Propofol

Propofol[7] is the active component of an intravenous anesthetic formulation used for induction and maintenance of general anesthesia. It is chemically termed 2,6-diisopropylphenol. The formulation was originally approved under the brand name Diprivan. Numerous generic offerings of this formulation now exist. Intravenous administration is used to induce unconsciousness after which anesthesia may be maintained using a combination of medications. It is manufactured as part of a sterile injectable emulsion formulation using soybean oil and lecithin, giving it a white milky coloration.[8]

Propofol
Ball-and-stick model of propofol
Clinical data
Trade namesDiprivan, others[1]
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: C
Dependence
liability		Physical: very low (seizures)
Psychological: no data
Addiction
liability		Moderate[2]
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityNA
Protein binding95–99%
MetabolismLiver glucuronidation
Onset of action15–30 seconds[5]
Elimination half-life1.5–31 hours[5]
Duration of action~5–10 minutes[5]
ExcretionLiver
Identifiers
  • 2,6-Diisopropylphenol
    2,6-bis(propan-2-yl)phenol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.016.551
Chemical and physical data
FormulaC12H18O
Molar mass178.275 g·mol−1
3D model (JSmol)
Solubility in waterΔGsolvH2O = -4.39kcal/mol[6]
  • CC(C)c1cccc(c1O)C(C)C
  • InChI=1S/C12H18O/c1-8(2)10-6-5-7-11(9(3)4)12(10)13/h5-9,13H,1-4H3 checkY
  • Key:OLBCVFGFOZPWHH-UHFFFAOYSA-N checkY
  (verify)

Recovery from propofol-induced anesthesia is generally rapid and associated with less frequent side effects[9] (e.g. drowsiness, nausea, vomiting) compared to other anesthetic agents. Propofol may be used prior to diagnostic procedures requiring anesthesia, in the management of refractory status epilepticus, and for induction and/or maintenance of anesthesia prior to and during surgeries. It may be administered as a bolus or an infusion, or some combination of the two.

First synthesized in 1973, by John B. Glen, a British veterinary anesthesiologist working for Imperial Chemical Industries (ICI, now AstraZeneca).[10] In 1986 propofol was introduced for therapeutic use as a lipid emulsion in the United Kingdom and New Zealand. Propofol (Diprivan) received FDA approval in October 1989. It is on the World Health Organization's List of Essential Medicines.[11]

Medical uses

Anesthesia

Propofol use to induce general anesthesia is now (2023) almost exclusively the drug of choice by anesthesiologists, having largely replaced other agents.[12]

It is often administered as part of an anesthesia maintenance technique called total intravenous anesthesia, using either manually programmed infusion pumps or computer-controlled infusion pumps in a process called target controlled infusion (TCI).[13]

Propofol is also used to sedate individuals who are receiving mechanical ventilation but not undergoing surgery, such as patients in the intensive care unit.[14] In critically ill patients, propofol is superior to lorazepam both in effectiveness and overall cost.[15] Propofol is relatively inexpensive compared to medications of similar use due to shorter ICU stay length.[15] One of the reasons propofol is thought to be more effective (although it has a longer half-life than lorazepam) is because studies have found that benzodiazepines like midazolam and lorazepam tend to accumulate in critically ill patients, prolonging sedation.[15]

Propofol has also been suggested as a sleep aid in critically ill adults in the ICU; however, the effectiveness of this medicine in replicating the mental and physical aspects of sleep for people in the ICU is not clear.[14]

Propofol can administered via a peripheral IV or central line. Propofol is often paired with fentanyl (for pain relief) in intubated and sedated people.[16] The two drugs are molecularly compatible in an IV mixture form.[16]

Propofol is also used for deepening of anesthesia in order to relieve laryngospasm. It may be used alone or followed by succinylcholine. Its use can avoid the need for paralysis and in some instances the potential side-effects of succinylcholine.[17]

Routine procedural sedation

Propofol is safe and effective for gastrointestinal endoscopy procedures (colonoscopies etc.). Its use in these settings results in a faster recovery compared to midazolam.[18] It can also be combined with opioids or benzodiazepines.[19][20][21] Because of its rapid induction and recovery time, propofol is also widely used for sedation of infants and children undergoing MRI procedures.[22] It is also often used in combination with ketamine with minimal side effects.[23]

