76. Dithering on distribution

It's the second Pharmacokinetics episode you never knew you wanted! Let’s talk about how antibiotics are distributed around the body once absorbed, using the examples of Amoxicillin and CallumShutUpicillin (listen to episode for clarification).

What exactly is the volume of distribution? Want a handy reference for the plasma protein binding of various antimicrobials? Then this is the episode for you! Check out our prep notes (including for this episode) here. 

Transcript

Jame: [00:00:00] Callum, I have to take issue with something that you said a little while ago. We were talking about, you know, tenacious D's, debut album and you were telling me that, tribute you didn't think was very good. You can't distribute some son. , speaking of which, aren't we going to talk about, distribution, today? Callum.

Callum: We are going to distribute some knowledge on distribution.

Jame: that's good. 

So yeah, we're going through our pharmacokinetics of antibiotics and, and sort of how that affects how we choose an antimicrobial. And, , so this, , we've already done one on absorption and bioavailability.

This one is on, distribution. So where does the antibiotic go when it gets absorbed? 

Callum: So, yeah, so this is where Ja comes into his own. He's been a a stealthy clinical pharmacologist for a long time and you probably never heard him [00:01:00] mention that 'cause he isn't going about it at all.

But we, we focus on the bug episodes, but I think I'm looking forward to hearing a bit of Jane wisdom, uh, about. getting into nitty gritty of pharmacokinetics and pharmacodynamics and how that is so important because when we make decisions about choosing an antimicrobial, which we are the brief introduction to before, I think actually that 

Jame: More you 

Callum: you think about it, obviously like most things, the more complicated it gets. So JA is going to walk us through a couple of things. Firstly, the factors affecting the distribution of an antibiotic or any drug really throughout the body. So that's vascular factors and drug factors. And then briefly talk about body fluid compartments and compartment models.

So how do we look at the different parts of the sort of fluid within body and and how drugs get to them? And then touch on something called the volume of distribution, which you may or may not have heard about, and what factors affect those. [00:02:00] Then you'll talk about penetrance of the drugs into different body cap, and then we'll be done.

So Jane, I'm very much listening uh, engaged here. am a loyal listener in this episode, but I will pop in with some questions when, when you go off on things that I don't 

Jame: Yeah, fine. No problem. Well, I, I will try and keep this simple. So when you're thinking about, you know, pharmacokinetics, you've got absorption, distribution, metabolism and excretion, absorption and distribution, or, or how does it get in and where does it go after it's in? And metabolism and excretion are, what does the body do to get rid of it?

And wh which. Where, where does it exit? So the distribution bit is really important to us as ID physicians because we want to know where the antibiotic is going to go to, because we want it to get to the target site where the bug is to kill the bug.

So what affects distribution? Well, you've got blood vessel factors or vascular factors, and you've got, drug factors.

So let's start with [00:03:00] vascular. So drugs will diffuse from the plasma. From the capillary beds into the interstitial space and then into the intracellular space. And, , the more, vascular, an organ or a tissue is like heart or lung or kidney, the more drug will be delivered to them compared to others like say, you know, fat or, or skin or bone., And. One factor in particular, which is important, is how leaky the capillaries are. Because if you've got something that's, you know, , hydrophilic, , say, and I'll, we'll come on to what that means in a second. It'll be difficult for it to leave the capillaries and get into the interstitial.

And, then in intracellular, space, there's like a lipid barrier, you know, at each of those, uh, junctures, I. But there are some ways to get drugs out. So some capillary bed, , epithelial cells, , have these. 60 to 80 [00:04:00] nanometer diameter pores, which allow, drugs to, to leave and get into the interstitial space, particularly in the intestine and the pancreas and other places that, you might not expect like the kidney. And in other places, endothelial cells are separated by, , not tight junctions, which you might have heard of, but by slit junctions. And these are gaps which allow large molecules to, , to move, into the interst and you can find those in the liver and bone marrow and lymph nodes and spleen. and these leak points will facilitate access of of the drugs to the interstitial fluid.

