Ep 2 – Propofol for the FRCA Primary

What is Propofol?

Propofol is a short-acting intravenous anesthetic agent used for the induction and maintenance of general anesthesia. It acts by enhancing GABAergic inhibition in the central nervous system, leading to sedation and hypnosis.

Propofol Pharmacology

• Name – Propofol
• Class – Phenol Derivative
• Chemical name – 2,6 di-isopropyl phenol
• Colour / appearance – White Opaque Liquid
• Additives – Egg Phosphatide and Soy Bean Oil
• Presented in 20 ml, 50ml or 100ml ampoule/bottle – Concentration 1 or 2 %
• Dose & route : Intravenous 1 – 2 mg/kg – Plasma conc. of 4-8 mcg/ml maintains anaesthesia
• History – Brough to market in 1986!

Pharmacodynamics of Propofol

• Mechanism: Potentiates endogenous GABA, although true mechanism not fully clear
• Actions: Hypnosis that is dose dependent – Will terminate epileptic seizure activity.
• Onset and Offset times: Onset is greater than one arm brain circulation – Offset is dependent on infusion time, a bolus dose will redistribute and offset within 10 minutes, clearance dependent on cardiac output, chiefly hepatic, but some renal too.

Side effects of Propofol

• CVS: Sympathetic inhibition – dropped venous tone – less pre load, dropped arterial lone, less SVR.
  • Cardiac output remains somewhat unaltered as these changes facilitate forward flow. But perfusion pressure across the system drops. It causes some myocardial negative inotropy but barely.
  • Arterial Vasodilation , myocardial depression, very rarely bradycardia
• RESP: Apnoea, laryngeal reflex obtundation, some bronchodilation
• CNS: coma, reduced cerebral o2 demand, reduced ICP/IOP Up to 10% can have paradoxical excitatory movements.
•  Due to inhibition of inhibitory structures, I think of it like, the drug doesn’t get to all the bits of the brain at the same rate, and parts are probably more susceptible than other parts.
• Metabolic : Infusion syndrome. High triglycerides, metabolic acidosis, arrythmias, renal failure, rhabdomyolysis
• Others: Pain on injection

Pharmacokinetics of Propofol

Absorption Not relevant as IV, note arterial injection is not a disaster – just onset time prolonged.

Propofol Distribution

• VOD 4 L/KG (highest of any induction agent) 
• Protein binding 98%   
• pKa 11 – 98% unionised at pH7.4
• Rapid redistribution occurs due to its lipid solubility, (it quickly gets into the brain) but as plasma levels drop it will begin to equilibrate across multiple tissues and organ systems and the CNS concentration will decline to sub clinical levels.

Propofol Metabolism

• Half-life 9.3 – 60 mins
• Liver metabolism to non active metabolites that are really cleared 40% conjugated to glucuronide and 60% metabolised to quinol which gets sulphated and excreted in urine
• Clearance exceeds hepatic blood flow suggesting some extra hepatic metabolic effects.

Elimination – Clearance 18.8 – 40.3 ml/kg/min

Noteables

• Long infusions exhibit progressively lengthening context sensitive half times – think, if you have managed to fill their fat stores which takes time to get in and time to get out.
• In kiddies – it appears that they are more prone to propofol infusion syndrome and its considered somewhat contraindicated in sub 16 year olds for PICU sedation
• Intra arterial injection leads to slower onset times, but no particular sequelae.

What is Propofol Infusion Syndrome?

Aka PRIS, an over zealous and prolonged infusion of propofol can lead to a state of significant metabolic derangement, where the electron transport chain in the mitochondria struggles to function,( at least this is demonstrated in animal models on all 4 elements of the electron transport chain I, II, III and IV) There are a few suggested mechanisms, but it appears that the propofol impersonates co-enzyme Q and this is critical for mitochondrial function.

It results in a developing metabolic acidosis, hyperkalaemia, rhabdomyolysis, and subsequent renal failure.

Can get Brugada like ECG changes (Coved T-wave with STE)

It is notably a cause of green urine (quinol, the metabolic product of propofol metabolism is has a green hue???

Blood tests should check creatinine kinase alongside plasma triglycerides

The state can be predicted based on the dosing to body weight that occurs, and monitoring plasma triglycerides can go some way to act as a warning sign of excess.

