Propofol

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Not to be confused with Profadol.
Propofol
Propofol.svg
Propofol3DanJ.gif
Systematic (IUPAC) name
2,6-diisopropylphenol
Clinical data
Pregnancy cat.
Legal status
Moderate
Routes Intravenous
Pharmacokinetic data
Bioavailability NA
Protein binding 95 to 99%
Metabolism Hepatic glucuronidation
Half-life 30 to 60 min
Excretion Hepatic
Identifiers
CAS number 2078-54-8 YesY
ATC code N01AX10
PubChem CID 4943
DrugBank DB00818
ChemSpider 4774 YesY
UNII YI7VU623SF YesY
KEGG D00549 YesY
ChEBI CHEBI:44915 YesY
ChEMBL CHEMBL526 YesY
Chemical data
Formula C12H18O 
Mol. mass 178.271 g/mol
 YesY (what is this?)  (verify)

Propofol (INN, marketed as Diprivan by Fresenius Kabi) is a short-acting, intravenously administered hypnotic/amnestic 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. It is approved for use in more than 50 countries, and generic versions are available.

Chemically, propofol is not related to barbiturates and has largely replaced sodium thiopental (Pentothal) for induction of anesthesia because recovery from propofol is more rapid and "clear" when compared with thiopental. Propofol is not considered an analgesic, so opioids such as fentanyl may be combined with propofol to alleviate pain.[1] Propofol has been referred to as milk of amnesia (a play on words of milk of magnesia), because of the milk-like appearance of its intravenous preparation.[2] It is on the WHO Model List of Essential Medicines, the most important medications needed in a health system.[3]

Medical uses[edit]

Propofol is used for induction and maintenance (in some cases) of anesthesia, having largely replaced sodium thiopental for this indication.[1] It can also be administered as part of an anaesthesia maintenance technique called total intravenous anaesthesia using either manually-programmed infusion pumps or computer-controlled infusion pumps in a process called target controlled infusion or TCI. Propofol is also used to sedate individuals who are receiving mechanical ventilation but are not undergoing surgery, such as patients in the intensive care unit. In critically ill patients, propofol has been found to be superior to lorazepam both in effectiveness and overall cost.[4] Propofol is also used for procedural sedation, for example during endoscopic procedures. Its use in these settings results in a faster recovery compared to midazolam.[5] Because of its fast induction and recovery time, propofol is also widely used for sedation of infants and children undergoing MRI.[6]

Other uses[edit]

Executions[edit]

The Missouri Supreme Court decided to allow the use of propofol to execute prisoners condemned to death. However, the first execution by administration of a lethal dose of propofol was halted on 11 October 2013 by governor Jay Nixon following threats from the European Union to limit the drug's export if it were used for that purpose.[7][8]

Recreational use[edit]

Recreational use of the drug via self-administration has been reported[9][10] (including among medical professionals, see below), but is relatively rare due to its potency and the level of monitoring required for safe use.[citation needed] Critically, the steep dose-response curve of the drug makes potential misuse very dangerous without proper monitoring, and deaths from self-administration continue to be reported.[11][12]

The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition.[13][14] The euphoria caused by propofol has been reported to be unlike that caused by other sedation agents; as one anesthetist reported, "I... remember my first experience using [administering] propofol: a young woman... emerging from a MAC anesthesia looked at me as though I were a masked Brad Pitt and told me that she felt simply wonderful."[15]

Recreational use of the drug has been described amongst medical staff, such as anesthetists who have access to the drug,[16] and is reportedly more common among anesthetists on rotations with short rest periods (as rousing is to a well-rested state).[17] Long-term use has been reported to result in addiction.[16][18]

Attention to the risks of off-label use of propofol increased in August 2009 due to the Los Angeles County coroner's conclusion that music icon Michael Jackson died from a mixture of propofol and the benzodiazepine drugs lorazepam and diazepam.[19][20][21][22] According to a 22 July 2009 search warrant affidavit unsealed by the district court of Harris County, Texas, Jackson's personal physician, Conrad Murray, administered 25 milligrams of propofol diluted with lidocaine shortly before Jackson's death.[20][21][23] Even so, as of 2009 propofol was not on a U.S Drug Enforcement Administration schedule.[17][24]

Adverse effects[edit]

One of propofol's most frequent side effects is pain on injection, especially in smaller veins. This pain arises from activation of the pain receptor, TRPA1,[25] found on sensory nerves and can be mitigated by pretreatment with lidocaine.[26] Empirically, less pain is experienced when infused at a slower rate in a large vein (antecubital fossa). Patients show great variability in their response to propofol, at times showing profound sedation with small doses.

