Jump to content

Propofol

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Ronhjones (talk | contribs) at 01:00, 28 July 2009 (Reverted edits by 99.147.87.135 to last revision by Nwbeeson (HG)). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Propofol
Clinical data
Pregnancy
category
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityNA
Protein binding95 to 99%
MetabolismHepatic glucuronidation
Elimination half-life30 to 60 min
ExcretionRenal
Identifiers
  • 2,6-Diisopropylphenol
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.016.551 Edit this at Wikidata
Chemical and physical data
FormulaC12H18O
Molar mass178.271 g/mol g·mol−1
3D model (JSmol)
  • CC(C)c1cccc(C(C)C)c1O

Propofol is a short-acting, intravenous, nonbarbiturate sedative agent used for the induction of general anesthesia for adults and children, maintenance of general anesthesia, and sedation in medical contexts, such as intensive care unit (ICU) sedation for intubated, mechanically ventilated adults, and in procedures such as colonoscopy and endoscopy, as well as in dental surgery. It has largely replaced sodium pentothal for induction of anesthesia. Recovery after propofol anaesthesia is rapid and 'clear' when compared to sodium pentothal.

Although propofol is not considered an analgesic drug,[1] one study has found a lower incidence of postoperative pain after propofol anesthesia compared to anesthesia with inhalation agents.[2] Propofol is approved for use in more than 50 countries.

As propofol is a potent sedative / hypnotic (dose dependent), anaesthesiologists usually premedicate their patient with IV opiates like fentanyl.

It is also commonly used in veterinary medicine.

Chemistry

20 ml ampoule of 1% propofol emulsion

Originally developed by Imperial Chemical Industries as ICI 35868, initial clinical trials followed in 1977 in a form solubilised in cremophor EL. However, due to anaphylactic reactions it was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water. This was re-launched in 1986 by AstraZeneca with the brand name Diprivan (shortened version of diisopropyl intravenous anesthetic). The current preparation is 1% propofol, 10% soybean oil and 1.2% purified egg phospholipid (emulsifier), with 2.25% of glycerol as a tonicity adjusting agent, and sodium hydroxide to adjust the pH. Diprivan contains EDTA as an antimicrobial agent. Newer generic formulations contain sodium metabisulfite or benzyl alcohol. Propofol emulsion appears as a highly opaque white fluid due to the scattering of light from the tiny (~150 nm) oil droplets that it contains. It resembles milk, and is jocularly called "milk of amnesia" by medical professionals.[3]

A water soluble prodrug form, fospropofol, has recently been developed and tested with positive results, being rapidly broken down once in the body by the enzyme alkaline phosphatase to form propofol. Marketed as Lusedra, this new formulation might well have superior properties for use in humans such as being more readily injectable and perhaps without the pain at injection site that often occurs with the traditional form of the drug. It was approved by the FDA in December 12, 2008.[4]

Pharmacology

Propofol is highly protein bound in vivo and is metabolised by conjugation in the liver.[5] Its rate of clearance exceeds hepatic blood flow, suggesting an extrahepatic site of elimination as well. It has several mechanisms of action,[6][7][8] both through potentiation of GABA-A receptor activity, thereby slowing the channel closing time,[9][10][11] and also acting as a sodium channel blocker.[12][13] Recent research has also suggested the endocannabinoid system may contribute significantly to propofol's anesthetic action and to its unique properties.[14]

The elimination half-life of propofol has been estimated to be between 2–24 hours. However, its duration of clinical effect is much shorter because propofol is rapidly distributed into peripheral tissues. When used for IV sedation, propofol typically wears off in minutes. Propofol is versatile; the drug can be given for short or prolonged sedation as well as for general anesthesia. Its use is not associated with nausea as is often seen with opioid medications. These characteristics of rapid onset and recovery along with its amnestic effects[15] have led to its widespread use for sedation and anesthesia.

Side effects

Aside from the hypotension (mainly through vasodilatation) and transient apnea following induction doses, one of propofol's most frequent side effects is pain on injection, especially in smaller veins. This pain can be mitigated by pretreatment with lidocaine.[16] Patients tend to show great variability in their response to propofol, at times showing profound sedation with small doses. A more serious but rare side effect is dystonia. Mild myoclonic movements are 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.

Another recently described rare, but serious, side effect is propofol infusion syndrome. This potentially lethal metabolic derangement has been reported in critically-ill patients after a prolonged infusion of high-dose propofol in combination with catecholamines and/or corticosteroids.[17]

Abuse

Despite a lack of analgesic properties, propofol has been reported to be used safely for the purposes of short-term recreation (though hazardous for long-term use)[18], as it produces mild euphoria, sexual hallucinations, and disinhibition[19][20] Use of propofol for recreation has occasionally been described, usually among medical staff such as anaesthetists who have access to the drug.[21]

However, abuse of the drug is rare due to its potency and the level of monitoring required to take it, and it has not been scheduled by the US Drug Enforcement Administration.[22] The steep dose response curve of the drug makes such abuse very dangerous without proper monitoring, and at least three deaths from self-administration have been recorded.[23][24]

