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  • All right so let's talk about this volume of distribution.

  • So we remember that concentration is equal to mass over volume.

  • And the concentration we always look at is the plasma concentration

  • and we say that's equal to the mass of drug absorbed divided by this thing called the volume of distribution

  • And so, in the perfect world, this drug would distribute evenly in the intravascular space and the extravascular space

  • but that doesn't happen.

  • And so, when we get these variations, we need a way of describing what's going on.

  • So, we gave a certain dose of drug (the mass) and we notice that the plasma concentration is not ideal.

  • And so, the way we describe that difference is with this term volume of distribution

  • Now remember, it's not a real volume. It's our way of saying, hey! If I didn't know any better, this plasma concentration isn't normal.

  • So something must be up with the volume that this drug is distributing it.

  • And so, that's why we call it the apparent volume of distribution.

  • Super huge. Remember, Apparent volume of distribution.

  • And so, you will never really calculate volume of distribution on your own clinically.

  • It's something that's normally given to you. It's a constant.

  • So, the firs tthing I want you to remember here is that the volume of distribution is not a variable.

  • Instead, it's an attribute of a drug. It's something that is given to you.

  • If you look at information on the drug, it will say what's the bioavailability? What is the volume of distribution?

  • And it might say you know what are the indications and standard dosages? Yada, yada, yada.

  • So, it's an attribute of the drug in relation to the average healthy person.

  • So, what does attribute mean?

  • Well, if you think of a person, what are attributes of a person?

  • He's nice, he's friendly, he's tall, he's short, he's fat, he's skinny.

  • Those are attributes and just like that, we have attributes for drugs.

  • It has a low bioavailability, high bioavailability, it's lipophilic, it's hydrophilic, it has a high volume of distribution, a low volume of distribution. Whatever.

  • Also, remember this that when it's measured experimentally, the use, most of the time, they use an average healthy person

  • and that's the volume of distribution that is published to you.

  • So, what it does is it tells us really where this drug likes to be.

  • So, drugs that like to stay in the plasma in relation to the total body water right

  • in relation to the total body water, the plasma concentration is much lower right.

  • Plasma we say you know it's about 2.5L. It's a little bit over 90% water

  • but the total body water is about 40L.

  • So for drugs that like to stay in the plasma, well it means it's distributing in a really small volume.

  • And so, when a drug has this attribute, we say it has a low volume of distribution.

  • Conversely, if a drug likes to stay in the extravascular compartments right which have a larger volume, we say this has a high volume of distribution.

  • So what are some ball park numbers?

  • Typically, I say you know if the volume of distribution let's say is less than 9L and this is really ball park,

  • I would say it has a low volume of distribution.

  • Whereas if a drug likes to stay in the extravascular space, it has a higher volume of distribution.

  • I would say greater than 40L.

  • Now you might say to me but wait, but wait, wait, wait, wait. You just told me the total body water is 40 L,

  • how can the volume that this drug distributes in be greater than 40L?

  • And my response is it's not a real volume. It's the apparent volume of distribution.

  • Because if I was to rearrange this equation and I say the volume of distribution is equal to the mass divided by the plasma concentration.

  • If this drug is highly bound to let's say it all goes into the fat extravascularly and the plasma concentration is super low,

  • I can get this apparent volume of distirbution that is very high.

  • I hope that makes sense.

  • So how do we use volume of distribution clinically?

  • Well clinically, it helps us figure out how much total drug you need to give in order to reach a desired plasma concentration.

  • So let's work that our really quick.

  • So here is this equation that a lot of books use.

  • The volume of distribution is equal to the amount of drug absorbed in the body divided by the plasma drug concentration.

  • And really quick, if you give a drug IV, how much of that is absorbed?

  • 100%

  • So you can kind of think of the amount of drug absorbed into the body as being equivalent to the amount of drug given IV right?

  • And if it's not given IV then we have to factor in the bioavailability.

  • So if I'm trying to figure out this IV dosage right or the mass of the drug, the total mass.

  • Now let's say all right, the IV dose a.k.a. the mass absorbed is equal to the plasma concentration (the concentration in the plasma) x the volume of distribution.

  • So I can just look at this and this will tell me a lot of things.

  • If I have a certain desired plasma concentration let's say 10mg/L,

  • if the drug has a high volume of distribution that means I have to give a larger dose

  • but if that drug has a lower volume of distribution that means I can give a lower dose right?

  • So it's directly proportional to the amount of dose you want to give for a given plasma concentration.

  • So what goes into the volume of distribution? How do we solve for it?

  • Well, one thing is size.

  • If a drug is really big, you tell me, does it like to stay in the plasma or will it easily get out into the extravascular space?

  • And so, you should be saying that if a drug is really big, if the molecular weight is high, what does that mean?

  • That means it's going to stay in the plasma thus it has a low volume of distribution. Low Vd.

  • What else?

  • Well we can say does this drug like to bind to plasma protein proteins? Or, does it like to bind to extravascular proteins?

  • And so, here we write plasma protein binding or extravascular protein binding.

  • If it's bound to plasma proteins, it's going to have a low volume of distribution.

