Propofol

Propofol

Clinical data
Trade names	Diprivan, others
AHFS/Drugs.com	Monograph
License data	US DailyMed: Propofol
Pregnancy category	AU: C
Dependence liability	Physical: very low (seizures) Psychological: no data
Addiction liability	Moderate
Routes of administration	Intravenous
ATC code	N01AX10 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	NA
Protein binding	95–99%
Metabolism	Liver glucuronidation
Onset of action	15–30 seconds
Elimination half-life	1.5–31 hours
Duration of action	~5–10 minutes
Excretion	Liver
Identifiers
IUPAC name 2,6-bis(propan-2-yl)phenol
CAS Number	2078-54-8 Y
PubChem CID	4943
IUPHAR/BPS	5464
DrugBank	DB00818 Y
ChemSpider	4774 Y
UNII	YI7VU623SF
KEGG	D00549 Y
ChEBI	CHEBI:44915 Y
ChEMBL	ChEMBL526 Y
CompTox Dashboard (EPA)	DTXSID6023523
ECHA InfoCard	100.016.551
Chemical and physical data
Formula	C12H18O
Molar mass	178.275 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(C)c1cccc(c1O)C(C)C
InChI InChI=1S/C12H18O/c1-8(2)10-6-5-7-11(9(3)4)12(10)13/h5-9,13H,1-4H3 Y Key:OLBCVFGFOZPWHH-UHFFFAOYSA-N Y
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Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Its uses include the starting and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation. It is also used for status epilepticus if other medications have not worked. It is given by injection into a vein, and the maximum effect takes about two minutes to occur and typically lasts five to ten minutes. Propofol is also used for medical assistance in dying in Canada.

The medication appears to be safe for use during pregnancy but has not been well studied for use in this case. It is not recommended for use during a cesarean section. It is not a pain medication, so opioids such as morphine may also be used; however, whether or not they are always needed is not clear. Propofol is believed to work at least partly via a receptor for GABA.

Propofol was discovered in 1977 and approved for use in the United States in 1989. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. It has been referred to as milk of amnesia (a play on "milk of magnesia"), because of the milk-like appearance of the intravenous preparation, and because of its tendency to suppress memory recall. Propofol is also used in veterinary medicine for anesthesia.

Medical uses

Anesthesia

To induce general anesthesia, propofol is the drug used almost always, having largely replaced sodium thiopental. It can also be 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). Propofol is also used to sedate individuals who are receiving mechanical ventilation but not undergoing surgery, such as patients in the intensive care unit. In critically ill patients, propofol is superior to lorazepam both in effectiveness and overall cost. Propofol is relatively inexpensive compared to medications of similar use due to shorter ICU stay length. One of the reasons propofol is thought to be more effective (although it has a longer half-life than lorazepam) is because studies have found that benzodiazepines like midazolam and lorazepam tend to accumulate in critically ill patients, prolonging sedation. Propofol has also been suggested as a sleep aid in critically ill adults in the ICU; however, the effectiveness of this medicine at replicating the mental and physical aspects of sleep for people in the ICU are not clear.

Propofol is often used instead of sodium thiopental for starting anesthesia because recovery from propofol is more rapid and "clear".

Propofol can be run through a peripheral IV or central line. Propofol is frequently paired with fentanyl (for pain relief) in intubated and sedated people. Both are compatible in IV form.

Procedural sedation

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

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 an insurance knock--even when patient dies as a result of Propofol injection.

Step 1 Midazolam 10-20mg 2-4ml of 5mg/ml preparation (pre-anesthetic, induces sleep in 1-2 minutes).

Step 2: Lidocaine 40mg 4ml of 1% preparation; pause to allow effect. (reduces possible burning in a peripheral vein due to Propofol).

Step 3: Propofol 1000mg 100ml of 10mg/ml preparation (loss of consciousness within 10 seconds, induces coma in 1-2 minutes; death may result from the Propofol but Rocuronium is always given.).

Step 4: Rocuronium 200mg 20ml of 10mg/ml preparation (cardiac arrest after Rocuronium injection usually occurs within 5 minutes of respiratory arrest).

