Propofol
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Propofol
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| Systematic (IUPAC) name | |
| 2,6-diisopropylphenol | |
| Identifiers | |
| CAS number | |
| ATC code | N01 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C12H18O |
| Mol. mass | 178.271 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | NA |
| Protein binding | 95 to 99% |
| Metabolism | Hepatic glucuronidation |
| Half life | 30 to 60 min |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status |
℞-only (U.S.) |
| Routes | Intravenous |
Propofol is a short-acting intravenous 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. It provides no analgesia.[1] Yet in some studies, when patients receive propofol compared to inhalation agents for anesthesia, postoperative pain is less after propofol.[2] Propofol is approved for use in more than 50 countries. It is also commonly used in veterinary medicine.
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[edit] Chemistry
Propofol is a water-immiscible oil and so is painful to inject. 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 However, due to anaphylactic reactions it was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water.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.[3] Fospropofol is a new water-soluble prodrug of propofol. It is rapidly converted into propofol by the enzyme alkaline phosphatase, and is now being developed for human use under the brand name Aquavan. [1]
[edit] Pharmacology
Propofol is highly protein bound in vivo and is metabolised by conjugation in the liver.[citation needed] 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.[4]
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 [5] have led to its widespread use for sedation and anesthesia.
[edit] 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.[6] 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.[7]
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.[8][9]
[edit] References
- ^ Miner JR, Burton JH. Clinical practice advisory: Emergency department procedural sedation with propofol. Annals of Emergency Medicine. 2007 Aug;50(2):182-7, 187.e1. Epub 2007 Feb 23.
- ^ Cheng, SS, Yeh, J, & Flood, P. (2008). Anesthesia matters: patients anesthetized with propofol have less postoperative pain than those anesthetized with isoflurane. Anesthesia and analgesia, 106(1), 264-9, table of contents.
- ^ Banaszczyk MG, Carlo AT, Millan V, Lindsey A, Moss R, Carlo DJ, Hendler SS. Propofol phosphate, a water-soluble propofol prodrug: in vivo evaluation. Anesthesia and Analgesia. 2002 Nov;95(5):1285-92
- ^ Fowler, CJ. "Possible involvement of the endocannabinoid system in the actions of three clinically used drugs." Trends Pharmacol. Sci. 2004 Feb;25(2):59-61.
- ^ Veselis, RA, Reinsel, RA, Feshchenko, VA, & Wroński, M (1997). The comparative amnestic effects of midazolam, propofol, thiopental, and fentanyl at equisedative concentrations. Anesthesiology, 87, 749-64.
- ^ Propofol Drug Information,Professional. drugs.com. Retrieved on 2007-01-02.
- ^ Vasile B, Rasulo F, Candiani A, Latronico N (2003). "The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome". Intensive care medicine 29 (9): 1417-25. doi:. PMID 12904852.
- ^ Iwersen-Bergmann S, Rösner P, Kühnau HC, Junge M, Schmoldt A. Death after excessive propofol abuse. International Journal of Legal Medicine. 2001;114(4-5):248-51.
- ^ Kranioti EF, Mavroforou A, Mylonakis P, Michalodimitrakis M. Lethal self administration of propofol (Diprivan). A case report and review of the literature. Forensic Science International. 2007 Mar 22;167(1):56-8. Epub 2006 Jan 23.
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