  • Low Vd

  • Where if it's bound to extravascular proteins right, if I measure the plasma concentration, it would be really low because very little of that drug is there

  • So I'd have a high volume of distribution. So it would increase it.

  • All right, what if it didn't bind to proteins.

  • Let's say it bound to got into fat or if it was really charged?

  • So what am I talking about?

  • I'm saying is this drug hydrophilic or is it lipophilic?

  • And so, if a drug is lipophilic, if it binds into fat, well we said fat was extravascular, that would be a high Vd.

  • If it was hydrophilic or really charged, I would say that's a low Vd because it stays in the plasma.

  • Now, finally here remember I was saying it has to be the average healthy person.

  • So, what are examples when a person's not healthy?

  • Well one is we said plasma protein bind?

  • What if they're really protein deficient and they dont have that super abundant plasma proetin called albumin which a lot of drugs bind to?

  • So, I'm just going to make a little note here.

  • Plasma protein, the one you should remember is albumin.

  • Albumin. It is the most abundant protein in the body and tons of stuff other than drugs just bind to it.

  • Calcium binds to it. What else binds to it?

  • Bilirubin binds to it.

  • So, that's one scenario if you're low plasma protein. What's another scenario?

  • Well, remember that if these big drugs they couldn't get out because they were too big, well what if we had increased capillary permeability?

  • Well then maybe the drugs that originally couldn't get out can now get out.

  • And so, when a person is like I was saying before in septic shock, that might affect the volume of distribution

  • from what was originally given to you or what was stated.

  • So all of these things here go into volume of distribution. These are all you know things that components of it.

  • And instead of thinking about these individually, we relate it to our core equation: Concentration = mass/volume.

  • Here are some examples of the apparent volume of distribution and I pulled these from Wikipedia.

  • And the point is here so you just can see some numbers.

  • Warfarin has a volume of distribution of 8L.

  • So like I said before, we would say that's a low volume of distribution and that means it's in the plasma

  • and the comments here are this reflects a high degree of plasma protein binding.

  • Here's Ethanol, Alcohol, notice that the volume if distribution is about 30L.

  • This is about equal to the total body water which is about 40L.

  • So what we say here is that Ethanol kind of just freely goes through and it's distributed in the total body water.

  • It goes from itnravascular to extravascular, intracellular to extracellular. It distributes evenly.

  • Now here is Chloroquine.

  • A famous drug that's been used to treat malaria.

  • Look at this volume of distribution. It is 150,000L and so what that means is that, I give a certain dose and the plasma concentration is really low.

  • Where did all that drug go?

  • Well here it says that it shows a highly lipophilic molecules which sequester into the body fat.

  • So, high volume of distribution means it's in the extravascular space.

  • Finally, some experimental drug. Volume of distribution of 8L, so we'd say that's low

  • and this is because it's a highly charged hydrophilic molecule.

  • So just the last comment on another way to think about it before we get into some pictures to help you really remember what volume of distribution is.

  • So you know here's a particular scenario:

  • I gave a certain amount of drug and the plasma concentration is really low.

  • So, it appears as if this drug distributed into a really, really, large volume right?

  • And that would be the case for something like Chloroquine.

  • So, let's do some pictures because pictures are really would help you solidify things in your head and help you remember.

  • So here are some comparisons.

  • So what we're going to do is say what happens when you have a low Vd, high VD, whatever?

  • So low volume of distribution - this right here is our vascular space, here is our extravascular space.

  • Vascular, Extravascular

  • And so, what we're going to do is just draw a little bit of drug and so this right here, represents the drug and I marked it here

  • And so, a low volume of distribution means that the drug likes to stay in the vascular or extravascular?

  • I hear you say, you got to be quick now. It means it's mostly in the vascular space.

  • So some of this drug can be free which is what this represents.

  • And some of this drug let's say is bound to plasma proteins and that's what I kind of drew in right here.

  • And so, the red is plasma protein binding.

  • And so, remember that only the free drug is "active". This is the drug that can really bind to receptors

  • whereas drugs that are bound to plasma proteins, this is the bound drug and we can say this is inactive.

  • Just a word to the wise.

  • So, a low Vd, most of that drug is in the vascular space and here we'll draw just one or two drug molecules in the extravascular space.

  • All right, so really quick now, you tell me. If I have a high volume of distribution, where's that drug going to be?

  • Good! It's going to be in the extravascular space.

  • So what are some examples of where it can be in the extravascular space?

  • Well it might bind into some proteins in the extravascular space and like we said before,

  • It can also get into the fat and muscle.

  • So here we draw the fat and the muscle and the green shows the drug is inside of there

  • and there also might be some free dug roaming around whereas if I was going to say what's going on here right? Very little drug.

  • And so, somewhere in-between I would say here's our picture. I have some bound drug, I have some free drug.

  • On the opposite side, I have maybe some bound drug and some free drug and maybe you know one or two is just getting into the fat or muscle.

  • So here is kind of this inbetween case

  • and typically, when we're in-between those numbers, we say oh if it's closer to the 30, 40 range, oh it's distributing into the total body water.