Callum: And that gonna make sense when you consider that obviously your body isn't designed, you know. Us using medication is a relatively recent invention. And , this anatomical features exist for nutrients for, you know, immune cells. So for other things to move in and out of the capillary 

Jame: Yeah. , and the drugs take advantage of that. Yes. , [00:05:00] and then there's the, the drug factors themselves. So, , you know, are how, how good are the, at crossing a phospholipid bile layer? , you know, so every cell is basically a phospholipid bile layer with some stuff in the middle. And if you want to get to the intracellular space, like macrolides are really good at doing this, then you need to be able to cross that.

In order to do that, you really have to be quite lipoic, , and not particularly polar. And that will allow you to distribute into. Into the cells, but also distribute into fat, uh, you know, for example. And how exactly do you interact with proteins in particular? Do you bind plasma proteins? , very well.

And so at this point, I think we have to talk about lipoic versus lipo or hydrophobic versus hydrophilic, depending on what your, you know, particular fancy is. Callum,

you 

Callum: Yeah. The way I think about it is you've got lipophilic or hydrophilic 

Jame: you're very positive. So you like, you like fillic things. I like phobic things. So I, [00:06:00] I, I'm, fine. I will stick to lipophilic, hydrophilic, for you, Callum. But what does that mean? So, lipophilic molecules will be, find it very easy to diffuse out of plasma in surrounding tissues, and they will favor distribution to lipid rich tissues. So if, , the drug has a net sort of negative charge, you know, you might call that a hydrophilic molecule, ill still might still be able to leave the capillary through these fenestrations that we've talked about before. But further penetrance into tissue will depend on the pH of the interstitial fluid, the drug pk, cr, our previous episode for that, and whether or not there are any. Saute carrier proteins that can be coopted. Those are your OAT and OCT carriers, that we mentioned before, in the tissue that you're talking about.

Callum: Just a brief what what makes a drug lipophilic or hydrophilic?

Jame: Um, whether or not it's polarly [00:07:00] charged. So if you are B because H2O, the, the O bit has a slight negative charge and the H bit has a slight positive charge. if if you are slightly polar yourself, then you'll be able to kinda. Form a weak, bond with one or the other, sides of those, water molecules.

And so that means that you will be more likely to, to, to remain in that solution. And if you don't have any charge whatsoever, then you will find it much easier to pass through a phospholipid bile air. , because the phospholipid biolay whole, whole thing is that it's got, , is that it's trying to keep, , molecules out, , of the cell.

 Yeah. And then let's talk about, plasma protein binding. So there's lots of plasma proteins that bind drugs. And reminder plasma proteins are things that the liver produces that go into, the bloodstream. But the main one and the one that everybody knows about is albumin. And each albumin molecule can contain a bunch of different binding sites, and they bind with weak electrical [00:08:00] polar bonds, so non-covalent bonds. And so that allows a bound drug to be stored in inverted commas and transported with the albumin, but also for it to be quickly released to become what's called free drug. And free drug is the bit that's not bound to albumin. And the importantly, that's the bit that has its pharmacological effect. So not many drugs, I can't, I don't, don't even know of any Callum actually have a pharmacological effect whilst they're still bound to albumin. And this is why. , To give an example of, of sort of interactions related to albumin. It's important never to add, , aspirin to warfarin, but it's okay to add warfarin to aspirin, because warfarin is, you know, bound to albumin, but it can be displaced by the aspirin. So if you get this, you know, massive increase in the amount of free warfarin because it's all been displaced and, and [00:09:00] becomes free, because aspirin is binding into the albumin, then you can get this massive increase in the INR. And I think that's how a bunch of other drugs also interact with, with warfarin to increase the INR. So yeah, so albumin is, is really important for transport of, of drug, but it also releases it fairly quickly. And the proportion of of bound to unbound drug will remain the same regardless of concentration. So. To give you an example here, Callum Aspirin is 50% protein bound, and that means, that half of it will always be bound of, of the total, concentration will be bound to plasma at any one time. So if you've got a one millimolar plasma concentration, 0.5 will be protein bound. But if you only have a 0.1 millimolar plasma concentration, only 0.05 Millimolars will be protein bound. Do you get what I mean? It's always a proportion of the total.

Callum: Yeah.

