Propofol

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Propofol
Propofol.svg
Propofol molecule ball.png
Clinical data
Trade names Diprivan, others [1]
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU:C
Dependence
liability 		Physical: Very High
Psychological: no data
Addiction
liability 		Moderate [2]
Routes of
administration 		Intravenous
Drug class GABA receptor agonist;
sedative;
hypnotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability NA
Protein binding 95–99%
Metabolism Liver glucuronidation
Onset of action 15–30 seconds [5]
Elimination half-life 1.5–31 hours [5]
Duration of action ~5–10 minutes [5]
Excretion Liver
Identifiers
  • 2,6-Diisopropylphenol
    2,6-bis(propan-2-yl)phenol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.016.551 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H18O
Molar mass 178.275 g·mol−1
3D model (JSmol)
Solubility in water ΔGsolvH2O = -4.39kcal/mol [6]
  • CC(C)c1cccc(c1O)C(C)C
  • InChI=1S/C12H18O/c1-8(2)10-6-5-7-11(9(3)4)12(10)13/h5-9,13H,1-4H3 Yes check.svgY
  • Key:OLBCVFGFOZPWHH-UHFFFAOYSA-N Yes check.svgY
   (verify)

Propofol [7] is the active component of an intravenous anesthetic formulation used for induction and maintenance of general anesthesia. It is chemically termed 2,6-diisopropylphenol. The formulation was 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. [8]

Contents

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

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

Uses

Anesthesia

To induce general anesthesia, propofol is the drug used almost exclusively, having largely replaced sodium thiopental. [12]

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

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

Propofol has also been suggested as a sleep aid in critically ill adults in 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. [14]

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. [16] The two drugs are molecularly compatible in an IV mixture form. [16]

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

Routine procedural sedation

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

COVID-19

In March 2021, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for Propofol‐Lipuro 1% to maintain sedation via continuous infusion in people older than sixteen with suspected or confirmed COVID-19 who require mechanical ventilation in an intensive care unit ICU setting. [24] [25] [26] [27] During the public health emergency, it was considered infeasible 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. [27] This EUA has since been revoked. [27]

Status epilepticus

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

Other uses

Assisted death in Canada

A lethal dose of propofol is used for medical assistance in dying in Canada to quickly induce deep coma and death, but rocuronium is always given as a paralytic ensuring death, even when the patient has died as a result of initial propofol overdose. [29]

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 exportation of this propofol for such use. [30] [31]

Recreational use

Recreational use of the drug via self-administration has been reported [32] [33] 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. [34] [35] The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition. [36] [37]

Recreational use of the drug has been described among medical staff, such as anesthetists who have access to the drug. [38] [39] It is reportedly more common among anesthetists on rotations with short rest periods, as usage generally produces a well-rested feeling. [40] Long-term use has been reported to result in addiction. [38] [41]

Attention to the risks of off-label use of propofol increased in August 2009 due to the Los Angeles County coroner's conclusion that musician Michael Jackson died from a mixture of propofol and the benzodiazepine drugs lorazepam, midazolam, and diazepam on 25 June 2009. [42] [43] [44] [45] 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. [43] [44] [46]

Manufacturing

Propofol as a commercial sterile emulsified formulation is considered difficult to manufacture. [47] [48] [49]

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. [50] Sterile emulsions represent complex formulation, the stability of which is dependent on the interplay of many factors such as micelle size and distribution. [51] [52] [53]

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, [54] found on sensory nerves and can be mitigated by pretreatment with lidocaine. [55] 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. [56] Reports of blood pressure drops of 30% or more are thought to be at least partially due to inhibition of sympathetic nerve activity. [57] This effect is related to the dose and rate of propofol administration. It may also be potentiated by opioid analgesics. [58]

Propofol can also cause decreased systemic vascular resistance, myocardial blood flow, and oxygen consumption, possibly through direct vasodilation. [59] There are also reports that it may cause green discoloration of the urine. [60]

