all right guys so we talked about the absorption of a drug so we take a drug via one of the administered routes the process by which the drug moves across particular membranes when it's not given iv gets into the actual bloodstream the systemic circulation so the process at which the drug moves into the systemic circulation is absorption we talked about all the different factors that are influencing absorption including the most important one bioavailability and the most important sub point of that first pass metabolism okay now we have to do is now that the blood is now that the drug is in the bloodstream now we need to do is talk about what happens to that drug how do we get that drug that's in the bloodstream to be distributed throughout the body to the different tissues or organs to exert its particular effects that's what we need to talk about now so when a drug is distributed right so we're taking this drug from the actual bloodstream it's in the systemic circulation it's going to get passed off to these different types of organs so it's going to move out of the bloodstream into these particular tissues that's the distribution process there's many different factors that influence distribution what is that first one blood flow there's so much variation in blood flow naturally so some organs get a little bit more blood flow and other organs get a little less blood flow it's a very straightforward concept so what organs would have an increase in the amount of blood flow pretty straightforward right so for example your kidneys would get a lot more blood flow the liver would get more blood flow the brain would get more blood flow so if there's an increase in blood flow to these tissues theoretically what would happen to the distribution of the drug there you'd likely potentially depending upon other factors may have more distribution of drug to these areas because you have more blood flow that's carrying the drug opposite situation here is other organs have decreased blood flow so when you think about this it's again it's only one factor so remember that just because a patient has a lot of blood flow going to a particular tissue doesn't mean that that drug is going to escape into the tissue so there's other factors that influence it that's all this scrap that i got to talk about but if you have more blood flow theoretically the distribution will be better if you have decreased blood flow theoretically the distribution to that tissue will be decreased so you're not going to be able to deliver as much drug because you don't have as much blood flow delivering that drug to the tissue so this would be things like the skin the adipose tissue things of that nature okay so when we say increased blood flow we're talking potentially a theoretical increase in distribution and whenever we say a decreased blood flow to a particular tissue we say there's a theoretical decrease in the distrebution but again that's just one of many factors now i think one of the important things to think about this clinically is if a patient has some type of shock state so for example a patient has shock whether this is septic shock cardiogenic shock hypovolemic shock whatever it is that will lead to a decrease in blood flow if there's a decrease in blood flow that means that you might not be able to deliver that drug as well to various different tissues of the body so what will happen to the distribution of the drug there may be a decrease in the distribution of the drug or delivery of the drug to the tissues and so that's an important concept to remember okay now the other factor that plays a huge role huge huge role here when we talk about a patient and the distribution of a drug to different tissues is capillary permeability it's pretty straightforward right for example i have this capillary here an organs such as maybe the liver the bone marrow the spleen they have very special types of capillaries called sinusoidal capillaries which are extremely leaky capillaries they got these big intracellular clefts they got all these different types of large fenestration pores and areas where drug can easily leak out of the blood into the tissue space or you also have what's called fenestrated capillaries and this would be like in the kidneys this would be in different glands but they also have these big fenestration pores they don't have as many tight junctions and so it's easy for drug to easily leak out of the systemic circulation into the different tissue spaces and easily distribute that drug so because of that in these types of tissues where you have sinusoidal finish rated capillaries what happens to the distribution of that drug you increase the distribution of that drug because now you have increased capillary permeability now in the opposite situation where you think about the blood-brain barrier or you think about other types of capillaries like continuous capillaries which is like for example the muscles in these situations you have no intercellular clefts you have no fenestration pores you have these big tight junctions between the cells which are really really reducing the ability of things to easily move out of this actual blood vessel and into the tissue spaces so the actual diffusion of drugs out of the blood and into the tissue spaces is really dependent upon two factors one is you need transporters so particular types of transporters to really facilitate the movement of that drug out of the blood into the tissue or you need a super super super hydrophobic drug okay in order to be able to push this drug out it has to be super lipid soluble and very small in order for this drug to be able to easily pass out of the actual capillary into the tissue space but theoretically what happens to the distribution of the drug in these types of capillaries where they're not very leaky there would be a decreased distribution and the only way that we'll be able to get that actual drug out of the capillaries into the tissues is if they have special transporters to push them out or