Propofol: Difference between revisions

{{Short description|Intravenous medication used in anesthesia}}

{{Distinguish|Propanol}}

{{cs1 config|name-list-style=vanc}}

{{Use dmy dates|date=March 2022}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 456484691

| drug_name =

| INN =

| type = <!-- empty -->

| image = Propofol.svg

| alt =

| image2 = Propofol molecule ball.png

| alt2 = Ball-and-stick model of propofol

| caption = <!-- Clinical data -->

| pronounce =

| tradename = Diprivan, others<ref>{{Cite web |title=Propofol |url=https://www.drugs.com/international/propofol.html |access-date=2 January 2019 |website=Drugs.com}}</ref>

| Drugs.com = {{drugs.com|monograph|Propofol}}

| MedlinePlus =

| licence_EU = <!-- EMA uses INN (or special INN_EMA) -->

| DailyMedID = Propofol

| licence_US = <!-- FDA may use generic or brand name (generic name preferred) -->

| pregnancy_AU = C

| pregnancy_AU_comment =

| pregnancy_category =

| addiction_liability = Moderate<ref name="What the ΔFosB?">{{cite journal | vauthors = Ruffle JK | title = Molecular neurobiology of addiction: what's all the (Δ)FosB about? | journal = The American Journal of Drug and Alcohol Abuse | volume = 40 | issue = 6 | pages = 428–437 | date = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 | quote = 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) | s2cid = 19157711 }}</ref>

| dependency_liability = [[Physical dependence|Physical]]: Very High <!-- {{Cawley MJ, Guse TM, Laroia A, Haith LR, Ackerman BH. Propofol withdrawal syndrome in an adult patient with thermal injury. Pharmacotherapy. 2003 Jul;23(7): 933-9. doi: 10.1592/phco.23.7.933.32728. PMID: 12885106 }} --><br />[[Psychological dependence|Psychological]]: no data

| class = [[GABA receptor agonist]];<br>[[sedative]];<br>[[hypnotic]]

| ATCvet =

| ATC_prefix = N01

| ATC_suffix = AX10

| ATC_supplemental = <!-- Legal status -->

| legal_AU = S4

| legal_AU_comment =

| legal_BR = C1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Rx-only

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = <ref name="Diprivan FDA label">{{Cite web |title=Diprivan- propofol injection, emulsion |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5cec3b97-5183-4a9d-accd-21e76c99d3dd |access-date=17 April 2021 |website=DailyMed}}</ref>

| legal_EU =

| legal_EU_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = Rx-only

<!-- Pharmacokinetic data -->| bioavailability = NA

| protein_bound = 95–99%

| metabolism = [[Liver]] [[glucuronidation]]

| metabolites =

| onset = 15–30 seconds<ref name="AHFS2016">{{Cite web |title=Propofol |url=https://www.drugs.com/monograph/Propofol.html |url-status=live |archive-url=https://web.archive.org/web/20161009184353/https://www.drugs.com/monograph/propofol.html |archive-date=9 October 2016 |access-date=21 January 2017 |publisher=The American Society of Health-System Pharmacists}}</ref>

| elimination_half-life = 1.5–31 hours<ref name=AHFS2016/>

| duration_of_action = ~5–10 minutes<ref name=AHFS2016/>

| excretion = [[Liver]]

<!-- Identifiers -->| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 2078-54-8

| CAS_supplemental =

| PubChem = 4943

| IUPHAR_ligand = 5464

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00818

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 4774

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = YI7VU623SF

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D00549

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 44915

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 526

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = <!-- Chemical and physical data -->

| IUPAC_name = 2,6-Diisopropylphenol <br /> 2,6-bis(propan-2-yl)phenol

| C = 12

| H = 18

| O = 1

| SMILES = CC(C)c1cccc(c1O)C(C)C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C12H18O/c1-8(2)10-6-5-7-11(9(3)4)12(10)13/h5-9,13H,1-4H3

| StdInChI_comment =

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = OLBCVFGFOZPWHH-UHFFFAOYSA-N

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility = ΔG_solv^H₂O = -4.39

| sol_units = [[kcal/mol]]<ref name="Arcario Mayne Tajkhorshid pp. 12075–12086">{{cite journal | vauthors = Arcario MJ, Mayne CG, Tajkhorshid E | title = Atomistic models of general anesthetics for use in in silico biological studies | journal = The Journal of Physical Chemistry B | volume = 118 | issue = 42 | pages = 12075–12086 | date = October 2014 | pmid = 25303275 | pmc = 4207551 | doi = 10.1021/jp502716m | publisher = American Chemical Society (ACS) }}</ref>

| specific_rotation =

<!-- Definition and medical uses -->'''Propofol'''<ref>{{Cite web | work = PubChem |title=Propofol |url=https://pubchem.ncbi.nlm.nih.gov/compound/4943 |access-date=2023-10-25 | publisher = U.S. National Library of Medicine |language=en}}</ref> 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 approved under the brand name '''Diprivan.''' Numerous generic versions have since been released. [[Intravenous therapy|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.<ref>{{Cite web |title=Making Stable, Sterile Propofol |url=https://www.microfluidics-mpt.com/blog/making-stable-sterile-propofol |access-date=2023-10-25 |website=www.microfluidics-mpt.com |language=en-us}}</ref>

Recovery from propofol-induced anesthesia is generally rapid and associated with less frequent side effects<ref>{{Cite web |title=Propofol |url=https://go.drugbank.com/drugs/DB00818 |access-date=2023-10-25 |website=go.drugbank.com |language=en}}</ref><ref>{{Cite journal |last=Glen |first=John Baird (Iain) |date=2018-09-25 |title=The Discovery and Development of Propofol Anesthesia: The 2018 Lasker-DeBakey Clinical Medical Research Award |url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2018.12756 |journal=JAMA |language=en |volume=320 |issue=12 |pages=1235–1236 |doi=10.1001/jama.2018.12756 |pmid=30208399 |issn=0098-7484}}</ref> (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 (medicine)|bolus]] or an [[Infusion therapy|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, later [[AstraZeneca]]),<ref>{{cite journal | vauthors = Glen JB |title=Try, try, and try again: personal reflections on the development of propofol |journal=British Journal of Anaesthesia |date=July 2019 |volume=123 |issue=1 |pages=3–9 |doi=10.1016/j.bja.2019.02.031|pmid=30982566 |s2cid=115198733 |doi-access=free }}</ref> 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 [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{Cite book |title=World Health Organization model list of essential medicines: 22nd list (2021) |vauthors=((World Health Organization)) |publisher=World Health Organization |year=2021 |location=Geneva |hdl=10665/345533 |id=WHO/MHP/HPS/EML/2021.02 |author-link=World Health Organization |hdl-access=free}}</ref>