Additional side effects include low blood pressure related to vasodilation, transient apnea following induction doses, and cerebrovascular effects. Propofol has more pronounced hemodynamic effects relative to many intravenous anesthetic agents.[27] Reports of blood pressure drops of 30% or more are thought to be at least partially due to inhibition of sympathetic nerve activity.[28] This effect is related to dose and rate of propofol administration. It may also be potentiated by opioid analgesics.[29] Propofol can also cause decreased systemic vascular resistance, myocardial blood flow, and oxygen consumption, possibly through direct vasodilation.[30]

As a respiratory depressant, propofol frequently produces apnea. The persistence of apnea can depend on factors such as premedication, dose administered, and rate of administration, and may sometimes persist for longer than 60 seconds.[31] Possibly as the result of depression of the central inspiratory drive, propofol may produce significant decreases in respiratory rate, minute volume, tidal volume, mean inspiratory flow rate, and functional residual capacity.[27]

Diminishing cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure are also characteristic of propofol administration.[32] In addition, propofol may decrease intraocular pressure by as much as 50% in patients with normal intraocular pressure.[33]

A more serious but rare side effect is dystonia.[34] 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.[citation needed]

Finally, propofol is also reported to induce priapism in some individuals,[35][36] and has been observed to suppress REM sleep stage and to worsen the poor sleep quality in some patients.[37]

Propofol infusion syndrome[edit]

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 substance in combination with catecholamines and/or corticosteroids.[38]

Contraindications and interactions[edit]

The respiratory effects of propofol are potentiated by other respiratory depressants, including benzodiazepines.[39] As with any other general anesthetic agent, propofol should be administered only where appropriately trained staff and facilities for monitoring are available, as well as proper airway management, a supply of supplemental oxygen, artificial ventilation, and cardiovascular resuscitation.[40]

Chemistry[edit]

Large vial filled with milky white fluid
A 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 relaunched in 1986 by ICI (now AstraZeneca) under the brand name Diprivan. The currently available preparation is 1% propofol, 10% soybean oil, and 1.2% purified egg phospholipid as an emulsifier, with 2.25% glycerol as a tonicity-adjusting agent, and sodium hydroxide to adjust the pH. Diprivan contains EDTA, a common chelation agent, that also acts alone (bacteriostatically against some bacteria) and synergistically with some other antimicrobial agents. Newer generic formulations contain sodium metabisulfite or benzyl alcohol as antimicrobial agents. Propofol emulsion is a highly opaque white fluid due to the scattering of light from the tiny (about 150-nm) oil droplets 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.[41]

Mechanism of action[edit]

Propofol has been proposed to have several mechanisms of action,[42][43][44] both through potentiation of GABAA receptor activity, thereby slowing the channel-closing time,[45][46][47] and also acting as a sodium channel blocker.[48][49] Recent research has also suggested that the endocannabinoid system may contribute significantly to propofol's anesthetic action and to its unique properties.[50] 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.[51]

Researchers have identified the site where propofol binds to GABAA receptors in the brain, on the second transmembrane domain of the beta subunit of the GABA A[52]

Pharmacokinetics[edit]

Propofol is highly protein-bound in vivo and is metabolised by conjugation in the liver.[53] The half-life of elimination of propofol has been estimated to be 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[54] have led to its widespread use for sedation and anesthesia.

Supply issues[edit]

On 4 June 2010, Teva Pharmaceutical Industries Ltd., an Israel-based pharmaceutical firm and a major supplier of the drug, announced the firm would no longer manufacture it. This aggravates an already existing shortage, caused by manufacturing difficulties at Teva and Hospira. A Teva spokesperson attributed the halt to ongoing process difficulties, and a number of pending lawsuits related to the drug.[55] In Switzerland, various preparations of the drug are supplied by Fresenius-Kabi, a German company.