Jame: Yeah. And then the last thing that we, we [00:10:00] should mention is sort of binding to tissues, uh, and, tissue binding sites. And so binding to tissue, like, say to muscle will, will drain in verte, commas the drug from the plasma, and will reduce the amount of plasma free, drug. And in, in the show notes out here, I've got an example of, it's not an antibiotic, but, digoxin, it's got a high affinity for sodium potassium at TPAs and skeletal muscle has lots of that. And so, , it tends to sort of soak up, , digoxin from the, from the plasma. And this will lead to the, , drug having a higher volume of distribution

Callum: Are there any antibiotics that have tissue binding?

Jame: , yes, there are. So in, in particular, , there's lots of tissue binding with the macrolides.

So they're, they're coming up again and again as, as something that, because their, their plasma levels are very unimpressive, Callum,

but. They, they're having their effect in tissues and in particular in the [00:11:00] intracellular space. And so they're, they sort of have an outsize effect based on what you would think you would get based on their vd.

Callum: Hmm.

Jame: , but now I think callam, we need to talk a little bit about compartments. 

Callum: So I'm sure everyone remembers from medical school or undergraduate degrees. If you did physiology or other, you know, whatever degree this this probably came And if it if it didn't, then maybe we'll just explain it. Very from from basics, but I guess you can devoid your body up into series of compartments, which theoretical, slight issue, but most studies look at 70 kilogram males, which Yeah, so we we look at that and we say, okay, there's a solid mass. So in that 70 kilogram person, about 40% of that person will have solid mass, and then 60% will be their total body water. So. Then you can further divide that up into the intracellular fluid or the [00:12:00] extracellular fluid.

Now, the intracellular fluid is the fluid inside the cells, and that's 40% of your total body water. The total body water is about 42 liters, and the intracellular fluid's, about 28 liters. Of that, the extracellular fluid is about 20%. Of the total body mass, so about a third of your total body water, and within the extracellular fluid you've got interstitial and plasma.

Jame: Yeah. And, and interstitial is about, 15% of total and plasma is about 5% of total. And so here it's about 3.5 liters. You know, o other people give different, proportions. Totally. So the. Plasma. Some say three and a half, some say four, some say five liters, something like that. But yeah, if you're, if you're using a 70 kilogram meal as an example, then about three and a half will be plasma.

So those are the kind of, [00:13:00] you know, proportions that we are we're talking about. 

Callum: A slight sidebar there, but one of the issues in pharmacology and studies is that generally speaking, it's an unhealthy young volunteers, and a lot of those are. I guess volume to the 70 kilogram male. So it means that we then have difficulty sometimes extrapolating that data to women or to,, the, um,, elderly 

Jame: Or, or to, or to 100 kilogram podcast hosts, as well. So I'm, I'm fully aware, Callum, that this is not, generalizable. You, you sitting there as a 70 kilogram male telling me, is the height of rudeness actually, if you don't mind

me saying. 

Callum: Okay.

Okay., 

Jame: But anyway, you know, and when we talk about where the drug distributes to, usually we, we will use a model because it's, you know, impossible to, , to determine the different concentrations in, in real life.

And actually, a lot of the time we will use a one compartment model, which just assumes that the [00:14:00] total body water. The, the 60% that we were talking about is one big vat and the drug just drops into that and,

Callum: Oh.

Jame: And then instantly distributes to throughout that, , 60 liters. And this is very, very simplistic, Callum. But I was told in medical school, but have not been able to verify that that accounts for something like two thirds of all drugs, , can be explained , by the one compartment model. And something like up to 95% can be explained by a one or a two compartment model. And again, I've not been able to verify that statistic since, researching this.

But that, that was what I was taught in medical school as well. And the two compartment model is that there is the central compartment, which is the plasma and the peripheral compartment, which is everything else, the intracellular fluid and interstitial, fluid as well. And in order for the drug to distribute, it distributes from the plasma to [00:15:00] the, peripheral compartment. And then in order for it to be eliminated, it has to move from the peripheral compartment back to the central compartment where it's then metabolized, and excreted. And, you know, above the two compartment model, it gets too complex for a, for a, simple naive clinical pharmacologists like myself.