==Uses==

===Anesthesia===

To induce general anesthesia, propofol is the drug used almost exclusively, having largely replaced [[sodium thiopental]].<ref>{{Cite web |title=Discovery and development of propofol, a widely used anesthetic |url=http://www.laskerfoundation.org/awards/show/discovery-and-development-propofol-widely-used-anesthetic/ |access-date=8 September 2020 |website=The Lasker Foundation |quote=Propofol is used today to initiate anesthesia in nearly 100% of general anesthesia cases worldwide.}}</ref>

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).<ref>{{Cite journal | vauthors = Gale T, Leslie K, Kluger M |date= December 2001 |title=Propofol anaesthesia via target controlled infusion or manually controlled infusion: effects on the bispectral index as a measure of anaesthetic depth |journal=Anaesthesia and Intensive Care |volume=29 |issue=6 |pages=579–584 |doi=10.1177/0310057X0102900602 |issn=0310-057X |pmid=11771598|s2cid= 27253877 |doi-access=free }}</ref>

Propofol is also used to sedate individuals who are receiving mechanical ventilation but not undergoing surgery, such as patients in the [[intensive care unit]].<ref name="Lewis_2018">{{cite journal | vauthors = Lewis SR, Schofield-Robinson OJ, Alderson P, Smith AF | title = Propofol for the promotion of sleep in adults in the intensive care unit | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD012454 | date = January 2018 | issue = 1 | pmid = 29308828 | pmc = 6353271 | doi = 10.1002/14651858.CD012454.pub2 }}</ref> In critically ill patients, propofol is superior to [[lorazepam]] both in effectiveness and overall cost.<ref name="Cox-2008">{{cite journal | vauthors = Cox CE, Reed SD, Govert JA, Rodgers JE, Campbell-Bright S, Kress JP, Carson SS | title = Economic evaluation of propofol and lorazepam for critically ill patients undergoing mechanical ventilation | journal = Critical Care Medicine | volume = 36 | issue = 3 | pages = 706–714 | date = March 2008 | pmid = 18176312 | pmc = 2763279 | doi = 10.1097/CCM.0B013E3181544248 }}</ref> Propofol is relatively inexpensive compared to medications of similar use due to shorter ICU stay length.<ref name="Cox-2008" /> One of the reasons propofol is thought to be more effective (although it has a longer half-life than [[lorazepam]]) is that studies have found that benzodiazepines like [[midazolam]] and lorazepam tend to accumulate in critically ill patients, prolonging sedation.<ref name="Cox-2008" />

Propofol has also been suggested as a [[sleep aid]] in critically ill adults in an ICU setting; however, the effectiveness of this medicine in replicating the mental and physical aspects of sleep for people in the ICU is not clear.<ref name="Lewis_2018" />

Propofol can be administered via a [[Intravenous therapy|peripheral IV]] or [[Central venous catheter|central line]]. Propofol is often paired with [[fentanyl]] (for pain relief) in intubated and sedated people.<ref name="Isert_1996">{{cite journal |vauthors=Isert PR, Lee D, Naidoo D, Carasso ML, Kennedy RA |date=June 1996 |title=Compatibility of propofol, fentanyl, and vecuronium mixtures designed for potential use in anesthesia and patient transport |journal=Journal of Clinical Anesthesia |volume=8 |issue=4 |pages=329–336 |doi=10.1016/0952-8180(96)00043-8 |pmid=8695138}}</ref> The two drugs are molecularly compatible in an IV mixture form.<ref name="Isert_1996" />

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.<ref name= "Gavel_2014">{{cite journal | vauthors = Gavel G, Walker RW | title = Laryngospasm in anaesthesia | journal = Continuing Education in Anaesthesia Critical Care & Pain | volume = 14 | issue = 2 | date = April 2014 | pages = 47–51 | doi = 10.1093/bjaceaccp/mkt031 | doi-access = free }}</ref>

===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]].<ref name="McQuaid-2008">{{cite journal |vauthors=McQuaid KR, Laine L |date=May 2008 |title=A systematic review and meta-analysis of randomized, controlled trials of moderate sedation for routine endoscopic procedures |journal=Gastrointestinal Endoscopy |volume=67 |issue=6 |pages=910–923 |doi=10.1016/j.gie.2007.12.046 |pmid=18440381}}</ref> It can also be combined with [[opioids]] or [[benzodiazepines]].<ref>Canadian National Formulary 2010</ref><ref>{{cite book |title=Appleton & Lange's 1999 drug guide |vauthors=Shannon MT, Wilson BA, Stang CL |date=1999 |publisher=Appleton & Lange |isbn=978-0-8385-0371-3 |location=Stamford, CT}}</ref><ref>Numorphan® (oxymorphone) package insert (English), Endo 2009</ref> Because of its rapid induction and recovery time, propofol is also widely used for sedation of infants and children undergoing [[MRI]] procedures.<ref>{{cite journal |vauthors=Machata AM, Willschke H, Kabon B, Kettner SC, Marhofer P |date=August 2008 |title=Propofol-based sedation regimen for infants and children undergoing ambulatory magnetic resonance imaging |journal=British Journal of Anaesthesia |volume=101 |issue=2 |pages=239–243 |doi=10.1093/bja/aen153 |pmid=18534971 |doi-access=free}}</ref> It is also often used in combination with [[ketamine]] with minimal side effects.<ref>{{cite journal |vauthors=Yan JW, McLeod SL, Iansavitchene A |date=September 2015 |title=Ketamine-Propofol Versus Propofol Alone for Procedural Sedation in the Emergency Department: A Systematic Review and Meta-analysis |journal=Academic Emergency Medicine |volume=22 |issue=9 |pages=1003–1013 |doi=10.1111/acem.12737 |pmid=26292077 |doi-access=free}}</ref>