COVID-19

In March 2021, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for Propofol‐Lipuro 1% to maintain sedation via continuous infusion in people older than sixteen with suspected or confirmed COVID-19 who require mechanical ventilation in an intensive care unit ICU setting.[24][25][26][27] In the circumstances of this public health emergency, it would not be feasible to require healthcare providers to seek to limit Fresenius Propoven 2% Emulsion or Propofol-Lipuro 1% only to be used for patients with suspected or confirmed COVID-19; therefore, this authorization does not limit use to such patients.[27]

Status epilepticus

Status epilepticus may be defined as seizure activity lasting beyond five minutes needing anticonvulsant medication. Several guidelines recommend the use of propofol for the treatment of refractory status epilepticus.[28]

Other uses

Assisted death in Canada

A lethal dose of propofol is used for medical assistance in dying in Canada to quickly induce deep coma and death, but rocuronium is always given—even when the patient dies as a result of propofol injection. The delivery order of IV medication is as follows:[29]

Step 1: Midazolam 10–20 mg given as 2−4 mL of 5 mg/mL preparation for pre-anesthesia, induces sleep in 1−2 minutes.

Step 2: Lidocaine 40 mg given as 4 mL of 1% preparation to reduce the burning sensation and pain associated with the injection of propofol.

Step 3: Propofol 1000 mg given as 100 mL of 10 mg/mL preparation. Loss of consciousness occurs within ten seconds and coma occurs in 1–2 minutes. Death may result from the propofol but rocuronium is still given.

Step 4: Rocuronium 200 mg given as 20 mL of 10 mg/mL preparation to induce respiratory arrest. Cardiac arrest subsequently follows about five minutes later due to hypoxia.

Executions

The US state of Missouri added propofol to its execution protocol in April 2012. However, Governor Jay Nixon halted the first execution by the administration of a lethal dose of propofol in October 2013 following threats from the European Union to limit the drug's export if it were used for that purpose.[30][31] The United Kingdom had already banned the export of medicines or veterinary medicines containing propofol to the United States.[32]

Recreational use

Recreational use of the drug via self-administration has been reported[33][34] but is relatively rare due to its potency and the level of monitoring required for safe use. Critically, a steep dose-response curve makes recreational use of propofol very dangerous, and deaths from self-administration continue to be reported.[35][36] The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition.[37][38]

Recreational use of the drug has been described among medical staff, such as anesthetists who have access to the drug.[39][40] It is reportedly more common among anesthetists on rotations with short rest periods, as usage generally produces a well-rested feeling.[41] Long-term use has been reported to result in addiction.[39][42]

Attention to the risks of off-label use of propofol increased in August 2009 due to the Los Angeles County coroner's conclusion that musician Michael Jackson died from a mixture of propofol and the benzodiazepine drugs lorazepam, midazolam, and diazepam on 25 June 2009.[43][44][45][46] According to a 22 July 2009 search warrant affidavit unsealed by the district court of Harris County, Texas, Jackson's physician, Conrad Murray, administered 25 milligrams of propofol diluted with lidocaine shortly before Jackson's death.[44][45][47] Even so, as of 2016, propofol was not on a US Drug Enforcement Administration schedule.[41][48]

Side effects

One of propofol's most common side effects is pain on injection, especially in smaller veins. This pain arises from activation of the pain receptor, TRPA1,[49] found on sensory nerves and can be mitigated by pretreatment with lidocaine.[50] Less pain is experienced when infused at a slower rate in a large vein (antecubital fossa). Patients show considerable 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.[51] Reports of blood pressure drops of 30% or more are thought to be at least partially due to inhibition of sympathetic nerve activity.[52] This effect is related to the dose and rate of propofol administration. It may also be potentiated by opioid analgesics.[53]

Propofol can also cause decreased systemic vascular resistance, myocardial blood flow, and oxygen consumption, possibly through direct vasodilation.[54] There are also reports that it may cause green discolouration of the urine.[55]

