All right, welcome back!
Let's jump in to section 3 here where we'll be talking about distribution and something called the apparent volume of distribution
and I just want to underline this word apparent right now and we'll come back to that in a little bit.
So, like we always do, let's start with a little review.
And so here we're dealing with pharmacokinetics still
and remember that the definition of pharmacokinetics was the change in drug concentration as that drug moves
through the different compartments of your body.
And so, there were 4 components of pharmacokinetics.
Do you remember what they were?
Well, we had an acronym that we used A.D.M.E.
A being for Absorption, D for Distribution, M for Metabolism and E being for Excretion.
So in the past, we covered absorption
and today, what we're going to do is focus on distribution.
Before we go any further though, we have to remember the core concepts that we have covered in the past.
So, what was the most important concept that I had you remember?
Well, hopefully you're saying that concentration is equal to mass over volume.
And so, in the past, when we dealt with absorption, we were really kind of just focused on this concept of mass.
We assumed a fix volume and we said you know how does the mass change as this drug gets into your body?
And we defined something called bioavailability.
And so, the way the practical definition of bioavailability was if I gave a certain amount of drug let's say by mouth,
how much of that drug ends up getting into the systemic circulation?
And the way we can figure that out is by using bioavailability.
And so here was the equation for it.
And we said the actual absorbed mass was equal to the total mass administered x the bioavailability of the route in which we administered that drug.
So it gives us the fraction of drug that is getting into the systemic circulation.
Now remember here that if I gave this drug IV, if this is IV, what's the bioavailability by definition of anything given IV?
Well the bioavailability is 1 or 100%
and so what that meant was the total mass that you administer IV is the total mass that gets absorbed or that gets into the systemic circulation
because when you give it IV, you're directly injecting it into the systemic circulation
but this is old news. You know this stuff already.
Now let's jump into volume.
So, in the past we assume that the volume really didn't change
And that we gave the drug and it went into the plasma and it didn't go anywhere else.
But now, we're talking about distribution.
So, volume is the key term when we think of distribution.
So what is distribution?
Distribution is the dispersion of the drug throughout your body
and the way I like to think about this is that the drug is going from one place to another.
So where does it start? What's the one place?
It starts in your vascular space.
What's the other?
It's going to your extravascular place.
And so when we think of distribution, if this is a vessel and we took all the cells out of this vessel, out of the blood
and all we're left with is plasma.
Remember, the plasma was what?
It's the blood minus the cells.
So if we started in the vascular space and I had a drug. The process of it going from this vascular space to the extravascular space is what we call distribution.
And remember that this extravascular space now is another volume we need to consider
and that's why we're dealing with volume here.
So what are some examples of the extravascular space where there might be fluids or places that drugs can get into.
Well, we have our interstitial space right?
Where else?
Well drugs can get into the fat. Drugs can get into the muscle.
And really because drugs are really getting you know we're looking at the water compartments of the body.
Well, remember that plasma was the blood minus the cells.
So, sometimes the intracellular space is associated with extravascular space.
So the cells inside the cells of the fat or inside the cells of the muscles, we know that we have water in those too.
So I'm just going to write here intracellular.
And so, these are all places that the drug can go outside of the plasma and these have a volume
and we need to consider it if we're going to figure out the plasma drug concentration.
So, before we jump into distribution, there's one more thing we want to cover
and that is just to quickly review this case that we had done in the past
and what we're going to do is differentiate this case which had no distribution from the next case which does have distribution.
So we've done this before.
We gave 10mg of a drug IV bolus but in the past, we assume that that drug stayed in only 1 compartment
and that compartment was the plasma.
So here, we were assuming no distribution and just to have a really simple model, we also assumed no elimination.
So what happened here?
So, I gave 10mg of drug. Here is my syringe right and here I have 10mg
and what I always want to do when I'm thinking of pharmacokinetics is figure out the plasma drug concentration.
So, we remember our most important concept: concentration is equal to mass divided by volume.
And so, because we only assumed one compartment, I said the mass was 10mg.
That was the amount of drug absorbed and administered because I gave it IV divided by the plasma volume
because we're trying to find the plasma concentration of 2.5L and if I solve for that, I get a concentration equal to 4mg/L
and because this drug is not distributing anywhere else and there is no elimination,
I know that from beginning to end, my plasma drug concentration is essentially 4mg/L all the way through.
So in the next case here which will be case 3 because we've already done case 2 when we considered IV administration of a drug
and we learned about bioavailability.
In the next case, we're going to look at distribution and we're going to assume a multi-compartment model.
So, the in case 3, drugs getting into and around our body.
So we have an IV bolus and let's just assume we're still giving this 10mg
and now we say there's multi-compartments. We have our plasma compartment and we have our extravascular compartment.
So, now we're dealing with distribution
and again we assume no elimination.
So we start off and say okay, I'm going to administer 10mg of a drug IV bolus and let's draw out these comparments.