===COVID-19===

{{anchor|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.<ref>{{Cite web |title=Propofol-Lipuro 1% (propofol) Injectable emulsion for infusion – 1,000 mg in 100 ml (10 mg /ml) : Fact Sheet for health Care Providers |url=https://www.bbraunusa.com/content/dam/b-braun/us/website/company/covid-files/210319_Propofol_EUA_Submission_to_FDA_hcp.pdf |access-date=5 March 2022 |website=Bbraunusa.com |archive-date=14 May 2021 |archive-url=https://web.archive.org/web/20210514065329/https://www.bbraunusa.com/content/dam/b-braun/us/website/company/covid-files/210319_Propofol_EUA_Submission_to_FDA_hcp.pdf |url-status=dead }}</ref><ref>{{Cite web |title=Letter RE: Emergency Use Authorization 096 |url=https://www.fda.gov/media/146680/download |access-date=5 March 2022 |website=Fda.gov}}</ref><ref>{{Cite web |title=Fact Sheet for Health Care Providers: Emergency Use Authorization (EUA) of Propofol-Lipuro 1% Injectable Emulsion for Infusion |url=https://www.fda.gov/media/146681/download |access-date=5 March 2022 |website=Fda.gov}}</ref><ref name="FDA EUA">{{Cite web |title=Emergency Use Authorization |url=https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization |access-date=17 April 2021 |website=U.S. [[Food and Drug Administration]] (FDA)}}</ref> During the public health emergency, it was considered unfeasible to limit Fresenius Propoven 2% Emulsion or Propofol-Lipuro 1% to patients with suspected or confirmed COVID-19, so it was made available to all ICU patients under mechanical ventilation.<ref name="FDA EUA" /> This EUA has since been revoked.<ref name="FDA EUA" />

===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.<ref>{{cite book |title=Harrison's Principles of Internal Medicine |vauthors=Rao VR, Lowenstein DH |date=2022 |publisher=McGraw Hill |isbn=978-1-264-26851-1 |veditors=Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J |edition=21st |chapter=Seizures and epilepsy. |chapter-url=https://accessmedicine.mhmedical.com/content.aspx?bookid=3095&sectionid=265447874}}</ref>

===Other uses===

====Assisted death in Canada====

A lethal dose of propofol is used for [[Euthanasia in Canada|medical assistance in dying in Canada]] to quickly induce deep coma and death, but [[Rocuronium bromide|rocuronium]] is always given as a [[paralytic]] ensuring death, even when the patient has died as a result of initial propofol overdose.<ref name="divisionsbc1">{{cite web |date=May 2017 |title=Medical Assistance in Dying (MAiD): Protocols and Procedures Handbook |url=https://divisionsbc.ca/sites/default/files/51936/Medical%20Assistance%20in%20Dying%20(MAID)%20Protocols%20and%20Procedures%20Handbook%20Comox%20Valley%202017%20-%202nd%20edition_0.pdf |work=Divisions of Family Practice |edition=2nd |vauthors=Reggler J, Daws T |location=Comox Valley, British Columbia}}</ref>

====Capital punishment====

Use of propofol as part of an execution protocol has been considered, although no individual has been executed using this agent. This is largely due to European manufacturers and governments banning the export of this propofol for such use.<ref>{{cite journal | vauthors = Kim E, Levy RJ | title = The role of anaesthesiologists in lethal injection: a call to action | journal = Lancet | volume = 395 | issue = 10225 | pages = 749–754 | date = February 2020 | pmid = 32014115 | pmc = 7416913 | doi = 10.1016/S0140-6736(19)32986-1 }}</ref><ref>{{Cite news |date=2013-11-15 |title=Lethal injection: Secretive US states resort to untested drugs |language=en-GB |work=BBC News |url=https://www.bbc.com/news/world-us-canada-24935868 |access-date=2023-11-08}}</ref>

====Recreational use====

Recreational use of the drug via self-administration has been reported<ref>{{cite journal | vauthors = Riezzo I, Centini F, Neri M, Rossi G, Spanoudaki E, Turillazzi E, Fineschi V | title = Brugada-like EKG pattern and myocardial effects in a chronic propofol abuser | journal = Clinical Toxicology | volume = 47 | issue = 4 | pages = 358–363 | date = April 2009 | pmid = 19514884 | doi = 10.1080/15563650902887842 | hdl = 11392/2357145 | s2cid = 22531823 }}</ref><ref>{{Cite news | vauthors = Belluck P |date=6 August 2009 |title=With High-Profile Death, Focus on High-Risk Drug |work=[[The New York Times]] |url=https://www.nytimes.com/2009/08/07/us/07propofol.html |url-status=live |access-date=7 August 2009 |archive-url=https://web.archive.org/web/20111111023529/http://www.nytimes.com/2009/08/07/us/07propofol.html |archive-date=11 November 2011 }}</ref> 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.<ref>{{cite journal | vauthors = Iwersen-Bergmann S, Rösner P, Kühnau HC, Junge M, Schmoldt A | title = Death after excessive propofol abuse | journal = International Journal of Legal Medicine | volume = 114 | issue = 4–5 | pages = 248–251 | year = 2001 | pmid = 11355404 | doi = 10.1007/s004149900129 | s2cid = 25963187 | citeseerx = 10.1.1.528.7395 }}</ref><ref>{{cite journal | vauthors = Kranioti EF, Mavroforou A, Mylonakis P, Michalodimitrakis M | title = Lethal self administration of propofol (Diprivan). A case report and review of the literature | journal = Forensic Science International | volume = 167 | issue = 1 | pages = 56–58 | date = March 2007 | pmid = 16431058 | doi = 10.1016/j.forsciint.2005.12.027 }}</ref> The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition.<ref>{{cite book | veditors = Sweetman SC | title = Martindale: The Complete Drug Reference | date = 2005 | edition = 34th | location = London | publisher = Pharmaceutical Press| pages = 1305–1307 | isbn = 978-0-85369-550-9 }}</ref><ref>{{cite book | vauthors = Baudoin Z | chapter = General anesthetics and anesthetic gases. | veditors = Dukes MN, Aronson JK | title = Meyler's Side Effects of Drugs | date = 2000 | edition = 14th | location = Amsterdam | publisher = Elsevier Science | page = 330 | isbn = 978-0-444-50093-9 }}</ref>

