Propofol

Propofol is a short-acting intravenous anesthetic agent used for the induction of general anesthesia in adult patients and pediatric patients older than 3 years of age; maintenance of general anesthesia in adult patients and pediatric patients older than 2 months of age; and sedation in medical contexts, such as intensive care unit (ICU) sedation for intubated, mechanically ventilated adults, and in procedures such as colonoscopy. It provides no analgesia.

Propofol is approved for the induction and maintenance of anesthesia in more than 50 countries.

It is also commonly used in veterinary medicine and many veterinary anaesthetists regard it as the induction agent of choice for small animals (dogs, cats etc) as it can be administered to effect, reducing the risk of accidental overdose.

Chemistry


Propofol is a water-immiscible oil and so cannot be injected per se. 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 However, due to anaphylactic reactions it was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water.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, has recently been developed and tested in animals with positive results, being rapidly broken down once in the body to form propofol. 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. Fospropofol disodium is rapidly converted into propofol by the enzyme alkaline phosphatase, and is now being developed for human use under the brand name Aquavan.

Pharmacology
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 receptor, 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, and its effects therefore wear off considerably within even a half hour of injection. This, together with its rapid effect (within minutes of injection) and the moderate amnesia it induces makes it an ideal drug for IV sedation.

Side effects
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 by medical staff such as anaesthesiologists 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. It has been rumored and not verifed that Michael Jackson was injected with propophol.