Propofol

The introduction of general anaesthetics in the mid-19th century revolutionised surgical procedures. What were once considered painful dangerous and often unsuccessful procedures have now become much safer, less painful and have much more predictable outcomes. For over a century anaesthesia was achieved using volatile gaseous anaesthetics such as, ether, nitrous oxide and chloroform (Figure 1.20).

31 | P a g e Figure 1.20. Early volatile gaseous anaesthetics

More recently intravenous anaesthetics have become the most popular method of inducing and maintain anaesthesia110. 2, 6-diisopropylphenol (propofol, Diprivan, Figure 1.18) is a fast acting sedative agent which was first introduced clinically in 1985111. Since its approval for the induction and maintenance of general anaesthesia by the food and drug administration (FDA) in 1989, propofol has become the most widely used intravenous general anaesthetic agent in the world112.

Propofol is a highly lipophilic alkyl phenol and as such has a low solubility in water and was originally prepared as 1% solution in Cremophor EL (CrEL). CrEL is a heterogeneous non-ionic surfactant which is produced by the reaction of castor oil with ethylene oxide. CrEL has been deemed as an unsuitable solvent in America, therefore, propofol is now prepared as an oil in water emulsion with 1% propofol, 10% soybean oil, 2.25% glycerol, and 1.2% egg lecithin110,113.

Propofol is renowned for a rapid onset of sedation, approximately 40 seconds after administration; this is due to a rapid equilibration between plasma and highly perfused brain tissues. With the peak effect occurring within 1-2 minutes and duration of effect between 4-8 minutes (following a single intravenous dose of 1.5- 2.5 mg/kg), propofol has a rapid emergence from sedation with little nausea or vomiting114.

In an effort to overcome the innate solubility issues seen with propofol, several water soluble alternatives have been synthesised. Propofol phosphate, propofol ethyl dioxy phosphate and fospropofol (Aquavan®, Lusedra) are all phosphate prodrugs of propofol (Figure 1.23). Collectively they all rely upon enzymatic

32 | P a g e cleavage of the phosphate moiety to release the parent drug and consequently they all have a markedly slower onset of sedation than the parent compound.

Figure 1.23. Phosphate prodrugs of propofol.

A major drawback to both propofol ethyl dioxy phosphate and fospropofol is that they liberate toxic compounds upon metabolism. Propofol ethyl dioxy phosphate liberates acetaldehyde, which has been linked to gastrointestinal tract cancer, whereas, fospropofol releases formaldehyde which is further metabolised to formate (Figure 1.24). Whilst formaldehyde is a naturally occurring metabolite from many cellular processes, elevated levels are thought to alter homeostasis within cells and may also play a role in enzyme induction, metabolic switching and cell proliferation115. The rapid conversion of formaldehyde to formate is mediated by aldehyde dehydrogenase in the liver and in erythrocytes and formate is further metabolised by 10-formyltetrahydrofolate dehydrogenase and tetrahydrofolate. On the basis of this the liberation of formaldehyde is not thought to be toxic in patients with normal levels of tetrahydrofolate 116,117.

33 | P a g e The most common adverse effect associated with propofol use is pain at the injection site (occurring in 80-90% of patients). Although this is often attributed to propofol’s lipid formulation, studies have shown that propofol can activate the TRPA1 receptor which is co-associated with TRVP1 receptors in 30% of nociceptive neurons. As a consequence the local anaesthetic lidocaine is generally administered prior to propofol use114,118.

Studies have shown propofol exerts its sedatory effects by modulating the inhibitory function of the GABAA receptor, specifically by decreasing cerebral

metabolism in the hippocampus, parietal, frontal and occipital lobes. This involves areas of sensory, motor and limbic systems119,120. Clinical relevant concentrations of propofol can markedly increase GABA induced Cl- current and a report published in 2003 showed that a point mutation in the β3 subunit of the GABAA receptor could

eliminate propofol activity121,122.

Propofol is also known to be a positive allosteric modulator of the strychnine sensitive glycine receptor123. With the role the GlyRs play in nociceptive pathways it is thought that the binding of propofol to GlyRs and the subsequent increase in Cl- could contribute to analgesia124. Reports have shown that sub-hypnotic doses of propofol (0.25mg/Kg) can reduce laser induced pain in human volunteers and intravenous administration of 0.25mg/Kg followed by 25μg/Kg/min can significantly reduce pain intensity125,126.

The short duration of action of propofol is due to a rapid redistribution and metabolism, primarily by the liver, into a range of inactive metabolites. The major route of metabolism for propofol is glucuronidation of the parent compound at the phenolic hydroxyl site (50-60% of the overall dose). The remaining is metabolised via ring hydroxylation to give the 4- hydroxyl propofol which is further subject to glucuronidation and sulfation. Glucuronidation is catalysed by uridine diphosphate- glucuronosyltransferases (UGT) such as UGT1A9, whereas sulfation is catalysed by sulfotransferases (SULTs). Oxidative metabolism of propofol is mediated via a range of cytochrome P450 enzymes (CYP450) including, CYP2C9 (removes around 50%), CYP2A6, 2C8, 2C18, 2C19, and 1A2 (Figure 1.25)127,128.

34 | P a g e Figure 1.25. The metabolic pathway of propofol in humans. UGT— uridine diphosphateglucuronosyltransferase, SULT — sulfotransferases, CYP — cytochrome P450 isozymes, GLU — glucuronide.

Propofol modulates receptors within the CNS, but in order for propofol to access the CNS it must first cross the blood brain barrier.