Prolonged infusion should not exceed 4mg/kg/hour

Historic fatality appears to be around 35% (earlier in time was very high, on negative trend)

This happens with propofol, and not with equivalent intralipid dosages (but remember high lipids can trigger a acute pancreatitis)

Treatment = stop the drug, supportive treatment

Core Concept

Ionisation has relevance across many different drugs. check out the PKA episode for the full low down!

The core of it, an ionised drug is unable to cross the fatty membranes that encapsulate cells, of the CNS / PNS

Therefore the degree of ionisation relates to how prompt to act a drug might be, the greater the unionised fatty soluble fraction the quicker it diffuses to where it needs to go.

There is an intrinsic balance of the molecule between these two states that is dictated by the environment within which it exists, the main factor that influences this is the pH. (The negative log of the concentration of hydrogen ions in a system/solution.)

And the way this ratio / balance is described in pharmacology is the pKa of the drug.

In a hypothetical system a drug with a pKa of 7.35 will, have a 50:50 mix of ionised to unionised molecule if the system is at pH 7.35

If you imagine a membrane that has a different pH environment on one side vs the other,

And have a drug that becomes unionised in acidic environments, it can cross the membrane, become ionised again and loose its ability to escape back across the membrane. (some drugs exhibit ion trapping on the fetal side of the placenta which is a more acidic realm)

Application clinically.

Starting out – work out a dose and see if it works…. Can always give more and in big ‘rugby’ lads, alcoholics who are not drunk or those with other alternative life styles, always worth having a second syringe drawn up.

Is synergistic with other sedating agents – midazolam, fentanyl clonidine/dexomedetomidine

And is often given alongside ketamine to stop a patient ‘having their eyes open when they shouldn’t when you’ve GA’d with ketamine…… ‘

TCI and TIVA is the future!

In resus once a patient is intubated, often starting at 10ml an hour of propofol and ramping it up as able into the 20s, as it takes a fair while to reach steady state if there is not a loading bolus. This approach does carry an increased risk of awareness, and in non-obtunded poorly patients you would run the risk of this. Remember depth of anaesthesia depends on the level of patient consciousness and the level of drug administered. Someone who was GCS 3 from an opiate overdose, will need initially fairly sparse amounts of propofol, but as the agent wears off you must escalate propofol. you do not want someone waking up 2 hours later and self-extubating on ITU whilst you are busy elsewhere!

What is that Propofol TCI formula??

TIVA protocol when you’ve not got a PK Pump with Schneider/Marsh/Eleveld

• 10 mg kg/h for 10 min,
• 8 mg kg/h for a further 10 min
• Then Continuous infusion of 4-6 mg kg/h

In Neuro head injured type patients, get them deep (30ml/hour propofol) and expect to be starting a metaraminol infusion alongside – the goal is to turn off their brain, and if you put a BIS on, you might be surprised at how not deep a fit young person is! Watch how much propofol you get through using Marsh Tiva on a 30 year old ! (although the counter point here is, a sedated extra dural patient who is being transferred, is yet to have a surgeon operating on them)

Great Drug, excellent obliteration of laryngeal reflexes, makes LMA/SGA/Auragain insertion very manageable (if you tried it with thiopentone, it would not go so well), if you’re interested Check out the Thiopentone Episode too!

References

Krajčová, A., Waldauf, P., Anděl, M. et al. Propofol infusion syndrome: a structured review of experimental studies and 153 published case reports. Crit Care 19, 398 (2015). https://doi.org/10.1186/s13054-015-1112-5

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“Thanks for listening guys… Every day you are getting better at this. Take it day by day, don’t overcook yourself, don’t freak out, and keep studying!”

Podcast Information

TRANSCRIPT Propofol – Gas Gas Gas Podcast for FRCA Primary

Introduction and Podcast Overview

00:00-00:33

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.

Topic Introduction: Propofol Overview

00:34-01:00

Hello, everyone. It’s James here at Gas Gas Gas. Today we’re going to talk about propofol. It is the most commonly used anaesthetic induction agent in the UK. You’ll find its use in induction in theatres, sedation in A&E resus, maintaining sedation in ITU patients. Very common. You will be already, or very soon to be, familiar with it.

