General anesthesia (GA) is a reversible drug-induced state of altered arousal required for more than 60,000 surgical procedures each day in the United States alone, making it one of the most common manipulations of the brain and central nervous system. 1 It comprises several specific behavioural and physiological traits – unconsciousness, amnesia, analgesia, and akinesia – with concomitant stability of the autonomic, cardiovascular, respiratory, and thermoregulatory systems. 2
Despite all the GA performed every day, so many years after the first demonstration of anesthesia in 1846 by William T. Morton in the “Ether Dome” of the Massachusetts General Hospital in Boston, the mechanisms by which general anesthetics can render an individual unconscious has remained incompletely understood. 3 This was in part due to the many decades where general anesthesia was achieved using only one general anesthetic drug to induce immobility, analgesia, amnesia and unconsciousness. In contrast to this period, where only one drug with a low therapeutic index was used4, nowadays much safer drugs with higher therapeutic indices are available, and we take advantage of the synergism resulting from the interactions between these drugs of different pharmacological classes (fig xx1). Synergistic interactions may be clinically useful, allowing the use of smaller doses of the individual drug (potentially decreasing side effects), but synergy is also present for the adverse effects (such ventilatory depression when benzodiazepines are combined with opioids) 5.
In this chapter, we will focus on the hypnotic component of anesthesia, which involves mainly inducing and maintaining unconsciousness while also providing amnesia (table xx1). We should however bear in mind that the different components of general anesthesia are much closely related than they might seem, and it is not always possible to isolate only one individual component, as hypnotic drugs can act on other components (e.g. immobility), and other non-hypnotic drugs can act on the hypnotic component (e.g. analgesia). This complexity of these interactions can be exemplified by the opioids, which besides the analgesic effect, they can also induce sedation. On the other hand, propofol, besides being an hypnotic, can also have analgesic properties6. Pharmacodynamically, both cause a decrease of pain perception and pain sensation, but due to different mechanisms. The sedative effects of propofol result mainly from cortical disruption as we will see further, whereas analgesia is mediated by a more specific modulation of nociceptive pathways. Still, both lead to analgesia, as analgesia refers to perception of pain, which implies consciousness6. In contrast to analgesic effects, antinociceptive mechanisms refer to a pathway-specific reduction of stimulus responses (not only conscious perception of painful stimuli but modulation of afferent noxious stimulation as well) 6.