Handbook of experimental pharmacology
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We do not know how general anesthetics cause their desired effects. Contrary to what has been thought until relatively recently, the clinical state of anesthesia consists of multiple components that are mediated via interaction of the anesthetic drugs with different targets on the molecular-cellular, the network, and the structural-anatomical levels. The molecular targets by which some of these drugs induce the different components of "anesthesia" may be rather specific: discrete mutations of single amino acids in specific proteins profoundly affect the ability of certain anesthetics to achieve specific endpoints. ⋯ The CNS appears to be susceptible to anesthetic neurotoxicity primarily at the extremes of ages, possibly via different pathways: in the neonate, during the period of most intense synaptogenesis, anesthetics can induce excessive apoptosis; in the aging CNS subtle cognitive dysfunction can persist long after clearance of the drug, and processes reminiscent of neurodegenerative disorders may be accelerated (Eckenhoff et al. 2004). At all ages, anesthetics affect gene expression-regulating protein synthesis in poorly understood ways. While it seems reasonable to assume that the vast majority of our patients completely restore homeostasis after general anesthesia, it is also time to acknowledge that exposure to these drugs has more profound and longer lasting effects on the brain than heretofore imagined.
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The release of transmitters through vesicle exocytosis from nerve terminals is not constant but is subject to modulation by various mechanisms, including prior activity at the synapse and the presence of neurotransmitters or neuromodulators in the synapse. Instantaneous responses of postsynaptic cells to released transmitters are mediated by ionotropic receptors. In contrast to metabotropic receptors, ionotropic receptors mediate the actions of agonists in a transient manner within milliseconds to seconds. ⋯ As these receptors display greatly diverging structural and functional features, a variety of different mechanisms are involved in the regulation of transmitter release via presynaptic ionotropic receptors. This text gives an overview of presynaptic ionotropic receptors and briefly summarizes the events involved in transmitter release to finally delineate the most important signaling mechanisms that mediate the effects of presynaptic ionotropic receptor activation. Finally, a few examples are presented to exemplify the physiological and pharmacological relevance of presynaptic ionotropic receptors.
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It belongs to the particularities of anaesthesia that the conscious response of the patient to drug therapy is not available for the adjustment of drug therapy and that the side-effects of anaesthetic drug therapy would be in general lethal if no special measures were taken such as artificial ventilation. Both conditions do not allow for a slow, time-consuming titration of drug effect towards the therapeutically effective window, but measures have to be taken to reach a therapeutic target fast (within seconds to a few minutes), reliably, and with precision. ⋯ Whereas TCI presents an open-loop dosing strategy (the past output does not influence the future input), current research deals with the model-based adaptive closed-loop administration of anaesthetics. In these systems the past output is used to adapt and individualize the initial pk-pd model to the patients and thus has an influence on future drug dosing which is based on the adapted model.
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Handb Exp Pharmacol · Jan 2008
ReviewInhibitory ligand-gated ion channels as substrates for general anesthetic actions.
General anesthetics have been in clinical use for more than 160 years. Nevertheless, their mechanism of action is still only poorly understood. In this review, we describe studies suggesting that inhibitory ligand-gated ion channels are potential targets for general anesthetics in vitro and describe how the involvement of y-aminobutyric acid (GABA)(A) receptor subtypes in anesthetic actions could be demonstrated by genetic studies in vivo.
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It is today generally accepted that anesthetics act by binding directly to sensitive target proteins. For certain intravenous anesthetics, such as propofol, barbiturates, and etomidate, the major target for anesthetic effect has been identified as the gamma-aminobutyric acid type A (GABA(A)) receptor, with particular subunits playing a crucial role. ⋯ For the less potent steroid anesthetic agents the picture is less clear, although a relatively small number of targets have been identified as being the most likely candidates. In this review, we summarize the most relevant clinical and experimental pharmacological properties of these intravenous anesthetics, the molecular targets mediating other endpoints of the anesthetic state in vivo, and the work that led to the identification of the GABA(A) receptor as the key target for etomidate and aminosteroids.