first order because it's it's a little bit more friendly and we desire that kind of profile than we do um zero order because zero order suggests that the body can only remove so much drug per unit of time it doesn't matter what the amount is or what what the situation um is is happening um so first order drugs tend to follow where there's a constant fraction and that fraction is 50% or 1/2 so at every halflife of that drug 1/2 uh or 50% of that drug concentration is gone and so that is also going to be influenced by the amount of drug that you give so it is dependent on the concentration or the dose that was given so for example if we look in this scenario you see here that the plasma concentration of drug in this on the y-axis is a non-logarithmic scale so it's 10 20 30 40 in a typical equal interval scale and then we see that time goes down the y uh the x-axis and you can see that the initial drug dose that must have been given of a which was IV which means 100% of the drug was administered into the blood or central circulation that if we were to determine the halflife of this drug then we would go from 100 to 50 and if you were to draw a line over you would get approximately 4 hours okay and so that's the that is the halflife of this drug and so you can be given a graph and simply determine the half-life by simply looking at this but it's important to get yourself oriented to the scale that's used in the yaxis and on this example for for first order drugs you can see that the scale is non logarithmic this changes when we make it logarithmic scale and the scale then becomes different and the line goes from being curved to straight and you may be saying to yourself I do not care so what i get it but the point is is if you're reading a pharmacocinetic study and dynamic study or you're being asked a question on your test or your boards then you need to be able to get oriented because they may be asking you to describe the characteristics of this drug and you may be given a graph where you are asked to interpret that and so being oriented is important because listen here when you go to zero order okay kinetics then the line is also straight but you have a non-logarithmic scale that's listed here okay and that's where the confusion comes so get oriented to the y ais but in this particular drug of drug A that was given IV we can see that it that the issue related to the dose and the amount that is removed per halflife is influenced by the initial dose what do I mean by that well what so this is if you go from 100 to um to the to 50 here then in the first halfife then 50 was removed 50 milligrams let's say what if the initial dose was 200 well then the first halflife it goes from 200 to 100 then that means 100 mg was removed and that's important because not only do we have a constant fraction or 50% at each halflife that's removed but it's influenced by the initial concentration of the drug the amount that is going to be removed that is different than what we see with uh zero order now with first order because of that constant fraction we see that every halfife we see that 50% is gone when you go to the next halfife another 50% but now a total of 75% is now gone and as you go to the fourth halfife that's where 93% of the drug has been removed that is no different than if you're administering the medication approximately four to five half- livives you start to achieve what is called the steadystate concentration and once you stop the drug after four to five half- lives depending on how long that half-life is of that drug that's when 90 plus% of the drug is removed or eliminated from the body now with zero order kinetics like I mentioned the yaxis is different it's non-logarithmic scale that generates a straight line but it's a constant amount and I underline the word amount because I want you to focus on that because if that could discern the right answer or the wrong answer on a board exam but it also points to the fact that it doesn't matter how much you give i.e it's independent of the drug concentration there's only so much that's going to be removed per unit of time period end of discussion and the drugs that follow that kind of profile things like aspirin dilantin at a certain dose they can result in toxicity that's very uh uh very significant even with small doses once that has occurred so this table summarizes the key points of what I just said and it highlights those points that you should know fundamentally about the way the body handles these drugs as they're being absorbed and moving around through the body for elimination because remember these are substances that aren't normally present the body sees them as foreign objects get rid of them right whether they does the body doesn't know that you're trying to do something good right um but it needs to get be able to get rid of it and that's the process in the study of pharmacocinetics the movement of drug throughout the body we'll talk about pharmacodnamics now this is a dose response curve phicodnamics is talking about the effect of the drug once it has arrived to the site of action what then does it do to that cell's physiology biochemistry uh the biologic reactions that are happening what is the effect in the body the physiologic or the pharmacologic effect and so if we look here we see that typically for dose response curve we look at what is the dose