This chapter is relevant to the aims of Section K2(i) from the 2017 CICM Primary Syllabus, which expects the exam candidate to demonstrate an understanding of the pharmacology of sedating drugs". Propofol is a staple of ICU sedation, and one would do well to become very familiar with its properties. This importance is reflected in the numerous questions on propofol from the Part One exam, which often ask the candidates to compare between propofol and another CNS depressant:
  • Question 9 from the second paper of 2019 (propofol vs midazolam)
  • Question 11 from the second paper of 2017 (propofol alone)
  • Question 14 from the second paper of 2015 (propofol alone)
  • Question 21 from the second paper of 2013 (propofol alone)
  • Question 5 from the first paper of 2012 (dexmedetomidine vs. propofol)
  • Question 7 from the second paper of 2010 (ketamine vs propofol)
  • Question 9(p.2) from the second paper of 2007 (ketamine vs propofol)

In summary:

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.

Chemical properties and molecular structure of propofol

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:

  • 1% propofol (10mg/ml)
  • 10% soybean oil
  • 1.2% purified egg phospholipid, a yolk component (people are usually not allergic to this; egg allergy is usually an allergy to egg albumin)
  • 2.25% glycerol, to adjust tonicity
  • Sodium hydroxide is also present to keep the pH between 6 and 8.5.
  • Sodium EDTA (Ethylenediaminetetraacetic acid) – as an antimicrobial additive, a minute amount.

Chemical Relatives


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. 

Administration and Absorption

Propofol has zero oral bioavailability; and in any case it is very bitter-tasting. It is invariably given intravenously.  

  • Bolus volume of distribution    = 4.1L/Kg
  • Steady state volume of distribution = 2-10 L/Kg
  • Bolus half life = 120 seconds
  • Half life from steady state = 5-12 hours

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.

Distribution of a propofol infusion

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 and Clearance

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.

Mechanism of action

Propofol seems to be a GABA receptor agonist, as far as anybody knows.

Effects of propofol

The non-sedation-related effects of propofol are:

  • Antiemetic – perhaps due to a dopamine (D2) receptor antagonism.
  • Antihistamine, antipruritic
  • Anticonvulsant?.. some choreiform movements have been observed, with opisthotonos. That’s all probably due to a subcortical glycine antagonism. Propofol does antagonize tonic-clonic seziures.
  • Cerebral blood flow is decreased: this could be good or bad.
  • Dose dependent respiratory depression – more than thiopentone
  • Decreased tidal volume and increased respiratory rate
  • Impaired or even completely abolished response to hypoxia and hypercapnea
  • Bronchodilation
  • Depressed laryngeal reflex
  • Green urine, as well as potentially green hair:  due to the phenols

Circulatory effects of propofol

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. 

  • Decreased preload, mainly due to sympathetic inhibition. Venous vascular resistance decreases with propofol, and as the result the walls of the venous compartment put less pressure on the venous volume. ​​Mean systemic filling pressure therefore also decreases. This appears to be an effect exerted by the sympathetic nervous system. In experiments by Hoka et al (1998), the propofol-induced change in MSFP was no longer apparent in animals whose sympathetic nervous system was blocked by hexamethonium.
  • Decreased afterload: systemic vascular resistance decreases with propofol. When Boer et al (1990) gave it to patients on a constant flow bypass pump, their SVR dropped by about 30%. To determine whether this is a direct vasodilator effect or some kind of sympatholytic voodoo, Robinson et al (1997) gave propofol directly into the forearm arteries of volunteers and found that it did absolutely nothing despite the presence of therapeutic plasma concentrations of propofol within the forearm. In short, arterial vasodilation is the effect of the sympathetic nervous system being turned off, and not a direct effect of propofol.
  • Maintained contractility  is observed by virtually all investigators, though classical textbooks tend to ascribe some sort of direct negative inotropic effect to propofol. The problem is separating the  direct effects of propofol on the heart from the direct effects of propofol on the sympathetic nervous system. One way would be to take whole denervated hearts or myofibrils. Sprung et al (2001) did exactly that. Sure, they found negative inotropic effects, but at propofol concentrations which are comically unlikely in clinical practice. Consider: the normal serum concentrations of propofol are around 44 μmol/L after bolus injection and 10 to 20 μmol/L during maintenance infusion. Sprung et al found that contractility of isolated cardiac myocytes tends to decrease by about 10% at doses of around 56 μmol/L, and by 20% at a preposterous 5.60 μmol/L (think of a 2000mg bolus). But that's a bunch of cardiac myocytes suspended in a nutrient goo. Add sympathylytic effects, decreased preload (but decreased afterload), and the picture becomes complicated by the interplay of conflicting and cooperating factors.
  • Net effect on cardiac output is minimal: Preload decreases, but so does afterload, and in the absence of much change in contractility the overall effect on the cardiac output is rather small. In fact, De Wit et al did not find any effect whatsoever, and made much of this fact ("Several textbooks describe a propofol-induced decrease in CO after an induction dose...  We show that this does not occur with a wide range of propofol effect site concentrations").
  • Decreased blood pressure is therefore the consequence of a decreased stressed volume in the presence of an unchanged cardiac output.