Exam Strategy and Structured Learning Approach

01:00-02:00

Today’s focus, as always, is on the exam, and odds are someone’s going to ask you about propofol or there might be the odd question on propofol. We’ve already covered a podcast on rocuronium, where there was an introduction to how to go about learning the information required for these drugs in a structured manner, and also then how to perhaps begin delivering it in an exam.

There’s a strong chance you might start your spiel, get to a certain point, and they catch you and say, “Ah, tell me more about the distribution profile of propofol in TCI,” and then you might take a different tangent. But it’s generally a good idea for all the core drugs to learn this spiel so that you have a solid grounding in the information about the drugs, and therefore, you could go about applying this information in a multitude of different manners throughout your career.

They don’t just want someone who can verbatim regurgitate information, but also understand why certain things are relevant in certain drugs in their utilisation day to day.

Model Answer Structure Framework

02:00-05:01

So, getting on with it, when you’re giving a model answer to “tell us about so-and-so the drug,” there’s an approach that you’ll be able to see on the show notes for this podcast. But broadly speaking, you name it, you define its class. If it’s got a particular chemical name, you can throw that out there. For propofol, that’ll be 2,6-diisopropylphenol.

I’m pretty sure there was a question either, I think, in one of the question banks or in one of the books – it wasn’t in my exam – which was “tell us about the pKa” or “what is the pKa of 2,6-diisopropylphenol?” Knowing that you wouldn’t have a Scooby-Doo unless you knew that propofol’s other name. So it is worth knowing, especially for the very, very commonly used drugs, because they expect a high degree of knowledge. They’re not going to ask you about vecuronium in quite the same detail, because that’d be mad.

So we’d go: name, class, chemical name, and then the colour and appearance. So this is a clear colourless solution, or this is a white liquid that comes in ampoules of twenty mils at 1% concentration. What additives might be found or how it’s presented. So you know thio is in that nitrogenous atmosphere; propofol has egg phosphatide and soybean. So you’re going to say important additives to know are blah. And then if it comes in multiple concentrations, demonstrating that you know there could be some 2% propofol, and you certainly wouldn’t want to mix that up with 1%. You’d find yourself in a lot of bother.

There may be some particular numbers relevant more so for your volatiles, like what the MAC is, what the blood gas and oil gas coefficients might be, what the boiling point of saturated vapour pressure might be. Good luck. And then dose route. So is it IV? Is it transdermal? Can you shoot it up someone’s nose? Is it intramuscular? And then a general dosage range is a worthwhile thing to be able to say about it as well: one to two milligrams per kilo in propofol, for example, depending on the age and shape, etc., of your patient.

Then you’re going to want to continue this structured approach and talk about the pharmacokinetics and the pharmacodynamics. So remembering that kinetics are absorption, distribution, metabolism, and elimination. And the dynamics being how it works, what actions it’ll have – how it works and what effects it will have on a person, the onset and offset times for the effects of the drug to take place, and then side effects of the drug. You should subdivide side effects into cardiovascular, respiratory, GI, neuro, metabolic for drugs that have a broad range of side effects, so you don’t forget stuff and that you look structured.

If you get asked about a drug in an exam and you start doing all that, you’ll be alright. They won’t just want you to vomit information, though. It’ll be: “tell us about a drug.” And then they’ll ask you, “Well, okay, so talk me through how anticholinesterases are used to reverse neuromuscular blockade. Why don’t we always use sugammadex?” Something like that.

So we’re going to get on with the model answer now. So I’m going to vomit this model answer at you. It’s worth listening to just because you’re going to pick up some information. I’m not doing this from memory; I’ve got it written in front of me, so don’t stress about that. You will develop these skills.

Complete Model Answer: Propofol

05:01-09:37

So, Doctor, tell me about propofol.

Propofol is a phenol derivative. Its chemical name, 2,6-diisopropylphenol, is a commonly used anaesthetic induction agent. Its appearance is of a white opaque liquid, presented in twenty, fifty mil or one hundred mil ampoules or bottles, at a concentration of 1% or 2%. Additives of note are egg phosphatide and soybean oil, although these aren’t often terribly implicated in allergy in patients.