Although propofol is widely used in the adult ICU setting, the side effects associated with medication seem to be more concerning in children. In the 1990s, multiple reported deaths of children in ICUs associated with propofol sedation prompted the FDA to issue a warning.[56]

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.[57] 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.[51]

Propofol administration also results in decreased cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure.[58] In addition, propofol may decrease intraocular pressure by as much as 50% in patients with normal intraocular pressure.[59]

A more serious but rare side effect is dystonia.[60] 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,[61][62] and has been observed to suppress REM sleep stage and to worsen the poor sleep quality in some patients.[63]

Rare side effects include:[64]

  • anxiety
  • changes in vision
  • cloudy urine
  • coughing up blood
  • delirium or hallucinations
  • difficult urination
  • difficulty swallowing
  • dry eyes, mouth, nose, or throat

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.[65]

Because of its lipid base, some hospital facilities require the IV tubing (of continuous propofol infusions) to be changed after 12 hours. This is a preventive measure against microbial growth and infection.[66]

Propofol infusion syndrome
Main article: Propofol infusion syndrome

A 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, sometimes in combination with catecholamines and/or corticosteroids.[67]

Interactions

The respiratory effects of propofol are increased if given with other respiratory depressants, including benzodiazepines.[68]

Pharmacology

Pharmacodynamics

Propofol has been proposed to have several mechanisms of action,[69][70][71] both through potentiation of GABAA receptor activity and therefore acting as a GABAA receptor positive allosteric modulator, thereby slowing the channel-closing time. At high doses, propofol may be able to activate GABAA receptors in the absence of GABA, behaving as a GABAA receptor agonist as well.[72][73][74] Propofol analogs have been shown to also act as sodium channel blockers.[75][76] Some research has also suggested that the endocannabinoid system may contribute significantly to propofol's anesthetic action and to its unique properties, as endocannabinoids also play an important role in the physiologic control of sleep, pain processing and emesis.[77][78] An EEG study on patients undergoing general anesthesia with propofol found that it causes a prominent reduction in the brain's information integration capacity.[79]

Propofol is an inhibitor of the enzyme fatty acid amide hydrolase, which metabolizes the endocannabinoid anandamide (AEA). Activation of the endocannabinoid system by propofol, possibly via inhibition of AEA catabolism, generates a significant increase in the whole-brain content of AEA, contributing to the sedative properties of propofol via CB1 receptor activation.[80] This may explain the psychotomimetic and antiemetic properties of propofol. By contrast, there is a high incidence of postoperative nausea and vomiting after administration of volatile anesthetics, which contribute to a significant decrease in the whole-brain content of AEA that can last up to forty minutes after induction.[78]

Pharmacokinetics
Large vial filled with milky white fluid
A 20 ml ampoule of 1% propofol emulsion, as sold in Australia by Sandoz

Propofol is highly protein-bound in vivo and is metabolized by conjugation in the liver.[81] 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. Onset is rapid, in as little as 15–30 seconds.[5] 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[82] have led to its widespread use for sedation and anesthesia.

History

John B. Glen, a veterinarian and researcher at Imperial Chemical Industries (ICI), spent thirteen years developing propofol, an effort for which he was awarded the 2018 Lasker Award for clinical research.

Originally developed as ICI 35868, propofol was chosen after extensive evaluation and structure–activity relationship studies of the anesthetic potencies and pharmacokinetic profiles of a series of ortho-alkylated phenols.[83]

First identified as a drug candidate in 1973, propofol entered clinical trials in 1977, using a form solubilised in cremophor EL.[84] However, due to anaphylactic reactions to cremophor, this formulation was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil and propofol mixture in water. The emulsified formulation was relaunched in 1986 by ICI (whose pharmaceutical division later became a constituent of AstraZeneca) under the brand name Diprivan. The preparation contains 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 an opaque white fluid due to the scattering of light from its tiny (about 150 nm) oil droplets.