that is needed to generate 50% of the desired effect versus what is the dose that is necessary to to exert the 100% of the pharmacologic effect in the majority of the patients and this is what you typically get is this um this sort of curved S-shaped curve right here and it's a non or it is a logarithmic scale on the concentration and so when you look at what the dose is or the concentration in the body that generates 50% of the desired effect that is called the EC50 or also known as the ED50 so E C50 is equal to the E D50 those are the same one is just the effective concentration obviously a certain dose has to be given to get that concentration or the effective dose at which 50% of the desired pharmacologic effect is happening and then at some concentration right we achieve the maximal effect where we hit a ceiling like giving more doesn't generate any more pharmacologic effect you have maxed out that effect and so we tend to look at these parameters as it relates to the phicodnamic response how much drug do I have to administer to exert the pharmacologic effect that I'm looking for and we will notice that amongst medications that different drugs have different doses to exert an equivalent response okay so there's called dose equivalency when we compare for example loop diuretics what makes ferosomide different from btanide versus tossomide I mean they're all loop diuretics they all work at the same mechanism location in the loop of Henley right the ascending loop of Henley but what makes them pharmacologically different well it's their pharmacocinetic profile and specifically and phicodnamic profile that the amount of drug that you give is different so for example bumax is 40 times more potent okay than ferosemide torsomide is four times more potent than ferosomide so what that means is for bumx or bumetanide which is 40 times more potent I don't have to administer as much medication to get the same effect of that of lasix or ferosomide and so the ED50 begins to be the thing that we reflect on as the potency of that drug i didn't say that something that's more potent is better it just means I have to give less drug to exert a pharmacologic effect so when you look at that that becomes our potency and so some drugs can have different ED50s obviously a drug that is we're administering smaller amounts like with bumetanide compared to ferosomide bumetanide has a smaller ED50 or EC50 than ferrosomide because it's more potent i didn't say it was better it's just more potent now at some drug concentration we're going to start to get what we call the lethal effect where we see a 50% of the lethal re effect that is seen at what dose that is the LD50 or LC50 but most people use LD50 and again if you've listened to the first part of this um lecture where we talked about the importance of this we talked about therapeutic index some drugs have a narrow window of opportunity or interval where they're safe to use in the effect is beneficial there's at some point where it starts to get toxic and starts having problems so we generally want a therapeutic index where the LD50 this spot right here is very far away from the ED50 so the wider that interval is the safer the drug is so someone tried to overdose or I accidentally gave too much medication to the drug because I did an wrong calculation or I drew up the wrong medicine then I'm less likely to cause a lethal effect or an adverse effect so we want drugs with a very large therapeutic index and mathematically that's just the numerator over denominator so the larger the numerator compared to the denominator the larger the therapeutic index and the safer the drug is in the context of a misuse or if somebody were to overdose and so when you look at these two drugs or when you I'm sorry when you look at this drug every drug has a ED50 and an LD50 most drugs coming to market now have very wide therapeutic indexes because we don't want errors we don't like drugs with narrow therapeutic indexes like doxin lithium venkcomyosin genttoyosin where we have to monitor the drug levels to determine the efficacy of the safety profile and to make sure that we're using it in the right window in the right context and this is the formulas that you need to know and as just a reminder the higher the TI the safer the drug so if they gave you an example of all these different therapeutic indexes and said which of the following drugs would be the safest in an overdose you just look at the drug with the largest therapeutic index and that's the right answer right or if you say if they ask you what characteristics of a drug allows it to be have a better therapeutic index then you're just saying well you want a large LD50 compared to the ED50 all you're doing is interpreting what it is it's not hard it's not rocket science but you need to understand the concept and when drugs are being developed by that manufacturer one of the things they're doing in phase one and phase two studies is trying to figure this out and make sure that we don't generate a drug that has a lot of problems and so you see a lot of the drugs where we do therapeutic drug monitoring because of issues of safety and efficacy you see that a lot of these drugs are old right they've been around for decades uh and and many years you don't see many new drugs come to market where we're required to monitor the drug levels because it's inconvenient