Class IV anaesthetic Chemistry Alkylphenol Routes of administration IV only Absorption Minimal oral bioavailability due to very high first-pass metabolism and high hepatic extraction ratio Solubility pKa 11; minimally soluble in water Distribution VOD=2-10 L/Kg; 98% protein-bound Target receptor GABA-A chloride channels, where propofol acts as a GABA-agonist Metabolism Metabolism is by glucouronide and sulphate conjugation, which happens mainly in the liver. Elimination All the metabolites are inactive and excreted renally, which can give the urine a healthy green tinge. Time course of action Bolus half life = 120 seconds
Half life from steady state = 5-12 hours
Mechanism of action Propofol binds to the β-subunit of the postsynaptic GABAA receptor, where it causes an inward directed chloride current that hyperpolarizes the postsynaptic membrane and inhibits neuronal depolarisation. Clinical effects
Anaesthesia, respiratory depression, decreased CMRO2, depressed cardiovascular reflexes. Also antipruritic and antiemetic effects.
Haemodynamic effects are largely indirect, i.e. the result of sympathetic depression.
- Stable cardiac output
- Decreased heart rate (blunted baroreceptor reflex)
- Decreased mean arterial pressure, mainly due to increased unstressed volume and decreased MSFP
- Decreased peripheral vascular resistance
- Decreased CVP
Direct effects of propofol on inotropy are minimal, at normal therapeutic doses.
Single best reference for further information Sahinovich et al (2018)
There is, in truth, no need to spend too long on making recommendations for further reading among peer-reviewed literature, because virtually everywhere you turn, there is an excellent article on propofol. There's one under every chair in the anaesthetics department. If a reader really needed something and were desperately trying to avoid a simple Google search, this paper by Sahinovich et al (2018) is a good representative of the genre.
The molecule of propofol is a sufficiently distinct structure that all should be able to recognise when they see it on a T-shirt. To be precise, what you are looking at here is 2,6 diisopropylphenol.
Raw untreated propofol is an oil with a slightly yellowish colour, which freezes near room temperature at 19°C. Chemically, it is a weak organic acid. The pKa is 11, so at pH 7.4 most of the drug is not water soluble, and needs some sort of other vehicle to carry it into the patient. This was originally somewhat difficult, as virtually all the non-polar solvent agents one might use to dissolve an oil like propofol have some kind of CNS activity themselves (looking at you, alcohol). At its initial commercial use, it was presented with a polyethoxylated castor oil, which was supposed to be relatively benign, but caused anaphylaxis in enough people that ultimately soybean oil was settled on as the vehicle.Thus, propofol is presented as a 1% emulsion of fat droplets in water, which give it the attractive milky colour by scattering light.
The vial contains:
Chemically, propofol is an alkylphenol; it is a phenol ring with two isopropyl groups. It would be pointless to describe other alkylphenols here, as that might present them as being somehow related to propofol, and they are clearly not - most are precursors in the synthesis of resins, adhesives, detergents or fuel additives. It would be better to discuss the hundreds of not-propofols which were tested in the course of many years by James & Glen (1980). Their paper is full of chemicals which did not make it, rejected for various very legitimate reasons (for example, profuse salivation, slow onset, or random chance of death with clinically relevant doses). The only chemically related drug which has entered common use is fospropofol, which is just propofol with a phosphate group substituted onto it. The whole point is that fospropofol is a water-soluble pro-drug, with various advantages of increased water solubility like for example no pain on injection.
Propofol has zero oral bioavailability; and in any case it is very bitter-tasting. It is invariably given intravenously.
Propofol is 98% protein bound, and it has the highest volume of distribution of any induction agent.
Now, this might make one ask, whether it is logical for a drug having high plasma protein binding to also have a small volume of distribution. Those proteins, one might point out, are all in the plasma, and therefore all the drug bound to them is also confined to the plasma. Following from this, propofol should have a very small volume of distribution, something like 0.1 L/kg. However, the known VOD of propofol is something like 2-10 L/kg. This because propofol, though avidly protein-bound in the circulation, is even more avidly lipid-bound, and distributes very effectively to every little droplet of triglyceride everywhere in your body. When Simons et al (1988) gave radioactive carbon-labelled propofol to volunteers, they found that within about 5 minutes the plasma concentration of propofol decreased to the point where its apparent volume of distribution was about 322 L on average, or 4.6L/kg for a 70kg person. Of the small amount of propofol remaining in the circulation at that stage, the vast majority (98%) would have been bound to protein.
Anyway. Onset of action is one arm-brain circulation. The propofol bolus doesn’t spend very long in the plasma compartment. It distributes rapidly to all fatty tissues. Usefully, that includes the brain. Propofol penetrates the placenta, but is usually held to be harmless for the foetus.
Context-sensitive half time after 3 hours of infusion is 10 minutes;
After 8 hours that rises to 30 minutes. And so on.
The context-sensitive half-time increases with prolonged infusions, as a massive cache of propofol builds up inside fat patients.
Metabolism is by glucouronide and sulphate conjugation, which happens mainly in the liver.
However, it seems the clearance rate exceeds hepatic blood flow, so there must be some extrahepatic site of metabolism. Furthermore, even people with moderate cirrhosis don’t seem to have much of a problem metabolizing normal quantities of propofol.
Clearance rate is rapid, 30-60ml/kg/min. That’s about 10 times faster than thiopentone.
CYP450 is the main enzyme system involved in this
40% is metabolised to a glucouronide
60% is metabolised to a quinol, which is then metabolised into a glucouronide and a sulfate.
All the metabolites are inactive and excreted renally, which can give the urine a healthy green tinge.
Clearance of propofol is decreased in neonates and the elderly.
Propofol seems to be a GABA receptor agonist, as far as anybody knows.
The non-sedation-related effects of propofol are:
The haemodynamic effects of propofol call for their own section, as they are often a stumbling point for young players. In their comments to the ancient Question 9(p.2) from the second paper of 2007, CICM examiners complained that "many candidates were confused by the direct versus the indirect cardiovascular effects" of propofol and ketamine. So, what are those effects, objectively, and why are they so confusing?
All people who have ever wielded propofol will immediately recognise that the use of this drug will make the blood pressure drop. To characterise this effect even further, De Wit et al (2016) performed some dose-response measurements on volunteers undergoing upper GI surgery. Their findings, and the meaty parts of their discussion section, are presented below.
As a general anaesthetic, propofol is indicated for the induction and maintenance of anaesthesia. The baseline dose is 2-3mg per Kg. This textbook number differs wildly from practical experience, because of massive individual variability.
Contraindications are all relative. For example, one would be reluctant to use vast amounts of propofol for a patient with severe haemodynamic instability, poor cardiac output, or shock. Broadly, it is contraindicated wherever any of the following are present:
The features of PRIS are :
A prelude to the bradycardia is a sudden onset RBBB with ST elevation in V1-V3; Kam’s article has the picture of this ECG. The mechanism is likely the inhibition by propofol of coenzyme Q and Cytochrome C.
This results in a failure of the electron transport chain, and thus the failure of ATP production.
In the event of such a breakdown of oxidative phosphorylation the metabolism becomes increasingly anaerobic, with massive amounts of lactate being produced. Furthermore, fatty acid metabolism is impaired- the conversion of FFAs to acetyl-CoA is blocked, and thus no ATP is produced by lipolysis. On top of that, unused free fatty acids leak into the bloodstream, contributing to the acidosis directly.
PRIS is more common in children. The treatment, unsurprisingly, is to stop the propofol. Charcoal hemoperfusion can be used to get rid of the excess fatty acids.