Propofol[7] is the active component of an intravenousanesthetic formulation used for induction and maintenance ofgeneral anesthesia. The formulation was approved under the brand nameDiprivan. Numerous generic versions have since been released.Intravenous administration is used to induceunconsciousness, after which anesthesia may be maintained using a combination of medications. It is manufactured as part of a sterile injectableemulsion formulation using soybean oil andlecithin, giving it a white milky coloration.[8]
Compared to other anesthetic agents, recovery from propofol-induced anesthesia is generally rapid and associated with less frequent side effects[9][10] (e.g., drowsiness, nausea, vomiting). Propofol may be used prior todiagnostic procedures requiring anesthesia, in the management of refractorystatus epilepticus, and for induction or maintenance of anesthesia prior to and duringsurgeries. It may be administered as abolus or aninfusion, or as a combination of the two.
To induce general anesthesia, propofol is the drug used almost exclusively, having largely replacedsodium thiopental.[13]
It is often administered as part of an anesthesia maintenance technique calledtotal intravenous anesthesia, using either manually programmed infusion pumps or computer-controlled infusion pumps in a process calledtarget controlled infusion (TCI).[14]
Propofol is also used to sedate people who are receiving mechanical ventilation but not undergoing surgery, such as patients in theintensive care unit.[15] In critically ill patients, propofol is superior tolorazepam both in effectiveness and overall cost.[16] Propofol is relatively inexpensive compared to medications of similar use due to shorter ICU stay length.[16] One of the reasons propofol is thought to be more effective (although it has a longer half-life thanlorazepam) is that studies have found that benzodiazepines likemidazolam and lorazepam tend to accumulate in critically ill patients, prolonging sedation.[16]
Propofol has also been suggested as asleep 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.[15]
Propofol can be administered via aperipheral IV orcentral line. Propofol is often paired withfentanyl (for pain relief) in intubated and sedated people.[17] The two drugs are molecularly compatible in an IV mixture form.[17]
Propofol is also used to deepen anesthesia to relievelaryngospasm. It may be used alone or followed bysuccinylcholine. Its use can avoid the need for paralysis and in some instances the potential side-effects of succinylcholine.[18]
Propofol is safe and effective for gastrointestinal endoscopy procedures (colonoscopies etc.). Its use in these settings results in a faster recovery compared tomidazolam.[19] It can also be combined withopioids orbenzodiazepines.[20][21][22] Because of its rapid induction and recovery time, propofol is also widely used for sedation of infants and children undergoingMRI procedures.[23] It is also often used in combination withketamine with minimal side effects.[24]
In March 2021, the U.S.Food and Drug Administration (FDA) issued anemergency use authorization (EUA) forPropofol‐Lipuro 1% to maintain sedation via continuous infusion in people older than sixteen with suspected or confirmed COVID-19 who require mechanical ventilation in anintensive care unit ICU setting.[25][26][27][28] 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.[28] This EUA has since been revoked.[29]
Status epilepticus may be defined as seizure activity lasting beyond five minutes and needing anticonvulsant medication. Several guidelines recommend the use of propofol for the treatment of refractory status epilepticus.[30]
A lethal dose of propofol is used formedical assistance in dying in Canada to quickly induce deep coma and death, butrocuronium is always given as aparalytic ensuring death, even when the patient has died as a result of initial propofol overdose.[31]
The use of propofol as part of an execution protocol has been considered, although no person has been executed using this agent. This is largely due to European manufacturers and governments banning the export of propofol for such use.[32][33]
Recreational use of the drug via self-administration has been reported[34][35] but is relatively rare due to its potency and the level of monitoring required for safe use. Critically, a steepdose-response curve makes recreational use of propofol very dangerous, and deaths from self-administration continue to be reported.[36][37] The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition.[38][39]
Recreational use of the drug has been described among medical staff, such asanesthetists who have access to the drug.[40][41] It is reportedly more common among anesthetists on rotations with short rest periods, as usage generally produces a well-rested feeling.[42] Long-term use has been reported to result in addiction.[40][43]
Attention to the risks ofoff-label use of propofol increased in August 2009, after the release of the Los Angeles County coroner's report that musicianMichael Jackson waskilled by a mixture of propofol and thebenzodiazepine drugslorazepam,midazolam, anddiazepam on 25 June 2009.[44][45][46][47] 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 withlidocaine shortly before Jackson's death.[45][46][48]
Propofol as a commercial sterile emulsified formulation is considered difficult to manufacture.[49][50][51]
It was initially formulated inCremophor for human use, but this original formulation was implicated in an unacceptable number ofanaphylactic events. It was eventually manufactured as a 1%emulsion in soybean oil.[52] Sterile emulsions represent complex formulation, the stability of which is dependent on the interplay of many factors such asmicelle size and distribution.[53][54]
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,[55] found on sensory nerves and can be mitigated by pretreatment withlidocaine.[56] 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 includelow blood pressure related tovasodilation, transientapnea following induction doses, and cerebrovascular effects. Propofol has more pronounced hemodynamic effects relative to many intravenous anesthetic agents.[57] Reports of blood pressure drops of 30% or more are thought to be at least partially due to inhibition ofsympathetic nerve activity.[58] This effect is related to the dose and rate of propofol administration. It may also be potentiated byopioid analgesics.[59]