  • So now you got the key terms down and just to make sure you remember here. What is that main plasma protein that drugs like to bind to?

  • That is albumin.

  • And when we measure concentration, do we measure extravascular concentration or the intravascular concentration

  • to determine volume of distribution?

  • Well, we measure the vascular or what's going on in the plasma right?

  • So key, key, key points.

  • So, here's an important point and it's a question that students commonly ask.

  • They say to me, "Hey, a lot of drugs don't work in the plasma. They don't work in the blood."

  • "We want drugs to let's say work on the heart or work in the you know other places. So, why do we care about the plasma drug concentration?"

  • And the reason is that we look at the plasma drug concentration because

  • we assume that, that plasma drug concentration is proportional to the target tissue concentration.

  • It's the most accessible site that we have to measure and we assume it's proportional to the target tissue concentration

  • and that's what's written right here.

  • Now, there are some exceptions to this and these are important exceptions and they're intentional exceptions right?

  • If I give a drug via an inhaler and let's say it's an anti-inflammatory drug,

  • Do I want that drug to get in the systemic circulation and you know cause effects - systemic side effects?

  • And the answer is no.

  • So when we give an inhaler, we might have a high target tissue concentration

  • but it's localized and so, the plasma concentration might not be very high right so, an inhaler

  • or you know if I give a lotion, if I give a lotion or if I use let's say eye drops right?

  • Those are all cases when we give a local administration of drugs and obviously violates this little rule here

  • but by enlarge, for most drugs we give IV or PO, the reason we care about volume of distribution and

  • the plasma drug concentration is because we assume it's proportional to the target tissue concentration.

  • So, if you have all these points down that we've gone through so far,

  • let's do a couple of questions to help you remember.

  • Okay, so volume of distribution, we're going to go from conceptual to practical now. So, here's our question.

  • We've got a person, they've got bacterial pneumonia.

  • Uh-oh! What are we going to do?

  • So we decide to give them some Erythromycin IV and we're trying to reach a certain plasma concentration.

  • Now what is this plasma concentration?

  • Well we want to inhibit this bacteria and so, there's something called the minimum antibiotic plasma concentration

  • And so, what this is, is the concentration which will inhibit bacterial growth

  • and we're telling you now that the concentration we want in our plasma is 20 mg/L.

  • We're also going to tell you that the volume of distribution of this drug and I'm making this up for easy numbers right now is 40 L.

  • So what should the IV dose be?

  • So numero uno, if you have a scratch piece of paper, I write down the things that I know.

  • Plasma concentration that I want (my desired plasma concentration) is 20 mg/L

  • and I know the volume of distribution is 40 L.

  • So the first thing you should do for every problem is what?

  • Write down - I mean after you do this - write down concentration = mass/volume.

  • Mass is the dose in mg. Volume of distribution. Concentration here is the plasma concentration.

  • So what am I trying to solve for?

  • Well I know the volume. I know the concentration. I'm trying to find the mass.

  • So, I rearrange this equation and I get mass = concentration x volume

  • and I remember that mass is the amount of drug absorbed. The concentration that I'm looking at is the plasma concentration

  • and when I look at the plasma concentration then the volume I use in a realistic case is the apparent volume of distribution.

  • So, the amount of drug absorbed and so remember that if I give it IV, that's also equal to the IV dose right

  • or the mass of the drug absorbed.

  • So here all I have to do now is plug in my numbers.

  • I want a plasma concentration of 20 mg/L and I know that the volume of distribution is equal to 40 L

  • and I always like to write my units because it helps me cancel things out and remember and it tells me if I'm doing this right or wrong.

  • And so, if I do this, I get an answer of 800 and the units then are mg.

  • And I know that's what I'm trying to solve for right?

  • What should the IV dose be.

  • Now, the reason I like this is because it's a system. It's a way to think about things.

  • Just as equally, you could've just remembered the equation for volume of distribution and that's what I wrote here

  • but I always recommend having a way to problem solve.

  • All right, let's do the same thing now and incorporate bioavailability and instead of giving this drug IV,

  • we're going to give it PO.

  • So absorption and distribution.

  • Now, we're putting 2 different components of pharmacokinetics here.

  • Same person, still has bacterial pneumonia and now, we decided to give them instead of an IV dosage, Erythromycin yet in oral dosage.

  • And so again, the minimum antibiotic concentration that we want in our plasma is 20 mg/L

  • and the volume of distribution is 40 L and the oral bioavailability which I can just write as F is 0.25.

  • So, what should the oral dose be?

  • So how should you solve this problem? What's the first thing you always should do?

  • Concentration = mass/volume.

  • And then I think about what's going on here.

  • So just like before mass = concentration x volume

  • and remember, this mass. Is this the absorbed mass or the administered mass?

  • This is the absorbed mass and so here, remember from you know from back to when we talked about bioavailability,

  • the mass, the actual absorbed mass = the total mass administered a.k.a. the dose PO or IV x the bioavailability PO.

  • And so I'm being specific to this problem.

  • And so, all I need to do now is just plug this into here.

  • And so, when I do that, I get the mass (the total mass administered) x the bioavailability = concentration x