Pharmacodynamics. Propofol is a CNS depressant. Intravenous injection of a therapeutic dose of propofol induces hypnosis, with minimal excitation, usually within a minute from the start of injection. The mechanism of action is not well understood. Propofol activates GABAA receptors directly, inhibits the NMDA receptor, blocks sodium channel, and modulates calcium influx through slow calcium ion channels. According to one view, general anesthetics such as propofol do not bind to ATP sites but transport kinesins and reduce their ability to transport critical cargos, which contributes to various anesthetic states (03).
Mechanism of loss of consciousness. The mechanisms underlying anesthesia-induced loss of consciousness are not clearly defined. Analysis of spectral EEG data during propofol infusion shows that mild sedation is accounted for by an increase in thalamic excitability that does not further increase during loss of consciousness, but there is a decrease in backward corticocortical connectivity from frontal to parietal cortices with no change in thalamocortical connectivity (04). High-density EEGs have been recorded in humans during gradual induction and emergence from unconsciousness with propofol to develop EEG signatures that track loss and recovery of consciousness (25). Loss of consciousness was marked simultaneously by an increase in low-frequency EEG power (< 1 Hz), the loss of spatially coherent occipital alpha oscillations (8-12 Hz), and the appearance of spatially coherent frontal alpha oscillations, which reversed with recovery of consciousness. According to a neurophysiological study, rapid induction of unconsciousness by propofol produces an abrupt change in network dynamics of the human brain, leading to a state in which neuronal activity is coupled to slow oscillations in the local field potentials (16). The local neuronal networks remain intact but become functionally isolated in time and space.
Computational models of electrophysiological oscillations in rats provide in vivo evidence that alpha oscillations (10 to 15 Hz) induced by propofol are synchronized between the thalamus and the medial prefrontal cortex, and with deepening levels of unconsciousness where movement ceases, coherent thalamocortical delta oscillations (1 to 5 Hz) develop distinct from concurrent slow oscillations (08). The pattern is like that in humans under propofol anesthesia and indicates that self-awareness and internal consciousness are impaired or abolished providing a neurophysiological biomarker of these states.
Effect on cerebral circulation and metabolism. A PET study has shown that general anesthesia with propofol is associated with a global metabolic and vascular depression in the human brain, with significant shifts in regional blood flow and metabolism indicating marked metabolic and vascular responsiveness in some cortical areas and thalamus (26). Metabolic reduction is significant in the thalamocortical network and the frontoparietal network (30). A study investigated the effects of propofol on cerebral microcirculation and oxygenation during craniotomies, and findings suggest alteration of the cerebral blood flow/cerebral metabolic rate for oxygen ratio in cortical brain regions, suggesting that propofol affects coupling of flow and metabolism in the cerebral microcirculation (14).
Neuroprotective effect. Evidence from functional brain imaging studies suggests that propofol-induced unconsciousness is associated with a global metabolic and vascular depression in the human brain. In a permanent middle cerebral artery occlusion model, propofol was shown to reduce infarct volume and neuronal damage for 7 days, suggesting long-term neuroprotective effect, which was attributed to the disodium edetate (EDTA) additive to propofol formulations for retarding bacterial and fungal growth (15). EDTA is a chelator of divalent ions, such as calcium, magnesium, and zinc, and exerts a neuroprotective effect by chelating surplus intracerebral zinc. Propofol also has an anxiolytic effect at doses that do not produce sedation.
Miscellaneous effects. Propofol reduces cerebral blood flow and intracranial pressure, is a potent antioxidant, and has antiinflammatory properties. Propofol is well known to be effective against status epilepticus that is refractory to standard anticonvulsants.
Pharmacokinetics. Following an intravenous bolus dose, there is rapid equilibration of propofol levels between plasma and highly perfused tissue of the brain, accounting for the rapid onset of anesthesia. Propofol is extensively bound to plasma proteins although the plasma level initially shows a steep decline due to both rapid distribution and high metabolic clearance. Propofol is eliminated mainly by hepatic conjugation to inactive glucuronide metabolites that account for about 50% of the administered dose and are excreted by the kidney. The terminal half-life of propofol after a 10-day infusion is 1 to 3 days. If the infusion rate in patients receiving propofol for extended periods is not reduced, it may result in excessively high blood concentrations of the drug.
Epidural blockade has a pharmacokinetics interaction with propofol possibly by reduction in hepatic and/or renal blood flow. An epidural dose of ropivacaine that blocks 20 segments reduced the target concentration of propofol by 30% compared with when no epidural blockade was used (28). This may require adjustment of dose of propofol.
Therapeutic drug monitoring. A gas chromatography-mass spectrometry method is rapid, sensitive, reliable, and suitable for qualitative and quantitative analysis of propofol in blood (31). The Pelorus 1000 (Sphere Medical) measures propofol concentrations of the whole blood in approximately 5 minutes with precision and accuracy suitable for elucidating propofol pharmacokinetics at clinically relevant concentrations without the need for sample preparation (20). High performance liquid chromatography (HPLC) is perhaps the most commonly reported method for the detection and quantification of propofol. It is considered by many to be the gold standard for validation purposes. HPLC may be used in conjunction with a variety of measurement techniques, with the most common being fluorometric detection. However, HPLC is not well suited to point-of-care applications due to its reliance on bulky and expensive equipment. Other methods of propofol detection include spectrophotometric detection and electrochemical techniques (07). Future work in this area will likely focus on improvements to sensitivity and specificity and on integrating sensors into technologies to enable automated and continuous measurement.
Pharmacogenetics and pharmacogenomics. Plasma levels of propofol metabolites show high interindividual variability, but no significant relationships have been revealed between the SNPs studied and propofol metabolism. The sex of the patient, however, has a pronounced effect on propofol metabolism, with women showing higher amounts of propofol glucuronide, 4-hydroxypropofol-1-glucuronide, and 4-hydroxypropofol-4-glucuronide; this explains the sex difference in systemic clearance of propofol (23).
