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]
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.
Since its introduction, propofol has become almost exclusively the drug of choice of anesthesiologists for the induction and maintenance of
general anesthesia, having largely replaced other agents.[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 Jacksondied 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]
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]
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]
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]
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
endocannabinoidanandamide (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
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.
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-radicaldepolymerization by propofol.[93]
Ciprofol is another derivative of propofol that is 4–6 times more potent than propofol. As of 2022[update] it is undergoing
Phase III trials. Ciprofol appears to have a lower incidence of injection site pain and respiratory depression than propofol.[94]
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