Recreational use of the drug has been described among medical staff, such as [[anesthetist]]s who have access to the drug.<ref name="Roussin">{{cite journal | vauthors = Roussin A, Montastruc JL, Lapeyre-Mestre M | title = Pharmacological and clinical evidences on the potential for abuse and dependence of propofol: a review of the literature | journal = Fundamental & Clinical Pharmacology | volume = 21 | issue = 5 | pages = 459–466 | date = October 2007 | pmid = 17868199 | doi = 10.1111/j.1472-8206.2007.00497.x | s2cid = 22477291 }}</ref><ref>{{cite journal | vauthors = Ward CF | title = Propofol: dancing with a "White Rabbit." | journal = California Society Anesthesiology Bulletin | date = 2008 | volume = 57 | issue = Spring | pages = 61–63 | url = https://csahq.org/docs/default-source/news-and-events-docs/csa-bulletin-docs/spring-2008/propofol_57_2.pdf | archive-url = https://web.archive.org/web/20170908190922/https://csahq.org/docs/default-source/news-and-events-docs/csa-bulletin-docs/spring-2008/propofol_57_2.pdf | archive-date=8 September 2017 | access-date = 24 November 2014 }}</ref> It is reportedly more common among anesthetists on rotations with short rest periods, as usage generally produces a well-rested feeling.<ref name="BMJ2009">{{cite journal | vauthors = Charatan F | title = Concerns mount over misuse of anaesthetic propofol among US health professionals | journal = BMJ | volume = 339 | pages = b3673 | date = September 2009 | pmid = 19737827 | doi = 10.1136/bmj.b3673 | s2cid = 9877560 }}</ref> Long-term use has been reported to result in addiction.<ref name=Roussin/><ref>{{cite journal | vauthors = Bonnet U, Harkener J, Scherbaum N | title = A case report of propofol dependence in a physician | journal = Journal of Psychoactive Drugs | volume = 40 | issue = 2 | pages = 215–217 | date = June 2008 | pmid = 18720673 | doi = 10.1080/02791072.2008.10400634 | s2cid = 15779389 }}</ref>

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]] [[Death of Michael Jackson|died]] from a mixture of propofol and the [[benzodiazepine]] drugs [[lorazepam]], [[midazolam]], and [[diazepam]] on 25 June 2009.<ref>{{Cite news | vauthors = Moore S |date=28 August 2009 |title=Jackson's Death Ruled a Homicide |work=[[The New York Times]] |url=https://www.nytimes.com/2009/08/29/us/29jackson.html |url-status=live |archive-url=https://web.archive.org/web/20131114065934/http://www.nytimes.com/2009/08/29/us/29jackson.html?hp |archive-date=14 November 2013 }}</ref><ref name="washingtonpost.com">{{Cite news | vauthors = Surdin A |date=25 August 2009 |title=Coroner Attributes Michael Jackson's Death to Propofol |newspaper=The Washington Post |url=https://www.washingtonpost.com/wp-dyn/content/article/2009/08/24/AR2009082402193.html |url-status=live |access-date=22 May 2010 |archive-url=https://web.archive.org/web/20121109132226/http://www.washingtonpost.com/wp-dyn/content/article/2009/08/24/AR2009082402193.html?hpid=moreheadlines |archive-date=9 November 2012 }}</ref><ref name="artsbeat.blogs.nytimes.com">{{Cite news | vauthors = Itzkoff D |date=24 August 2009 |title=Coroner's Findings in Jackson Death Revealed |work=The New York Times |url=http://artsbeat.blogs.nytimes.com/2009/08/24/coroners-findings-in-jackson-death-revealed/?hp |url-status=live |access-date=22 May 2010 |archive-url=https://web.archive.org/web/20100611151136/http://artsbeat.blogs.nytimes.com/2009/08/24/coroners-findings-in-jackson-death-revealed/?hp |archive-date=11 June 2010 }}</ref><ref>{{Cite magazine |date=25 August 2009 |title=Jackson's Death: How Dangerous Is Propofol? |url=http://www.time.com/time/arts/article/0,8599,1918363,00.html |url-status=dead |magazine=Time |archive-url=https://web.archive.org/web/20100725002645/http://www.time.com/time/arts/article/0,8599,1918363,00.html |archive-date=25 July 2010 |access-date=22 May 2010 }}</ref> 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.<ref name="washingtonpost.com" /><ref name="artsbeat.blogs.nytimes.com" /><ref>{{Cite web |title=Michael Jackson search warrant |url=https://www.scribd.com/doc/19058649/Michael-Jackson-search-warrant |url-status=live |archive-url=https://web.archive.org/web/20160305092954/https://www.scribd.com/doc/19058649/Michael-Jackson-search-warrant |archive-date=5 March 2016 |access-date=12 August 2015 |publisher=[[Scribd]] }}</ref>

==Manufacturing==

Propofol as a commercial sterile emulsified formulation is considered difficult to manufacture.<ref>{{cite journal | vauthors = Rooimans T, Damen M, Markesteijn CM, Schuurmans CC, de Zoete NH, van Hasselt PM, Hennink WE, van Nostrum CF, Hermes M, Besseling R, Vromans H | display-authors = 6 | title = Development of a compounded propofol nanoemulsion using multiple non-invasive process analytical technologies | journal = International Journal of Pharmaceutics | volume = 640 | pages = 122960 | date = June 2023 | pmid = 37061210 | doi = 10.1016/j.ijpharm.2023.122960 | pmc = 10101488 }}</ref><ref>{{cite journal | vauthors = Zorrilla-Vaca A, Arevalo JJ, Escandón-Vargas K, Soltanifar D, Mirski MA | title = Infectious Disease Risk Associated with Contaminated Propofol Anesthesia, 1989-2014(1) | language = en-us | journal = Emerging Infectious Diseases | volume = 22 | issue = 6 | pages = 981–992 | date = June 2016 | pmid = 27192163 | doi = 10.3201/eid2206.150376 | pmc = 4880094 }}</ref><ref>{{Cite patent | country = WO | number = 2014033751A2|title=Pharmaceutical composition of propofol|gdate=2014-03-06| inventor = Pramanick S, Gurjar S, Mehta SS | assign1 = Emcure Pharmaceuticals Limited |url=https://patents.google.com/patent/WO2014033751A2/en}}</ref>