Developments

A water-soluble prodrug form, fospropofol, has been developed and tested with positive results. Fospropofol is rapidly broken down by the enzyme alkaline phosphatase to form propofol. Marketed as Lusedra, this formulation may not produce the pain at injection site that often occurs with the conventional form of the drug. The U.S. Food and Drug Administration (FDA) approved the product in 2008.[85] However fospropofol is a Schedule IV controlled substance with the DEA ACSCN of 2138 in the United States unlike propofol.[86]

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.[87] In 2013, a propofol binding site on mammalian GABAA receptors has been identified by photolabeling using a diazirine derivative.[88] Additionally, it was shown that the hyaluronan polymer present in the synovia can be protected from free-radical depolymerization by propofol.[89]

Ciprofol is another derivative of propofol that is 4–6 times more potent than propofol. Currently undergoing Phase III trials, ciprofol appears to have a lower incidence of injection site pain and respiratory depression than propofol.[90]

References
  1. "Propofol". Drugs.com. Retrieved 2 January 2019.
  2. Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. Propofol is a general anesthetic, 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)
  3. Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  4. "Diprivan- propofol injection, emulsion". DailyMed. Retrieved 17 April 2021.
  5. "Propofol". The American Society of Health-System Pharmacists. Archived from the original on 9 October 2016. Retrieved 21 January 2017.
  6. Arcario MJ, Mayne CG, Tajkhorshid E (October 2014). "Atomistic models of general anesthetics for use in in silico biological studies". The Journal of Physical Chemistry B. American Chemical Society (ACS). 118 (42): 12075–12086. doi:10.1021/jp502716m. PMC 4207551. PMID 25303275.
  7. "Propofol". PubChem. U.S. National Library of Medicine. Retrieved 25 October 2023.
  8. "Making Stable, Sterile Propofol". www.microfluidics-mpt.com. Retrieved 25 October 2023.
  9. "Propofol". go.drugbank.com. Retrieved 25 October 2023.
  10. Glen, John B. (July 2019). "Try, try, and try again: personal reflections on the development of propofol". British Journal of Anaesthesia. 123 (1): 3–9. doi:https://doi.org/10.1016/j.bja.2019.02.031. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  11. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  12. "Propofol - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 25 October 2023.
  13. Gale T, Leslie K, Kluger M (December 2001). "Propofol anaesthesia via target controlled infusion or manually controlled infusion: effects on the bispectral index as a measure of anaesthetic depth". Anaesthesia and Intensive Care. 29 (6): 579–584. doi:10.1177/0310057X0102900602. ISSN 0310-057X. PMID 11771598. S2CID 27253877.
  14. Lewis SR, Schofield-Robinson OJ, Alderson P, Smith AF (January 2018). "Propofol for the promotion of sleep in adults in the intensive care unit". The Cochrane Database of Systematic Reviews. 1 (1): CD012454. doi:10.1002/14651858.CD012454.pub2. PMC 6353271. PMID 29308828.
  15. 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". Critical Care Medicine. 36 (3): 706–714. doi:10.1097/CCM.0B013E3181544248. PMC 2763279. PMID 18176312.
  16. Isert PR, Lee D, Naidoo D, Carasso ML, Kennedy RA (June 1996). "Compatibility of propofol, fentanyl, and vecuronium mixtures designed for potential use in anesthesia and patient transport". Journal of Clinical Anesthesia. 8 (4): 329–336. doi:10.1016/0952-8180(96)00043-8. PMID 8695138.
  17. Gavel G, Walker RW (April 2014). "Laryngospasm in anaesthesia". Continuing Education in Anaesthesia Critical Care & Pain. 14 (2): 47–51. doi:10.1093/bjaceaccp/mkt031.
