Ep 4 – Volume of Distribution For The FRCA Primary
8 November 2024
Contents
This Episode Cracks on with a make believe…. concept!
Volume of Distribution is an important concept to understand as it is a building block to thinking about multi-compartmental pharmacokinetics.
Check out the multi-compartmental madness episodes if you want to jump ahead
Madness Part 1 - Madness Part 2
It bears relevance when thinking about drugs action in broad context. DO bear in mind that it is a tool for thinking about drugs, and is more a crude pharmacological concept than a reality.
What is Volume of Distribution?
Volume of distribution (Vd) is a pharmacokinetic parameter that describes the extent to which a drug disperses into body tissues relative to the plasma. It is calculated as the ratio of the amount of drug given to the plasma concentration at time zero.
Volumes?
In my mind I think about it as a series of bath tubs, reservoirs, pints and shot glasses,
- Each drug has a particular set of vessels
- Each patient has a particular mix of differing vessels, depending on if they’re an Olympic swimmer or eater
These vessels sort of relate
- To the shot glass : the patients plasma,
- The pint glass, their extracellular fluid,
- The bathtub, all their fluid, including intracellular
- The reservoir the patient adipose tissue.
Now its important to bear in mind that whilst thinking about it conceptually like this helps to frame it
VODs don’t correlate directly to any physiological volumes, because drugs dissolve/soak into varying ‘vessels’ at varying rates.
But by thinking in this way across all drugs it will warm you up to thinking about the pharmacokinetic models involved in TIVA and modelling in your brain how volatiles are taken up by life forms.
The factors that influence the VOD include
i.e. the properties of the drug naturally dictate how it behaves in the patient – think lipid solubility, molecular size, its charge, pKa and plasma protein binding
And the properties of the patient dictate the drugs behaviour too, if they are a particularly soggy heart failure patient, liver failure or renally impaired, or if they are a monstrous weightlifter with enormous muscle mass.
Some Broad Examples of Drugs
Examples from Peck
- Pancuronium – highly charged, small VOD 17.5 litres. / 0.28L/Kg
- Roc is 0.2L/Kg (drugbank.com)
- Chloroquine (anti malarial) 10000 litres! (think intracellular sequestration)
To Sharpen this up
VOD is the apparent volume into which a drug disperses to produce a measured plasma concentration
VD = Dose / Plasma concentration at time zero
VD = 100mg / 1mg/L… VD = 100L
This equation relies on the simplified concept of a single physiological compartment.
Two different flavours of units have been given here, and this is because
L/kg means its indexed to a body mass
Litres means the volume it apparently disperses into, with no indexing to weight
Reality complicates this by adding more compartments in order to reflect it a bit more closely. Breaking it down into a plasma compartment / ‘central compartment’s a muscle or tissue compartment and a fat compartment….
But then you will have to think about how fast these compartments soak up drug, and drip drug back out into the circulation
TCI models make these headaches theoretically go away , check out polycompartmental madness episodes 1 and 2 for this in full pharmacokinetic its glory
These models think about these as compartments where drugs go quickly or slowly and their theoretical volumes of these compartments based on height weight age etc..
Model answer and Questions
Doctor: what do you understand about volume of distribution and how might it influence drug dose choice
- Volume of distribution is the apparent volume a drug rapidly diffuses into at administration to a patient at time zero. Volume of Distribution is calculated by dividing the quantity of drug dosed by the measured plasma concentration
- If the goal is to achieved a specific plasma concentration of a
- drug then the dose required to achieve that can be calculated if the volume of distribution of said drug is known.
What pathological states influence differences in volume of distribution (hepatic renal cardiac impairment fluid accumulation)
Young kids are watery relative to adults
Old people more fat,less water than their youthful counterparts (and have less albumin too)
Application clinically.
Can use VOD and patient information to identify a dose that will achieve a certain plasma concentration – and then know if this concentration is within the therapeutic window of the drug.
L/kg means its indexed to a body mass
can otherwise describe a litre volume it apparently disperses into.
Clinically, its use isn’t daily…. But having a grasp of VOD is the first step in perceiving the equilibrating nature of drugs introduced to people as infact there are a multitude of distributions dependent on all the differing tissues in a body system, those that are wetter, drier, fattier as well as the nature of their perfusion and if there are structural barriers to their diffusion (BBB).