But there are multi compartment models that extend way beyond this. Again, in medical school I was told about a 17 compartment model that had been created for a drug. , but this, I think, falls way beyond the scope of an ID physician. I don't think that you need to know about that except to that sometimes you have to think about the drug moving from the.

Central compartment of the plasma into the peripheral compartment, which is the tissues.

Callum: Yeah.

Jame: Let's talk about the volume of distribution. So this is a, occasionally difficult to understand concept, but it is the thing that we use to comment on the [00:16:00] distribution of a drug. how it's defined is it's the volume in liters that contain the total body content of the drug at a concentration equal to that present in plasma. I hope that's clear. Callum,

Callum: Just to rephrase that, just so I make sure I'm getting this right, because I've used this quite lot and I I, I think about it, but I always find it a bit difficult to wrap my head around what it actually means. So, So we know what the concentration as plasma is. And the volume in liters that contain the total body content of drug at the concentration equal.

So essentially if you have a high volume of distribution, then that would represent a drug that easily has moved from the plasma into the sort of peripheral compartment. So the interstitial fluid, um, intracellular fluid.

Jame: Yes.

Callum: And if you had a low volume of distribution that would represent a drug that is staying in the plasma well, so maybe something that's highly protein bound and Is hydrophilic

Jame: Yes. [00:17:00] So let's, , let's give a couple of examples and then people will know what we mean. Say that to keep the number simple. Let's say that plasma is five liters, and let's say that I gave you a gram of. A, uh, drug and then, you know, it doesn't matter any old drug. Uh, and

Callum: give.

Jame: I can't, because I'm about to use that as the second example. I can't because I don't have those precise numbers. Callum, can you just let me finish this? All right. I, I, I, I give you a gram of shut up and let me talk coill. Alright? And, and so I give you a gram of that, right? and then I measure the plasma concentration just, you know, five or 10 minutes after I've, I've given it and it's, it's disseminated throughout the plasma. And I get a plasma concentration of 200 milligrams per, per liter. And I know you've only got five liters in you, right? [00:18:00] And so I, I'll then say to myself, okay, well I've got,, I've given him a gram and I've got 200, milligrams per liter is the concentration. So if I divide that gram by the 200 milligrams per liter concentration, I get five. So the volume of distribution is five liters. And sometimes people do this thing where they divide it by 70 to give you a VD sort of proportion, but it's that that 70 where that, where's that 70 come from Ka. It comes from the 70 kilogram mail. , of, yester year. So I just think that kind of makes it a bit fuzzy and, and sort of you're just arbitrarily dividing it by 70 for no particular reason.

So there is a liters per kilogram, notation that people sometimes use, and you can see it if you go and look for this on like drug mag or something like that. If you get that and you want to convert it into liters outright, just multiply the number by 17, you'll, get the

right number. 

So let's take a second [00:19:00] example here, Callum, where I give you amoxicillin. IV at a dose of 1000 milligrams, and then 10 minutes later I give you the plasma concentration and it's 50. Well, what's the volume distribution there? So I gave you a thousand milligrams, and then the concentration is 50. So I divide a thousand by 50 and I'll get 20. So, I'll have a volume of distribution of 20 liters. And that's a real example, so that is still an example of a fairly protein bound, fairly low volume of distribution, drug. , but the. You know, these vds can go up to hundreds of liters if they have something that leaves the plasma almost entirely. So we've got, you know, hydrophilic antibiotics like say, beta-lactams, Amy Glycosides and Glycopeptides. , they will have a small VD and be consequently, predominantly renally cleared with the low intracellular penetrance. Contrast that if you [00:20:00] like, with the lipophilic antibiotics that have, will probably have a large volume of distribution.

They will see no reason to stay in the plasmin. So they will, they will go out and they, , will have a good intracellular penetrance. That would be an example, say like the, the macrolides fluoroquinolones. And as well. There's some things that you have to think about. , with the vd, think factors that affect it would include, , protein binding, , and competition for, for binding sites.

If, if binding sites are taken up by other drugs, that would increase the amount of free drug that you're talking about. 'cause remember, it's only the free drug that will be able to distribute from the central compartment to the peripheral compartment. 

Callum: So the constant, so to calculate appointment distribution, it's the total amount of drug and body at time zero. Uh, Over the plasma concentration of drug at time zero. And time zero you're saying is 10 minutes after administration.