  18. McQuaid KR, Laine L (May 2008). "A systematic review and meta-analysis of randomized, controlled trials of moderate sedation for routine endoscopic procedures". Gastrointestinal Endoscopy. 67 (6): 910–923. doi:10.1016/j.gie.2007.12.046. PMID 18440381.
  19. Canadian National Formulary 2010
  20. Shannon MT, Wilson BA, Stang CL (1999). Appleton & Lange's 1999 drug guide. Stamford, CT: Appleton & Lange. ISBN 978-0-8385-0371-3.
  21. Numorphan® (oxymorphone) package insert (English), Endo 2009
  22. 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): 239–243. doi:10.1093/bja/aen153. PMID 18534971.
  23. Yan JW, McLeod SL, Iansavitchene A (September 2015). "Ketamine-Propofol Versus Propofol Alone for Procedural Sedation in the Emergency Department: A Systematic Review and Meta-analysis". Academic Emergency Medicine. 22 (9): 1003–1013. doi:10.1111/acem.12737. PMID 26292077.
  24. "Propofol-Lipuro 1% (propofol) Injectable emulsion for infusion – 1,000 mg in 100 ml (10 mg /ml) : Fact Sheet for health Care Providers" (PDF). Bbraunusa.com. Retrieved 5 March 2022.
  25. "Letter RE: Emergency Use Authorization 096". Fda.gov. Retrieved 5 March 2022.
  26. "Fact Sheet for Health Care Providers: Emergency Use Authorization (EUA) of Propofol‐Lipuro 1% Injectable Emulsion for Infusion". Fda.gov. Retrieved 5 March 2022.
  27. "Emergency Use Authorization". U.S. Food and Drug Administration (FDA). Retrieved 17 April 2021.
  28. Rao VR, Lowenstein DH (2022). "Seizures and epilepsy.". In Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J (eds.). Harrison's Principles of Internal Medicine (21st ed.). McGraw Hill. ISBN 978-1-264-26851-1.
  29. Reggler J, Daws T (May 2017). "Medical Assistance in Dying (MAiD): Protocols and Procedures Handbook" (PDF). Divisions of Family Practice (2nd ed.). Comox Valley, British Columbia.
  30. Lyman R (18 August 2013). "Death Row Improvises, Lacking Lethal Mix". The New York Times. Archived from the original on 8 July 2017.
  31. "After EU threats, Missouri halts execution by Propofol injection". Al Jazeera America. 12 October 2013. Archived from the original on 12 October 2013.
  32. Article 4A of Export Control Order 2008 – provisions supplementing "the torture Regulation"
  33. Riezzo I, Centini F, Neri M, Rossi G, Spanoudaki E, Turillazzi E, Fineschi V (April 2009). "Brugada-like EKG pattern and myocardial effects in a chronic propofol abuser". Clinical Toxicology. 47 (4): 358–363. doi:10.1080/15563650902887842. hdl:11392/2357145. PMID 19514884. S2CID 22531823.
  34. Belluck P (6 August 2009). "With High-Profile Death, Focus on High-Risk Drug". The New York Times. Archived from the original on 11 November 2011. Retrieved 7 August 2009.
  35. 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): 248–251. CiteSeerX 10.1.1.528.7395. doi:10.1007/s004149900129. PMID 11355404. S2CID 25963187.
  36. Kranioti EF, Mavroforou A, Mylonakis P, Michalodimitrakis M (March 2007). "Lethal self administration of propofol (Diprivan). A case report and review of the literature". Forensic Science International. 167 (1): 56–58. doi:10.1016/j.forsciint.2005.12.027. PMID 16431058.
  37. In Sweetman SC (Ed.). Martindale: The Complete Drug Reference 2005. 34th Edn London pp. 1305–7
  38. 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
  39. Roussin A, Montastruc JL, Lapeyre-Mestre M (October 2007). "Pharmacological and clinical evidences on the potential for abuse and dependence of propofol: a review of the literature". Fundamental & Clinical Pharmacology. 21 (5): 459–466. doi:10.1111/j.1472-8206.2007.00497.x. PMID 17868199. S2CID 22477291.
