Propofol

Source: Wikipedia, the free encyclopedia.
Not to be confused with Propanol.

Propofol
Ball-and-stick model of propofol
Clinical data
Trade namesDiprivan, others[1]
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: C
seizures)
Psychological: no data
Addiction
liability		Moderate[2]
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityNA
Protein binding95–99%
MetabolismLiver glucuronidation
Onset of action15–30 seconds[5]
Elimination half-life1.5–31 hours[5]
Duration of action~5–10 minutes[5]
ExcretionLiver
Identifiers
  • 2,6-Diisopropylphenol
    2,6-bis(propan-2-yl)phenol
kcal/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 checkY
  • Key:OLBCVFGFOZPWHH-UHFFFAOYSA-N checkY
  (verify)

Propofol

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

surgeries. It may be administered as a bolus or an infusion
, or some combination of the two.

First synthesized in 1973, by

FDA approval in October 1989. It is on the World Health Organization's List of Essential Medicines.[11]

Uses

Anesthesia

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

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

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.

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

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

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.

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

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]

  • 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.[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

Main article: 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,

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

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

Large vial filled with milky white fluid
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

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

alkylated phenols.[88]

First identified as a drug candidate in 1973, propofol entered clinical trials in 1977, using a form solubilized in

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

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]

References

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External links

Wikimedia Commons has media related to Propofol.
  • "Propofol". Drug Information Portal. U.S. National Library of Medicine.
  • GB patent 1472793, John B Glen & Roger James, "Pharmaceutical Compositions", published 1977-05-04, assigned to Imperial Chemical Industries Ltd 
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