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. [61]

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. [62] 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. [56]

Propofol administration also results in decreased cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. [63] In addition, propofol may decrease intraocular pressure by as much as 50% in patients with normal intraocular pressure. [64]

A more serious but rare side effect is dystonia. [65] 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 ]

Propofol is also reported to induce priapism in some individuals, [66] [67] and has been observed to suppress REM sleep stage and to worsen the poor sleep quality in some patients. [68]

Rare side effects include: [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. [70]

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. [71]

Propofol infusion syndrome

A rare, but serious, side effect is propofol infusion syndrome. This potentially lethal metabolic derangement has been reported in critically ill patients after a prolonged infusion of high-dose propofol, sometimes in combination with catecholamines and/or corticosteroids. [72]

Interactions

The respiratory effects of propofol are increased if given with other respiratory depressants, including benzodiazepines. [73]

Pharmacology

Pharmacodynamics

Propofol has been proposed to have several mechanisms of action, [74] [75] [76] both through potentiation of GABAA receptor activity and therefore acting as a GABAA receptor positive allosteric modulator, thereby slowing the channel-closing time. At high doses, propofol may be able to activate GABAA receptors in the absence of GABA, behaving as a GABAA receptor agonist as well. [77] [78] [79] Propofol analogs have been shown to also act as sodium channel blockers. [80] [81] 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. [82] [83] An EEG study on patients undergoing general anesthesia with propofol found that it causes a prominent reduction in the brain's information integration capacity. [84]

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. [85] 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. [83]

Pharmacokinetics

A 20 ml ampoule of 1% propofol emulsion, as sold in Australia by Sandoz 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. [86] The half-life of elimination of propofol has been estimated to be between 2 and 24 hours. However, its duration of clinical effect is much shorter, because propofol is rapidly distributed into peripheral tissues. When used for IV sedation, a single dose of propofol typically wears off within minutes. Onset is rapid, in as little as 15–30 seconds. [5] Propofol is versatile; the drug can be given for short or prolonged sedation, as well as for general anesthesia. Its use is not associated with nausea as is often seen with opioid medications. These characteristics of rapid onset and recovery along with its amnestic effects [87] 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. [88]

First identified as a drug candidate in 1973, propofol entered clinical trials in 1977, using a form solubilized in cremophor EL. [89] 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 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 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. [90]

By incorporation of an azobenzene unit, a photoswitchable version of propofol (AP2) was developed in 2012 that allows for optical control of GABAA receptors with light. [91] In 2013, a propofol binding site on mammalian GABAA receptors has been identified by photolabeling using a diazirine derivative. [92] Additionally, it was shown that the hyaluronan polymer present in the synovia can be protected from free-radical depolymerization by propofol. [93]

Ciprofol is another derivative of propofol that is 4–6 times more potent than propofol. As of 2022 it is undergoing Phase III trials. Ciprofol appears to have a lower incidence of injection site pain and respiratory depression than propofol. [94]

Propofol has also been studied for treatment resistant depression. [95]

Related Research Articles

General anaesthetics are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma that causes lack of awareness to painful stimuli, sufficient to facilitate surgical applications in clinical and veterinary practice. General anaesthetics do not act as analgesics and should also not be confused with sedatives. General anaesthetics are a structurally diverse group of compounds whose mechanisms encompass multiple biological targets involved in the control of neuronal pathways. The precise workings are the subject of some debate and ongoing research.

<span class="mw-page-title-main">Ketamine</span> Dissociative anesthetic and anti-depressant

Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and pain management. It is a novel compound that was derived from phencyclidine in 1962 in pursuit of a safer anesthetic with fewer hallucinogenic effects.

