Propofol

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}}{{Infobox drug/maintenance categoriesTemplate:Yesno | drug_name = | INN = | _drugtype =

| _has_physiological_data= | _has_gene_therapy=

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Psychological: no dataPropofol CIntravenousDiprivan, others<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>GABA_A receptor agonist;
sedative;
general anestheticN01 | _legal_data=S4<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>C1Rx-onlyPOM<ref name="Diprivan FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Rx-onlyRx-only

| _other_data=2,6-Diisopropylphenol
2,6-bis(propan-2-yl)phenol

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Propofol<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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 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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Recovery from propofol-induced anesthesia is generally rapid and associated with less frequent side effects<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</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 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, later AstraZeneca),<ref>Template:Cite journal</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 World Health Organization's List of Essential Medicines.<ref name="WHO22nd">Template:Cite book</ref>

Uses

Anesthesia

To induce general anesthesia, propofol is the drug used almost exclusively, having largely replaced sodium thiopental.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</ref>

Propofol is also used to sedate people who are receiving mechanical ventilation but not undergoing surgery, such as patients in the intensive care unit.<ref name="Lewis_2018">Template:Cite journal</ref> In critically ill patients, propofol is superior to lorazepam both in effectiveness and overall cost.<ref name="Cox-2008">Template:Cite journal</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 peripheral IV or central line. Propofol is often paired with fentanyl (for pain relief) in intubated and sedated people.<ref name="Isert_1996">Template:Cite journal</ref> The two drugs are molecularly compatible in an IV mixture form.<ref name="Isert_1996" />

Propofol is also used to deepen anesthesia 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">Template:Cite journal</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">Template:Cite journal</ref> It can also be combined with opioids or benzodiazepines.<ref>Canadian National Formulary 2010</ref><ref>Template:Cite book</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>Template:Cite journal</ref> It is also often used in combination with ketamine with minimal side effects.<ref>Template:Cite journal</ref>

COVID-19

Template:Anchor 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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="FDA EUA">{{#invoke:citation/CS1|citation |CitationClass=web }}</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Status epilepticus

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.<ref>Template:Cite book</ref>

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 as a paralytic ensuring death, even when the patient has died as a result of initial propofol overdose.<ref name="divisionsbc1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Capital punishment

The 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 propofol for such use.<ref>Template:Cite journal</ref><ref>Template:Cite news</ref>

Recreational use

Recreational use of the drug via self-administration has been reported<ref>Template:Cite journal</ref><ref>Template:Cite news</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>Template:Cite journal</ref><ref>Template:Cite journal</ref> The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition.<ref>Template:Cite book</ref><ref>Template:Cite book</ref>

Recreational use of the drug has been described among medical staff, such as anesthetists who have access to the drug.<ref name="Roussin">Template:Cite journal</ref><ref>Template:Cite journal</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">Template:Cite journal</ref> Long-term use has been reported to result in addiction.<ref name=Roussin/><ref>Template:Cite journal</ref>

Attention to the risks of off-label use of propofol increased in August 2009, after the release of the Los Angeles County coroner's report that musician Michael Jackson had died from a mixture of propofol and the benzodiazepine drugs lorazepam, midazolam, and diazepam on 25 June 2009.<ref>Template:Cite news</ref><ref name="washingtonpost.com">Template:Cite news</ref><ref name="artsbeat.blogs.nytimes.com">Template:Cite news</ref><ref>Template:Cite magazine</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Manufacturing

Propofol as a commercial sterile emulsified formulation is considered difficult to manufacture.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite patent</ref>

It was initially formulated in Cremophor for human use, but this original formulation was implicated in an unacceptable number of anaphylactic events. It was eventually manufactured as a 1% emulsion in soybean oil.<ref name="pmid30982566">Template:Cite journal</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</ref> found on sensory nerves and can be mitigated by pretreatment with lidocaine.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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 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">Template:Cite journal</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>Template:Cite journal</ref> This effect is related to the dose and rate of propofol administration. It may also be potentiated by opioid analgesics.<ref>Template:Cite journal</ref>

Propofol can also cause decreased systemic vascular resistance, myocardial blood flow, and oxygen consumption, possibly through direct vasodilation.<ref>Template:Cite journal</ref> There are also reports that it may cause green discoloration of the urine.<ref>Template:Cite journal</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>Template:Cite journal</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>Template:Cite journal</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>Template:Cite journal</ref> In addition, propofol may decrease intraocular pressure by as much as 50% in patients with normal intraocular pressure.<ref>Template:Cite journal</ref>

A more serious but rare side effect is dystonia.<ref>Template:Cite journal</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.Template:Citation needed

Propofol is also reported to induce priapism in some individuals,<ref name="Annals Priapism">Template:Cite journal</ref><ref name="Fuentesa">Template:Cite journal</ref> and has been observed to suppress REM sleep and to worsen the poor sleep quality in some patients.<ref>Template:Cite journal</ref>

Rare side effects include:<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</ref>

Propofol infusion syndrome

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} 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.<ref>Template:Cite journal</ref>

Interactions

The respiratory effects of propofol are increased if given with other respiratory depressants, including benzodiazepines.<ref name="WebMD 2009-08-24">Template:Cite news</ref>

Pharmacology

Pharmacodynamics

Propofol has been proposed to have several mechanisms of action,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite book</ref> both through potentiation of GABA_A receptor activity and therefore acting as a 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_A receptor agonist as well.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Propofol analogs have been shown to also act as sodium channel blockers.<ref>Template:Cite journal</ref><ref>Template:Cite journal</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 emesis.<ref>Template:Cite journal</ref><ref name="Schelling_2006" /> An 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">Template:Cite journal</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 CB1 receptor activation.<ref>Template:Cite journal</ref> 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.<ref name="Schelling_2006">Template:Cite journal</ref>

Pharmacokinetics

File:Propofol.jpg

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.<ref>Template:Cite journal</ref> 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.<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>Template:Cite journal</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 ortho-alkylated phenols.<ref>Template:Cite journal</ref>

First identified as a drug candidate in 1973, propofol entered clinical trials in 1977, using a form solubilized in cremophor EL.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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 as an antioxidant and benzyl alcohol as an antimicrobial agent. Propofol emulsion is an opaque white fluid due to the 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 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

By incorporation of an azobenzene unit, a photoswitchable version of propofol (AP2) was developed in 2012 that allows for optical control of GABA_A receptors with light.<ref name="anie201205475">Template:Cite journal</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">Template:Cite journal</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">Template:Cite journal</ref>

Ciprofol is another derivative of propofol that is 4–6 times more potent than propofol. Template:Asof it is undergoing Phase III trials. Ciprofol appears to have a lower incidence of injection site pain and respiratory depression than propofol.<ref name=Chen2022BMCA>Template:Cite journal</ref>

Propofol has also been studied for treatment resistant depression.<ref>Template:Cite journal</ref>

Veterinary uses

In November 2024, the US Food and Drug Administration approved PropofolVet Multidose, the first generic propofol injectable emulsion for dogs.<ref name="FDA PropofolVet" /><ref name="Recent Animal Drug Approvals">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> PropofolVet Multidose is approved for use as an injectable anesthetic in dogs.<ref name="FDA PropofolVet" />

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.<ref name="FDA PropofolVet" /> In addition, the FDA determined that PropofolVet Multidose contains no inactive ingredients that may significantly affect the bioavailability of the active ingredient.<ref name="FDA PropofolVet" /> PropofolVet Multidose is sponsored by Parnell Technologies Pty. Ltd. based in New South Wales, Australia.<ref name="FDA PropofolVet">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

External links

• Template:Cite patent