Propofol

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Propofol
Systematic (IUPAC) name
2,6-Diisopropylphenol
Identifiers
CAS number	2078-54-8
ATC code	N01AX10
PubChem	4943
DrugBank	APRD01201
ChemSpider	4774
Chemical data
Formula	C12H18O
Mol. mass	178.271 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	NA
Protein binding	95 to 99%
Metabolism	Hepatic glucuronidation
Half life	30 to 60 min
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	B (U.S.), C (Au)
Legal status	℞-only (U.S.)
Routes	Intravenous

Propofol is a short-acting intravenous nonbarbiturate sedative agent used for the induction of general anesthesia for adults and children, maintenance of general anesthesia, and sedation in medical contexts, such as intensive care unit (ICU) sedation for intubated, mechanically ventilated adults, and in procedures such as colonoscopy and endoscopy, as well as in dental surgery. Its widespread use as an anesthetic induction agent has largely replaced that of sodium pentothal. Although propofol is not considered an analgesic drug,^[1] one study has found a lower incidence of postoperative pain after propofol anesthesia compared to anesthesia with inhalation agents.^[2] Propofol is approved for use in more than 50 countries. It is also commonly used in veterinary medicine.

Chemistry

20 ml ampoule of 1% propofol emulsion

Originally developed by 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 However, due to anaphylactic reactions it was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water.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 diisopropyl intravenous 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. It resembles milk, and is jocularly called "milk of amnesia" by medical professionals.^[3]

A water soluble prodrug form, fospropofol, has recently been developed and tested with positive results, being rapidly broken down once in the body by the enzyme alkaline phosphatase to form propofol. Marketed as Lusedra, 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. It was approved by the FDA in December 12, 2008.^[4]

Pharmacology

Propofol is highly protein bound in vivo and is metabolised by conjugation in the liver.^[5] Its rate of clearance exceeds hepatic blood flow, suggesting an extrahepatic site of elimination as well. It has several mechanisms of action,^[6][7][8] both through potentiation of GABA-A receptor activity, thereby slowing the channel closing time,^[9][10][11] and also acting as a sodium channel blocker.^[12][13] Recent research has also suggested the endocannabinoid system may contribute significantly to propofol's anesthetic action and to its unique properties.^[14]

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^[15] have led to its widespread use for sedation and anesthesia.

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.^[16] 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 common, 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.^[17]

Abuse

Abuse of propofol as a recreational drug has been reported, usually among medical staff such as anaesthetists who have access to the drug.^[18] However, abuse of the drug is rare due to its potency and the level of monitoring required to take it, and it has not been scheduled by the US Drug Enforcement Administration.^[19] 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.^[20][21] News reports citing unnamed law enforcement sources suggest Diprivan was found by law enforcement officers in the home of Michael Jackson following his June 25, 2009 death. These reports are consistent with claims that the medication might have played a role in his death.^[22]

References

External links

• Diprivan web site run by AstraZeneca
• Detailed pharmaceutical information