not only to the patient but it's inconvenient quite honestly to the providers having to manage those patients to have to order a lab get the level interpret it and then make sure I make a do a dose adjustment i mean it's annoying um and it costs money and it prohibits patient care so you see that with a lot of these drugs that are listed here which are all very relevant and used in clinical practice that that that they're all many of them are older but it doesn't negate that they're still useful we do use them and they're still very much a part of practice but they're used for that they they have issues and so sometimes we monitor levels for efficacy we also sometimes even do it make sure they're even taking the medication now in this example we're talking about like there's some questions up here which drug is more potent well if you look at drug A which is an agonist to some receptor enzyme whatever right it's the phicodnamic response and then drug B well which one of them is more potent okay remember potency has to do with the ED50 so you just pick the one with the lowest EC50 or ED50 and that would be drug A right because it has the smallest EC50 or ED50 i don't have to give very much drug compared to drug B to get the same effect right they're both causing the same effect but what dose do you need to give now it says here which drug is more effective well you can't say neither one of them because you're just giving equal potent doses they both exert the same effect it's a trick question right and that's where people who don't understand the concept of potency or ED50 or EC50s can misunderstand that and they may say that again I and the reason I bring this up because people say oh it's more potent so it's more effective no it has nothing to do with efficacy has to do with how much drug I give to exert the pharmacologic effect now when you look at this example right drug A versus drug B right these are these are examples of like opioids some that are pure opioid agonist versus agonist antagonist so looking at drugs like buprenorphine versus fentinil well fentinil is going to be far more potent I'm sorry more effective at pain control than than buprenorphine is and so the effect right the overall maximal effect is not going to be the same so therefore if you had somebody on a pure opioid agonist like morphine fentanyl methadone dilotted you would never add a partial agonist antagonist to that regimen you're going to worsen their pain because you have something that's of lower efficacy in that situation okay now what's happening here in this scenario well you have drug A that's being used and now all of a sudden drug A's curve shifts to the right which means now I've got to give more of a drug right drug concentration to exert the same effect so what happened well this is usually an example of competitive antagonism i must be administering a medicine that's competing with the same binding site and so the effect that I got from drug A is lost because it's being competing against with some other agent through the same pathway and so maybe I'm increasing the elimination of the drug maybe I'm competing with it at this local at the receptor and so who's going to win well whoever is there with more power right so if I give more and more and more of drug A I will override the effects of drug B okay if I want to inhibit complete activity of drug A I just give more and more of drug B or I because I will start to lose the overall effect now what happens in this scenario look here you got drug A right and here's drug A so it move the the curve shifted there's no other drugs that were administered but over time what can happen is that you see that the dose has to go up that's something called tolerance and this is what tolerance looks like pharmacodnamically where the drug that you were giving back here okay maybe when they started therapy is now not the same dose of drug that they are here we see that all the time with opioids and chronic pain management over time they're going to need a larger and larger dose i.e the curve is going to shift to the right in order to exert the same pharmacologic efficacy in that patient and that's what happens and that's what tolerance looks like when you look at drug A and now the curve here is now here well something else has been administered and it's usually an irreversible antagonist and as a result we see now the change in the maximal efficacy of that drug okay so we're not seeing the curve shift to the right we're seeing it shift down and becoming less effective and that's usually what we see with drug interactions that where there's an irreversible um antagonist present so that lays the groundwork for the basics principles of pharmaccoinetics and pharmacodnamics from a standpoint of when a study is done what are they measuring and what are they looking at for time it also becomes relevant as you characterize a drug as it relates to how the body is going to handle it and eliminate it is this a first order drug versus a zeroorder drug again majority of drugs are are first order but when you have that zeroorder drug it requires a little bit more attention and how you manage those patients on that particular medication and I'm going to build on that in part three where we go through the details of ADME absorption distribution metabolism and wrapping up with elimination from the body