Canadian journal of anaesthesia = Journal canadien d'anesthésie
-
The Cys-loop ligand-gated ion channel superfamily is a major group of neurotransmitter-activated receptors in the central and peripheral nervous system. The superfamily includes inhibitory receptors stimulated by γ-aminobutyric acid (GABA) and glycine and excitatory receptors stimulated by acetylcholine and serotonin. The first part of this review presents current evidence on the location of the anesthetic binding sites on these channels and the mechanism by which binding to these sites alters their function. The second part of the review addresses the basis for this selectivity, and the third part describes the predictive power of a quantitative allosteric model showing the actions of etomidate on γ-aminobutyric acid type A receptors (GABA(A)Rs). ⋯ These binding sites function allosterically. Certain conformations of a receptor bind the anesthetic with greater affinity than others. Time-resolved photolabelling of some sites occurs within milliseconds of channel opening on the nAChR but not before. In GABA(A)Rs, electrophysiological data fit an allosteric model in which etomidate binds to and stabilizes the open state, increasing both the fraction of open channels and their lifetime. As predicted by the model, the channel-stabilizing action of etomidate is so strong that higher concentrations open the channel in the absence of agonist. The formal functional paradigm presented for etomidate may apply to other potent general anesthetic drugs. Combining photolabelling with structure-function mutational studies in the context of allosteric mechanisms should lead us to a more detailed understanding of how and where these important drugs act.
-
Today's general anesthetics were developed empirically according to their ability to produce memory blockade, analgesia, immobility, and unconsciousness. Thus, a major outstanding question remains: How do anesthetics produce their desirable behavioural end points at the molecular level? Understanding the mechanisms underlying memory blockade is of particular importance, because some patients experience the unexpected recall of events during anesthesia while others experience persistent memory deficits in the postoperative period. This review provides a brief summary of the acute memory-blocking properties of general anesthetics and the neuronal substrates that most likely contribute to memory loss. ⋯ Anesthetics target different receptors and brain regions to modify the various forms of memory. In the hippocampus, extrasynaptic γ-aminobutyric acid subtype A receptors may play a particularly important role. Knowledge regarding the molecular basis of memory blockade may help to address memory disorders associated with the anesthetic state.
-
Postoperative cognitive decline in the elderly has emerged as a major health concern. In addition, there is a growing interest in the potential relationship between general anesthetic exposure and the onset and progression of Alzheimer's disease (AD). The available evidence of a possible association between anesthesia, surgery, and long-term cognitive effects, including AD, deserves consideration. In this review, we summarize the evidence for anesthesia-induced neurotoxicity in the elderly, while highlighting the limitations of existing data, and we put the literature into perspective for the clinician. ⋯ The possible relation between anesthetic neurotoxicity, postoperative cognitive dysfunction, and AD remains elusive. It remains unclear whether postoperative cognitive decline in the elderly is related more to perioperative stress and related medical co-morbidities.
-
The hippocampal formation occupies a central position for the processing of sensory input into learned, remembered, and consciously retrievable information. The mechanisms by which anesthetic drugs interfere with these processes are now emerging. We review the current understanding of the role of the hippocampal formation in the generation of memory traces and how anesthetics might interfere with its function. ⋯ Anesthesiologists routinely induce the most fascinating pharmacologic effects in existence, the reversible interference of anesthetics with higher cognitive functions. Understanding how the drugs in our custody exert their effects should be our contribution to mankind's universal knowledge base.
-
To review the mechanisms of sedative-hypnotic action with respect to the risk of delirium imparted by drugs that act on γ-amino-butyric-acid type A receptors or α(2) adrenoceptors. ⋯ Herein we present our hypothesis that alternate mechanisms of hypnotic action may differentiate the deleriogenic properties of the two classes of sedatives. Future studies should focus on whether a causal relationship can be established between sedative administration, sleep disruption, and delirium.