Recent developments[edit]

By incorporation of an azobenzene unit, a photoswitchable version of propofol (AP2) was developed in 2012 that allows for optical control of GABAA receptors with light.[56] In 2013, a propofol binding site on mammalian GABAA receptors has been identified by photolabeling using a Diazirine derivative.[57] Additionally, it was shown that the hyaluronan polymer present in the synovia can be protected from free-radical depolymerization by propofol.[58]

References[edit]

  1. ^ a b 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 23 February 2007.
  2. ^ Euliano TY, Gravenstein JS (2004). "A brief pharmacology related to anesthesia". Essential anesthesia: from science to practice. Cambridge, UK: Cambridge University Press. p. 173. ISBN 0-521-53600-6. Retrieved 2 June 2009. 
  3. ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. p. 6. Retrieved 22 April 2014. 
  4. ^ Cox, CE.; Reed, SD.; Govert, JA.; Rodgers, JE.; Campbell-Bright, S.; Kress, JP.; Carson, SS. (March 2008). "Economic evaluation of propofol and lorazepam for critically ill patients undergoing mechanical ventilation.". Crit Care Med 36 (3): 706–14. doi:10.1097/CCM.0B013E3181544248. PMC 2763279. PMID 18176312. 
  5. ^ McQuaid, KR.; Laine, L. (May 2008). "A systematic review and meta-analysis of randomized, controlled trials of moderate sedation for routine endoscopic procedures.". Gastrointest Endosc 67 (6): 910–23. doi:10.1016/j.gie.2007.12.046. PMID 18440381. 
  6. ^ Machata, AM; Willschke, H; Kabon, B; Kettner, SC; Marhofer, P (August 2008). "Propofol-based sedation regimen for infants and children undergoing ambulatory magnetic resonance imaging.". British journal of anaesthesia 101 (2): 239–43. doi:10.1093/bja/aen153. PMID 18534971. 
  7. ^ Death Row Improvises, Lacking Lethal Mix, By RICK LYMAN, New York Times, 18 August 2013
  8. ^ After EU threats, Missouri halts execution by Propofol injection Al Jazeera America October 12th 2013
  9. ^ Riezzo I, Centini F, Neri M, Rossi G, Spanoudaki E, Turillazzi E, Fineschi V (2009). "Brugada-like EKG pattern and myocardial effects in a chronic propofol abuser". Clin Toxicol (Phila) 47 (4): 358–63. doi:10.1080/15563650902887842. PMID 19514884. 
  10. ^ Belluck, Pam (6 August 2009). "With High-Profile Death, Focus on High-Risk Drug". New York Times. Retrieved 7 August 2009. 
  11. ^ Iwersen-Bergmann S, Rösner P, Kühnau HC, Junge M, Schmoldt A (2001). "Death after excessive propofol abuse". International Journal of Legal Medicine 114 (4–5): 248–51. doi:10.1007/s004149900129. PMID 11355404. 
  12. ^ Kranioti EF, Mavroforou A, Mylonakis P, Michalodimitrakis M. (22 March 2007). "Lethal self-administration of propofol (Diprivan): A case report and review of the literature". Forensic Science International 167 (1): 56–8. doi:10.1016/j.forsciint.2005.12.027. PMID 16431058. 
  13. ^ In Sweetman SC (Ed.). Martindale: The Complete Drug Reference 2005. 34th Edn London pp. 1305–7
  14. ^ Baudoin Z. General anesthetics and anesthetic gases. In Dukes MNG and Aronson JK (Eds.). Meyler's Side Effects of Drugs 2000. 14th Edn Amsterdam pp. 330
  15. ^ C.F. Ward, 2008, Propofol: Dancing with a "White Rabbit", CSA Bulletin, pp. 61-63, accessed 24 November 2014.
  16. ^ a b Roussin A, Montastruc JL, Lapeyre-Mestre M (21 October 2007). "Pharmacological and clinical evidences on the potential for abuse and dependence of propofol: a review of the literature". Fundamental and Clinical Pharmacology 21 (5): 459–66. doi:10.1111/j.1472-8206.2007.00497.x. PMID 17868199. 
  17. ^ a b Charatan F (2009). "Concerns mount over recreational use of propofol among US healthcare professionals". BMJ 339: b3673. doi:10.1136/bmj.b3673. PMID 19737827. 