  40. Ward CF (2008). "Propofol: dancing with a "White Rabbit."" (PDF). California Society Anesthesiology Bulletin. 57 (Spring): 61–63. Archived from the original (PDF) on 8 September 2017. Retrieved 24 November 2014.
  41. Charatan F (September 2009). "Concerns mount over misuse of anaesthetic propofol among US health professionals". BMJ. 339: b3673. doi:10.1136/bmj.b3673. PMID 19737827. S2CID 9877560.
  42. Bonnet U, Harkener J, Scherbaum N (June 2008). "A case report of propofol dependence in a physician". Journal of Psychoactive Drugs. 40 (2): 215–217. doi:10.1080/02791072.2008.10400634. PMID 18720673. S2CID 15779389.
  43. Moore S (28 August 2009). "Jackson's Death Ruled a Homicide". The New York Times. Archived from the original on 14 November 2013.
  44. Surdin A (25 August 2009). "Coroner Attributes Michael Jackson's Death to Propofol". The Washington Post. Archived from the original on 9 November 2012. Retrieved 22 May 2010.
  45. Itzkoff D (24 August 2009). "Coroner's Findings in Jackson Death Revealed". The New York Times. Archived from the original on 11 June 2010. Retrieved 22 May 2010.
  46. "Jackson's Death: How Dangerous Is Propofol?". Time. 25 August 2009. Archived from the original on 25 July 2010. Retrieved 22 May 2010.
  47. "Michael Jackson search warrant". Scribd. Archived from the original on 5 March 2016. Retrieved 12 August 2015.
  48. "DEA may limit drug eyed in Jackson case". Associated Press. 15 July 2009. Archived from the original on 6 April 2012.
  49. Matta JA, Cornett PM, Miyares RL, Abe K, Sahibzada N, Ahern GP (June 2008). "General anesthetics activate a nociceptive ion channel to enhance pain and inflammation". Proceedings of the National Academy of Sciences of the United States of America. 105 (25): 8784–8789. doi:10.1073/pnas.0711038105. PMC 2438393. PMID 18574153.
  50. "Propofol Drug Information, Professional". m drugs.com. Archived from the original on 23 January 2007. Retrieved 2 January 2007.
  51. Sebel PS, Lowdon JD (August 1989). "Propofol: a new intravenous anesthetic". Anesthesiology. 71 (2): 260–277. doi:10.1097/00000542-198908000-00015. PMID 2667401. S2CID 34331379.
  52. Robinson BJ, Ebert TJ, O'Brien TJ, Colinco MD, Muzi M (January 1997). "Mechanisms whereby propofol mediates peripheral vasodilation in humans. Sympathoinhibition or direct vascular relaxation?". Anesthesiology. 86 (1): 64–72. doi:10.1097/00000542-199701000-00010. PMID 9009941. S2CID 31288656.
  53. "New awakening in anaesthesia—at a price". Lancet. 329 (8548): 1469–70. 1987. doi:10.1016/s0140-6736(87)92214-8. S2CID 28545161.
  54. Larijani GE, Gratz I, Afshar M, Jacobi AG (October 1989). "Clinical pharmacology of propofol: an intravenous anesthetic agent". DICP. 23 (10): 743–749. doi:10.1177/106002808902301001. PMID 2683416. S2CID 43010280.
  55. Lee JS, Jang HS, Park BJ (August 2013). "Green discoloration of urine after propofol infusion". Korean Journal of Anesthesiology. 65 (2): 177–179. doi:10.4097/kjae.2013.65.2.177. PMC 3766788. PMID 24024005.
  56. Parke TJ, Stevens JE, Rice AS, Greenaway CL, Bray RJ, Smith PJ, et al. (September 1992). "Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports". BMJ. 305 (6854): 613–616. doi:10.1136/bmj.305.6854.613. PMC 1883365. PMID 1393073.
  57. Langley MS, Heel RC (April 1988). "Propofol. A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic". Drugs. 35 (4): 334–372. doi:10.2165/00003495-198835040-00002. PMID 3292208.
  58. Bailey JM, Mora CT, Shafer SL (June 1996). "Pharmacokinetics of propofol in adult patients undergoing coronary revascularization. The Multicenter Study of Perioperative Ischemia Research Group". Anesthesiology. 84 (6): 1288–1297. doi:10.1097/00000542-199606000-00003. PMID 8669668. S2CID 26019589.