And! extracorporeal sites of distribution (circuit, filters, oxygenator etc)
In Summary
VOD is a theoretical concept used to crudely explore the notion that drugs soak into people in different ways depending on the characteristics of the drug and the person.
It is a stepping stone to thinking about compartmentalising humans into their constituent fleshy parts. It can be used to calculate doses required to achieve target plasma volumes, but note that these calculations relate to time zero only, and this is a fairly pointless thing because as we all know that propofol with rapid bolus achieves unconsciousness until it rapidly redistributes in the human and that concentration in their plasma (and by extension in their brain) rapidly recedes unless you add more propofol to them.
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Transcript of Volume of distribution episode
Introduction and Podcast Overview
00:00-00:39
Please listen carefully. Hello, and welcome to Gas, Gas, Gas, your one-stop podcast for the FRCA primary exam. This podcast will fill your brain with information. Listen to it, think about it, and check out the show notes on the website. There you will find the core diagrams you need to be able to draw and describe for the exam. This podcast can squeeze into your day - listen while you’re driving to work, cooking dinner, maybe when you’re on call, or in the gym. Eventually the revision is going to end. But for now, expect facts, concepts, model answers and the odd tangent. Remember to rate and follow the show to hear much, much, much more.
Conceptual Understanding: Volume of Distribution as a Concept
00:39-01:39
Today in Gas, Gas, Gas we’re going to talk about volume of distribution. I remember that this originally really bamboozled me, because it seemed as if it didn’t really fit with reality. And then I realised that it doesn’t fit with reality because actually it’s a concept and a crude pharmacological mechanism for thinking about how drugs fill people up to varying degrees depending on the natures of the drug.
So volume of distribution is a concept, it’s not a reality. Very important distinction. It is a useful tool, however, because it allows you to think about how these drugs equilibrate throughout a human being, and these situations occur with volatile anaesthetics, opiates, propofols, any drug ultimately distributes throughout a human being in some way, shape, or form, and understanding that is important to its use.
Conceptual Model: Vessels and Compartments
01:39-02:58
So now that we understand that this is a concept and not a reality, we can create our own mechanism with which to think about it. And I initially think about these as a series of vessels within a human being. I think about the shot glass volume, the pint volume, the bathtub volume, and then the reservoir volume - really, really big.
I then think that each drug has a particular vessel that it likes to fit into, i.e., its volume of distribution, and that each patient ultimately is a mix of differing vessels, depending on if they are an Olympic swimmer - lots of muscle, not much fat - or an Olympic eater, still a fair bit of muscle to carry the weight, but a lot of fat with which drugs could soak into.
Physiological Correlates:
These concepts, these vessels, somewhat relate to the patient. So a shot glass, think about that as the patient’s plasma. The pint glass is their extracellular fluid. The bathtub, it’s all their fluid, including intracellular fluid, and the reservoir, the patient’s adipose tissue. This is one way of thinking about it.
You also might be tempted to divide it down into actually individual organs and their tendency to take up agent. That becomes more important when thinking about pharmacological models of drug distribution, i.e., TIVA. And that’s where volume of distribution is really important in understanding because then you’ve got to think about those fiddly models. More fudgery here and fudge factors.
Important Principle: VD Doesn’t Correlate with Physiology
03:00-03:24
Volume of distributions don’t correlate directly to any particular physiological volume in your human being, in your dog, in your cat, in your life form, because drugs dissolve and soak into varying vessels at different rates. Remember, we’re talking about these vessels as volumes, not the patient’s blood vessels.
Factors Influencing Volume of Distribution
03:24-04:54
We’re now into the meat of it, and we need to think about the factors that influence the volume of distribution.
Patient Factors:
I mentioned muscly people, fat people, you could also say exceedingly slim, cachectic people, old people and babies.
Drug Properties:
It’s important to consider how the drug might naturally dictate its behaviour throughout the patient, i.e., the lipid solubility of the drug, the molecular size, if it’s charged, what its pKa might be and subsequently how it might spread around people, and the plasma protein binding characteristics of the drug.
Pathological States:
As we mentioned, there are human properties that influence how the drug distributes throughout the person. It’s also important to think about pathological states that might influence drug distribution throughout the person. We mentioned cachexia just then, but also if patients are particularly soggy and water burdened, i.e., those with heart failure, those with liver failure, or renally impaired patient on ITU who is just about to go on the filter because they’re just one big human puddle.
