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In the movie Awake, the protagonist of the film regains consciousness while undergoing open-heart surgery but finds himself incapable of movement or communication. While the action of the film proceeds from there, this initial premise of intra-operative awareness is not without grounds in reality. Instances of this sort are experienced by one or two out of every 10,000 patients (John and Prichep 2005). While occurrences such as these are both rare and typically do not involve pain, they do elucidate the point that even the most modern anesthetic agents sometimes leave much to be desired (Lagasse 2002). For this reason, among others, the delivery of anesthesia has developed into a specialized art form due to the fact that scientific understanding of how these powerful drugs achieve their effects, as well as how to enhance them, has lagged behind the majority of other fields of drug research (Hemmings and Antognini 2006).
Numerous current anesthetics possess both clinical and structural commonalities with ether, a drug which was employed successfully as an anesthetic for the first time by William Morton, a Boston dentist, in 1846 (Orser 2008). Subsequently, the practice of general anesthesia has come to include 40 million patients in North America alone. However, progress in anesthetic care has arisen primarily from improved drug delivery and risk management (Lagasse 2002).
As the strongest depressors of nervous system function employed in medicine today, modern general anesthetics affect both heart function and respiration, the result being they possess a fine margin of safety between what comprises a therapeutic dose, and what represents a toxic, or even lethal, one (Lagasse 2002). Such a narrow margin as this represents one reason why patients who are already under cardiac or respiratory distress - such as trauma victims or those undergoing heart surgery - must receive an attenuated dose, potentially leading to the rare instances of intra-operative awareness described above.
While strides have been made in the applications of general anesthesia, building the groundwork for complex operations such as open-heart surgery and organ transplants, the strong neurodepressive capabilities of these drugs lend themselves to an increased likelihood of death from the drugs, rather than the surgery itself, during an operation (Orser 2008). Further, as the rate of anesthesia-related mortality has held steady at one death per 13,000 for the prior 15 years, it is apparent that the limits of safe delivery of these drugs has been reached. Lastly, the side effects of anesthesia, from respiratory failure to cognitive impairment, may also be rooted in the incomplete understanding of the influences of modern anesthetics on the central nervous system (Orse 2008).
Empirical to Experimental: Moving Towards Cellular Actions
Modern general anesthetics were all developed empirically, that is, for their capabilities to affect the ideal state of being anesthetized. There are five aspects of this state: analgesia, immobility, unconsciousness, sedation, and amnesia. It is through the examination of the ways in which general anesthetics produce these effects that scientists are beginning to better understand the drugs themselves (Schneider and Koch 2007). What is being revealed in these studies is that the effects of general anesthetics are achieved via very specific exchanges with certain cells of the nervous system, such exchanges producing each of the five distinct traits of the anesthetic state (John and Prichep 2005). These discoveries will enable scientists to move into the next iteration of general anesthetic drugs, ones which are specialized, specific and targeted and can be utilized in concert to achieve only the desired effects without the drawbacks (Hemmings and Antognini 2006).
There are two main categories of anesthetics: those delivered by inhalation, such as isoflurane; and those delivered intravenously, as in the case of propofol. While general anesthetics seem to cause a complete sleep, the state which occurs is akin to a medically induced coma (Schneider and Koch 2007). In an effort to further understand the underpinnings of the effects of these drugs, both MRI and PET technologies have been utilized to identify many of the areas of the brain and neural pathways which participate in producing the aspects of being anesthetized. For example, drug interactions on the spinal cord are responsible for the motionless state of general anesthetics, whereas anesthetic action on the hippocampus is associated with memory impairment (Orser 2008).
Since consciousness is an intricate process whose fundaments are still under debate by neuroscientists, there is some difficulty in isolating a singular anatomical locale of unconsciousness during anesthesia (Lagasse 2002). A theory which is currently popular maintains that it is merely a result of "cognitive unbinding" - an induced cessation of interaction between the numerous regions of the brain which typically work together in higher cognition (Orser 2008). However, scientists are engaged in promising research pertaining to the specific mechanisms of anesthetics at the cellular level within the nervous system: that is, how these drugs inhibit the transmission of neural impulses.
