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 the volume of distribution.
And so, all I need to do now is divide both sides by bioavailability
and if I do that, it cancels out here, comes under here, F and I get this equation.
So remember, this guy is my dose and here it's my dose PO.
So I rearrange this and I get the dose = concentration x the volume of distribution divided by the bioavailability.
So I just plug in my numbers now and I have 20 mg/L. I multiply by volume distribution of 40 L. The liters cancel out.
I'm left with 800 mg in the numerator. The bioavailability is 0.25 which is the same thing as 1/4 and remember, bioavailability has no units
and so, this comes out to multiply by the reciprocal 3200 mg or 3.2 grams.
So really quick, if the bioavailability was 50%, what should the dose be?
Good! 1600 because it would just be 1/2 in the denominator here.
So you know here a lot of people say oh here's another equation that you should just memorize.
I disagree
The 2 equations that we've done so far which we can derive all these other ones are concentration is mass over volume
and the absorbed mass is equal to the total mass administered x bioavailability.
From these, you can really derive the equation for volume of distribution, for the dose you need to give
and you can include this component of bioavailability.
So, if you got all this down, we have some stop, think and repeat questions that you can do.
And so, do these and then give yourself a little bit of a stretch, move your legs and when we come back, we're going to do metabolism.
I really hope to see you there. Take care.
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