It was initially formulated in [[Cremophor]] for human use, but this original formulation was implicated in an unacceptable number of [[Anaphylaxis|anaphylactic]] events. It was eventually manufactured as a 1% [[emulsion]] in soybean oil.<ref name="pmid30982566">{{cite journal | vauthors = Glen JB | title = Try, try, and try again: personal reflections on the development of propofol | journal = British Journal of Anaesthesia | volume = 123 | issue = 1 | pages = 3–9 | date = July 2019 | pmid = 30982566 | doi = 10.1016/j.bja.2019.02.031 | s2cid = 115198733 | doi-access = free }}</ref> Sterile emulsions represent complex formulation, the stability of which is dependent on the interplay of many factors such as [[micelle]] size and distribution.<ref>{{Cite web |title=Hospira recalls lot of Propofol Injectable Emulsion |url=https://www.europeanpharmaceuticalreview.com/news/173149/hospira-recalls-lot-of-propofol-injectable-emulsion/ |access-date=2023-11-08 |website=European Pharmaceutical Review |language=en}}</ref> <ref>{{Cite web |title=Understanding Emulsion Formulation {{!}} Ascendia Pharmaceuticals |url=https://ascendiapharma.com/newsroom/2021/11/08/emulsion-formulation |access-date=2023-11-08 |website=ascendiapharma.com |language=en}}</ref><ref>{{Cite web |title=Stability of Emulsion - an overview {{!}} ScienceDirect Topics |url=https://www.sciencedirect.com/topics/chemical-engineering/stability-of-emulsion#:~:text=The%20factors%20that%20influence%20the,increasing%20the%20stability%20of%20emulsion. |access-date=2023-11-09 |website=www.sciencedirect.com}}</ref>

==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]],<ref>{{cite journal | vauthors = Matta JA, Cornett PM, Miyares RL, Abe K, Sahibzada N, Ahern GP | title = General anesthetics activate a nociceptive ion channel to enhance pain and inflammation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 25 | pages = 8784–8789 | date = June 2008 | pmid = 18574153 | pmc = 2438393 | doi = 10.1073/pnas.0711038105 | doi-access = free }}</ref> found on sensory nerves and can be mitigated by pretreatment with [[lidocaine]].<ref>{{Cite web |title=Propofol Drug Information, Professional |url=https://www.drugs.com/MMX/Propofol.html |url-status=live |archive-url=https://web.archive.org/web/20070123141308/http://www.drugs.com/MMX/Propofol.html |archive-date=23 January 2007 |access-date=2 January 2007 |publisher=m drugs.com }}</ref> 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 [[hypotension|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.<ref name="Sebel PS 1989">{{cite journal | vauthors = Sebel PS, Lowdon JD | title = Propofol: a new intravenous anesthetic | journal = Anesthesiology | volume = 71 | issue = 2 | pages = 260–277 | date = August 1989 | pmid = 2667401 | doi = 10.1097/00000542-198908000-00015 | s2cid = 34331379 | doi-access = free }}</ref> Reports of blood pressure drops of 30% or more are thought to be at least partially due to inhibition of [[sympathetic nerve]] activity.<ref>{{cite journal | vauthors = Robinson BJ, Ebert TJ, O'Brien TJ, Colinco MD, Muzi M | title = Mechanisms whereby propofol mediates peripheral vasodilation in humans. Sympathoinhibition or direct vascular relaxation? | journal = Anesthesiology | volume = 86 | issue = 1 | pages = 64–72 | date = January 1997 | pmid = 9009941 | doi = 10.1097/00000542-199701000-00010 | s2cid = 31288656 | doi-access = free }}</ref> This effect is related to the dose and rate of propofol administration. It may also be potentiated by [[opiate|opioid analgesics]].<ref>{{Cite journal |year=1987 |title=New awakening in anaesthesia—at a price |journal=Lancet |volume=329 |issue=8548 |pages=1469–70 |doi=10.1016/s0140-6736(87)92214-8 |s2cid=28545161}}</ref>

Propofol can also cause decreased [[systemic vascular resistance]], myocardial blood flow, and oxygen consumption, possibly through direct vasodilation.<ref>{{cite journal | vauthors = Larijani GE, Gratz I, Afshar M, Jacobi AG | title = Clinical pharmacology of propofol: an intravenous anesthetic agent | journal = DICP| volume = 23 | issue = 10 | pages = 743–749 | date = October 1989 | pmid = 2683416 | doi = 10.1177/106002808902301001 | s2cid = 43010280 }}</ref> There are also reports that it may cause green discoloration of the urine.<ref>{{cite journal | vauthors = Lee JS, Jang HS, Park BJ | title = Green discoloration of urine after propofol infusion | journal = Korean Journal of Anesthesiology | volume = 65 | issue = 2 | pages = 177–179 | date = August 2013 | pmid = 24024005 | pmc = 3766788 | doi = 10.4097/kjae.2013.65.2.177 }}</ref>

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.<ref>{{cite journal | vauthors = Parke TJ, Stevens JE, Rice AS, Greenaway CL, Bray RJ, Smith PJ, Waldmann CS, Verghese C | display-authors = 6 | title = Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports | journal = BMJ | volume = 305 | issue = 6854 | pages = 613–616 | date = September 1992 | pmid = 1393073 | pmc = 1883365 | doi = 10.1136/bmj.305.6854.613 }}</ref>

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.<ref>{{cite journal | vauthors = Langley MS, Heel RC | title = Propofol. A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic | journal = Drugs | volume = 35 | issue = 4 | pages = 334–372 | date = April 1988 | pmid = 3292208 | doi = 10.2165/00003495-198835040-00002 | doi-access = free }}</ref> 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]].<ref name="Sebel PS 1989" />

Propofol administration also results in decreased cerebral blood flow, cerebral metabolic oxygen consumption, and [[intracranial pressure]].<ref>{{cite journal | vauthors = Bailey JM, Mora CT, Shafer SL | title = Pharmacokinetics of propofol in adult patients undergoing coronary revascularization. The Multicenter Study of Perioperative Ischemia Research Group | journal = Anesthesiology | volume = 84 | issue = 6 | pages = 1288–1297 | date = June 1996 | pmid = 8669668 | doi = 10.1097/00000542-199606000-00003 | s2cid = 26019589 | doi-access = free }}</ref> In addition, propofol may decrease [[intraocular pressure]] by as much as 50% in patients with normal intraocular pressure.<ref>{{cite journal | vauthors = Reilly CS, Nimmo WS | title = New intravenous anaesthetics and neuromuscular blocking drugs. A review of their properties and clinical use | journal = Drugs | volume = 34 | issue = 1 | pages = 98–135 | date = July 1987 | pmid = 3308413 | doi = 10.2165/00003495-198734010-00004 | s2cid = 46973781 }}</ref>

