Propofol is quite insoluble in water. Originally developed by ICI (Imperial Chemical Industries) as ICI 35868, initial clinical trials followed in 1977 in a form solubilised in cremophor EL. However, due to anaphylactic reactions it was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water. This was re-launched in 1986 by AstraZeneca with the brand name Diprivan (shortened version of DI-isoPRopyl IV ANesthetic). The current preparation is 1% propofol, 10% soybean oil and 1.2% purified egg phospholipid (emulsifier), with 2.25% of glycerol as a tonicity adjusting agent, and sodium hydroxide to adjust the pH. Diprivan contains EDTA as an antimicrobial agent. Newer generic formulations contain sodium metabisulfite or benzyl alcohol. Propofol emulsion appears as a highly opaque white fluid due to the scattering of light from the tiny (~150 nm) oil droplets that it contains.
A water soluble form of the drug, propofol phosphate or Fospropofol, has recently been developed and tested in animals with positive results, being rapidly broken down once in the body by the enzyme alkaline phosphatase to form propofol. Marketed as Aquavan, this new formulation might well have superior properties for use in humans such as being more readily injectable and perhaps without the pain at injection site that often occurs with the traditional form of the drug.
Propofol is highly protein bound in vivo and is metabolised by conjugation in the liver. Its rate of clearance exceeds hepatic blood flow, suggesting an extrahepatic site of elimination as well. Its mechanism of action is uncertain, but it is postulated that its primary effect may be potentiation of the GABA-A and glycine receptors, possibly by slowing the channel closing time. Recent research has also suggested the endocannabinoid system may contribute significantly to propofol's anesthetic action and to its unique properties.
The elimination half-life of propofol has been estimated to be between 2–24 hours. However, its duration of clinical effect is much shorter because propofol is rapidly distributed into peripheral tissues. When used for IV sedation propofol typically wears off in minutes. Propofol is versatile; the drug can be given for short or prolonged sedation as well as for general anesthesia. Its use is not associated with nausea as is often seen with opioid medications. These characteristics of rapid onset and recovery along with its amnestic effects have led to its widespread use for sedation and anesthesia.
Aside from the hypotension (mainly through vasodilatation) and transient apnea following induction doses, one of propofol's most frequent side effects is pain on injection, especially in smaller veins. This pain can be mitigated by pretreatment with lidocaine. Patients tend to show great variability in their response to propofol, at times showing profound sedation with small doses. A more serious but rare side effect is dystonia. Mild myoclonic movements are not uncommon, as with other intravenous hypnotic agents. Propofol appears to be safe for use in porphyria, and has not been known to trigger malignant hyperpyrexia.
Another recently described rare, but serious, side effect is propofol infusion syndrome. This potentially lethal metabolic derangement has been reported in critically-ill patients after a prolonged infusion of high-dose propofol in combination with catecholamines and/or corticosteroids.
Abuse of propofol as a recreational drug has been reported, usually among medical staff such as anaesthetists who have access to the drug. Despite a lack of analgesic properties, propofol's sedative action presumably produces euphoric effects. The steep dose response curve of the drug makes such abuse very dangerous without proper monitoring, and several deaths have been recorded.
Propofol and midazolam versus propofol alone for sedation following coronary artery bypass grafting: A randomized, placebo-controlled trial
Apr 01, 2002; SUMMARY The aim was to compare the efficacy and side-effects of Propofol combined with a constant, low dose of midazolam...