<span class="mw-page-title-main">Sodium thiopental</span> Barbiturate general anesthetic

Sodium thiopental, also known as Sodium Pentothal, thiopental, thiopentone, or Trapanal, is a rapid-onset short-acting barbiturate general anesthetic. It is the thiobarbiturate analog of pentobarbital, and an analog of thiobarbital. Sodium thiopental was a core medicine in the World Health Organization's List of Essential Medicines, but was supplanted by propofol. Despite this, thiopental is listed as an acceptable alternative to propofol, depending on local availability and cost of these agents. It was previously the first of three drugs administered during most lethal injections in the United States, but the US manufacturer Hospira stopped manufacturing the drug in 2011 and the European Union banned the export of the drug for this purpose. Although thiopental abuse carries a dependency risk, its recreational use is rare.

Dissociatives, colloquially dissos, are a subclass of hallucinogens that distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of such action, dissociatives are unique in that they do so in such a way that they produce hallucinogenic effects, which may include dissociation, a general decrease in sensory experience, hallucinations, dream-like states or anesthesia. Despite most dissociatives' main mechanism of action being tied to NMDA receptor antagonism, some of these substances, which are nonselective in action and affect the dopamine and/or opioid systems, may be capable of inducing more direct and repeatable euphoria or symptoms which are more akin to the effects of typical "hard drugs" or common drugs of abuse. This is likely why dissociatives are considered to be addictive with a fair to moderate potential for abuse, unlike psychedelics. Despite some dissociatives, such as phencyclidine (PCP) possessing stimulating properties, most dissociatives seem to have a general depressant effect and can produce sedation, respiratory depression, nausea, disorientation, analgesia, anesthesia, ataxia, cognitive and memory impairment as well as amnesia.

<span class="mw-page-title-main">Isoflurane</span> General anaesthetic given via inhalation

Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia, due to airway irritation with isoflurane. Isoflurane is given via inhalation.

<span class="mw-page-title-main">Sevoflurane</span> Inhalational anaesthetic

Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane.

<span class="mw-page-title-main">General anaesthesia</span> Medically induced loss of consciousness

General anaesthesia (UK) or general anesthesia (US) is a method of medically inducing loss of consciousness that renders a patient unarousable even with painful stimuli. This effect is achieved by administering either intravenous or inhalational general anaesthetic medications, which often act in combination with an analgesic and neuromuscular blocking agent. Spontaneous ventilation is often inadequate during the procedure and intervention is often necessary to protect the airway. General anaesthesia is generally performed in an operating theater to allow surgical procedures that would otherwise be intolerably painful for a patient, or in an intensive care unit or emergency department to facilitate endotracheal intubation and mechanical ventilation in critically ill patients. Depending on the procedure, general anaesthesia may be optional or required. Regardless of whether a patient may prefer to be unconscious or not, certain pain stimuli could result in involuntary responses from the patient that may make an operation extremely difficult. Thus, for many procedures, general anaesthesia is required from a practical perspective.

<span class="mw-page-title-main">Theories of general anaesthetic action</span> How drugs induce reversible suppression of consciousness

A general anaesthetic is a drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anaesthetist/anesthesiologist to induce or maintain general anaesthesia to facilitate surgery.

<span class="mw-page-title-main">Anesthetic</span> Drug that causes anesthesia

An anesthetic or anaesthetic is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two broad classes: general anesthetics, which result in a reversible loss of consciousness, and local anesthetics, which cause a reversible loss of sensation for a limited region of the body without necessarily affecting consciousness.

Awareness under anesthesia, also referred to as intraoperative awareness or accidental awareness during general anesthesia (AAGA), is a rare complication of general anesthesia where patients regain varying levels of consciousness during their surgical procedures. While anesthesia awareness is possible without resulting in any long-term memory of the experience, it is also possible for victims to have awareness with explicit recall, where they can remember the events related to their surgery.

Postoperative nausea and vomiting (PONV) is the phenomenon of nausea, vomiting, or retching experienced by a patient in the post-anesthesia care unit (PACU) or within 24 hours following a surgical procedure. PONV affects about 10% of the population undergoing general anaesthesia each year. PONV can be unpleasant and lead to a delay in mobilization and food, fluid, and medication intake following surgery.

