Chemically identified as 2,6-diisopropylphenol, propofol is a widely used intravenous anesthetic and sedative. It induces and maintains general anesthesia for surgical procedures. It also provides sedation in various medical settings, including diagnostic procedures and intensive care units. Its distinctive milky white appearance comes from its specialized lipid emulsion formulation.
Early Development and Synthesis
Propofol’s development began with John B. Glen, a British veterinary anesthesiologist at Imperial Chemical Industries (ICI). Propofol was first identified as a promising drug candidate in 1973. Glen, in collaboration with chemist Roger James, systematically screened numerous chemical compounds to find an improved anesthetic.
Initially known by its code name, ICI 35868, propofol demonstrated superior anesthetic properties in early animal tests. It proved to be 1.8 times more potent than thiopentone, an existing anesthetic, and offered rapid onset without inducing muscle twitching. The research aimed for an agent with swift action and quick recovery, overcoming the limitations of older anesthetics like thiopentone, which often resulted in prolonged unconsciousness.
Pure propofol is an oily substance at room temperature and possesses poor solubility in water. This meant a suitable carrier vehicle was necessary for intravenous administration. Finding an appropriate delivery method became a significant hurdle in its development.
Clinical Trials and Regulatory Approval
Clinical trials for propofol commenced in 1977, with an initial formulation that used Cremophor EL as a solubilizing agent. However, this early version caused severe adverse reactions, including severe anaphylactic responses in some patients. Consequently, this formulation was withdrawn from clinical development around 1980.
John Glen advocated for an alternative formulation, believing the drug itself was safe. Researchers successfully created a stable and safe oil-in-water emulsion: a 1% propofol solution suspended in a 10% soybean oil emulsion. This lipid-based formulation, often described as a “milk of amnesia” due to its appearance, proved effective and well-tolerated in subsequent human trials.
With this refined formulation, propofol, marketed under the brand name Diprivan, received its first regulatory approvals. It was approved for medical use in the United Kingdom and New Zealand in 1986. The U.S. Food and Drug Administration (FDA) granted its approval for propofol in October 1989.
Widespread Adoption in Anesthesia
After regulatory approvals, propofol rapidly gained widespread acceptance in anesthetic practice globally. Its rapid onset (typically within 15 to 30 seconds) and swift, clear-headed recovery made it highly advantageous. Patients experienced less post-operative drowsiness, nausea, and vomiting.
Propofol largely superseded sodium thiopental as the preferred intravenous induction agent for general anesthesia. Its versatility allowed it to be used not only for inducing but also for maintaining general anesthesia, as well as for providing sedation in various medical procedures and in intensive care settings. By 2016, the World Health Organization formally recognized propofol as an “essential medicine,” highlighting its global significance.