  59. Reilly CS, Nimmo WS (July 1987). "New intravenous anaesthetics and neuromuscular blocking drugs. A review of their properties and clinical use". Drugs. 34 (1): 98–135. doi:10.2165/00003495-198734010-00004. PMID 3308413. S2CID 46973781.
  60. Schramm BM, Orser BA (May 2002). "Dystonic reaction to propofol attenuated by benztropine (cogentin)". Anesthesia and Analgesia. 94 (5): 1237–40, table of contents. doi:10.1097/00000539-200205000-00034. PMID 11973196.
  61. Vesta KS, Martina SD, Kozlowski EA (May 2006). "Propofol-induced priapism, a case confirmed with rechallenge". The Annals of Pharmacotherapy. 40 (5): 980–982. doi:10.1345/aph.1G555. PMID 16638914. S2CID 36563320.
  62. Fuentes EJ, Garcia S, Garrido M, Lorenzo C, Iglesias JM, Sola JE (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.
  63. Kondili E, Alexopoulou C, Xirouchaki N, Georgopoulos D (October 2012). "Effects of propofol on sleep quality in mechanically ventilated critically ill patients: a physiological study". Intensive Care Medicine. 38 (10): 1640–1646. doi:10.1007/s00134-012-2623-z. PMID 22752356. S2CID 21206446.
  64. "Propofol (Intravenous Route) Side Effects - Mayo Clinic". Mayoclinic.org. Retrieved 24 January 2022.
  65. "AstraZeneca – United States Home Page" (PDF). .astrazeneca-us.com. Archived from the original (PDF) on 4 October 2011. Retrieved 8 June 2013.
  66. Kim TE, Shankel T, Reibling ET, Paik J, Wright D, Buckman M, et al. (1 January 2017). "Healthcare students interprofessional critical event/disaster response course". American Journal of Disaster Medicine. 12 (1): 11–26. doi:10.5055/ajdm.2017.0254. PMID 28822211.
  67. Vasile B, Rasulo F, Candiani A, Latronico N (September 2003). "The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome". Intensive Care Medicine. 29 (9): 1417–1425. doi:10.1007/s00134-003-1905-x. PMID 12904852. S2CID 23932736.
  68. Doheny K, Chang L, Vila Jr H (24 August 2009). "Propofol Linked to Michael Jackson's Death". WebMD. Archived from the original on 28 August 2009. Retrieved 26 August 2009.
  69. Trapani G, Altomare C, Liso G, Sanna E, Biggio G (February 2000). "Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery". Current Medicinal Chemistry. 7 (2): 249–271. doi:10.2174/0929867003375335. PMID 10637364.
  70. 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 & Therapeutics. 14 (2): 95–106. doi:10.1111/j.1527-3458.2008.00043.x. PMC 6494023. PMID 18482023.
  71. Vanlersberghe C, Camu F (2008). "Propofol". Modern Anesthetics. Handbook of Experimental Pharmacology. Vol. 182. pp. 227–52. doi:10.1007/978-3-540-74806-9_11. ISBN 978-3-540-72813-9. PMID 18175094.
  72. Trapani G, Latrofa A, Franco M, Altomare C, Sanna E, Usala M, et al. (May 1998). "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. 41 (11): 1846–1854. doi:10.1021/jm970681h. PMID 9599235.
  73. 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". The Journal of Pharmacology and Experimental Therapeutics. 297 (1): 338–351. PMID 11259561.
  74. Krasowski MD, Hong X, Hopfinger AJ, Harrison NL (July 2002). "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. 45 (15): 3210–3221. doi:10.1021/jm010461a. PMC 2864546. PMID 12109905.
  75. 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". European Journal of Anaesthesiology. 20 (3): 220–224. doi:10.1017/s0265021503000371. PMID 12650493. S2CID 25072723.
  76. Haeseler G, Karst M, Foadi N, Gudehus S, Roeder A, Hecker H, et al. (September 2008). "High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues". British Journal of Pharmacology. 155 (2): 265–275. doi:10.1038/bjp.2008.255. PMC 2538694. PMID 18574460.