if they're extremely small and hydrophobic and i think the best example here is the brain now clinically why is this important you know if a patient has something called septic shock so when a patient has septic shock what happens in septic shock is that they have extreme extreme increase in their capillary permeability they actually call this a capillary leak syndrome so whenever there's an increase in capillary permeability what happens to the actual distribution what happens to the actual concentration of the drug inside of the blood so the concentration of the drug inside of the blood will do what well if i'm giving the drug and distributing it to the tissues that's leaking out of the blood into the tissues what happens to the actual concentration of that drug in the blood it'll decrease the serum concentration of the blood and in patients who are septic we want to actually have high serum concentrations of the drug so that it can work longer over a particular period of time and so what happens is this will actually increase the distribution of that drug and that will actually decrease the serum concentration of that drug and so that's an important thing to remember is that that's why i'm critically ill individuals when we give them particular antibiotics we actually want to give them high dose antibiotics because their distribution of the drug is extremely high they're leaking a lot of it out into the actual tissues which may not be tissues that we need the drug to go to and because of that we don't have very high serum concentrations of the drug so whenever a patient is superseptic we have to give them tons and tons of like large dose antibiotics to be able to get the concentration of the drug in the blood to relatively high concentration to exert its effects so it's an extremely important concept here all right so we got blood flow capillary permeability pretty straight concept for a concept with blood flow increased blood flow increased distribution decreased blood flow decreased distribution super leaky capillaries increased distribution very very tight junctions very very not leaky capillaries decreased distribution only way we can get the drugs out is by transporters or very hydrophobic small drugs all right that brings us to the next concept with factors affecting distribution which is protein binding this can be plasma protein or tissue protein binding but more particularly plasma protein binding let's come down and talk about that now all right so the next part that we have to talk about is protein binding so we went over you know blood flow we went over capillary permeability and how that affects distribution the next thing is protein binding how does that affect the distribution of the drug the delivery of the blood to the actual organs or tissues that it needs to go to it to exert its effect now when you think about this it's pretty straightforward you know our liver is responsible for making a very special type of protein a special type of plasma protein called albumin that's one of those and then our kidneys are responsible for making sure that we don't put much of that albumin into the urine right so they want to maintain the albumin in the urine so i'm sorry maintain the albumin in the actual blood so whenever you have a patient who has normal kidney function normal liver function you should be able to prevent the excretion of albumin into the urine and you should be able to make a certain amount of albumin into the blood now albumin is extremely important because it loves to bind on to particular drugs inside the blood some of them so let's pretend for a second you have to distribute a particular drug through the body into the different tissues if i have a drug that's extremely protein bound so here's my drug in blue and it's all going to be binding onto this albumin that means that the amount of albumin that's actually inside free not bound to protein is very low so in situations when you have a high protein bound drug so high plasma protein bound drug what happens to the actual amount of free drug then there is a decrease in free drug and so because of that this is all that you have to be able to distribute or move out of the bloodstream into the particular tissues to exert its effect so therefore what happens to the distribution of this drug would it increase or decrease well the amount of drug that i'm actually delivering to the tissues is going to decrease so what happens to the actual distribution i'm going to decrease the actual distribution now one of the things that's actually really important here to remember is that whenever you have a particular drug that's highly protein bound it's going to stay in the plasma so this generally will concentrate in the plasma so it'll be higher concentrations inside the plasma now one of the cool things is that after a particular amount of time let's say that this is a drug it's supposed to be maybe it's an anti-seizure medication like phosphoenotone phosphate is actually a pretty heavily albumin-bound drug what happens is the free phosphoenotone will actually move out of the actual bloodstream diffuse into the actual tissues inside of the brain and inhibit specific types of seizure activity what happens is as the actual phosphoenotone is either metabolized and excreted the concentration in a free amount of it decreases so what happens is some of it's actually bound to albumin will start acting as a reservoir and they'll start releasing small amounts of the albumin over time sorry small amounts of the phosphoenotone into the bloodstream and so what's really cool to remember about this high protein bound is that these things can act as reservoirs and as the concentration of the free drug decreases the amount of plasma protein-bound drug will start acting as a reservoir and releasing small amounts of that actual drug into the blood stream and increasing the free concentration so that is an important thing and it allows for the drug to be able to have a longer lasting effect all right