It is an intravenous drug dosed at one to two milligrams per kilo, sometimes more if they are very large or an alcoholic, aiming for a plasma concentration of like four to eight mics per mil. That’ll maintain anaesthesia during operation. More relevant in TCI…

Pharmacodynamics

Considering the pharmacodynamics of propofol, its mechanism: it likely potentiates endogenous GABA. The true mechanism of action of how it induces hypnosis is not entirely elucidated. Its actions are hypnosis that is dose-dependent. It also is a useful antiepileptic in status epilepticus when inducing anaesthesia. Its onset time is greater than one arm-brain circulation, about thirty to forty seconds. Offset is dependent on infusion time. A bolus dose redistributes quite quickly, offsets within ten minutes or so. Larger doses or prolonged infusions are going to take longer to wear off.

Side Effects

There are some important side effects to consider with propofol. Cardiovascularly, it inhibits sympathetic activity, leading to a drop in venous tone, i.e., less preload. A drop in arterial tone, leading to less systemic vascular resistance. Cardiac output is somewhat preserved, but these changes lead to a drop in perfusion pressure across the system. Cardiac output is relatively preserved. It is also a myocardial negative inotrope, but not very much.

From a respiratory perspective, propofol causes apnoea. It also will obtund laryngeal reflexes, highly useful in siting LMAs, and causes a degree of bronchodilation.

Its CNS effects naturally induce hypnosis. Looking at it from a physiology perspective, it reduces cerebral oxygen demand. It leads to a reduction in intracranial and intraocular pressure. Some patients – ten percent of them – have paradoxical excitatory movements at induction. This is likely due to inhibition of inhibitory structures within the brain.

Just for you guys, I like to think that the drug doesn’t get to all the parts of the brain equally, and also some parts of the brain are more susceptible than other parts. You’ve probably seen them get a bit stiff looking straight up at you, been a bit freaked out that the patient is looking at you and they should be falling asleep with propofol. And you could also think about it as it’s like the excitatory phase of a gas induction. They’re not quite deep enough that you’ve anaesthetised all of their brain, so they get a bit wriggly and disinhibited. Anyway, moving on.

Metabolic Effects

Continual infusions of high-dose propofol leads to propofol infusion syndrome. This is characterised with high triglycerides, a metabolic acidosis, arrhythmias, rhabdomyolysis and renal failure, and it’s fairly bad news.

Other things of note: it does sting on injection. This can be countered with some lidocaine or the use of a larger vein.

Pharmacokinetics

From a pharmacokinetic perspective, it’s not an orally administered drug, so I’m not concerned about absorption. From distribution perspective, it’s got a high volume of distribution relative to other induction agents at four litres per kilo. It is ninety-eight percent protein bound, again the highest of all the induction agents, and a pKa of 11, the highest of all induction agents, leading to it being 98% unionised at a pH of 7.4, which is very conveniently going to mean that there’s a lot of agent available to cross membranes and have positive effects leading to hypnosis.

Its lipid solubility does, however, mean that it’s going to rapidly redistribute to other organ systems and tissues, hence why actually the offset time of a single bolus is quite short.

From a metabolic perspective, the half-life ranges from 9.3 to 60 minutes and is quite context-sensitive. It’s metabolised by the liver. Forty percent is conjugated to a glucuronide. Sixty percent is metabolised to quinol, which then gets sulphated and excreted in urine. The clearance, though, does exceed hepatic blood flow, and this suggests that there’s some extrahepatic metabolism also occurring alongside. Its clearance could be considered as a range between 18 to 40 mils per kilo.

Clinical Considerations and Practical Use

09:37-10:45

The key things to tell you when we’re using propofol is that in sick people it is remarkably good at dropping blood pressure, and you’d be rather mad to be using it as an induction agent in someone who’s awake, who needs to be asleep when their blood pressure is crap, because a sufficient amount to get them off to sleep is probably a dangerous amount.

If they’ve got low blood pressure, other drugs like ketamine, you could talk about etomidate, but nobody uses it, or taking a very midazolam-fentanyl heavy with a whiff of propofol approach would be safer than a standard fentanyl “night-night” sort of picture.