And so, if I was going to visually represent them, I could say all right I would have my plasma space here or my vascular space here
and then I have my extravascular space here.
Now, we need to remember that this isn't you know fluid you know continuum.
There's something separating the vascular space from the extravascular space
and hopefully, you're telling me that that thing is separating is a vascular endothelium.
And so that's what this green guy here represents and so I say, Oh I have a vascular endothelium.
And so, what we're going to consider like we always do with pharmacokinetics is if I administer this 10mg of drug IV bolus,
what happens to the plasma concentration with time as this drug is moving through the different compartments of the body?
So, what do we always do first, before we graph anything, before we do any pharmacokinetics question,
we always remember concentration is mass over volume.
That is always the first thing that you should go to no matter what.
And so, now I need to figure out what's going on.
So, let's just you know think okay, I've got a syringe
right I guess the syringe isn't as pretty as the other one.
I gave 10mg of drug right here.
And so, I want to figure out what this plasma concentration is.
So I say, Oh I gave 10mg of drug and it distributed into a volume of 2.5L.
And so, I'm just going to draw in some drug here.
So, this right here is the time (T) equals 0. So, we'll say at T is equal to 0 hours.
And so, coming to my little graph right here, I would say, Oh that would mean that this time T=0.
When I injected the drug, I have a concentration of 4mg/L.
Now, unfortunately, it's not this simple because we know that this drug is going to distribute into the extravascular space.
So, let's see that happen.
Boom, boom, boom, boom. That was pretty cool , eh? I took way too long.
Okay, so now that this drug is distributed into a larger volume, what has now happened to my plasma concentration?
Well, my plasma concentration has gone down a little bit.
And so, if I was to assume that the concentration here was equal to the you know concentration here,
really I can just use my core equation and try to solve for the concentration of the drug.
So what do I mean?
If I was going to consider an ideal situation, I would say the total mass absorbed is the concentration is equal to
the total mass absorbed divided by the volume which the drug is distributed in.
And so this volume we oftentimes just represent as Vd (Volume of distribution).
So now I look at this and I say all right we'll distribute it in a volume of 2.5L and into a volume of 7.5L
and so if I do that, I get okay at a short time later. Let's say it took an hour for this to occur.
So, at T=1 hour, I have 10ml of drug and I know it's distributed into a volume of 10L.
So I get 10mg/L. No, 10mg/10L or 1mg/L. Sorry about that.
So, now let's draw this graph.
So, I know that at T=1 hour. So let's say this is 1 hour. This is 2 hours, whatever.
As time goes on, I know that this is diffusing across this membrane and therefore, the concentration is going to drop
and I get something that kind of looks like this
and this here let's just say that the 1mg/L.
So, remember that this is the ideal situation and the only reason I could you know tell you what the plasma concentration was
is that I had to assume that I had the same concentration of drug on both sides.
So I wrote this right here.
This is the ideal situation assuming that drug concentration is the same on both sides
and also, that there is no elimination occurring.
But we know we don't always deal with this ideal situation
and we know that the drug is not always going to be the same concentration on both sides.
So, because of this, we have this term called volume of distribution.
And so, if I was to - let's just scratch all of this right now and let's redraw a couple of pictures thinking of this term, volume of distribution.
So what is the volume of distribution?
Well, you can think of the volume of distribution as the total mass absorbed divided by the plasma concentration.
So, if I was to give a drug and let's say this was a really big drug and it couldn't get across this vascular endothelium
If I was say to - let's just say I draw the drug, okay and let's say we only have 2 molecules here.
Well what would that - okay, I gave a certain amount of drug right. We know this was let's just say 10mg still
and then I measured the plasma concentration and I notice in this case the plasma concentration is pretty high.
So what would that do to my volume of distribution or what does it appear that the volume in which this drug is distributed is, right?
So if I have a high concentration and I only gave a low amount of drug, it appears as if the volume in which this drug is distributed is really low.
So in this case, we say Oh this drug has a low volume of distirbution because it stays within the plasma.
Now let's give you the converse scenario.
Now, let's say I give - let's use a different color. Let's say it was green.
Now, let's say I gave that same 10mg but instead of it staying in the plasma, most of this drug is in the extravascular space.
Now remember the actual body volume is not changing right?
The body stays the same
but if I gave 10mg of drug just like I did last time but I measured the plasma concentration
and the concentration is really low. If I didn't know any better, I would think to myself
Oh the only explanation for this plasma concentration being really low is that this drug must've distributed into a really large volume
or at least it appears as if this drug distributed into a really large volume.
And so, what that would mean is that I have what we call that as a large volume of distribution.
So, remember it's not the actual volume that it's distributing in, it's what it appears as if the volume is.
And so, when I see that, I say Oh a large volume of distribution really means that
very little of that drug is staying in the plasma. Most of it is going into the extravascular space.
Hopefully, that makes sense to you.
If not, we're going to jump into volume of distribution in detail on the next slide.
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