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Propofol (INN)
Ball-and-stick model of propofol
Systematic (IUPAC) name
Clinical data
  • AU: C
  • US: B (No risk in non-human studies)
Legal status
Physical: very low (seizures)
Psychological: no data
Routes of
Pharmacokinetic data
Bioavailability NA
Protein binding 95% to 99%
Metabolism Hepatic glucuronidation
Biological half-life 30 to 60 min
Excretion Hepatic
CAS Registry Number  Y
ATC code N01
PubChem CID:
DrugBank  Y
ChemSpider  Y
Chemical data
Formula C12H18O
Molecular mass 178.271 g/mol

Propofol marketed as Diprivan, 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.

Propofol has largely replaced sodium thiopental for induction of anesthesia because recovery from propofol is more rapid and "clear" when compared with thiopental. Propofol is not a pain medication, so opioids such as fentanyl may be combined with propofol to alleviate pain.[2] Whether or not this is always needed is unclear.[3] 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.[4] It is on the WHO Model List of Essential Medicines, the most important medications needed in a health system.[5] It is approved for use in more than 50 countries, and generic versions are available.


  • Medical uses 1
    • Anesthesia 1.1
    • Procedural sedation 1.2
  • Other uses 2
    • Executions 2.1
    • Recreational use 2.2
  • Side effects 3
    • Propofol infusion syndrome 3.1
    • CBS genetic defects 3.2
  • Interactions 4
  • Mechanism of action 5
  • Pharmacokinetics 6
  • Chemistry 7
  • Society and culture 8
    • Supply issues 8.1
  • Recent developments 9
  • References 10
  • External links 11

Medical uses


Propofol is used for induction and maintenance (in some cases) of anesthesia, having largely replaced sodium thiopental.[2] It can also be administered as part of an anaesthesia maintenance technique called total intravenous anesthesia 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.[6]

Procedural sedation

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.[7] Because of its fast induction and recovery time, propofol is also widely used for sedation of infants and children undergoing MRI.[8] It is also often used in combination with ketamine as the two together have lower rates of side effects.[9]

Other uses


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.[10][11]

Recreational use

Recreational use of the drug via self-administration has been reported[12][13] (including among medical professionals, see below), but is relatively rare due to its potency and the level of monitoring required for safe use. 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.[14][15]

The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition.[16][17] 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."[18]

Recreational use of the drug has been described amongst medical staff, such as anesthetists who have access to the drug,[19] and is reportedly more common among anesthetists on rotations with short rest periods (as rousing is to a well-rested state).[20] Long-term use has been reported to result in addiction.[19][21]

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.[22][23][24][25] 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.[23][24][26] Even so, as of 2009 propofol was not on a U.S Drug Enforcement Administration schedule.[20][27]

Side effects

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,[28] found on sensory nerves and can be mitigated by pretreatment with lidocaine.[29] 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.[30] Reports of blood pressure drops of 30% or more are thought to be at least partially due to inhibition of sympathetic nerve activity.[31] This effect is related to dose and rate of propofol administration. It may also be potentiated by opioid analgesics.[32] Propofol can also cause decreased systemic vascular resistance, myocardial blood flow, and oxygen consumption, possibly through direct vasodilation.[33]

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.[34] 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.[30]

Diminishing cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure are also characteristics of propofol administration.[35] In addition, propofol may decrease intraocular pressure by as much as 50% in patients with normal intraocular pressure.[36]

A more serious but rare side effect is dystonia.[37] 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.

Propofol is also reported to induce priapism in some individuals,[38][39] and has been observed to suppress REM sleep stage and to worsen the poor sleep quality in some patients.[40]

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.[41]

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 substance in combination with catecholamines and/or corticosteroids.[42]

CBS genetic defects

People with this gene have trouble processing sulphites (one of the potential ingredients), and should discuss use of this drug with their specialist.


The respiratory effects of propofol are increased if given with other respiratory depressants, including benzodiazepines.[43]

Mechanism of action

Propofol has been proposed to have several mechanisms of action,[44][45][46] both through potentiation of GABAA receptor activity, thereby slowing the channel-closing time,[47][48][49] and also acting as a sodium channel blocker.[50][51] Recent research has also suggested that the endocannabinoid system may contribute significantly to propofol's anesthetic action and to its unique properties.[52] 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.[53]

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 receptor.[54]


Propofol is highly protein-bound in vivo and is metabolised by conjugation in the liver.[55] 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[56] have led to its widespread use for sedation and anesthesia.