A more serious but rare side effect is [[dystonia]].<ref>{{cite journal | vauthors = Schramm BM, Orser BA | title = Dystonic reaction to propofol attenuated by benztropine (cogentin) | journal = Anesthesia and Analgesia | volume = 94 | issue = 5 | pages = 1237–40, table of contents | date = May 2002 | pmid = 11973196 | doi = 10.1097/00000539-200205000-00034 | doi-access = free }}</ref> 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|date=November 2014}}

Propofol is also reported to induce [[priapism]] in some individuals,<ref name="Annals Priapism">{{cite journal | vauthors = Vesta KS, Martina SD, Kozlowski EA | title = Propofol-induced priapism, a case confirmed with rechallenge | journal = The Annals of Pharmacotherapy | volume = 40 | issue = 5 | pages = 980–982 | date = May 2006 | pmid = 16638914 | doi = 10.1345/aph.1G555 | s2cid = 36563320 }}</ref><ref name="Fuentesa">{{cite journal | vauthors = Fuentes EJ, Garcia S, Garrido M, Lorenzo C, Iglesias JM, Sola JE | title = Successful treatment of propofol-induced priapism with distal glans to corporal cavernosal shunt | journal = Urology | volume = 74 | issue = 1 | pages = 113–115 | date = July 2009 | pmid = 19371930 | doi = 10.1016/j.urology.2008.12.066 }}</ref> and has been observed to suppress REM sleep stage and to worsen the poor sleep quality in some patients.<ref>{{cite journal | vauthors = Kondili E, Alexopoulou C, Xirouchaki N, Georgopoulos D | title = Effects of propofol on sleep quality in mechanically ventilated critically ill patients: a physiological study | journal = Intensive Care Medicine | volume = 38 | issue = 10 | pages = 1640–1646 | date = October 2012 | pmid = 22752356 | doi = 10.1007/s00134-012-2623-z | s2cid = 21206446 | doi-access = free }}</ref>

Rare side effects include:<ref>{{Cite web |title=Propofol (Intravenous Route) Side Effects - Mayo Clinic |url=https://www.mayoclinic.org/drugs-supplements/propofol-intravenous-route/side-effects/drg-20488192?p=1 |access-date=24 January 2022 |website=Mayoclinic.org}}</ref>

* 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.<ref>{{Cite web |title=AstraZeneca – United States Home Page |url=http://www1.astrazeneca-us.com/pi/diprivan.pdf |url-status=dead |archive-url=https://web.archive.org/web/20111004154816/http://www1.astrazeneca-us.com/pi/diprivan.pdf |archive-date=4 October 2011 |access-date=8 June 2013 |publisher=.astrazeneca-us.com }}</ref>

Because of propofol's formulation (using lecithin and soybean oil) it is prone to bacterial contamination, despite the presence of the bacterial inhibitor benzyl alcohol; consequently, 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 potential infection.<ref>{{cite journal | vauthors = Kim TE, Shankel T, Reibling ET, Paik J, Wright D, Buckman M, Wild K, Ngo E, Hayatshahi A, Nguyen LH, Denmark TK, Thomas TL | display-authors = 6 | title = Healthcare students interprofessional critical event/disaster response course | journal = American Journal of Disaster Medicine | volume = 12 | issue = 1 | pages = 11–26 | date = 1 January 2017 | pmid = 28822211 | doi = 10.5055/ajdm.2017.0254 }}</ref>

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 [[catecholamine]]s and/or [[corticosteroid]]s.<ref>{{cite journal | vauthors = Vasile B, Rasulo F, Candiani A, Latronico N | title = The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome | journal = Intensive Care Medicine | volume = 29 | issue = 9 | pages = 1417–1425 | date = September 2003 | pmid = 12904852 | doi = 10.1007/s00134-003-1905-x | s2cid = 23932736 }}</ref>

== Interactions ==

The respiratory effects of propofol are increased if given with other [[hypoventilation|respiratory depressant]]s, including [[benzodiazepine]]s.<ref name="WebMD 2009-08-24">{{Cite news | vauthors = Doheny K, Chang L, Vila Jr H |date=24 August 2009 |title=Propofol Linked to Michael Jackson's Death |publisher=[[WebMD]] |url=http://www.webmd.com/pain-management/news/20090824/propofol-linked-to-michael-jacksons-death |url-status=live |access-date=26 August 2009 |archive-url=https://web.archive.org/web/20090828022308/http://www.webmd.com/pain-management/news/20090824/propofol-linked-to-michael-jacksons-death |archive-date=28 August 2009 }}</ref>