  18. ^ Bonnet U, Harkener J, Scherbaum N (June 2008). "A case report of propofol dependence in a physician". J Psychoactive Drugs 40 (2): 215–7. doi:10.1080/02791072.2008.10400634. PMID 18720673. 
  19. ^ Moore, Solomon (28 August 2009). "Jackson’s Death Ruled a Homicide". New York Times. 
  20. ^ a b Surdin, Ashley (25 August 2009). "Coroner Attributes Michael Jackson's Death to Propofol". The Washington Post. Retrieved 22 May 2010. 
  21. ^ a b Itzkoff, Dave (24 August 2009). "Coroner's Findings in Jackson Death Revealed". The New York Times. Retrieved 22 May 2010. 
  22. ^ "Jackson's Death: How Dangerous Is Propofol?". Time. 25 August 2009. Retrieved 22 May 2010. 
  23. ^ http://www.scribd.com/doc/19058649/Michael-Jackson-search-warrant.  Missing or empty |title= (help)
  24. ^ DEA may limit drug eyed in Jackson case. Associated Press. 15 July 2009.
  25. ^ "General anesthetics activate a nociceptive ion channel to enhance pain and inflammation". Pnas.org. Retrieved 8 June 2013. 
  26. ^ "Propofol Drug Information, Professional". m drugs.com. Retrieved 2 January 2007. 
  27. ^ a b Sebel PS, Lowden JD (1989). Propofol: a new intravenous anesthetic. Anesthesiology; 71(2):260-77.
  28. ^ Robinson B, Ebert T, O'Brien T, et al. Mechanisms whereby propofol mediates peripheral vasodilation in humans (1997). Anesthesiology; 86:64-72.
  29. ^ New awakening in anaesthesia—at a price. Lancet 1987; 8548: 1469-70.
  30. ^ Larijani G, Gratz I, Afshar M, et al. Clinical pharmacology of propofol: an intravenous anesthetic agent [published erratum appears in DICP 1990 Jan; 24: 102]. DICP 1989; 23: 743-9.
  31. ^ Langley M, Heel R. Propofol. A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic. Drugs 1988; 35: 334-72.
  32. ^ Bailey J, Mora C, Shafer S. Pharmacokinetics of propofol in adult patients undergoing coronary revascularization. Anesthesiology 1996; 84: 1288-97.
  33. ^ Reilly C, Nimmo W. New intravenous anaesthetics and neuromuscular blocking drugs. A review of their properties and clinical use. Drugs 1987; 34: 115-9.
  34. ^ Schramm BM, Orser BA (2002). Dystonic reaction to propofol attenuated by benztropine (Cogentin). Anesth Analg, 94, 1237–40.
  35. ^ Vesta, Kimi; Shaunta' Martina, Ellen Kozlowski (25 April 2009). "Propofol-Induced Priapism, a Case Confirmed with Rechallenge". The Annals of Pharmacotherapy 40 (5): 980–982. doi:10.1345/aph.1G555. PMID 16638914. 
  36. ^ Fuentes, Ennio; Silvia Garcia; Manuel Garrido; Cristina Lorenzo; Jose Iglesias; Juan Sola (July 2009). "Successful treatment of propofol-induced priapism with distal glans to corporal cavernosal shunt". Urology 74 (1): 113–115. doi:10.1016/j.urology.2008.12.066. PMID 19371930. 
  37. ^ "Effects of propofol on sleep quality in mechanically ventilated critically ill patients: a physiological study - Eumorfia Kondili, Christina Alexopoulou, Nectaria Xirouchaki, Dimitris Georgopoulos". http://icmjournal.esicm.org/. Retrieved 2 October 2012. 
  38. ^ 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:10.1007/s00134-003-1905-x. PMID 12904852. 
  39. ^ Doheny, Kathleen; Louise Chang; Hector Vila Jr (24 August 2009). "Propofol Linked to Michael Jackson's Death". WebMD. Retrieved 26 August 2009. 
  40. ^ "AstraZeneca - United States Home Page". .astrazeneca-us.com. Retrieved 8 June 2013. 
  41. ^ "Drugs@FDA: FDA Approved Drug Products". Accessdata.fda.gov. Retrieved 8 June 2013. 
  42. ^ Trapani G, Altomare C, Liso G, Sanna E, Biggio G (February 2000). "Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery". Curr. Med. Chem. 7 (2): 249–71. doi:10.2174/0929867003375335. PMID 10637364. 
