A Mini Review of Propofol's Discovery

Discovery of Propofol

            From the mid-19^th through mid-20^th century, the primary method of anesthesia involved inhalation of volatile liquids with or without combination of an intravenous induction agent; these procedures had relatively long recovery times and unwanted side effects (Glen, 2018; Trapani et al., 2000). Therefore, a team at Imperial Chemical Industries (ICI; later AstraZeneca) sought to find a compound that could produce similar intravenous anesthesia as the inspiring induction compound, thiopentone, but rapidly metabolize for easier maintenance of doses, faster recovery times, and potentially fewer side effects (Glen, 2018).

            Developing such a compound was initially unsuccessful as potential compounds had to work on targets expressed in the central nervous system (CNS; Glen, 2018; Trapani et al., 2000). To deliver an anesthetic to the CNS, a compound had to be relatively lipophilic while intravenous administration required an aqueous solution that proved difficult to produce. However, in the 1960s-70s Bayer showed, through two unsuccessful candidates, plausibility through the use of a new surfactant, Cremophor, that allowed compounds with poor water solubility to be delivered intravenously. The new surfactant allowed ICI to then test variants from a previously known lead compound, 2,6-diethylphenol, which led to the synthesis of 2,6-diisopropylphenol [ICI 35868], or Propofol (Glen, 2018).The synthetic drug Propofol was chosen by John. B. Glen from a screening of lipophilic compounds (to get into the CNS) as it showed promising anesthetic qualities such as rapid recovery times and the ability to repeatedly inject without prolonging recovery times like thiopentone (Glen, 2018). But, Propofol had more challenges in clinical trials as it produced anaphylactic responses that stalled its wide-spread marketability for another 13 years. Eventually, the surfactant was related to the anaphylactic responses and replaced with an emulsion of lipids (Trapani et al., 2000) that led to Propofol’s approval in the United Kingdom in 1986 and the US in 1989 (Glen, 2018).

Propofol works in part by positive modulation of GABAergic activity via GABA_A receptors thought to contain an α or β subunit and by presynaptic inhibition of GABA reuptake (Trapani et al., 2000). The potentiated GABAergic signaling then allows an influx of chlorine that hyperpolarizes neurons making them less likely to fire. Propofol also works at other similar ion-gated chlorine channels such as glycine and can inhibit acetylcholine and glutamate receptors as well as sodium channels that may have clinical relevance for treating epileptic disorders (Trapani et al., 2000). Propofol is primarily used to reduce pain and anxiety in surgery via anesthetic induction or maintenance within 40-60 seconds through either continuous or intermittent bolus doses with duration of action around 10 minutes for clinically relevant doses (Symington et al., 2006). Side effects for Propofol include a relatively narrow therapeutic index for risk of progression into deep sedation (i.e., over sedation), hypoxia, hypotension (Symington et al., 2006), apnea (Trapani et al., 2000), and pain on injection (Matta et al., 2008).

In relation to an older anesthetic, Ketamine, the primary improvements Propofol offers is in its safety profile. Indeed, many academics surveyed to ask what new drug was most transformative cited Propofol due to its superior side effect profile over previous anesthetics (Bateman et al., 2015). The side effect profile of Ketamine includes possible emergence delirium, increased blood pressure and heart rate, and nausea and vomiting. Conversely, Propofol has relatively few of these side effects (mentioned prior) and is highly rated by both physicians and patients (Thomas et al., 2011). As for my reflection on Propofol, the most interesting future modification seems to be in studies looking at the combination of Propofol and Ketamine, or “Ketofol.” The logic of the combination is Propofol has a slightly increased risk for over sedation, while the hypertension and increased heart rate from Ketamine may offset some of Propofol’s increased sedation effects (Thomas et al., 2011).  However, while Ketofol may reduce the needed dose of Propofol or perhaps provide a more quality sedation, the initial results are mixed on the improvement over Propofol alone (Thomas et al., 2011). 

Commercialization of Propofol

            Propofol, trademarked as Diprivan, was originally marketed by Imperial Chemical Industries in the United Kingdom that was later absorbed by AstraZeneca (Glen, 2018). The original patent for Propofol in the US investigated its use as an anesthetic in animals (US05559880) in 1975. However, many patients showed poor acceptance of the original compound that led to several more patents and variations of Propofol such as US5714520A in 1985 patenting an emulsion formulation of Propofol many generic compounds also emulate. Since that time, several patents continue to be submitted assessing changes to the formulation of Propofol to improve its therapeutic profile. While it is unclear when AstraZeneca’s patent expired due to the large number of formulation change submissions, the earliest US-FDA approved and marketed generic came from Fresenius Kabi in 1989 (“FDA Approved Drug Products”, n.d.). The FDA lists no approved Propofol drug products from AstraZeneca; the last filing from AstraZeneca sought relabeling of product information for pediatric use in 2001 (“Drug Approval Package”, 2007). There are currently four FDA approved and marketed Propofol or generic Diprivan formulations from Hospira, Watson Labs Inc, Sagent Pharms, and Fresenius Kabi (“FDA Approved Drug Products”, n.d.).