Throughout the majority of the past century, it was thought anesthetics worked via disruption of the lipid components of the cellular membrane (John and Prichep 2005). The majority of these drugs are fat-soluble with markedly differing structures, ranging from inert gases to highly complex steroids. This diversity lent itself to the notion that anesthetics achieved their effects in some nonspecific manner to inhibit neuronal activity. However, current research has demonstrated that anesthetics interface with receptors on nerve cells. Groups of receptors possess slightly different versions, though, which tend to cluster in differing regions of the central nervous system. Thus, if a certain receptor subtype is only present on a certain population of cells, such will regulate which cells the anesthesia works upon. Modern research is working to single-out which receptor variants are targeted by today's anesthetics, describe the resultant interaction which alters the cell's function, and elucidate how both the beneficial and deleterious effects of the drugs arise from those cellular changes (John and Prichep 2005).
Receptor Proteins and Anesthesia
Of the multitude of neurotransmitters which act upon synapses, the one which has garnered the most attention in anesthesia research is GABA, or gamma aminobutyric acid (Hemmings et al. 2005). As an inhibitory neurotransmitter, GABA acts to depress the capability of neurons to react to excitatory stimuli from other cells, thus aiding in regulating overall equilibrium in the nervous system (Orser 2008). Thus, it is thought that GABA holds a pivotal role in the functions of anesthetics.
The majority of post-synaptic GABA-interacting receptors on cells are classified as ligand-gated ion channels (John and Prichep 2005). As the ligand, GABA, adheres to the receptor, the receptor alters its shape, providing a temporary channel which allows negatively charged ions to enter (John and Prichep 2005). This creates a negative potential, inhibiting any excitatory electrical pulse from being produced by the cell (Orser 2008).
GABA subtype A, or GABAA, is thought to be the principal target for these drugs (Schneider and Koch 2007). It is known that GABAA also plays a significant role in the beneficial effects of other hypnotic and sedative agents, as in the case of Valium and related benzodiazipans. GABAA receptor activity increases even at very low doses of benzodiazipans, a function which is proven when reversal agents that inhibit benzodiazipan from adhering at the GABAA receptor are observed to quickly attenuate the effects of those drugs (Schneider and Koch 2007).
In the case of anesthetics, reversal agents which may help indicate receptor sites do not exist. However, researchers have utilized samples from numerous parts of the brain, as well as in vitro neuron samples, to demonstrate that both inhaled and intravenous anesthetics extend the duration of postsynaptic electric impulses created by GABAA receptors (Lagasse 2002).
It is theorized that anesthetics augment the action of GABAA receptors by adhering to discrete amino acids or via interaction at specific binding sites, extending the duration of the opening of the channel, which prolongs the repressive actions of GABA agents at the receptor (Orser 2008). With elevated doses, anesthetics may activate the GABA receptors alone (Orser 2008).
GABAA receptors vary both pharmacologically and structurally (Hemmings et al. 2005). There are five subunit parts which comprise the GABAA receptor, parts which can be ordered in various ways, producing differing configurations. In mammals, there are at least 19 distinct GABAA receptor subunits, the majority of these possessing variant subtypes, resulting in a potentially high number of combinations. However, there are three commonly observed subunits in neurons: alpha, beta and gamma. It is the composition of the receptor's five subunits that drastically affects its pharmacological traits: the difference of only one subunit in the GABAA receptor's configuration is able to determine if and how it will interact with an anesthetic drug. Since differing GABAA receptor subtypes populate differing areas of the brain, scientists can describe how particular effects of anesthetics are produced in various regions of the central nervous system by studying the interaction of the the drugs and their receptors (Hemmings et al. 2005).
GABAA, Memory Impairment, and Anesthesia
In order to identify the receptor's which influence the memory-impairing aspects of general anesthetics, researchers concentrate on the GABAA receptors of the hippocampus (John and Prichep 2005). It is known that anesthetics produce amnesia at doses substantially lower than those necessary for immobility or unconsciousness (Orser 2008). However, for unexplained reasons, certain patients possess surprising recollections of occurrences during surgery (Orser 2008). Therefore, by identifying the target receptors for the memory-impairing effects of anesthesia, scientists could potentially identify those at risk for intra-operative awareness via the patient's dearth of those receptors (Schneider and Koch 2007).