Jame: Yeah. Or, [00:21:00] yeah, because usually most of the, vD calculations have been done with IV drugs, so

if it was oral, you would have to give it a bit more time,

so you would have to u usually, actually most of oral absorption is done by 20 or 30 minutes in, which is another good reason for, Having an orals first approach to treating anything other than severe sepsis.

 So you see a lot of people using IVs because they want to get in fast. Well, I mean, if you're doing that, fine, but you better make sure that the difference between 10 minutes and 30 minutes, you know, so that that's a 20 minute time gap. You better make sure that that's the difference between life and death, because other than that, you're doing nothing. , for the patient by, by giving an IV 

Callum: Do you think that holds true? Because other PK studies are done in healthy volunteers, like if someone is actually sick, does, does that affect your, your gut absorption at all and.

Jame: Well, I mean, you have to make sure that the patient's got a functioning gut. And so if you aren't sure of that, then yeah, [00:22:00] by all means, use iv and, and you know, well, let me give you an example, captain. This is sort of going back a little bit to the previous episode. But I, have just been on general medicine, , take, as you know, for the month of, of January, 2024, and. I was coming across quite a lot of people who were not in septic shock, who didn't really have that much in the way of, you know, hypotension or even tachycardia on occasion. But were given IVs anyway. I. Just to be sure, and I think there's some pretty convincing evidence these days that if you are not, treating, septic shock in the patient as a working gut, orals are just as good as iv and,

and that data's coming from a ton of trials in a ton of different situations.

Uh, So that's the factors that affect the volume of distribution or the VD as you termed it What about penig?

so the, the penetrance kind of depends on [00:23:00] all of those factors that I, that I discussed in, in, , amalgamation and. Before I go on all the, the one and two compartment models will treat all the different tissue compartments as being comparable, but that is, you know, not true. And we, you know, we'll have to cover this separately because it's just too big to do, , now, but, you know, , penetrance to say the brain. , that's controlled by how good you are at crossing the blood brain barrier. And some antibiotics are good at it and some aren't. Some are good at crossing an inflamed meninges and some are not, et cetera, et cetera. , the heart usually you're concerned about that 'cause you're treating endovascular infections.

So you'll want something that's kind of highly plasma bound. But, you know, dissemination to the skin is not necessarily a given penetrance to the lung. Penetrance of the prostate. We're not mentioning any of this sort of stuff, but it is a feature of, of kind of, when you're treating the infections and, and particularly when you're choosing an antibiotic to say, [00:24:00] go into a micro guide or, or a antimicrobial advice.

You'll be taking all those things into account. Whether or not you know it, because the studies that prove this drug works, whereas that one doesn't, will have factored that into their selection of that, drug 

historically. 

But yeah, what I did then callam, is I've got a table in the show notes here, and, there's two, and what I went through.

All of the antibiotics, all the ones that we mentioned in the previous episode, and a few, , that we didn't, , that, that are IV because obviously it was focusing on highly bioavailable, uh, antibiotics at that time. And I've noted down their molecular weight in Daltons, they're protein binding and percentage and their volume of distribution.

And the resources that I used for that were either drug bank.ca, or the medicines.org.uk. The e medicines compendium, where all the [00:25:00] drug companies, put their regulatory documents on their, , SPC and their patient information Leaflets are all available there. So then, I'm not sure I want to really go through this.

I might just pull out a few interesting, you know, interesting bits. Kalan, why don't you talk about flu oxacillin. Protein binding.

Callum: uh, well, actually there was something else I wanted to talk about, but I guess we should start narrow and then broaden out. Alright, go ahead.

so, yeah, so flufloxacillin, so that in the UK is our first line treatment for Scag, casus, breia, and lots of other severe infections. 

Jame: American listeners, nafcillin or, or dicloxacillin, depending on your

flavor. 

Callum: Uh, So Oxacillin, so it's a sort of moderate size molecule, I guess, at 553. Daltons 

Jame: Four hundred, four hundred and fifty three.

Callum: oh yeah, I can't read. Yeah. Wow. Screwed this up.