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 greater than age sixteen with suspected or confirmed COVID‑19 who require mechanical ventilation in an intensive care unit ICU setting. In the circumstances of this public health emergency, it would not be feasible to require healthcare providers to seek to limit Fresenius Propoven 2% Emulsion or Propofol-Lipuro 1% only to be used for patients with suspected or confirmed COVID‑19; therefore, this authorization does not limit use to such patients.

Other uses

Executions

The US state of Missouri added propofol to its execution protocol in April 2012. However, Governor Jay Nixon halted the first execution by the administration of a lethal dose of propofol in October 2013 following threats from the European Union to limit the drug's export if it were used for that purpose. The United Kingdom had already banned the export of medicines or veterinary medicines containing propofol to the United States.

Recreational use

Recreational use of the drug via self-administration has been reported 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. The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition.

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

Attention to the risks of off-label use of propofol increased in August 2009 due to the Los Angeles County coroner's conclusion that music icon Michael Jackson died from a mixture of propofol and the benzodiazepine drugs lorazepam, midazolam, and diazepam on June 25, 2009. According to a July 22, 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. Even so, as of 2016, propofol was not on a US Drug Enforcement Administration schedule.

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, found on sensory nerves and can be mitigated by pretreatment with lidocaine. 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[1].

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. Reports of blood pressure drops of 30% or more are thought to be at least partially due to inhibition of sympathetic nerve activity. This effect is related to the dose and rate of propofol administration. It may also be potentiated by opioid analgesics.

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

Although propofol is heavily used in the adult ICU setting, the side effects associated with propofol seem to be of greater concern in children. In the 1990s, multiple reported deaths of children in ICUs associated with propofol sedation prompted the FDA to issue a warning.

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. 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.

Diminishing cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure are also characteristics of propofol administration. In addition, propofol may decrease intraocular pressure by as much as 50% in patients with normal intraocular pressure.

A more serious but rare side effect is dystonia. 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.

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

Rare

• 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.

Because of its lipid base, 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 infection.

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.

Interactions

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

Pharmacology

Pharmacodynamics

Propofol has been proposed to have several mechanisms of action, 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. Propofol analogs have been shown to also act as sodium channel blockers. Some research has also suggested that the endocannabinoid system may contribute significantly to propofol's anesthetic action and to its unique properties. EEG research upon those undergoing general anesthesia with propofol finds that it causes a prominent reduction in the brain's information integration capacity.

Pharmacokinetics

A 20 ml ampoule of 1% propofol emulsion, as sold in Australia by Sandoz

Propofol is highly protein-bound in vivo and is metabolised by conjugation in the liver. 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. 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 have led to its widespread use for sedation and anesthesia.

History

John B. Glen, a veterinarian and researcher at Imperial Chemical Industries (ICI) spent 13 years developing propofol, an effort which led to the awarding to him of the prestigious 2018 Lasker Award for clinical research. Propofol was originally developed as ICI 35868. It was chosen for development after extensive evaluation and structure–activity relationship studies of the anesthetic potencies and pharmacokinetic profiles of a series of ortho-alkylated phenols.

First identified as a drug candidate in 1973, clinical trials followed in 1977, using a form solubilised in cremophor EL. However, due to anaphylactic reactions to cremophor, this formulation was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water. The emulsified formulation was relaunched in 1986 by ICI (now AstraZeneca) under the brand name Diprivan. The currently available preparation is 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 or benzyl alcohol as antimicrobial agents. Propofol emulsion is a highly opaque white fluid due to the scattering of light from the tiny (about 150-nm) oil droplets it contains: Tyndall Effect.

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. However fospropofol is a Schedule IV controlled substance with the DEA ACSCN of 2138 in the United States unlike propofol.

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. In 2013, a propofol binding site on mammalian GABA_A receptors has been identified by photolabeling using a diazirine derivative. Additionally, it was shown that the hyaluronan polymer present in the synovia can be protected from free-radical depolymerization by propofol.

External links

• "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