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.[57] However fospropofol is a controlled substance unlike propofol.

Society and culture

Supply issues

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.[58] In Switzerland, various preparations of the drug are supplied by Fresenius-Kabi, a German company.

Recent developments

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.[59] In 2013, a propofol binding site on mammalian GABAA receptors has been identified by photolabeling using a Diazirine derivative.[60] Additionally, it was shown that the hyaluronan polymer present in the synovia can be protected from free-radical depolymerization by propofol.[61]


  1. ^ Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am J Drug Alcohol Abuse 40 (6): 428–437. PMID 25083822. doi:10.3109/00952990.2014.933840.
    The knowledge of ΔFosB induction in chronic drug exposure provides a novel method for the evaluation of substance addiction profiles (i.e. how addictive they are). Xiong et al. used this premise to evaluate the potential addictive profile of propofol (119). Propofol is a general anaesthetic, however its abuse for recreational purpose has been documented (120). Using control drugs implicated in both ΔFosB induction and addiction (ethanol and nicotine), similar ΔFosB expression was apparent when propofol was given to rats. Moreover, this cascade was shown to act via the dopamine D1 receptor in the NAc, suggesting that propofol has abuse potential (119). ... Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker.
  2. ^ a b Miner, JR; Burton, JH (Aug 2007). "Clinical practice advisory: Emergency department procedural sedation with propofol". Annals of Emergency Medicine 50 (2): 182–7.  
  3. ^ Wakai, A; Blackburn, C; McCabe, A; Reece, E; O'Connor, G; Glasheen, J; Staunton, P; Cronin, J; Sampson, C; McCoy, SC; O'Sullivan, R; Cummins, F (29 July 2015). "The use of propofol for procedural sedation in emergency departments.". The Cochrane database of systematic reviews 7: CD007399.  
  4. ^ Euliano TY, Gravenstein JS (2004). "A brief pharmacology related to anesthesia". Essential anesthesia: from science to practice. Cambridge, UK: Cambridge University Press. p. 173.  
  5. ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. p. 6. Retrieved 22 April 2014. 
  6. ^ 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.  
  7. ^ 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.  
  8. ^ 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.  
  9. ^ Yan, JW; McLeod, SL; Iansavitchene, A (20 August 2015). "Ketamine-Propofol Versus Propofol Alone for Procedural Sedation in the Emergency Department: A Systematic Review and Meta-analysis.". Academic emergency medicine : official journal of the Society for Academic Emergency Medicine.  
  10. ^ Death Row Improvises, Lacking Lethal Mix, By RICK LYMAN, New York Times, 18 August 2013
  11. ^ After EU threats, Missouri halts execution by Propofol injection Al Jazeera America October 12th 2013
  12. ^ 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.  
  13. ^ Belluck, Pam (6 August 2009). "With High-Profile Death, Focus on High-Risk Drug". New York Times. Retrieved 7 August 2009. 
  14. ^ 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.  
  15. ^ 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.  
  16. ^ In Sweetman SC (Ed.). Martindale: The Complete Drug Reference 2005. 34th Edn London pp. 1305–7
  17. ^ 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
  18. ^ C.F. Ward, 2008, Propofol: Dancing with a "White Rabbit", CSA Bulletin, pp. 61-63, accessed 24 November 2014.
  19. ^ 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.  
  20. ^ a b Charatan F (2009). "Concerns mount over recreational use of propofol among US healthcare professionals". BMJ 339: b3673.  
  21. ^ Bonnet U, Harkener J, Scherbaum N (June 2008). "A case report of propofol dependence in a physician". J Psychoactive Drugs 40 (2): 215–7.  
  22. ^ Moore, Solomon (28 August 2009). "Jackson’s Death Ruled a Homicide". New York Times. 
  23. ^ a b Surdin, Ashley (25 August 2009). "Coroner Attributes Michael Jackson's Death to Propofol". The Washington Post. Retrieved 22 May 2010. 