Jame: You gonna leave this in or you gonna

rerecord? Yeah. [00:26:00] In who Alright, fine.

Callum: the, and it's hydrophilic. And the interesting thing, and this is, I always come back to this when I've got someone, and it's not going right, which is that it's 95% protein bound, and so it's gonna stick in the plasma and it's volume of distribution is 13 liters, which is relatively low. No. Very low. Very low. Yeah. Yeah.

And so it does make you think. Does, it, Is it getting into to tissues? So, know, we, we use it at very high doses when we're using it intravenously. Like say two grams, six hourly or eight grams total daily 

Jame: Yep. Yep. 

Callum: But when you're giving an oral flufloxacillin and you're maybe using 500 milligrams every six 

that, I think that's more where this starts to come into play. You know, you're, it is highly protein bound. It's getting, um, spoil this for the next episode, it'll be getting metabolized and eliminated. So not that much of that drug is actually gonna be getting into 

Jame: tissue 

Callum: And so then it's highly [00:27:00] surprising that someone with a skin soft tissue infection and you give them that relatively low dose of oxacillin compared to what we can give IV doesn't respond adequately, but then when you give them a drug that.

Gets into tissue better. So let's maybe look at doxycycline as a quick comparator. So doxycycline is around about the same size, but the differences there is it's lipophilic, and although it's protein bounding is still quite high. So quoted to 80 to 93% compared to 95%. For focal coill, its volume of distribution is 52, so it's much higher.

And that's coming down to mainly it being lipophilic. So. I guess it, it is quite complicated. There's like a lot of different factors to, to weigh up when you're making this antibiotic selection. And I don't think it's as easy as saying, you know, lipophilic good, hydrophilic bad, or, you know, low volume distribution, good, high volume distribution, bad, 

Jame: Well, no, no, no. Not at all. Uh, not at all. [00:28:00] Yeah.

Callum: I think There is some niche points where, where knowing the sort of level of detail of antibiotics can be helpful. So one thing that I wanted to bring up, um, James spoken a lot so I can keep talking and I'll let him in, Meropenem versus er tappen.

Jame: Okay.

Callum: So there's two carbapenems. They have relatively similar S spectrum, um, Meropenem mainly having the addition of pseudomonal cover and also probably a bit more robust against some of our sort of carbapenemase, betalactamase type of things.

Uh, they're both hydrophilic, uh, so they've got charge, but the protein binding, so Meropenem. I think nobody would argue that Meropenem is a great antibiotic if you want to kill all the bacteria, including the friendly ones. Uh, but it's only 2% protein bound, so it's right the, into the tissues.

And that's reflected. This isn't enough, a super high, um, volume of distribution. So it's 17 to 24, which is maybe surprisingly [00:29:00] low, but when you look at it for different body spaces. So does it get into It gets into the CNS very well. Does it get into the prostate? Yes. It gets into the it gets into lots of different body compartments very easily.

I. And sometimes I think you can easily say like, oh, meropenem to ertapenem makes sense. But ertapenem in contrast is very highly protein bound, uh, greater than 85%, and uh, it's volume distributions lower at 8.4. It doesn't seem like that big a difference. But then, you know, say you've got someone and they've got like a carbapenemase producing intra and it's in a joint and you've got a septic arthritis, that actually might mean the difference between clinical response and not clinical response.

I think it's slightly difficult because we're getting into a level of nuance, which isn't really ever gonna come out in a clinical trial. Like I don't think you could, you know, you might be able to say Meropenem versus ertapenem for this clinical condition, but whether you could ever turn around and say like, [00:30:00] know, this protein binding 

Jame: oh, well no, but Cal, there is that signal that, , the, in, in people with low albumin state in intensive care with, with a low albumin, that there. There tins or there's a signal for higher failure rates with ertapenem and you know, people, you, you might be thinking, you know, why, why would that happen?

Well, remember, it's the free bit of the drug that has its effect, but it's also the free bit that gets pissed out. And what people are thinking is that you just aren't getting. Highly maintained plasma levels with, with ertapenem, if you've got a low albumin because there's just not enough albumin to bind to.

And so the free ertapenem gets renal. Sweet. So, yeah, I mean, I, I mean, again, not proven in an RCT, but you know, it's an interesting signal, isn't it?

