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  • 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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All right, welcome back!

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B1 中級

藥品流通概述-藥理學講座4 (Drug Distribution Overview - Pharmacology Lect 4)

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    Yu Syuan Luo 發佈於 2021 年 01 月 14 日
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