This drug is a staple of ICU sedation, and one would do well to become very familiar with its properties.

Chemical properties and molecular structure

2,6 diisopropylphenol is an alkylphenol;  it is a phenol ring with two isopropyl groups.


Chemically, it is a weak organic acid. The pKa is 11, so at pH 7.4 most of the drug is fat-soluble.
Thus, 90% is not ionized at a physiologic pH.

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


Alkylphenols are a diverse group. 

The only chemically related one 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.  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

It is 98% protein bound.

Thus, it has the highest volume of distribution of any induction agent.

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-life after 3 hours of infusion is 10 minutes;
After 8 hours that rises to 30 minutes. And so on.
The context-sensitive half-life  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

Well, it’s a general anaesthetic. However, propofol also has numerous non-sedation-related effects:

    • 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


      • Impaired or completely abolished the arterial baroreflex response to hypotension;
      • This means, a shocked patient who is compensating for their shock will stop compensating, and crash hideously on induction.
    • Dose-dependent decreased heart rate and decreased cardiac output
    • Dose-dependent vasodilation and hypotension – more than thiopentone

Indications for Use

  • For induction of anaesthesia:
      • The baseline dose is 2-3mg per Kg. This textbook number differs wildly from practical experience, because of massive individual variability.


  • Hemodynamic instability, poor cardiac output, or shock.
  • 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.

Acute Toxicity and Overdose

  • One can imagine that these would be largely sedation-related.
  • One would manage such an event by completing the process of anaesthetic airway control and ventilation.


A lot of this information comes from “Goodman & Gilman's The Pharmacological Basis of Therapeutics” 11th ed by Brunton et al, and   “Basic & Clinical Pharmacology” 11th ed. By Katzung et al.


There is a chapter devoted to propofol in the excellent “Clinical Anaesthesiology “  by Morgan Mikhail and Murray.


There is a good article about propofol clearance.


Furthermore, the ever-so-helpful AstraZeneca people have a PI document in PDF for you to read.


Propofol infusion syndrome is well covered by Kam (Yes, THAT Kam)