  43. ^ Kotani Y, Shimazawa M, Yoshimura S, Iwama T, Hara H. The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties. CNS Neuroscience and Therapeutics. 2008 Summer;14(2):95–106. doi:10.1111/j.1527-3458.2008.00043.x PMID 18482023
  44. ^ Vanlersberghe C, Camu F. Propofol. Handbook of Experimental Pharmacology. 2008;(182):227-52. doi:10.1007/978-3-540-74806-9_11 PMID 18175094
  45. ^ Trapani G, Latrofa A, Franco M, Altomare C, Sanna E, Usala M, Biggio G, Liso G. Propofol analogues. Synthesis, relationships between structure and affinity at GABAA receptor in rat brain, and differential electrophysiological profile at recombinant human GABAA receptors. Journal of Medicinal Chemistry. 21 May 1998;41(11):1846–54. doi:10.1021/jm970681h PMID 9599235
  46. ^ Krasowski MD, Jenkins A, Flood P, Kung AY, Hopfinger AJ, Harrison NL (April 2001). "General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility". J. Pharmacol. Exp. Ther. 297 (1): 338–51. PMID 11259561. 
  47. ^ Krasowski MD, Hong X, Hopfinger AJ, Harrison NL. 4D-QSAR analysis of a set of propofol analogues: mapping binding sites for an anesthetic phenol on the GABA(A) receptor. Journal of Medicinal Chemistry. 18 July 2002;45(15):3210–21. doi:10.1021/jm010461a PMID 12109905
  48. ^ Haeseler G, Leuwer M (March 2003). "High-affinity block of voltage-operated rat IIA neuronal sodium channels by 2,6 di-tert-butylphenol, a propofol analogue". Eur J Anaesthesiol 20 (3): 220–4. doi:10.1017/s0265021503000371. PMID 12650493. 
  49. ^ Haeseler G, Karst M, Foadi N, Gudehus S, Roeder A, Hecker H, Dengler R, Leuwer M. High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues. British Journal of Pharmacology. 2008 Sep;155(2):265-75. doi:10.1038/bjp.2008.255 PMID 18574460
  50. ^ Fowler CJ (February 2004). "Possible involvement of the endocannabinoid system in the actions of three clinically used drugs". Trends Pharmacol. Sci. 25 (2): 59–61. doi:10.1016/j.tips.2003.12.001. 
  51. ^ Lee U, Mashour GA, Kim S, Noh GJ, Choi BM. (2009). Propofol induction reduces the capacity for neural information integration: implications for the mechanism of consciousness and general anesthesia. Conscious Cogn. 18(1):56–64.doi:10.1016/j.concog.2008.10.005 PMID 19054696
  52. ^ http://phys.org/news/2013-09-propofol-discovery-aid-anesthetics.html
  53. ^ Favetta P, Degoute C-S Perdrix J-P, Dufresne C, Boulieu R, Guitton J (2002). "Propofol metabolites in man following propofol induction and maintenance". British Journal of Anaesthesia 88 (5): 653–8. doi:10.1093/bja/88.5.653. 
  54. ^ Veselis RA, Reinsel RA, Feshchenko VA, Wroński M (October 1997). "The comparative amnestic effects of midazolam, propofol, thiopental, and fentanyl at equisedative concentrations". Anesthesiology 87 (4): 749–64. doi:10.1097/00000542-199710000-00007. PMID 9357875. 
  55. ^ "Teva won't make more of powerful sedative.". 
  56. ^ Stein M, et al. (September 2012). "Azo-Propofols: Photochromic Potentiators of GABAA Receptors". Angewandte Chemie International Edition 51 (42): 15000–4. doi:10.1002/anie.201205475. PMID 22968919. 
  57. ^ Yip G, Z.-W Chen, Edge C J, Smith E H, Dickinson R, Hohenester, E, Townsend R R, Fuchs K, Sieghart W, Evers A S, Franks N P (September 2013). "A propofol binding site on mammalian GABAAreceptors identified by photolabeling". Nature Chemical Biology 9 (11): 715–720. doi:10.1038/nchembio.1340. 
  58. ^ Kvam C, Granese D, Flaibani A, Pollesello P, Paoletti S. (1993). "Hyaluronan can be protected from free-radical depolymerization by 2, 6-diisopropylphenol, a novel radical scavenger". Biochem. Biophys. Res. Comm. 193 (3): 927–33. doi:10.1006/bbrc.1993.1714. PMID 8391811. 

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