==Pharmacology==

===Pharmacodynamics===

Propofol has been proposed to have several mechanisms of action,<ref>{{cite journal | vauthors = Trapani G, Altomare C, Liso G, Sanna E, Biggio G | title = Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery | journal = Current Medicinal Chemistry | volume = 7 | issue = 2 | pages = 249–271 | date = February 2000 | pmid = 10637364 | doi = 10.2174/0929867003375335 }}</ref><ref>{{cite journal | vauthors = Kotani Y, Shimazawa M, Yoshimura S, Iwama T, Hara H | title = The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties | journal = CNS Neuroscience & Therapeutics | volume = 14 | issue = 2 | pages = 95–106 | date = Summer 2008 | pmid = 18482023 | pmc = 6494023 | doi = 10.1111/j.1527-3458.2008.00043.x }}</ref><ref>{{Cite book | vauthors = Vanlersberghe C, Camu F |title=Modern Anesthetics |chapter=Propofol |series=Handbook of Experimental Pharmacology |year=2008 |isbn=978-3-540-72813-9 |volume=182 |pages=227–52 |doi=10.1007/978-3-540-74806-9_11 |pmid=18175094 |issue=182}}</ref> both through potentiation of [[GABA A receptor|GABA_A]] receptor activity and therefore acting as a [[GABAA receptor positive allosteric modulator|GABA_A receptor positive allosteric modulator]], thereby slowing the channel-closing time. At high doses, propofol may be able to activate GABA_A receptors in the absence of GABA, behaving as a [[GABA receptor agonist|GABA_A receptor agonist]] as well.<ref>{{cite journal | vauthors = Trapani G, Latrofa A, Franco M, Altomare C, Sanna E, Usala M, Biggio G, Liso G | display-authors = 6 | title = Propofol analogues. Synthesis, relationships between structure and affinity at GABAA receptor in rat brain, and differential electrophysiological profile at recombinant human GABAA receptors | journal = Journal of Medicinal Chemistry | volume = 41 | issue = 11 | pages = 1846–1854 | date = May 1998 | pmid = 9599235 | doi = 10.1021/jm970681h }}</ref><ref>{{cite journal | vauthors = Krasowski MD, Jenkins A, Flood P, Kung AY, Hopfinger AJ, Harrison NL | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 297 | issue = 1 | pages = 338–351 | date = April 2001 | pmid = 11259561 }}</ref><ref>{{cite journal | vauthors = Krasowski MD, Hong X, Hopfinger AJ, Harrison NL | title = 4D-QSAR analysis of a set of propofol analogues: mapping binding sites for an anesthetic phenol on the GABA(A) receptor | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 15 | pages = 3210–3221 | date = July 2002 | pmid = 12109905 | pmc = 2864546 | doi = 10.1021/jm010461a }}</ref> Propofol analogs have been shown to also act as [[sodium channel]] blockers.<ref>{{cite journal | vauthors = Haeseler G, Leuwer M | title = High-affinity block of voltage-operated rat IIA neuronal sodium channels by 2,6 di-tert-butylphenol, a propofol analogue | journal = European Journal of Anaesthesiology | volume = 20 | issue = 3 | pages = 220–224 | date = March 2003 | pmid = 12650493 | doi = 10.1017/s0265021503000371 | doi-broken-date = 16 August 2024 | s2cid = 25072723 }}</ref><ref>{{cite journal | vauthors = Haeseler G, Karst M, Foadi N, Gudehus S, Roeder A, Hecker H, Dengler R, Leuwer M | display-authors = 6 | title = High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues | journal = British Journal of Pharmacology | volume = 155 | issue = 2 | pages = 265–275 | date = September 2008 | pmid = 18574460 | pmc = 2538694 | doi = 10.1038/bjp.2008.255 }}</ref> 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 [[Vomiting|emesis]].<ref>{{cite journal | vauthors = Fowler CJ | title = Possible involvement of the endocannabinoid system in the actions of three clinically used drugs | journal = Trends in Pharmacological Sciences | volume = 25 | issue = 2 | pages = 59–61 | date = February 2004 | pmid = 15106622 | doi = 10.1016/j.tips.2003.12.001 }}</ref><ref name="Schelling_2006" /> An [[Electroencephalography|EEG]] study on patients undergoing general anesthesia with propofol found that it causes a prominent reduction in the brain's information integration capacity.<ref name="Lee">{{cite journal | vauthors = Lee U, Mashour GA, Kim S, Noh GJ, Choi BM | title = Propofol induction reduces the capacity for neural information integration: implications for the mechanism of consciousness and general anesthesia | journal = Consciousness and Cognition | volume = 18 | issue = 1 | pages = 56–64 | date = March 2009 | pmid = 19054696 | doi = 10.1016/j.concog.2008.10.005 | s2cid = 14699319 }}</ref>

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 [[Cannabinoid receptor type 1|CB1]] receptor activation.<ref>{{cite journal | vauthors = Patel S, Wohlfeil ER, Rademacher DJ, Carrier EJ, Perry LJ, Kundu A, Falck JR, Nithipatikom K, Campbell WB, Hillard CJ | display-authors = 6 | title = The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase | journal = British Journal of Pharmacology | volume = 139 | issue = 5 | pages = 1005–1013 | date = July 2003 | pmid = 12839875 | pmc = 1573928 | doi = 10.1038/sj.bjp.0705334 }}</ref> This may explain the [[Psychotomimetism|psychotomimetic]] and [[antiemetic]] properties of propofol. By contrast, there is a high incidence of postoperative nausea and vomiting after administration of [[Inhalational anesthetic|volatile anesthetics]], which contribute to a significant decrease in the whole-brain content of AEA that can last up to forty minutes after induction.<ref name="Schelling_2006">{{Cite journal | vauthors = Schelling G |date=2006 |title=Effects of General Anesthesia on Anandamide Blood Levels in Humans |url=https://pubs.asahq.org/anesthesiology/article/104/2/273/630/Effects-of-General-Anesthesia-on-Anandamide-Blood |access-date=2022-12-11 |journal=Anesthesiology|volume=104 |issue=2 |pages=273–277 |doi=10.1097/00000542-200602000-00012 |pmid=16436846 |s2cid=27303365 |doi-access=free }}</ref>

===Pharmacokinetics===

[[Image:Propofol.jpg|thumb|A 20&nbsp;ml ampoule of 1% propofol emulsion, as sold in Australia by [[Sandoz]]|alt=Large vial filled with milky white fluid]]

Propofol is highly protein-bound ''in vivo'' and is metabolized by [[xenobiotic conjugation|conjugation]] in the liver.<ref>{{cite journal | vauthors = Favetta P, Degoute CS, Perdrix JP, Dufresne C, Boulieu R, Guitton J | title = Propofol metabolites in man following propofol induction and maintenance | journal = British Journal of Anaesthesia | volume = 88 | issue = 5 | pages = 653–658 | date = May 2002 | pmid = 12067002 | doi = 10.1093/bja/88.5.653 | doi-access = free }}</ref> The [[biological half-life|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.<ref name="AHFS2016" /> 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<ref>{{cite journal | vauthors = Veselis RA, Reinsel RA, Feshchenko VA, Wroński M | title = The comparative amnestic effects of midazolam, propofol, thiopental, and fentanyl at equisedative concentrations | journal = Anesthesiology | volume = 87 | issue = 4 | pages = 749–764 | date = October 1997 | pmid = 9357875 | doi = 10.1097/00000542-199710000-00007 | s2cid = 30185553 | doi-access = free }}</ref> 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 ''[[arene substitution patterns|ortho]]''-[[alkylated]] [[phenol]]s.<ref>{{cite journal | vauthors = James R, Glen JB | title = Synthesis, biological evaluation, and preliminary structure-activity considerations of a series of alkylphenols as intravenous anesthetic agents | journal = Journal of Medicinal Chemistry | volume = 23 | issue = 12 | pages = 1350–1357 | date = December 1980 | pmid = 7452689 | doi = 10.1021/jm00186a013 }}</ref>

