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Propofol

Topic: Chemistry

 From HandWiki - Reading time: 20 min
Short description: Intravenous medication used in anesthesia
Propofol
Propofol.svg
Ball-and-stick model of propofol
Clinical data
Trade namesDiprivan, others[1]
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: C
Dependence
liability		Physical: very low (seizures)
Psychological: no data
Addiction
liability		Moderate[2]
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • BR: Class C1 (Other controlled substances)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only [3]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityNA
Protein binding95–99%
MetabolismLiver glucuronidation
Onset of action15–30 seconds[4]
Elimination half-life1.5–31 hours[4]
Duration of action~5–10 minutes[4]
ExcretionLiver
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC12H18O
Molar mass178.275 g·mol−1
3D model (JSmol)
Solubility in waterΔGsolvH2O = -4.39kcal/mol[5]
  (verify)

Propofol[6] 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 originally approved under the brand name Diprivan. Numerous generic offerings of this formulation now exist. 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.[7]

Recovery from propofol-induced anesthesia is generally rapid and associated with less frequent side effects[8] (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, now AstraZeneca).[9] 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.[10]

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.[11]

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).[12]

Propofol is also used to sedate individuals who are receiving mechanical ventilation but not undergoing surgery, such as patients in the intensive care unit.[13] In critically ill patients, propofol is superior to lorazepam both in effectiveness and overall cost.[14] Propofol is relatively inexpensive compared to medications of similar use due to shorter ICU stay length.[14] 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.[14]

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.[13]

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.[15] The two drugs are molecularly compatible in an IV mixture form.[15]

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.[16]

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.[17] It can also be combined with opioids or benzodiazepines.[18][19][20] Because of its rapid induction and recovery time, propofol is also widely used for sedation of infants and children undergoing MRI procedures.[21] It is also often used in combination with ketamine with minimal side effects.[22]

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.[23][24][25][26] 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.[26] This EUA has since been revoked.[26]

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.[27]

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. [28]

Capital punishment

Use of this compound as part of an execution protocol have been considered though no individual has been executed using this agent. This is largely due to European manufactures and governments banning the exportation of this compound for such use.[29][30]

Recreational use

Recreational use of the drug via self-administration has been reported[31][32] 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.[33][34] The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition.[35][36]

Recreational use of the drug has been described among medical staff, such as anesthetists who have access to the drug.[37][38] It is reportedly more common among anesthetists on rotations with short rest periods, as usage generally produces a well-rested feeling.[39] Long-term use has been reported to result in addiction.[37][40]

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.[41][42][43][44] 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.[42][43][45]

Manufacturing

Propofol as a commercial sterile emulsified formulation is considered difficult to manufacture.[46][47][48]

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

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

Propofol can also cause decreased systemic vascular resistance, myocardial blood flow, and oxygen consumption, possibly through direct vasodilation.[58] There are also reports that it may cause green discoloration of the urine.[59]

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.[60]

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.[61] 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.[55]

Propofol administration also results in decreased cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure.[62] In addition, propofol may decrease intraocular pressure by as much as 50% in patients with normal intraocular pressure.[63]

A more serious but rare side effect is dystonia.[64] 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,[65][66] and has been observed to suppress REM sleep stage and to worsen the poor sleep quality in some patients.[67]

Rare side effects include:[68]

  • 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.[69]

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.[70]

Propofol infusion syndrome

Main page: Medicine: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.[71]

Interactions

The respiratory effects of propofol are increased if given with other respiratory depressants, including benzodiazepines.[72]

Pharmacology

Pharmacodynamics

Propofol has been proposed to have several mechanisms of action,[73][74][75] 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.[76][77][78] Propofol analogs have been shown to also act as sodium channel blockers.[79][80] 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.[81][82] An EEG study on patients undergoing general anesthesia with propofol found that it causes a prominent reduction in the brain's information integration capacity.[83]

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.[84] 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.[82]

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 conjugation in the liver.[85] 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.[4] 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[86] 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.[87]

First identified as a drug candidate in 1973, propofol entered clinical trials in 1977, using a form solubilized in cremophor EL.[88] 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.[89]

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.[90] In 2013, a propofol binding site on mammalian GABAA receptors has been identified by photolabeling using a diazirine derivative.[91] Additionally, it was shown that the hyaluronan polymer present in the synovia can be protected from free-radical depolymerization by propofol.[92]

Ciprofol is another derivative of propofol that is 4–6 times more potent than propofol. Currently undergoing Phase III trials, ciprofol appears to have a lower incidence of injection site pain and respiratory depression than propofol.[93]

Propofol has also been studied for treatment resistant depression.[94]