And with Merepenium, you don't have to worry about that.

I suppose the other one that I should mention is ceftriaxone. So it's also got a, you know, about 90%, protein binding, , a low [00:31:00] volume of distribution is really all of the, , the beta-lactams do. That actually is what allows it to be dosed at once a day because again, it's only the free bit that gets excreted. And so that sort of almost contributes to its long half-life.

, there, the, the high levels of protein, , binding that you get. So yeah, so it loyal listeners can go and have a look at that table. We'll have a link to it in the show notes and you all know where the. Print notes for the episode, are anyway, they're at the, at the sort of footer at the end of our, of

the 

podcast 

Callum: someone should make a top Trump style card game for this.

Jame: Well, I mean, empiric should be right on this.

Um. 

Callum: we've uh, shout out to Empiric, which is a excellent card game for learning infections and antibiotics. Maybe we need to cover that in more detail at some 

point, 

Jame: Yeah, yeah. , to be, to be continued. But then the second table cam is perhaps more interesting because of course, , all the beta laptops are, are [00:32:00] hydrophilic. But that's not true of all the other,

Callum: beta are all, they're all relatively similar sizes, although the protein binding and volume distribution's 

Jame: I mean that, that does vary a lot. Yes, but I mean, they are all basically, you know, between 300 and 600, daltons, not so table two, which opens with Vancomycin at 1400 Daltons and Alva Van at 1800 Daltons.

Callum: Yeah, that's that's 

Jame: Yeah, that's massive. And if you've ever seen, I mean, I, I had a talk, where I, I sort of had penicillin's molecular structure up against Vancomycins molecular structure, and it's just, you know, it's just several times bigger.

It's, it's huge. And it looks like a honeycomb almost. There's so many bits to it. But yeah, vancomycin, it's big. It's hydrophilic. That means it's gonna have real difficulty moving out of plasma. And so it's vd, it's quite low. It's between 28 and 70 liters. Still a little bit of it leaves the plasma, you [00:33:00] know, it's not entirely in there. , and very, , middling protein binding, about 55%. Compare that if you like, with its long-acting cousin DBA dalbavancin, which is almost 96% protein bound. And so that's why, and has a lower VD of about 14 liters, and that's why it is, clears much more slowly from the plasma. , and so it's got this long half-life.

That means that you can give it, you know, once a week. , yeah, if that, yeah. So that's the, that's the difference between the long-acting Lanco peptides and the short-acting ones.

Callum: I, I've been trying to read the, the volume of distribution to see which is the highest, and I thought I had a winner at TIG Cyclone, which was four 90 to six 30. Which is very high and kind of makes sense 'cause we know that OC cyclone's, you know, licensed for intrabdominal infection and, you know, it's I think a fairly useful antibiotic when you're, when you're a bit stuck.

But maybe it's so good for, for bacteremia. [00:34:00] Um, 'cause it doesn't stay in the plasma that 

well 

Jame: well or, or has that dogma been driven by the large fallen move distribution, but anyway, to be

continued 

Callum: Yeah. Tragedy of CYC 

Jame: But yes, that's not the winner 

Callum: I saw a Romy, a Romy, what's going on? Volume of distribution 2,177. What does that even, how, what does 

Jame: We should talk about this. So that is the difference as you go up, , the macrolides from the erything to Claro to Azithromycin is that you get much more, , lipid solubility and, therefore volume of distribution goes up like several fold. And so the Clare's, VD is between 190 and 300. So that's quite a lot, isn't it? But Azithromycin just leaves the plasma instantly and just goes to the tissues. So it's VD is 2,177 liters, as you said, and that. You, if you saw that, you'd think, oh, [00:35:00] well it's, it's useless, you know, as an antibiotic. And, and it is for bacteremia where the problem is within the bloodstream and it doesn't really stay in the bloodstream. But if your problem is in the tissues or in particular if it's in the cells, like say a mycoplasma pneumonia, which a bunch of people might be encountering based on my, time in gen med, there seems to be a bit of a surge in mycoplasma

going on at the 

Callum: Yeah. Yeah, I've seen that as 

well. 