And you could think about the weightlifter with a huge amount of muscle mass and things might behave a bit differently then, but it’s probably less of a thing.
Units and Practical Understanding
04:54-05:26
So I hope now we’ve got a bit of a grasp that volume of distribution is a fudge concept that goes on to think about other things in greater detail. It’s influenced by the characteristics of the human as well as the characteristics of the drug, and to also say that the units of volume of distribution also confused the crap out of me, because it comes in either a large litre number or a small litre per kilo number.
And it took me a while to figure out that they’re one and the same, but the thing perhaps like thirty litres per kilo, for example, as a random number out of the air. That’s an indexed volume of distribution to the weight of the patient, which might make it a bit simpler to comprehend.
Examples: Extreme Cases
05:26-06:12
A few quick examples of drugs with different volumes of distributions. These are lifted straight from PECK, which is an excellent pharmacology book that you should all read and not leave reading till the last minute because you are scared of it, like me.
So pancuronium, a very, very commonly used drug these days, it’s highly charged and has a small volume of distribution, so 17.5 litres or 0.28 litres per kilo, although, interestingly enough, drugbank.com suggests that rocuronium’s indexed litre per kilo is 0.2. So maybe we should have used rocuronium instead of pancuronium in PECK.
The counter to this, the other extreme, is chloroquine, an anti-malarial. It has a volume of distribution of ten thousand litres, and that’s because it is sort of soaked up intracellularly and it’s sequestered away, which makes it appear that it distributes into a far larger volume because of the measured concentration in the plasma once it’s all been sucked up.
Formal Definition and Formula
06:12-07:55
So lots of talking. And now the most important thing is what’s the definition? I’ve said loads of stuff.
So volume of distribution is the apparent volume into which a drug disperses to produce a measured plasma concentration, i.e., if you give them ten milligrams of Drug X and then immediately measure the plasma concentration of Drug X, and it is one microgram per mil, you can then use that to suggest how much space that drug has ended up dissolving into within the person.
The Formula:
The formula for volume of distribution - there are two depending on how you look at it, but the crux is the volume of distribution is equal to the dose given divided by the plasma concentration at time zero, i.e., you give that dose in one vein and then take a sample from another vein.
Time Zero Problem:
Technically at time zero, although as you can understand and consider as you drive, run, gym or sit listening to my dulcet tones elsewhere, clearly you can’t do it at time zero because if you did, the distribution would be ridiculous because it might not have got round yet. So I would argue that an arm-brain circulation time or two would have to occur for you to be able to measure something and then actually it’s not time zero anymore.
So that’s why this is a concept and not actually something you can apply really, really, really. But as you’ll come to find with a lot of the science behind anaesthesia, to actually truly explain how things work in a human being requires incredible levels of detail, and that’s excessive for what we need. And that’s why fudge factors exist.
Clinical Applications: TIVA Models
08:02-09:00
So to bring these concepts a little bit closer to reality in situations where we might use them, the one that immediately jumps to most people’s minds is TIVA. So we’re thinking about these models that try and figure out how much drug to give to achieve a certain concentration of the drug, either in the plasma or at a theoretical place within the model - at least the effect site, i.e., your CNS - and these utilise pharmacokinetic data.
Volumes of distribution, but also the rates at which the drug diffuses from the plasma to the muscle, from the plasma to the fatty bits, but also counter to that, the rate at which the drug diffuses from the fatty bits back into the plasma, which vary depending on how full those reservoirs within the body are.
So there’s a number of transfer rates to and fro as well as clearance from plasma into, for example, non-functioning metabolites - that is the exit point from your model.
Clinical Applications: Volatile Anaesthetics
09:00-10:23
Another situation to think about, which actually is probably something you’re going to be doing more of at the start of your training, is putting volatile anaesthetics into people, which also follows volume of distribution characteristics. And actually, you can see it in action much more than a TIVA model, because you’ve got to get a certain amount of drug into several compartments.
One of those compartments is your anaesthetic circuit, another compartment is the patient’s lungs, another compartment is the patient’s plasma, and another compartment is their brain and their fatty muscly bits.
Observable Example:
And you can see how this works, ‘cause they soak up sevoflurane real quick, and if you fill that circuit with plenty of sevoflurane, they’ll soak it up faster. But as they’re waking up, their MAC drops really quick ‘cause it dumps out of their plasma, dumps out of their brain and muscles, but then you get stuck at like 0.2-0.3 MAC for a bit and it slowly ekes out because that’s the rate at which the sevoflurane comes out of their fat compartment, into their plasma, into the lungs, and back into the circuit.
