Propofol

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
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Propofol (INN, marketed as Diprivan by AstraZeneca) is a short-acting, intravenously administered hypnotic agent. Its uses include the induction and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation. Propofol is also commonly used in veterinary medicine. Propofol is approved for use in more than 50 countries, and generic versions are available.

Chemically, propofol is unrelated to barbiturates, and has largely replaced sodium thiopental (Pentothal) for induction of anesthesia as recovery from propofol is more rapid and "clear" as compared to thiopental. Propofol is not considered an analgesic, so opioids such as fentanyl may be combined with propofol to alleviate pain.^[1] Due to its amnestic effects and appearance as a white liquid, propofol has been humorously dubbed "milk of amnesia" by medical professionals.^[2]

Chemistry

20-mL ampoule of 1% propofol emulsion, as sold in Australia by Sandoz

Propofol was originally developed in the UK by Imperial Chemical Industries as ICI 35868. Clinical trials followed in 1977, using a form solubilised in cremophor EL. However, due to anaphylactic reactions to cremophor, this formulation was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water. The emulsified formulation was re-launched in 1986 by ICI (now AstraZeneca) under the brand name Diprivan (abbreviated version of diisopropyl intravenous anesthetic). The currently available 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 is a highly opaque white fluid due to the scattering of light from the tiny (~150 nm) oil droplets that it contains.

A water-soluble prodrug form, fospropofol, has recently been developed and tested with positive results. Fospropofol is rapidly broken down by the enzyme alkaline phosphatase to form propofol. Marketed as Lusedra, this new formulation may not produce the pain at injection site that often occurs with the traditional form of the drug. The US Food and Drug Administration approved the product in 2008.^[3]

Pharmacology

Propofol is highly protein-bound in vivo and is metabolised by conjugation in the liver.^[4] Its rate of clearance exceeds hepatic blood flow, suggesting an extrahepatic site of elimination as well. It has several mechanisms of action,^[5][6][7] both through potentiation of GABA-A receptor activity, thereby slowing the channel-closing time,^[8][9][10] and also acting as a sodium channel blocker.^[11][12] Recent research has also suggested that the endocannabinoid system may contribute significantly to propofol's anesthetic action and to its unique properties.^[13]

The half life of elimination of propofol has been estimated at between 2 and 24 hours. However, its duration of clinical effect is much shorter, because propofol is rapidly distributed into peripheral tissues. When used for IV sedation, a single dose of propofol typically wears off within 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^[14] have led to its widespread use for sedation and anesthesia.

EEG research upon those undergoing general anesthesia with propofol finds that it causes a prominent reduction in the brain's information integration capacity at gamma wave band frequencies.^[15]

Contraindications and interactions

The respiratory effects of propofol are potentiated by other respiratory depressants, including benzodiazepines.^[16]

As with any other general anesthetic agent, propofol should only be administered where appropriately trained staff and facilities for monitoring are available, as well as proper airway managment, a supply of supplemental oxygen, artificial ventilation and cardiovascular resuscitation. ^[17]

Adverse effects

Aside from low blood pressure (mainly through vasodilation) 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.^[18] Patients 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.^[19] 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.

It has been reported that the euphoria caused by propofol is unlike other sedation agents, "I even remember my first experience using propofol: a young woman who was emerging from a MAC anesthesia looked at me as though I were a masked Brad Pitt and told me that she felt simply wonderful" —C.F. Ward, M.D.^[20]

Propofol has reportedly induced priapism in some individuals.^[21][22]

Propofol infusion syndrome

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.^[23]

Non-medical use

There are reports of self-administration of propofol for recreational purposes.^[24][25] Short-term effects include mild euphoria, hallucinations, and disinhibition.^[26][27] Long-term use has been reported to result in addiction.^[28][29] Such use of the drug has been described amongst medical staff such as anaesthetists who have access to the drug,^[28] Abuse is reported to be more common among anaesthetists on rotas (rotations) with short rest periods as abusers report rousing to a well-rested state.^[30] Abuse of the drug is relatively rare due to its potency and the level of monitoring required to take it safely. Propofol has not yet been scheduled by the US Drug Enforcement Administration.^[31][30] The steep dose-response curve of the drug makes potential abuse very dangerous without proper monitoring, and at least three deaths from self-administration have been recorded.^[32][33]

Attention to the risks of non-medical use of propofol increased in August of 2009 due to the Los Angeles County coroner's conclusion that Michael Jackson died from a mixture of propofol and the benzodiazepine drug lorazepam.^{[34][35][36][37]} According to a July 22 search warrant affidavit unsealed by the district court of Harris County, Texas, Jackson's personal physician administered 25 milligrams of propofol diluted with lidocaine shortly before his death.^[38][39][40]

See also

• Propofol infusion syndrome
• Death of Michael Jackson

References

Mosalli R. Successful treatment of Propofol induced refractory status epilepticus with calcium gluconate . Curr Pediatr Res 2010; 14 (1): 43-45 , http://pediatricresearch.info/article/view/1169

External links

• Diprivan web site run by AstraZeneca
• Detailed pharmaceutical information