  77. Fowler CJ (February 2004). "Possible involvement of the endocannabinoid system in the actions of three clinically used drugs". Trends in Pharmacological Sciences. 25 (2): 59–61. doi:10.1016/j.tips.2003.12.001. PMID 15106622.
  78. Schelling G (2006). "Effects of General Anesthesia on Anandamide Blood Levels in Humans". Anesthesiology. 104 (2): 273–277. doi:10.1097/00000542-200602000-00012. PMID 16436846. S2CID 27303365. Retrieved 11 December 2022.
  79. Lee U, Mashour GA, Kim S, Noh GJ, Choi BM (March 2009). "Propofol induction reduces the capacity for neural information integration: implications for the mechanism of consciousness and general anesthesia". Consciousness and Cognition. 18 (1): 56–64. doi:10.1016/j.concog.2008.10.005. PMID 19054696. S2CID 14699319.
  80. Patel S, Wohlfeil ER, Rademacher DJ, Carrier EJ, Perry LJ, Kundu A, et al. (July 2003). "The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase". British Journal of Pharmacology. 139 (5): 1005–1013. doi:10.1038/sj.bjp.0705334. PMC 1573928. PMID 12839875.
  81. Favetta P, Degoute CS, Perdrix JP, Dufresne C, Boulieu R, Guitton J (May 2002). "Propofol metabolites in man following propofol induction and maintenance". British Journal of Anaesthesia. 88 (5): 653–658. doi:10.1093/bja/88.5.653. PMID 12067002.
  82. 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): 749–764. doi:10.1097/00000542-199710000-00007. PMID 9357875. S2CID 30185553.
  83. James R, Glen JB (December 1980). "Synthesis, biological evaluation, and preliminary structure-activity considerations of a series of alkylphenols as intravenous anesthetic agents". Journal of Medicinal Chemistry. 23 (12): 1350–1357. doi:10.1021/jm00186a013. PMID 7452689.
  84. Lasker Foundation. "Discovery and development of propofol, a widely used anesthetic". The Lasker Foundation. Retrieved 25 July 2020.
  85. "Drugs@FDA: FDA Approved Drug Products". U.S. Food and Drug Administration (FDA). Archived from the original on 13 August 2014. Retrieved 8 June 2013.
  86. "Controlled Substnaces" (PDF). Diversion Control Division. Drug Enforcement Administration, U.S. Department of Justice. 1 September 2022. Archived (PDF) from the original on 17 April 2014. Retrieved 15 June 2014. pp. 3. accessed 23. January 2016
  87. Stein M, Middendorp SJ, Carta V, Pejo E, Raines DE, Forman SA, et al. (October 2012). "Azo-propofols: photochromic potentiators of GABA(A) receptors". Angewandte Chemie. 51 (42): 10500–10504. doi:10.1002/anie.201205475. PMC 3606271. PMID 22968919.
  88. Yip GM, Chen ZW, Edge CJ, Smith EH, Dickinson R, Hohenester E, et al. (November 2013). "A propofol binding site on mammalian GABAA receptors identified by photolabeling". Nature Chemical Biology. 9 (11): 715–720. doi:10.1038/nchembio.1340. PMC 3951778. PMID 24056400.
  89. Kvam C, Granese D, Flaibani A, Pollesello P, Paoletti S (June 1993). "Hyaluronan can be protected from free-radical depolymerisation by 2,6-diisopropylphenol, a novel radical scavenger". Biochemical and Biophysical Research Communications. 193 (3): 927–933. doi:10.1006/bbrc.1993.1714. PMID 8391811.
  90. Chen BZ, Yin XY, Jiang LH, Liu JH, Shi YY, Yuan BY (August 2022). "The efficacy and safety of ciprofol use for the induction of general anesthesia in patients undergoing gynecological surgery: a prospective randomized controlled study". BMC Anesthesiology. 22 (1): 245. doi:10.1186/s12871-022-01782-7. PMC 9347095. PMID 35922771.
Wikimedia Commons has media related to Propofol.
  • "Propofol". Drug Information Portal. U.S. National Library of Medicine.
  • GB patent 1472793, John B Glen & Roger James, "Pharmaceutical Compositions", published 1977-05-04, assigned to Imperial Chemical Industries Ltd
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