Indications and contraindications

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:

  • Extreme haemodynamic fragility
  • Allergy to any of the ampoule contents
  • Ridiculously high serum triglycerides
  • Very high intracranial pressure


  • Some say, co-induction with midazolam and propofol has a synergistic effect.
  • Some also say that with fentanyl or alfentanil, the opisthotonic rigidity is worse.

Chronic Toxicity: Propofol Infusion Syndrome (PRIS)

  • This tends to happen after about 48 hours of propofol infusion, at over 4mg/kg/hr (that is around 28ml/hr of straight propofol, for a normal 70kg male)

The features of PRIS are :

  •     Acute bradycardia leading to asystole
  •     Heart failure, cardiogenic shock
  •     Metabolic acidosis (HAGMA)
  •     Rhabdomyolysis
  •     Hyperlipidaemia
  •     Fatty liver

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.


Sahinovic, Marko M., Michel MRF Struys, and Anthony R. Absalom. "Clinical pharmacokinetics and pharmacodynamics of propofol." Clinical pharmacokinetics 57.12 (2018): 1539-1558.

James, Roger, and John B. Glen. "Synthesis, biological evaluation, and preliminary structure-activity considerations of a series of alkylphenols as intravenous anesthetic agents." Journal of medicinal chemistry 23.12 (1980): 1350-1357.

Goodchild, C. S., and Juliet M. Serrao. "Propofol-induced cardiovascular depression: science and art." BJA: British Journal of Anaesthesia 115.4 (2015): 641-642.

De Wit, F., et al. "The effect of propofol on haemodynamics: cardiac output, venous return, mean systemic filling pressure, and vascular resistances.British Journal of Anaesthesia 116.6 (2016): 784-789.

Hoka, Sumio, et al. "Propofol-induced increase in vascular capacitance is due to inhibition of sympathetic vasoconstrictive activity." The Journal of the American Society of Anesthesiologists 89.6 (1998): 1495-1500.

Sprung, Juraj, et al. "The effects of propofol on the contractility of failing and nonfailing human heart muscles." Anesthesia & Analgesia 93.3 (2001): 550-559.

Boer, F., et al. "Effect of propofol on peripheral vascular resistance during cardiopulmonary bypass." British Journal of Anaesthesia 65.2 (1990): 184-189.

Robinson, B. J., et al. "Mechanisms whereby propofol mediates peripheral vasolidation in humans: sympathoinhibition or direct vascular relaxation?." The Journal of the American Society of Anesthesiologists 86.1 (1997): 64-72.

Piriou, V., et al. "Effects of propofol on haemodynamics and on regional blood flows in dogs submitted or not to a volaemic expansion." European journal of anaesthesiology 16.9 (1999): 615-621.

Simons, P. J., et al. "Disposition in male volunteers of a subanaesthetic intravenous dose of an oil in water emulsion of 14C-propofol." Xenobiotica 18.4 (1988): 429-440.