Propofol

• 1. Introduction

  ›

  Propofol is an intravenous anesthetic that looks like milk. Drawn into a syringe, it is an opaque white fluid, a color it owes to the soybean oil and lecithin that carry the active ingredient. Doctors use it to start general anesthesia in operating rooms around the world, and the World Health Organization lists it among its Essential Medicines. Yet the drug has a strange double life. Why did a veterinary anesthesiologist, rather than a human-medicine specialist, end up creating it? What does it actually do inside the brain? And why does a substance so gentle under expert care become so dangerous without it?

  13811

• 2. The Veterinarian's Drug

  ›

  In 1973, a British veterinary anesthesiologist named John B. Glen synthesized the compound while working for Imperial Chemical Industries, known as ICI. The company's pharmaceutical division later became part of AstraZeneca. Glen would spend thirteen years on the project. The compound carried the laboratory code ICI 35868, and it was chosen after extensive testing of a series of ortho-alkylated phenols. Researchers compared how potent each candidate was as an anesthetic and how the body handled it.

  Clinical trials began in 1977 with propofol dissolved in a solvent called Cremophor EL. Some patients suffered anaphylactic reactions to it, so that version was withdrawn from the market. Chemists went back to the bench and reformulated the drug as an emulsion of soya oil and propofol in water.

  The emulsion reached patients in the United Kingdom and New Zealand in 1986, sold by ICI under the brand name Diprivan. The United States followed in October 1989, when the Food and Drug Administration approved it. Many generic versions have since appeared.

  A vial of Diprivan holds 1% propofol, 10% soybean oil and 1.2% purified egg phospholipid as the emulsifier. Glycerol at 2.25% adjusts its tonicity, and sodium hydroxide adjusts its acidity. The recipe also includes EDTA, a chelating agent that works against some bacteria on its own and alongside other antimicrobial agents. Newer generics swap in sodium metabisulfite as an antioxidant and benzyl alcohol as an antimicrobial. Even so, sterile emulsions are complex to make, because their stability depends on factors such as the size and distribution of the micelles.

  In 2018, Glen received the Lasker Award for clinical research for his work on the drug.

  1112148586

• 3. Inside the Operating Room

  ›

  Sodium thiopental was once the usual way to put a patient under, and propofol has largely replaced it. Today propofol is used almost exclusively to induce general anesthesia. Recovery is generally quick, and it infrequently brings drowsiness, nausea or vomiting. It can be given as a bolus, as an infusion, or as a combination of the two.

  Many anesthetists keep patients asleep with a technique called total intravenous anesthesia. The drug flows through infusion pumps that are either programmed by hand or computer-controlled. The computer-controlled process is called target controlled infusion.

  Colonoscopies and other gastrointestinal endoscopy procedures show how far the drug reaches beyond surgery. Patients recover faster than they do with midazolam. Propofol can be combined with opioids or benzodiazepines, and it is often paired with ketamine with minimal side effects. Fast induction and recovery also make it a common choice for sedating infants and children during MRI scans.

  Fentanyl, a pain reliever, is often given alongside propofol in intubated and sedated people. The two are molecularly compatible in an IV mixture, and propofol can run through a peripheral IV or a central line. Propofol also helps when a patient develops laryngospasm. Anesthetists deepen the anesthesia with it, either alone or followed by succinylcholine. Using it alone can spare the patient paralysis and the possible side effects of succinylcholine.

  Not everyone who receives propofol is having an operation, though. Some are lying in an intensive care unit for days.

  1518241920

• 4. Intensive Care

  ›

  For critically ill patients on mechanical ventilation, propofol outperforms lorazepam in both effectiveness and overall cost. Studies have found that benzodiazepines such as midazolam and lorazepam tend to accumulate in these patients and prolong sedation. That may explain propofol's edge, even though propofol has the longer half-life of the two. Shorter ICU stays make it relatively inexpensive compared with similar medications.

  Researchers have also suggested propofol as a sleep aid for critically ill adults. Whether it reproduces the mental and physical aspects of real sleep is unclear.

  Status epilepticus may be defined as seizure activity lasting beyond five minutes and needing anticonvulsant medication. Several guidelines recommend propofol for refractory cases, where other treatments have failed.

  In March 2021, the FDA issued an emergency use authorization for Propofol-Lipuro 1%. It covered continuous-infusion sedation in people older than sixteen with suspected or confirmed COVID-19 who needed mechanical ventilation in an ICU. Officials judged it unfeasible to limit Fresenius Propoven 2% Emulsion or Propofol-Lipuro 1% to those patients alone. Both products were made available to every ICU patient on a ventilator. That authorization has since been revoked.

  1716648726

• 5. How It Works

  ›

  On an EEG, patients under propofol show a prominent reduction in the brain's capacity to integrate information. The proposed explanation starts with the GABAA receptor. Propofol is thought to act as a positive allosteric modulator there, slowing the time the receptor channel takes to close. At high doses it may even activate the receptor without GABA being present, behaving as an agonist. Propofol analogs also seem to block sodium channels.

  Some research points to a second pathway through the endocannabinoid system, which also helps control sleep, pain processing and vomiting. Propofol inhibits fatty acid amide hydrolase, the enzyme that breaks down the endocannabinoid anandamide, or AEA. As a result, AEA rises across the whole brain, and activation of the CB1 receptor contributes to the sedation. This may explain propofol's psychotomimetic and antiemetic properties.

  Volatile anesthetics tell the opposite story. They lower whole-brain AEA content for up to forty minutes after induction, and they bring a high incidence of postoperative nausea and vomiting.