in the opposite situation here where you have a drug where very little of it is actually protein bound very little of it is protein bound and tons of this drug is actually going to be free drug so in that situation we have a very decreased plasma protein actually actually important important here plasma protein so protein binding so decrease protein bound and again plasma what happens is that you're going to have tons of free drug and if you have tons of free drug you have tons of drug that can easily because here's the thing can albumen here's the reason why this is important to remember can this big honkin album molecule easily cross this blood this actual vascular structure can an albumin molecule easily move out of the bloodstream no because it's too dang big for us to be able to allow for that it's also charged so it's too large it's charged and it's hydrophilic which means that the ability of this drug to move out of the bloodstream into the tissues will not occur that's why the distribution of the drug is actually decreased because it's bound to plasma proteins plasma proteins should not be able to leak out of the plasma and into the interstitial fluid so the amount of free is the only one that would be able to pass if i have a lot of this drug that is in the free form and very little of it is actually bound to albumin now all of this can easily pass across this actual blood vessel and into the tissue spaces so there's an increase in the actual distribution of the drug and then again this will actually concentrate in the tissues or we can say in the extracellular fluid of some kind whether this be i'm sorry we these can actually concentrate in the interstitial fluid so we'll put in the intracellular fluid and interstitial okay extremely important to remember that now think about this clinically if a patient has chronic kidney disease this is why i was talking about this in the beginning chronic kidney disease what happens to their ability to maintain the albumin levels in the blood it decreases and so what happens is you start actually causing lots of albumin to be lost in the urine so what happens to the levels of albumin inside of the actual bloodstream what happens to it the levels of albumin in the bloodstream will start to plummet and you get a lot of this type of effect here where there's an increased amount of the free drug increased distribution and a lot of it can concentrate in the tissues the other situation here is if you have a patient who has cirrhosis so if you have a patient has some type of liver disease or liver failure and their ability to be able to produce the actual albumin decreases if the amount of albumin decreases you get this situation where you have lots of free drugs high amounts of distribution easy for it to be able to concentrate in the intracellular fluid and the interstitial fluid and exert its effects so that's an important thing to remember because this is how you get toxic side effects okay so whenever you have a patient who has liver failure or ckd you're going to decrease the amount of plasma protein binding of the drug and allow up for a heavy distribution of the drug and that's an important concept to remember okay my friends the next thing that we have to talk about here since we're right here is solubility of the drug this is another important point but it's actually probably the easiest one thank goodness you're like dude i can't my brain's on fire i can't remember them as much don't worry this one's an easy one for once when you talk about solubility again you're talking about the ability of the drug to move easily across the actual blood vessel the cell membrane of the blood vessel into the interstitial fluids and then cross the actual cell membrane of the actual cells or organs that it's supposed to distribute to if i think about albumin right this determines my degree of protein binding of the drug so if i had a drug like this what would this drug be able to easily pass across this tissue and then again into the cells no if this big honking hydrophilic charged large protein molecule heck no but if i had a drug here the free drug and this free drug is small it's nonpolar meaning that it's not charged it's hydrophobic meaning that it's extremely lipid soluble loves lipid this thing can pass through here so easily and can easily distribute out of the blood into the tissues and this would be a very high distribution so you have high distribution of a drug whenever there is an increase in the nonpolar hydrophobic or small nature of the drug now think about this again you have a drug that's bound to albumin high protein binding means that they're going to have less distribution of the drug right all right so this would this thing be able to pass here we already said no but if i have a drug that's like really large and it's charged doesn't that kind of look like albumin a little bit so if i have a drug that's super big like albumin it's polar like albumin and it's hydrophilic meaning it loves water hates lipids like albumin is this thing going to be able to easily pass no so the distribution is going to drop and a lot of it will stay concentrated inside of the blood so the ones that have low distribution will stay in the blood concentrating the blood the ones that have high distribution will concentrate into the actual tissue spaces important to remember because the last concept and probably the most important concept when we're talking about distribution is the volume of distribution the apparent volume of distribution all right guys let's talk about volume of distribution with volume of distribution this is basically the hypothetical theoretical volume that will occupy a drug within our with respect to our total body fluid or total body water if you will so for example that consists of our plasma volume our interstitial fluid volume and our intracellular fluid volume if the drug were to occupy all of these different types of compartments it would have a very large volume of distribution if it