It can also be used for brief sedation with boluses, TCI sedation, which is probably actually easier to manage than to bolus it. If you’re doing a cardioversion, just use it. I tend to give 10 to 20 milligram aliquots and give it plenty of time to work because they’re probably in AF. Expecting a dose range depending on how frail the patient is from like 40 to 100 milligrams of propofol to achieve enough sedation that they stop responding to voice, then you zap them.

Deep Dive: pKa Explanation

10:45-12:50

So the examiners then might say “You mentioned pKa. Could you explain this in further detail for us, and in what other drugs it might bear relevance to function?” And you go, “Oh god, yeah, alright.”

So I’m going to tell you that pKa is a way of putting a number on the water-lipid dissociation coefficient relative to the pH of a system. Don’t forget to also consider the pure definition of pKa, which is that number relates to the pH at which the agent in question is in a fifty-fifty ionised-unionised state.

So with propofol, the pKa is eleven, which is far away from a physiological pH. And at pKa, if you were to take that propofol and put it into a liquid that had a pH of eleven, fifty percent of that propofol would be unionised and fifty percent of it would be ionised.

The ionised element is kind of useless from a pharmaceutical, pharmacological perspective. Can’t do anything when it’s ionised because it won’t cross membranes because they’re negatively charged. This is why pKa is relevant, because, as you can imagine, if you have a larger fraction of unionised agent lurking in the plasma trying to get to its effect site, it’s gonna get there quicker.

So, taking that propofol with a pKa of 11, which is the highest pKa of the induction agents, and putting it in a pH 7.4, 98% of it is unionised, so there’s a huge amount of molecule that is quite highly lipid-soluble now, wants to get across those membranes, is going to get where it needs to go.

This is also a way to think about how other drugs work, and it is relevant to many other drugs. The opiates, it’s very important to learn the pKas of them, as well as your local anaesthetic agents, which have varying pKas that lead to varying amount of agent available to cross that membrane in your neurons and influence those sodium channels. pKa is one of the direct influences of onset time. The more unionised, the faster the onset.

Clinical Experience and Dosing Considerations

12:50-14:18

So, I remember my very first day of anaesthesia. I was with an anaesthetist who just handed me some drugs and went, “Go on, then.” Obviously that on reflection was ridiculous, but we got on with it, and I gave a one point eight milligram per kilo dose or so to the patient.

Nowadays I don’t think about the dose more than I look at the shape of the patient, the age of the patient, their alcohol consumption or other illicit drugs use, how anxious they are, how half asleep they are if it’s a fractured neck of femur patient who’s already hypoactive delirious, and use all these things to weigh up the dose I’m going to give.

It’s always better to start with a smaller amount and work your way up. You don’t want to find yourself in limbo where a patient’s flailing and a bit disinhibited but not actually anaesthetised, although that’s quite a rare situation. It’s much better than finding yourself with a systolic that’s fifty and having to do something stupid like CPR or give adrenaline because you’re a bit heavy handed.

Propofol is really synergistic with other drugs, especially if you let those other drugs work sufficiently, i.e., fentanyl and midazolam. If you get them in and let them work for at least five minutes, then the induction dose of propofol is markedly reduced.

Target Controlled Infusion (TCI) Concepts

14:18-15:00

The other thing I want to make you aware of, although you’re going to need to read and learn about it or listen to a future podcast, is the pharmacokinetics of a target controlled infusion of propofol. These use models to understand how big the wet bit, how big the fatty bit, how big the effect site bit, and the muscly bit of a patient might be, and then work out how the propofol shifts between all these different compartments to try and project a plasma and subsequently an effect site concentration to keep someone asleep with a propofol infusion.

It’s quite a long topic, so we’re going to do it later. But also bear in mind that there is a bit of a back of a napkin TCI formula where you give ten milligrams per kilo for ten minutes, eight milligrams per kilo for another ten minutes, and then render a continuous infusion at six milligrams per kilogram per hour – all of those things – and titrate to how deeply the patient is.

Conclusion and Call to Action

15:00-15:45

So that is propofol with Gas Gas Gas. My name’s James. Thank you very much for listening. I hope you can go on to think about propofol and anaesthetic a range of kiddies to grannies today. Enjoy.

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 detail 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.