And you’re constrained by the diffusion rate from that final compartment. Unfortunately, that keeps your patient a bit anaesthetised for a bit longer.
And there you go, volume of distribution of a volatile anaesthetic in action with a compartment model that you can see and think about to try and manipulate to the best of your ability to try and wake your patients up faster, or finish writing your notes.
Model Answer: Clinical Application
10:23-13:16
Now’s the time of the podcast when we talk model answers, model questions. Remember, guys, I’ve prepared this. It’s not off the top of my head, so don’t stress too hard. Having a good grasp of these concepts is important, and here we go.
“Doctor, what do you understand about volume of distribution and how might it influence drug choice?”
“Hmm, okay, hello. Volume of distribution is the apparent volume a drug rapidly ends up in, or diffuses into, at administration to a patient at time zero. It can be calculated by dividing the quantity of drug dosed divided by the measured plasma concentration at time zero.”
Clinical Relevance:
“It could influence the choice of drug dose by enabling you to calculate how much is required to achieve a certain plasma concentration in a patient. If you are aiming for a specific window of therapy, this comes about a little bit when calculating gentamicin, but isn’t done in common practice.”
“You could rearrange that equation into volume of distribution times the measured or your target concentration equals drug dose, and you could use that to work out the dose of the drug. This isn’t really ever done. It’s already sort of been done for us by people figuring out how much drug achieves how much level of hypnosis, but for the purpose of modelling how the drug behaves inside the human over longer periods of time, i.e., keeping them asleep, that’s when it can be useful to think about it like that.”
Practical Understanding:
“So clinically, volume of distribution is not really used in a daily manner in its literal sense, but the concepts apply. When you give a drug, you have to think about how long it works for, how it redistributes and what behaviour it might elicit in your patient. And you’re thinking about that constantly, even though you’re not thinking, ‘Well, what’s my dose of drug concentration versus the volume of distribution, da da da da.’ You have a feel for it.”
“But being able to take that feel and put it down on paper in a structured manner, in a semi-scientific manner, is important. It’s the stepping stone to thinking about the pharmacokinetic models of TIVA and how sevoflurane behaves in a human, amongst some other drugs.”
Special Clinical Situations
13:16-13:43
“It’s also interesting to think about the fact that you might have other sites of distribution that are extracorporeal. We’ve talked about circuits. You could think about the filter in ITU for kidney replacement therapy or oxygenators in ECMO, or your bypass system - that could be an extra realm of space.”
“It’s also perhaps worth thinking about that if your patient exsanguinates, you’ve lost quite a lot of drug that’s floating around in them. This is important, particularly in obstetrics, where you might need to give a second dose of antibiotic if the patient has done a spot of exsanguination and you need to re-dose them to make sure that you reduce the odds of infection.”
Summary and Key Takeaways
13:43-14:09
“So in summary, volume of distribution is a theoretical concept. It’s used to crudely explore the notion that drugs soak into people in a varying number of ways dependent on the characteristics of the drug and the human. We could use it if we wanted to calculate doses and achieve therapeutic windows, although bear in mind that the concepts we’ve talked about here are only for single time points, so then it re-equilibrates and then it’s useless again.”
“If you want to go into a deeper dive, there’s loads of pharmacokinetics looking at the volume of distributions graphed over time, which is the stepping stone into these TIVA models.”
Conclusion and Call to Action
14:09-14:48
So thank you all for listening. I hope volume of distribution isn’t too heavy, and I hope I’ve managed to enable you to jump the gun on some of the awkward bamboozlements that I experienced, and you’re in a stronger position to learn it more quickly now by listening to this. Thank you very much for listening. Please like, subscribe, click the appropriate buttons at your leisure to say cheers, and I’ll see you for the next one.
I think we’re going to do pKa, another pharmacological concept. If you found it useful or awful, please like and subscribe and rate the show. Definitely check out the show notes for those diagrams and the details of this content. It is a bucket of content to get to grips with. Keep working at it and you will get better, faster, and stronger. It is vital to keep your interest alive for the science that we’re covering and not overcook yourself. You will be amazed by what you know come exam day. Don’t freak out, keep studying.
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