only occupied the plasma would have a very low volume of distribution if it occupied a little bit of maybe the plasma a little bit of the interstitial fluid would have some type of like medium little bit of like a in between volume of distribution that's the basic concept so when i talk about these i want to talk about three types a low volume of distribution a volume and distribution that's somewhere in the middle and a high volume of distribution now if you take into consideration all the things that we talked about that blood flow capillary permeability degree of protein binding solubility all of these things play a role within volume of distribution low blood flow to a particular tissue you're going to have low distribution to the tissue if you have a decreased capillary permeability you're not going to distribute that blood to the tissues as well so they'll have a decreased distribution if you have a drug that's extremely plasma protein bound to albumin right what's going to happen then the distribution of that drug is actually going to do what it's going to be decreased because if you don't have if you have a lot of that drug that's actually bound to albumin that's going to be a problematic issue because not as much of it's going to diffuse out of the actual blood into the interstitial spaces and into the actual tissues so it's important to remember that if a drug is actually hydrophilic it's very large it's a charged molecule very polar it's not going to be able to leave the blood easily and get into the tissue spaces so all of these things play a role within volume distribution so imagine here i take a drug here and this drug that has a low volume distribution will be heavily protein bound if it's heavily protein-bound it's going to be able to move no there's going to be less free drug and then a lot of it bound to the actual albumin on top of that whatever is free this drug is very large charged and polar is going to be able to easily pass through no if there's decreased blood flow to this tissue what's going to happen there's going to be decreased distribution and if there is a decrease in capillary permeability what's going to happen to the ability of this drug to leak out it's going to decrease so all of these things come into play now because of that this drug is primarily occupying only one of these three compartments let's say i make up a theoretical volume here that within the plasma that's four liters interstitial fluid i don't know eight liters and then the volume inside of the cells of our entire body cells 12 liters so total volume and again i'm just making this up is going to be 24 liters okay out of that 24 liters that this drug could be occupied in what is it only occupied in it's only occupied in four liters so because of that this the vd of this drug is epox approximately somewhere around four liters so because of that this drug would be very heavily concentrated inside of the blood plasma so this drug concentrates in the plasma extremely important to remember that and the reason why it would is because it's either heavily protein bound high molecular weight charged polar uh also decreased capillary blood flow decreased capillary permeability okay these are big big things to remember now if you take for consideration here another thing let's say you have another drug this drug a little bit of his protein bound a little bit of it not a ton is protein bound though so you have another drug that has some degree of protein binding but not a ton of protein binding it also is maybe lower molecular weight okay so it's not as big maybe it's a little bit smaller lower molecular weight but it's still like hydrophilic so it still has some type of charge to it a little bit of charge this one's heavily charged heavily polar but this one's a little bit hydrophilic not as significantly protein-bound and it is smaller because of that this drug will easily be able to to some degree move out of the blood vasculature occupy some of the actual volume inside of our interstitial spaces so maybe it can have a little bit of volume that's in the interstitial spaces and it can also occupy some of the volume of our plasma so because of that what do we say over here 4 liters 8 liters and 12 liters that was a total of 24 liters if that's the case then this drug is occupying two vascular two of the compartments one is the plasma and one is the interstitial fluid so theoretically its volume of distribution will be four liters plus eight liters that's 12 liters so the volume of distribution is somewhere and again i'm making all these numbers up it's 12 liters so because of that you're going to see this in the plasma it'll concentrate in the plasma and maybe into the interstitial fluid and maybe even a small amount into the actual cells but primarily a little bit between these two compartments here yes you know the last one high volume of distribution you have a drug and literally almost none of it is bound to albumin so because that you have most of it is actually free drug and on top of that this drug is small it's non-polar it's hydrophobic lipid soluble you have a increased blood flow increased capillary permeability tons of this drug is going to leak out into the interstitial spaces and then tons of it is going to leak into the actual tissue cells because it's very lipid soluble it's very non-polar again it has a lot of blood flow to the area increased capillary permeability and not much of it is actually plasma protein bound because of that this drug is occupying all three compartments it's occupying the 4 liter compartment the 8 liter compartment and the 12 liter compartment that means that the volume of distribution is dragging again i'm just making it up is approximately 24 liters so this will accommodate it'll be in all body compartments so a part of our total body water now obviously you know drugs can have insanely insanely high volumes of distribution i made these numbers up sometimes it give you to give you an example there's a drug called