First identified as a drug candidate in 1973, propofol entered clinical trials in 1977, using a form solubilized in [[cremophor EL]].<ref>{{Cite web | author = Lasker Foundation |title=Discovery and development of propofol, a widely used anesthetic |url=http://www.laskerfoundation.org/awards/show/discovery-and-development-propofol-widely-used-anesthetic/ |access-date=25 July 2020 |website=The Lasker Foundation}}</ref> However, due to [[anaphylaxis|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 lecithin|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 ([[bacteriostatic]]ally against some bacteria) and synergistically with some other [[antimicrobial]] agents. Newer generic formulations contain [[sodium metabisulfite]] as an antioxidant and [[benzyl alcohol]] as antimicrobial agent. Propofol emulsion is an opaque white fluid due to the [[Tyndall Effect|scattering of light]] from the emulsified micelle formulation.

== 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.<ref>{{Cite web |title=Drugs@FDA: FDA Approved Drug Products |url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails |url-status=live |archive-url=https://web.archive.org/web/20140813131107/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails |archive-date=13 August 2014 |access-date=8 June 2013 |publisher=U.S. [[Food and Drug Administration]] (FDA) }}</ref>

By incorporation of an [[azobenzene]] unit, a photoswitchable version of propofol (AP2) was developed in 2012 that allows for optical control of [[GABAA receptor|GABA_A receptors]] with light.<ref name="anie201205475">{{cite journal | vauthors = Stein M, Middendorp SJ, Carta V, Pejo E, Raines DE, Forman SA, Sigel E, Trauner D | display-authors = 6 | title = Azo-propofols: photochromic potentiators of GABA(A) receptors | journal = Angewandte Chemie | volume = 51 | issue = 42 | pages = 10500–10504 | date = October 2012 | pmid = 22968919 | pmc = 3606271 | doi = 10.1002/anie.201205475 }}</ref> In 2013, a propofol binding site on mammalian GABA_A receptors has been identified by photolabeling using a [[diazirine]] derivative.<ref name="nchembio.1340">{{cite journal | vauthors = Yip GM, Chen ZW, Edge CJ, Smith EH, Dickinson R, Hohenester E, Townsend RR, Fuchs K, Sieghart W, Evers AS, Franks NP | display-authors = 6 | title = A propofol binding site on mammalian GABAA receptors identified by photolabeling | journal = Nature Chemical Biology | volume = 9 | issue = 11 | pages = 715–720 | date = November 2013 | pmid = 24056400 | pmc = 3951778 | doi = 10.1038/nchembio.1340 }}</ref> Additionally, it was shown that the [[hyaluronan]] polymer present in the [[synovia]] can be protected from [[free-radical]] [[depolymerization]] by propofol.<ref name="kvam">{{cite journal | vauthors = Kvam C, Granese D, Flaibani A, Pollesello P, Paoletti S | title = Hyaluronan can be protected from free-radical depolymerisation by 2,6-diisopropylphenol, a novel radical scavenger | journal = Biochemical and Biophysical Research Communications | volume = 193 | issue = 3 | pages = 927–933 | date = June 1993 | pmid = 8391811 | doi = 10.1006/bbrc.1993.1714 }}</ref>

[[Ciprofol]] is another derivative of propofol that is 4–6 times more potent than propofol. {{asof|2022}} it is undergoing [[Phases of clinical research#Phase III|Phase III]] trials. Ciprofol appears to have a lower incidence of injection site pain and respiratory depression than propofol.<ref name=Chen2022BMCA>{{cite journal | vauthors = Chen BZ, Yin XY, Jiang LH, Liu JH, Shi YY, Yuan BY | title = The efficacy and safety of ciprofol use for the induction of general anesthesia in patients undergoing gynecological surgery: a prospective randomized controlled study | journal = BMC Anesthesiology | volume = 22 | issue = 1 | pages = 245 | date = August 2022 | pmid = 35922771 | pmc = 9347095 | doi = 10.1186/s12871-022-01782-7 | doi-access = free }}</ref>

Propofol has also been studied for [[treatment resistant depression]].<ref>{{cite journal | vauthors = Wu G, Xu H | title = A synopsis of multitarget therapeutic effects of anesthetics on depression | journal = European Journal of Pharmacology | volume = 957 | pages = 176032 | date = October 2023 | pmid = 37660970 | doi = 10.1016/j.ejphar.2023.176032 | s2cid = 261479363 }}</ref>

== References ==

{{reflist}}

== External links ==

{{Commons category}}

* {{Cite web |title=Propofol |url=https://druginfo.nlm.nih.gov/drugportal/name/propofol |website=Drug Information Portal |publisher=U.S. National Library of Medicine}}

* {{cite patent |country=GB |number=1472793 |status=patent |title=Pharmaceutical Compositions |pubdate=1977-05-04 |fdate=1974-03-28 |pridate=1974-03-28 |invent1=John B Glen |invent2=Roger James |assign1=Imperial Chemical Industries Ltd |url=https://worldwide.espacenet.com/publicationDetails/biblio?II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=19770504&CC=GB&NR=1472793A&KC=A}}

{{General anesthetics}}

{{Sedatives}}

{{GABAAR PAMs}}

{{Glycinergics}}

{{AstraZeneca}}

{{Portal bar|Medicine}}

{{Authority control}}

[[Category:Drugs developed by AstraZeneca]]

[[Category:Chemical substances for emergency medicine]]

[[Category:General anesthetics]]

[[Category:GABAA receptor positive allosteric modulators]]

[[Category:GABAA receptor agonists]]

[[Category:Glycine receptor agonists]]

[[Category:Alkylphenols]]

[[Category:World Health Organization essential medicines]]

[[Category:Wikipedia medicine articles ready to translate]]

[[Category:Isopropyl compounds]]