<span class="mw-page-title-main">Remifentanil</span> Synthetic opioid analgesic

Remifentanil, marketed under the brand name Ultiva is a potent, short-acting synthetic opioid analgesic drug. It is given to patients during surgery to relieve pain and as an adjunct to an anaesthetic. Remifentanil is used for sedation as well as combined with other medications for use in general anesthesia. The use of remifentanil has made possible the use of high-dose opioid and low-dose hypnotic anesthesia, due to synergism between remifentanil and various hypnotic drugs and volatile anesthetics.

<span class="mw-page-title-main">Bupivacaine</span> Local anaesthetic drug

Bupivacaine, marketed under the brand name Marcaine among others, is a medication used to decrease sensation in a specific small area. In nerve blocks, it is injected around a nerve that supplies the area, or into the spinal canal's epidural space. It is available mixed with a small amount of epinephrine to increase the duration of its action. It typically begins working within 15 minutes and lasts for 2 to 8 hours.

<span class="mw-page-title-main">Etomidate</span> Short-acting anaesthetic and sedative drug

Etomidate is a short-acting intravenous anaesthetic agent used for the induction of general anaesthesia and sedation for short procedures such as reduction of dislocated joints, tracheal intubation, cardioversion and electroconvulsive therapy. It was developed at Janssen Pharmaceutica in 1964 and was introduced as an intravenous agent in 1972 in Europe and in 1983 in the United States.

<span class="mw-page-title-main">Dexmedetomidine</span> Anxiolytic, sedative, and pain medication

Dexmedetomidine, sold under the trade name Precedex among others, is a drug used in humans for sedation. Veterinarians use dexmedetomidine for similar purposes in treating cats, dogs, and horses. It is also used in humans to treat acute agitation associated with schizophrenia or bipolar I or II disorder.

<span class="mw-page-title-main">Alfaxalone</span> Chemical compound

Alfaxalone, also known as alphaxalone or alphaxolone and sold under the brand name Alfaxan, is a neuroactive steroid and general anesthetic which is used currently in veterinary practice as an induction agent for anesthesia and as an injectable anesthetic. Though it is more expensive than other induction agents, it often preferred due to the lack of depressive effects on the cardiovascular system. The most common side effect seen in current veterinary practice is respiratory depression when Alfaxan is administered concurrently with other sedative and anesthetic drugs; when premedications aren't given, veterinary patients also become agitated and hypersensitive when waking up.

Total intravenous anesthesia (TIVA) refers to the intravenous administration of anesthetic agents to induce a temporary loss of sensation or awareness. The first study of TIVA was done in 1872 using chloral hydrate, and the common anesthetic agent propofol was licensed in 1986. TIVA is currently employed in various procedures as an alternative technique of general anesthesia in order to improve post-operative recovery.

The effects of early-life exposures to anesthesia on the brain in humans are controversial. Evidence from nonhuman primate research suggests significant developmental neurotoxicity and long-term social impairment, with a dose–response relationship where repeated exposures cause a more severe impact than single ones. Research in humans has not found conclusive clinical evidence of cognitive impairment; however, systematic reviews imply the possibility of greater behavioural impairments in children exposed to anesthesia before the age of three than control subjects.

<span class="mw-page-title-main">Talmage Egan</span> American academic

Talmage D. Egan is an anesthesiologist, academic, entrepreneur, and author. He is a professor and chair in the department of anesthesiology, and an adjunct professor in the departments of pharmaceutics, bioengineering, and neurosurgery at the University of Utah School of Medicine.

<span class="mw-page-title-main">Ciprofol</span> Intravenous medication used in general anaesthesia

Ciprofol is a novel 2,6-disubstituted phenol derivative that is used for the intravenous induction of general anesthesia. A short-acting and highly selective γ-aminobutyric acid agonist, ciprofol is 4–6 times more potent than other phenol derivatives such as propofol or fospropofol.

References

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  3. ↑ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
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