warfarin so warfarin its volume of distribution is somewhere around like eight liters approximately so it's somewhere around eight liters because of that in a real world it's not not very high so it's somewhere around 8 liters that's not a ton so most of warframe we would consider this a low volume of distribution that's what we would actually consider to be it'd be more of a low volume of distribution so because of that because it's a low volume of distribution it would primarily concentrate in the actual blood plasma and that's great because guess what warfarin is supposed to do act as a blood thinner supposed to interact with the clotting proteins inhibit the clotting proteins and basically help to thin the blood out preventing clots from forming so that would be a good thing that's why you would want this actually have a low volume of distribution because you want it to stay in the area where it exerts its effect think about another drug and again i just like this one because the volume distribution is absolutely insane i can't say i've ever prescribed it but if you ever do for malaria chloroquine cork volume of distribution is about 150 000 liters that's more than our entire total body water and that may seem insane but it's because most of this drug almost all of it none of it is plasma protein bound it's heavily bound to the proteins inside of our tissue cells it's extremely hydrophobic super small nonpolar has a good way of being able to distribute beautifully throughout all of our body tissues so it can occupy so much volume there's so much drug that can actually be occupied by such a large volume so because of that this would have an extremely high volume of distribution which we want to exert its effect on the various tissues that malaria can actually cause problems with so this is a big concept to understand so again volume of distribution is dependent upon a lot of this stuff that we just talked about and whenever we give particular drugs we want them to have a volume of distribution again particularly depending upon what area we're trying to get them to work in alright guys so now let's talk about some questions that help us to really understand a little bit more about the distribution of a drug so here we're going to talk a little bit about something called bioavailability remember i told you it was a very important concept about so we have a drug here in nin 610 it's an investigational cholesterol lowering agent has a very high molecular weight so it's a very large molecule and it's extensively bound to albumin meaning it's heavily protein bound if you have a drug that's very high molecular weight and it's extensively protein bound is it going to be able to leave the vascular system and go out into the tissues and have therefore a large volume of distribution think about it guys here's our situation here if we have something that's very a large molecule it's also very hydrophilic and it's also heavily protein bound what do you think is going to happen to the distribution of the drug it's going to be very poor so this will have a very low volume of distribution because it's going to stay in the vascular system it's not going to leak out if we have something that is again very small it's also very hydrophobic it's not extensively protein bound it would have a high volume of distribution so in this situation what we expect it's going to have a low apparent volume of distribution why high molecular weight heavily protein bound and also another particular reason is that it's likely going to be hydrophilic and probably polar all right let's move on to the next question here we got a 40 year old male patient 70 kilograms was recently diagnosed with an infection uh due to what's called misa methicillin i'm sorry myrsa methicillin resistant staphylococcus aureus so mrsa he was given a 2 000 milligram dose of vancomycin as a loading dose for that infection the peak plasma concentration of vancomycin was 28.5 what is the apparent volume of distribution of this drug based upon that do you guys remember how we kind of went about the calculations here so we remember that volume of distribution is equal to the actual bioavailability times the dose divided by the peak plasma concentration so if we take that into consideration here how do we kind of go about doing this the bioavailability of this drug is given what iv if it's given iv what is that it's a hundred percent that means a hundred percent of this drug is getting into the circulation so it's going to be one then we take into consideration the dose that we're going to give them which is 2 000 milligrams and then what we're going to do is we're going to divide that by the concentration that we were able to achieve in the circulation after we gave this dose and that was 28.5 so if we take 2000 divided by 28.5 that would give us how much of the drug is being distributed throughout all of the actual compartments or volume within side of the body so what does that give us then if we go ahead and do that we get 2000 divided by 28.5 to give us about 70.1 liters so that is a extremely decently large volume of distribution here but if we also take into consideration here that we have to have this and the apparent volume of distribution is per liters per kilogram what are we going to consider here so then we actually have to take 70.1 liters and divide by 70 kilograms so then if we take that at 70 divided by pretty much 70 what would that give us that'll get us about 1 liter per kg so our volume of a distribution in the situation is about one liter per kg it's an important concept alright guys so that kind of finishes off our discussion on distribution with pharmacokinetics i hope it made sense i hope that you guys really did enjoy it in the next lecture we're going to continue on with the pharmacokinetic series and the next thing we're going to talk about a little bit more is something called metabolism and really understanding that we'll do some cases there so i hope to see you guys there [Music] you