  24. ^ a b Itzkoff, Dave (24 August 2009). "Coroner's Findings in Jackson Death Revealed". The New York Times. Retrieved 22 May 2010. 
  25. ^ "Jackson's Death: How Dangerous Is Propofol?". Time. 25 August 2009. Retrieved 22 May 2010. 
  26. ^ "Michael Jackson search warrant".  
  27. ^ DEA may limit drug eyed in Jackson case. Associated Press. 15 July 2009.
  28. ^ "General anesthetics activate a nociceptive ion channel to enhance pain and inflammation". Retrieved 8 June 2013. 
  29. ^ "Propofol Drug Information, Professional". m Retrieved 2 January 2007. 
  30. ^ a b Sebel, PS; Lowden, JD (1989). "Propofol: a new intravenous anesthetic". Anesthesiology 71 (2): 260–77.  
  31. ^ Robinson, B; Ebert, T; O'Brien, T; et al. "Mechanisms whereby propofol mediates peripheral vasodilation in humans (1997)". Anesthesiology 86: 64–72.  
  32. ^ "New awakening in anaesthesia—at a price". Lancet 8548: 1469–70. 1987. 
  33. ^ Larijani, G; Gratz, I; Afshar, M; et al. (1989). "Clinical pharmacology of propofol: an intravenous anesthetic agent [published erratum appears in DICP 1990 Jan; 24: 102]". DICP 23: 743–9. 
  34. ^ Langley, M; Heel, R (1988). "Propofol. A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic". Drugs 35: 334–72.  
  35. ^ Bailey, J; Mora, C; Shafer, S (1996). "Pharmacokinetics of propofol in adult patients undergoing coronary revascularization". Anesthesiology 84: 1288–97.  
  36. ^ Reilly, C; Nimmo, W (1987). "New intravenous anaesthetics and neuromuscular blocking drugs. A review of their properties and clinical use". Drugs 34: 115–9. 
  37. ^ Schramm, BM; Orser, BA (2002). "Dystonic reaction to propofol attenuated by benztropine (Cogentin)". Anesth Analg 94: 1237–40.  
  38. ^ 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.  
  39. ^ 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.  
  40. ^ Eumorfia Kondili, Christina Alexopoulou, Nectaria Xirouchaki, Dimitris Georgopoulos. "Effects of propofol on sleep quality in mechanically ventilated critically ill patients: a physiological study". Intensive Care Medicine 38: 1640–1646.  
  41. ^ "AstraZeneca - United States Home Page" (PDF). Retrieved 8 June 2013. 
  42. ^ 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.  
  43. ^ Doheny, Kathleen; Louise Chang; Hector Vila Jr (24 August 2009). "Propofol Linked to Michael Jackson's Death".  
  44. ^ 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.  
  45. ^ Kotani, Y; Shimazawa, M; Yoshimura, S; Iwama, T; Hara, H (Summer 2008). "The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties". CNS Neuroscience and Therapeutics 14 (2): 95–106.  
  46. ^ Vanlersberghe C, Camu F. Propofol. Handbook of Experimental Pharmacology. 2008;(182):227-52. doi:10.1007/978-3-540-74806-9_11 PMID 18175094
  47. ^ 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
  48. ^ 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.  
  49. ^ 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
  50. ^ 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.  
  51. ^ Haeseler, G; Karst, M; Foadi, N; Gudehus, S; Roeder, A; Hecker, H; Dengler, R; Leuwer, M (Sep 2008). "High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues". British Journal of Pharmacology 155 (2): 265–75.  
  52. ^ 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.  
  53. ^ 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.  
  54. ^
  55. ^ 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.  
  56. ^ 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.  
  57. ^ "Drugs@FDA: FDA Approved Drug Products". Retrieved 8 June 2013. 
  58. ^ "Teva won't make more of powerful sedative.". 
  59. ^ Stein M, et al. (September 2012). "Azo-Propofols: Photochromic Potentiators of GABAA Receptors". Angewandte Chemie International Edition 51 (42): 15000–4.  
  60. ^ 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.  
  61. ^ 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.  

External links

  • Diprivan web site run by AstraZeneca
  • Detailed pharmaceutical information
  • U.S. National Library of Medicine: Drug Information Portal – Propofol
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