            Diprivan is commonly listed as a popular and widely used anesthetic as evidenced by academics and physicians (Bateman et al., 2015) and being listed on the World Health Organization’s list of essential medicines (Madera et al., n.d.); however, actual statistics for such statements are lacking. One study surveying the American College of Gastroenterology found that 25% of used sedatives were Propofol based (Patel et al., 2017) and one report from statista.com reported Propofol’s US market share at $246 million USD in 2013 (“Market Size of Propofol”, n.d.). In 2010, Fresenius Kabi reported worldwide Propofol sales of EUR 3,672 million with an end profit of EUR 737 million (Ross, 2011). Propofol owes its success to multiple factors such as fast acting mechanisms (Trapani et al., 2000; Symington, 2006), low clinically relevant doses of less than 10 mg/kg (Symington, 2006), ease and comfort of use relative to gaseous forms of anesthesia, and relative cost effectiveness (Madera et al., n.d.).

            Propofol’s growing use was not without setbacks. Even after the initial problems of anaphylactic responses that nearly abolished early Propofol formulations from continued research was resolved (Glen, 2018), continued issues arose. For instance, sufficient evidence emerged of an apparent increase in patient mortality during pediatric use that led to the FDA issuing a warning of Propofol’s use (“FDA Issues Warning”, 2001; since redacted). Additionally, the newer emulsion formulations containing lipids had increased risk of contamination that could lead to postoperative infections (Bennett, 1995) and one record of spreading Hepatitis C. Two suppliers at the time, Teva Pharmaceuticals and Baxter, were required to pay millions of dollars to an infected individual (Hvisdas et al., 2013). The backlash against the pharmaceutical companies, several recalls and a closed manufacturing facility of another provider, Hospira, and increasing FDA pressure for compliance, are all thought to have played pivotal roles in the eventual Propofol shortage that began around 2010 through 2013 (Hvisdas et al., 2013). During the shortage, further issues surrounding contamination were recorded that only exacerbated issues surrounding Propofol (Neff et al., 2018). Following these events, Propofol became branded as a high-liability drug that Teva Pharmaceuticals never returned to supplying after the legal case brought against them (Hvisdas et al., 2013). Indeed, the ramifications of the Propofol shortage are apparent enough that the Fresenius Kabi website includes an entire page dedicated to informing the public about the manufacturing of Diprivan and how future shortages are planned to be circumvented (“How Fresenius Kabi”, n.d.).

            Other complications surrounding Propofol stem from its abuse potential. In 2009, celebrity Michael Jackson died from an acute overdose (Jackson, 2018). The reaction to Jackson’s death sent doubts into the use of Propofol for the general public (Landau, 2011) as well as regulatory agencies such as the United States Drug Enforcement Administration (“DEA might tighten restrictions”, n.d.). Concerns are also being raised about increased reporting of medical professionals’ abuse of Propofol (Belluck, 2009; Early et al., 2013), with particular concerns surrounding the fact that Propofol at the time was a non-scheduled drug. Indeed, given that Propofol is increasingly being shown to have mechanisms similar to other drugs of abuse (Lian, 2013), as well as the relatively low therapeutic index between clinically relevant doses (typically < 10 mg/kg) and preclinical LD50s (42-53 mg/kg; Pasin et al., 2015), some may still feel that the DEA’s classification of Propofol as a Schedule IV drug (i.e., relatively low abuse potential; “Schedules of control”, 2010), is not far enough.

            A final point of controversy surrounding Propofol is its potential use in lethal injections. Throughout the early 2000s, many US states used a three-drug protocol but, in 2012, Missouri attempted to switch to using Propofol as a one-drug protocol for lethal injections (Caplan, 2016). After the announcement from Missouri, Fresenius Kabi, Teva, and Hospira all put controls on the distribution of Propofol and the European Union threatened to limit exports of the drug to US (Caplan, 2016; Salter, 2013); these measures effectively stopped Missouri before its first execution using Propofol (Salter, 2013).

            Despite the complications, Propofol continues to be widely used throughout the US (Hvisdas et al., 2013). Indeed, even as recent as 2014 Fresenius Kabi issued a failed suit against Watson Laboratories for patent infringement (Andrews, 2014), indicating Propofol’s continued profitability. Propofol continues to have many advantages over other anesthetics (e.g., Bateman et al., 2015) with the primary concern of its narrow therapeutic index attenuable by the presence of anesthesiologists. Thus, Propofol may continue to be a popular choice of anesthetics until a new compound with a similar profile but broader therapeutic index is discovered.

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