Jame: Or other intracellular pathogens like say legionella, clam dola, things like that, then , you will, then you might prefer something like clarithromycin nor azithromycin because you know, it's got this enhanced intracellular effect, which partly explains why, although they're not. Really all that bioavailable. They have this outsize effect, which means the oral layer, they're basically just as good as they are. ,

quite big molecules too. 747 and 748 Daltons [00:36:00] respectively. 

Callum: maybe we, we've gotten to the end of the and and I could look at this table for a while 'cause I find it very easy to read. Uh, so thanks for putting that together and also pretty comprehensive. There's probably antibiotics that you want to know that you've missed.

right, you want us to add lines to the table, I mean Jane, not me. Then you could email us, uh, with some sort of, uh, suggestion and we'd be happy to add 

them. 

Jame: Tha thanks. Call.

Thanks

for this.

 But yeah, people can look in their own time and, , you know, all, all this information is, is publicly available. Is there anything else that sort of stands out to you? I, I guess the Quin loans also have quite high vd, , you know, between 90 and sort of 200 depending on which one you're looking at.

Callum: What else stands Uh, Meite is quite interesting. It's quite small. 171. It's lipophilic. It's less than 20% protein bound. It doesn't have a massive volume of distribution at 36 to 77. that's quite that's quite interesting. Kind of Explains it, it gets into abscesses, [00:37:00] it gets into pretty 

Jame: Yeah. Yeah.

Callum: What's the lowest volume of distribution?

Jame: The lowest. That's probably

Callum: Is only seven. Yeah. And, and highly protein bound as well. And big, , 1600 Daltons. , but yeah, I suppose that does all that sort of, might make it good for, for sort of plasma, , plasma stuff, which is kind of what we use it

you know, You've got your initial batch remic in a, in a severe illness, and you need to have drugs that are gonna stick in the plasma to get rid of that. But then it sort of comes down to what your primary source is you know, you're not batch remic initial thing.

It's usually a batch emia a secondary to X. So then it comes down to where is the site of infection and that should change it. So rather than saying we're gonna treat staph bacteremia. We say we're gonna treat staph or bacteremia with the primary source being 

X. 

Jame: like pneumonia or urine or an endovascular device,

you know, And

all that sort of things. Yeah. Yeah.

Callum: does sort of come out, but you know, I guess sometimes we [00:38:00] say bacteremia equals risk management and instead we should say infection focus with breia. And maybe it does affect your therapy, shouldn't be the same treatment for all battery 

Jame: Yeah. And, and I suppose we do kind of do that a wee bit with, like, to take Daptomycin as an example. Daptomycin is it, it's a big molecule. It gets trapped by surfactant. It's not inactivated. It gets trapped by surfactant, Callum. And that means that it can't then go on and sort of bind its target side. And so that's why it doesn't work, in, for lung infections. So people like know bits and pieces like that, but they don't have like a. Comprehensive overview of, all these little sort of bits and pieces about distribution. Neither do I, by the way. , I'm not saying that I do and nobody else does, but like, you know, they're, people might know these, a fact about this drug and a fact about that drug, and it might be related to the distribution. But [00:39:00] they, you don't have an idea about the sort of gestalt of it.

Callum: Yeah. So I think to summarize my thoughts on this is that I feel like this is something that I've come back to over the years in patients where you're in a tricky situation, you're kind of going maybe a bit off piece because the usual primary options aren't available, or the comp the affect's got complicated or you're, you're not succeeding and it's useful to, to think about these things and and I guess the things that Jame has talking, taken us through there.

Was, you know, what the vascular factors and the drug factors relating to distribution, whether something's lipoic or hydrophilic, how plasma protein bound it is. uh, then it's volume of distribution throughout the different tissues and what affects that. And finally, it's penetrance into uh, body compartments, which we haven't gone into depth about we will in the future.

And then finally, uh, summarizing that all with the molecular weight. The Lipophilicity, the protein binding and the volume of [00:40:00] distribution and together that gives you quite a bit of information. It's not the full picture we're gonna come back to, and you should go Bla blathering about bioavailability.

And thank you Jane, for talking me through that because I feel like I understand it a bit better now.

Jame: Ah, that's a lovely compliment. End on thanks.