Extrasynaptic GABAA receptors have a part in anesthetic action as well (Westphalen and Hemmings 2003). Concentrations of these receptors are found in particular regions of the brain, such as the hippocampus, in addition to the cerebellum and cortex. Such receptors have been found to generate a low-amplitude current, which, when enhanced, interferes with communication. With doses well below those required to cause immobility, two of the most common injectable anesthetics, propofol and etomidate, as well as the inhaled anesthetic isoflurane, have been observed to increase the amplitude of the current up to 35-fold. This sensitivity to very small doses of anesthetics at the extrasynaptic GABAA receptors, while, at the same drug concentrations, negligible changes occur in the postsynaptic current, has lead researchers to focus on the extrasynaptic GABAA receptors as the likely site of anesthesia's amnesia-inducing effects (Westphalen and Hemmings 2003).
The key factor as to why these extrasynaptic GABAA receptors are so sensitive to anesthetics is their structure - namely, whether or not they contain an alpha-5 subunit, a constituent which is typically absent in the postsynaptic receptors (Hemmings and Antognini 2006). Neuroscientific research supports this finding in that normal hippocampal-dependent memory functions rely, in part, on alpha-5 subunit containing GABAA receptors (Cheng et al. 2006). Further experimentation has confirmed, in mice, that genetically engineered subjects, lacking the alpha-5 subunit, do not evince memory-related symptoms of anesthesia when given etomidate, whereas wild type mice (who possess the alpha-5 subunit), were sensitive to the amnesia-inducing effects of the drugs (Cheng et al. 2006).
Such studies have also demonstrated that the lack of alpha-5 GABAA receptors does not play a role in any of the other effects of anesthesia: hypnosis, sedation, immobility and responses to painful stimuli were equivalent in both groups of mice (Cheng et al. 2006). These findings indicate that the memory-inhibiting aspects of etomidate can be singled out from the drug's other effects based on the pharmacology of discrete receptor subunits (Cheng et al. 2006).
Concurrent research has been exploring both the immobilizing and hypnotic properties of general anesthetics. Having identified the GABAA receptor delta subunit as conferring a sensitivity to neurosteroids, mice lacking these structures have been genetically engineered (Spigelmen et al. 2003). Predictably, these mice were less sensitive to alphaxalone, a steroid-based anesthetic which causes unconsciousness. However, the mice's response to other, non-steroidal anesthetics was unchanged in comparison to the control group of wild type mice. Results such as these further indicate that different categories of general anesthetics hone in on specific subpopulations of GABAA receptors (Spigelmen et al. 2003).
Such research has revolutionized the former notion that since anesthetics possess markedly differing chemical structures they necessarily generate their varying effects by some general mechanism (Orser 2008). Rather, the empirical development of these drugs apparently happened upon chemicals which produce analogous results, though each in a distinct manner (John and Prichep 2005).
From General to Specific: Targeted Anesthetic Effects
Modern studies suggest that by utilizing anesthetic agents which target or avoid certain GABAA receptors that the effects of anesthesia can be selected for as required. Such drugs are in development for other uses. Sedative-hypnotic drugs which do not affect the alpha-5 subunit, and therefore would be without the memory-impairing actions of certain sleeping pills and benzodiazepine sedatives, are in the preclinical stages (Cheng et al. 2006). The possible capabilities of other drugs, ones which do affect alpha-5 subunits to induce amnesia, could be invaluable in the surgical setting, where blocking a patient's memory, while being able to avoid depressing the cardiovascular system or respiratory function, could be extremely beneficial (Orser 2008). Combined with other agents, a strong memory-inhibiting drug could be utilized to prevent instances of intra-operative awareness. By itself, it could potentially aid in treating individuals suffering from post-traumatic stress disorder by preventing recall of painful memories.
Target-specific anesthetics will usher in a new era of anesthesiology, one in which the profound neurodepression of current anesthetics, and the concurrent danger, are avoidable. Anesthesiologists, armed with numerous compounds, each of which produces a single desirable effect, could render a patient pain-free but conversant, or sedated and immobile but still aware, during surgery. The opportunity that exists in anesthesia is to move past the era of ether into a truly modern modality of care.
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