References

  1. ↑ "Propofol". https://www.drugs.com/international/propofol.html. 
  2. ↑ "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse 40 (6): 428–437. November 2014. doi:10.3109/00952990.2014.933840. PMID 25083822. "Propofol is a general anesthetic, however its abuse for recreational purpose has been documented (120). Using control drugs implicated in both ΔFosB induction and addiction (ethanol and nicotine), similar ΔFosB expression was apparent when propofol was given to rats. Moreover, this cascade was shown to act via the dopamine D1 receptor in the NAc, suggesting that propofol has abuse potential (119)". 
  3. ↑ "Diprivan- propofol injection, emulsion". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5cec3b97-5183-4a9d-accd-21e76c99d3dd. 
  4. ↑ 4.0 4.1 4.2 4.3 "Propofol". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/Propofol.html. 
  5. ↑ "Atomistic models of general anesthetics for use in in silico biological studies". The Journal of Physical Chemistry B (American Chemical Society (ACS)) 118 (42): 12075–12086. October 2014. doi:10.1021/jp502716m. PMID 25303275. 
  6. ↑ "Propofol" (in en). PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/4943. 
  7. ↑ "Making Stable, Sterile Propofol" (in en-us). https://www.microfluidics-mpt.com/blog/making-stable-sterile-propofol. 
  8. ↑ "Propofol" (in en). https://go.drugbank.com/drugs/DB00818. 
  9. ↑ "Try, try, and try again: personal reflections on the development of propofol". British Journal of Anaesthesia 123 (1): 3–9. July 2019. doi:10.1016/j.bja.2019.02.031. PMID 30982566. 
  10. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  11. ↑ "Propofol - an overview | ScienceDirect Topics". https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/propofol. 
  12. ↑ "Propofol anaesthesia via target controlled infusion or manually controlled infusion: effects on the bispectral index as a measure of anaesthetic depth". Anaesthesia and Intensive Care 29 (6): 579–584. December 2001. doi:10.1177/0310057X0102900602. ISSN 0310-057X. PMID 11771598. 
  13. ↑ 13.0 13.1 "Propofol for the promotion of sleep in adults in the intensive care unit". The Cochrane Database of Systematic Reviews 1 (1): CD012454. January 2018. doi:10.1002/14651858.CD012454.pub2. PMID 29308828. 
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  18. ↑ Canadian National Formulary 2010
  19. ↑ Appleton & Lange's 1999 drug guide. Stamford, CT: Appleton & Lange. 1999. ISBN 978-0-8385-0371-3. 
  20. ↑ Numorphan® (oxymorphone) package insert (English), Endo 2009
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  41. ↑ "Jackson's Death Ruled a Homicide". The New York Times. 28 August 2009. https://www.nytimes.com/2009/08/29/us/29jackson.html. 
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  43. ↑ 43.0 43.1 "Coroner's Findings in Jackson Death Revealed". The New York Times. 24 August 2009. http://artsbeat.blogs.nytimes.com/2009/08/24/coroners-findings-in-jackson-death-revealed/?hp. 
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  48. ↑ Pramanick S, Gurjar S, Mehta SS, "Pharmaceutical composition of propofol", WO patent 2014033751A2, issued 2014-03-06, assigned to Emcure Pharmaceuticals Limited
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  50. ↑ "Hospira recalls lot of Propofol Injectable Emulsion" (in en). https://www.europeanpharmaceuticalreview.com/news/173149/hospira-recalls-lot-of-propofol-injectable-emulsion/. 
  51. ↑ "Understanding Emulsion Formulation | Ascendia Pharmaceuticals" (in en). https://ascendiapharma.com/newsroom/2021/11/08/emulsion-formulation. 
  52. ↑ "Stability of Emulsion - an overview | ScienceDirect Topics". https://www.sciencedirect.com/topics/chemical-engineering/stability-of-emulsion#:~:text=The%20factors%20that%20influence%20the,increasing%20the%20stability%20of%20emulsion.. 
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  56. ↑ "Mechanisms whereby propofol mediates peripheral vasodilation in humans. Sympathoinhibition or direct vascular relaxation?". Anesthesiology 86 (1): 64–72. January 1997. doi:10.1097/00000542-199701000-00010. PMID 9009941. 
  57. ↑ "New awakening in anaesthesia—at a price". Lancet 329 (8548): 1469–70. 1987. doi:10.1016/s0140-6736(87)92214-8. 
  58. ↑ "Clinical pharmacology of propofol: an intravenous anesthetic agent". DICP 23 (10): 743–749. October 1989. doi:10.1177/106002808902301001. PMID 2683416. 
  59. ↑ "Green discoloration of urine after propofol infusion". Korean Journal of Anesthesiology 65 (2): 177–179. August 2013. doi:10.4097/kjae.2013.65.2.177. PMID 24024005. 
  60. ↑ "Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports". BMJ 305 (6854): 613–616. September 1992. doi:10.1136/bmj.305.6854.613. PMID 1393073. 
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  62. ↑ "Pharmacokinetics of propofol in adult patients undergoing coronary revascularization. The Multicenter Study of Perioperative Ischemia Research Group". Anesthesiology 84 (6): 1288–1297. June 1996. doi:10.1097/00000542-199606000-00003. PMID 8669668. 
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