Propofol can also cause decreasedsystemic vascular resistance, myocardial blood flow, and oxygen consumption, possibly through direct vasodilation.[60] There are also reports that it may cause green discoloration of the urine.[61]
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.[62]
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.[63] Possibly as the result of depression of the central inspiratory drive, propofol may produce significant decreases inrespiratory rate,minute volume,tidal volume, mean inspiratory flow rate, andfunctional residual capacity.[57]
Propofol administration also results in decreased cerebral blood flow, cerebral metabolic oxygen consumption, andintracranial pressure.[64] In addition, propofol may decreaseintraocular pressure by as much as 50% in patients with normal intraocular pressure.[65]
Propofol is also reported to inducepriapism in some individuals,[67][68] and has been observed to suppress REM sleep and to worsen the poor sleep quality in some patients.[69]
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.[71]
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.[72]
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 withcatecholamines and/orcorticosteroids.[73]
Propofol has been proposed to have several mechanisms of action,[75][76][77] both through potentiation ofGABAA receptor activity and therefore acting as aGABAA 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 aGABAA receptor agonist as well.[78][79][80] Propofol analogs have been shown to also act assodium channel blockers.[81][82] Some research has also suggested that theendocannabinoid 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 ofsleep, pain processing andemesis.[83][84] AnEEG study on patients undergoing general anesthesia with propofol found that it causes a prominent reduction in the brain's information integration capacity.[85]
Propofol is an inhibitor of the enzymefatty acid amide hydrolase, which metabolizes theendocannabinoidanandamide (AEA). Activation of theendocannabinoid system by propofol, possibly via inhibition of AEAcatabolism, generates a significant increase in the whole-brain content of AEA, contributing to the sedative properties of propofol viaCB1 receptor activation.[86] This may explain thepsychotomimetic andantiemetic properties of propofol. By contrast, there is a high incidence of postoperative nausea and vomiting after administration ofvolatile anesthetics, which contribute to a significant decrease in the whole-brain content of AEA that can last up to forty minutes after induction.[84]
A 20 ml ampoule of 1% propofol emulsion, as sold in Australia bySandoz
Propofol is highly protein-boundin vivo and is metabolized byconjugation in the liver.[87] Thehalf-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 itsamnestic effects[88] have led to its widespread use for sedation and anesthesia.
First identified as a drug candidate in 1973, propofol entered clinical trials in 1977, using a form solubilized incremophor EL.[90] However, due toanaphylactic reactions to cremophor, this formulation was withdrawn from the market and subsequently reformulated as anemulsion of asoya oil and propofol mixture in water. The emulsified formulation was relaunched in 1986 by ICI (whose pharmaceutical division later became a constituent ofAstraZeneca) under the brand name Diprivan. The preparation contains 1% propofol, 10%soybean oil, and 1.2% purifiedegg phospholipid as an emulsifier, with 2.25%glycerol as atonicity-adjusting agent, andsodium hydroxide to adjust the pH. Diprivan containsEDTA, a commonchelation agent, that also acts alone (bacteriostatically against some bacteria) and synergistically with some otherantimicrobial agents. Newer generic formulations containsodium metabisulfite as an antioxidant andbenzyl alcohol as an antimicrobial agent. Propofol emulsion is an opaque white fluid due to thescattering of light from the emulsified micelle formulation.
A water-solubleprodrug form,fospropofol, has been developed and tested with positive results. Fospropofol is rapidly broken down by the enzymealkaline phosphatase to form propofol. Marketed asLusedra, this formulation may not produce the pain at the 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.[91]
By incorporation of anazobenzene unit, a photoswitchable version of propofol (AP2) was developed in 2012 that allows for optical control ofGABAA receptors with light.[92] In 2013, a propofol binding site on mammalian GABAA receptors has been identified by photolabeling using adiazirine derivative.[93] Additionally, it was shown that thehyaluronan polymer present in thesynovia can be protected fromfree-radicaldepolymerization by propofol.[94]
Ciprofol is another derivative of propofol that is 4–6 times more potent than propofol. As of 2022[update] it is undergoingPhase III trials. Ciprofol appears to have a lower incidence of injection site pain and respiratory depression than propofol.[95]
In November 2024, the USFood and Drug Administration approved PropofolVet Multidose, the first generic propofol injectable emulsion for dogs.[97][98] PropofolVet Multidose is approved for use as an injectable anesthetic in dogs.[97]
PropofolVet Multidose contains the same active ingredient (propofol injectable emulsion) as the approved brand name drug product, PropoFlo 28, which was first approved on 4 February 2011.[97] In addition, the FDA determined that PropofolVet Multidose contains no inactive ingredients that may significantly affect the bioavailability of the active ingredient.[97] PropofolVet Multidose is sponsored by Parnell Technologies Pty. Ltd. based in New South Wales, Australia.[97]
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GB patent 1472793, John B. Glen; Roger James & Bob-James Munroe, "Pharmaceutical Compositions", published 4 May 1977, assigned to Imperial Chemical Industries LtdArchived 5 June 2021 at theWayback Machine