  In the body, propofol is highly protein-bound and is metabolized by conjugation in the liver. Onset can take as little as 15-30 seconds, and its amnestic effects add to its appeal for sedation. Unlike opioid medications, it is not associated with nausea.

  The elimination half-life has been estimated at anywhere from 2 to 24 hours. Yet a single sedation dose typically wears off within minutes, because the drug is rapidly distributed into peripheral tissues.

  7973818384

• 6. The Price of Sleep

  ›

  Pain on injection is one of propofol's most common side effects, especially in smaller veins, where the drug activates the sensory nerve pain receptor TRPA1. Pretreating with lidocaine or injecting more slowly into a large vein in the antecubital fossa eases it. Patients also vary considerably in their response, and small doses sometimes produce profound sedation.

  Blood pressure can fall by 30% or more. That drop is thought to stem at least partly from inhibited sympathetic nerve activity, and it depends on the dose and the rate of administration. Opioid analgesics can potentiate it. Propofol can also lower systemic vascular resistance, myocardial blood flow and oxygen consumption, possibly through direct vasodilation.

  Breathing is the other great concern. As a respiratory depressant, propofol frequently produces apnea, which can sometimes last longer than 60 seconds. How long depends on premedication, dose and rate. It may also reduce respiratory rate, minute volume, tidal volume, mean inspiratory flow rate and functional residual capacity. Benzodiazepines and other respiratory depressants magnify these effects. For this reason, propofol should be given only where trained staff and monitoring facilities are available, with airway management, supplemental oxygen, artificial ventilation and cardiovascular resuscitation at hand.

  Inside the head, cerebral blood flow, cerebral metabolic oxygen consumption and intracranial pressure all fall. In patients with normal intraocular pressure, the drug can lower it by as much as 50%. Mild myoclonic movements are common, and dystonia is a rarer, more serious effect. Some patients notice green urine. Propofol has also been reported to induce priapism and to suppress REM sleep, worsening sleep quality in some. On the safer side, it appears to be safe in porphyria and has not been known to trigger malignant hyperthermia.

  The milky formulation itself carries a hazard. Lecithin and soybean oil make it prone to bacterial contamination despite the inhibitor benzyl alcohol. Some hospitals therefore require IV tubing for continuous infusions to be changed after 12 hours.

  In the 1990s, multiple reported deaths of children in ICUs associated with propofol sedation prompted the FDA to issue a warning. Side effects seem to worry clinicians more in children than in adults.

  A rare but serious complication, propofol infusion syndrome, is a potentially lethal metabolic derangement. It has been reported in critically ill patients after a prolonged infusion of high-dose propofol, sometimes combined with catecholamines or corticosteroids.

  5052576846

• 7. Outside the Operating Room

  ›

  In Canada, medical assistance in dying uses a lethal dose of propofol to induce deep coma and death quickly. Rocuronium is always given as a paralytic as well, which ensures death even if the patient has already died from the initial overdose.

  Propofol has also been considered for execution protocols, but no one has been executed with it. The main obstacle is that European manufacturers and governments have banned its export for that use.

  Recreational self-administration has been reported but is relatively rare, because of the drug's potency and the monitoring it requires. A steep dose-response curve makes it very dangerous, and deaths from self-administration continue to be reported. People seek mild euphoria, hallucinations and disinhibition. Use has been described among medical staff with access to the drug, such as anesthetists. It is reportedly more common among those on rotations with short rest periods, since it produces a well-rested feeling. Long-term use has been reported to result in addiction.

  Attention to off-label risks grew in August 2009, when the Los Angeles County coroner's report concluded that musician Michael Jackson was killed on the 25th of June 2009. The cause was a mixture of propofol and the benzodiazepines lorazepam, midazolam and diazepam. A search warrant affidavit from the 22nd of July 2009, unsealed by the district court of Harris County, Texas, said Jackson's physician, Conrad Murray, administered 25 milligrams of propofol diluted with lidocaine shortly before the death.

  On the 26th of October 2021, Samsung executive Lee Jae-yong was convicted of illegally using propofol multiple times between 2015 and 2020 at a plastic surgery clinic. His sentence was a fine of US$60,055.

  2729314041

• 8. Descendants and New Patients

  ›

  In 2008, the FDA approved Lusedra, the brand name for fospropofol, a water-soluble prodrug of propofol. The enzyme alkaline phosphatase rapidly breaks it down into propofol in the body. It may avoid the injection-site pain that the conventional drug often causes.

  Light became a research tool in 2012, when scientists added an azobenzene unit to create a photoswitchable version called AP2. It allows optical control of GABAA receptors. In 2013, a propofol binding site on mammalian GABAA receptors was identified by photolabeling with a diazirine derivative. Researchers also showed that propofol can protect hyaluronan, a polymer in synovial fluid, from free-radical depolymerization.

  Ciprofol, another derivative, is 4-6 times more potent than propofol and is undergoing Phase III trials. It appears to cause less injection-site pain and less respiratory depression. Propofol itself has also been studied for treatment-resistant depression.

  The drug has now reached animal patients too. In November 2024, the FDA approved PropofolVet Multidose, the first generic propofol injectable emulsion for dogs. Its active ingredient matches that of the brand-name product PropoFlo 28, first approved on the 4th of February 2011. The FDA determined that none of its inactive ingredients significantly affect bioavailability. The sponsor is Parnell Technologies Pty. Ltd., based in New South Wales, Australia.

  8788899391