References

  1. ^ Miner JR, Burton JH. Clinical practice advisory: Emergency department procedural sedation with propofol. Annals of Emergency Medicine. 2007 Aug;50(2):182–7, 187.e1. Epub 2007 Feb 23.
  2. ^ Cheng SS, Yeh J, & Flood P. (2008). Anesthesia matters: patients anesthetized with propofol have less postoperative pain than those anesthetized with isoflurane. Anesthesia and analgesia, 106(1), 264–9, table of contents.
  3. ^ Euliano TY, Gravenstein JS (2004). "A brief pharmacology related to anesthesia". Essential anesthesia: from science to practice. Cambridge, UK: Cambridge University Press. p. 173. ISBN 0-521-53600-6. {{cite book}}: |access-date= requires |url= (help); External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help)
  4. ^ "www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails".
  5. ^ Favetta P, Degoute C-S, Perdrix J-P, Dufresne C, Boulieu R, and Guitton J (2002). Propofol metabolites in man following propofol induction and maintenance. British Journal of Anaesthesia, 88, 653–8.
  6. ^ Trapani G, Altomare C, Liso G, Sanna E, Biggio G. Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery. Current Medicinal Chemistry. 2000 Feb;7(2):249-71. PMID 10637364
  7. ^ Kotani Y, Shimazawa M, Yoshimura S, Iwama T, Hara H. The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties. CNS Neuroscience and Therapeutics. 2008 Summer;14(2):95–106. PMID 18482023
  8. ^ Vanlersberghe C, Camu F. Propofol. Handbook of Experimental Pharmacology. 2008;(182):227-52. PMID 18175094
  9. ^ Trapani G, Latrofa A, Franco M, Altomare C, Sanna E, Usala M, Biggio G, Liso G. Propofol analogues. Synthesis, relationships between structure and affinity at GABAA receptor in rat brain, and differential electrophysiological profile at recombinant human GABAA receptors. Journal of Medicinal Chemistry. 1998 May 21;41(11):1846–54. PMID 9599235
  10. ^ Krasowski MD, Jenkins A, Flood P, Kung AY, Hopfinger AJ, Harrison NL. 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 of Pharmacology and Experimental Therapeutics. 2001 Apr;297(1):338-51. PMID 11259561
  11. ^ Krasowski MD, Hong X, Hopfinger AJ, Harrison NL. 4D-QSAR analysis of a set of propofol analogues: mapping binding sites for an anesthetic phenol on the GABA(A) receptor. Journal of Medicinal Chemistry. 2002 Jul 18;45(15):3210–21. PMID 12109905
  12. ^ Haeseler G, Leuwer M. High-affinity block of voltage-operated rat IIA neuronal sodium channels by 2,6 di-tert-butylphenol, a propofol analogue. European Journal of Anaesthesiology. 2003 Mar;20(3):220-4. PMID 12650493
  13. ^ Haeseler G, Karst M, Foadi N, Gudehus S, Roeder A, Hecker H, Dengler R, Leuwer M. High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues. British Journal of Pharmacology. 2008 Sep;155(2):265-75. PMID 18574460
  14. ^ Fowler, CJ. "Possible involvement of the endocannabinoid system in the actions of three clinically used drugs." Trends Pharmacol. Sci. 2004 Feb;25(2):59–61.
  15. ^ Veselis RA, Reinsel RA, Feshchenko VA, & Wroński M (1997). The comparative amnestic effects of midazolam, propofol, thiopental, and fentanyl at equisedative concentrations. Anesthesiology, 87, 749-64.
  16. ^ "Propofol Drug Information, Professional". drugs.com. Retrieved 2007-01-02. {{cite web}}: External link in |publisher= (help)
  17. ^ Vasile B, Rasulo F, Candiani A, Latronico N (2003). "The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome". Intensive care medicine. 29 (9): 1417–25. doi:10.1007/s00134-003-1905-x. PMID 12904852.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Brugada-like EKG pattern and myocardial effects in a chronic propofol abuser
  19. ^ In Sweetman SC (Ed.). Martindale: The Complete Drug Reference 2005. 34th Edn London pp. 1305–7
  20. ^ Baudoin Z. General anaesthetics and anaesthetic gases. In Dukes MNG and Aronson JK (Eds.). Meyler's Side Effects of Drugs 2000. 14th Edn Amsterdam pp. 330
  21. ^ Roussin A, Montastruc JL, Lapeyre-Mestre M. (October 21 2007). "Pharmacological and clinical evidences on the potential for abuse and dependence of propofol: a review of the literature". Fundamental and Clinical Pharmacology (5): 459-66. PMID 17868199. {{cite journal}}: Check date values in: |date= (help)CS1 maint: multiple names: authors list (link)
  22. ^ Jana Winter (2009-07-06). "Michael Jackson's Doctor Not Licensed to Prescribe Controlled Drugs in California". Fox News.
  23. ^ Iwersen-Bergmann S, Rösner P, Kühnau HC, Junge M, Schmoldt A (2001). "Death after excessive propofol abuse". International Journal of Legal Medicine. 114 (4–5): 248–51.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Kranioti EF, Mavroforou A, Mylonakis P, Michalodimitrakis M. (March 22 2007). "Lethal self administration of propofol (Diprivan): A case report and review of the literature". Forensic Science International. 167 (1): 56-8. accessdate= Jan 23 2006. {{cite journal}}: Check date values in: |date= (help); Missing pipe in: |page= (help)CS1 maint: multiple names: authors list (link)

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Propofol&oldid=304587650"