Douglas E. Raines

Inhaled anesthetics and immobility: Mechanisms, mysteries, and minimum alveolar anesthetic concentration

Studies using molecular modeling, genetic engineering, neurophysiology/pharmacology, and whole animals have advanced our understanding of where and how inhaled anesthetics act to produce immobility (minimum alveolar anesthetic concentration; MAC) by actions on the spinal cord. Numerous ligand- and voltage-gated channels might plausibly mediate MAC, and specific animo acid sites in certain receptors present likely candidates for mediation. However, in vivo studies to date suggest that several channels or receptors may not be mediators (e.g., &ggr;-aminobutyric acid A, acetylcholine, potassium, 5-hydroxytryptamine-3, opioids, and &agr;2-adrenergic), whereas other receptors/channels (e.g., glycine, N-methyl-d-aspartate, and sodium) remain credible candidates.

Automated Documentation Error Detection and Notification Improves Anesthesia Billing Performance

Background:Documentation of key times and events is required to obtain reimbursement for anesthesia services. The authors installed an information management system to improve record keeping and billing performance but found that a significant number of their records still could not be billed in a timely manner, and some records were never billed at all because they contained documentation errors. Methods:Computer software was developed that automatically examines electronic anesthetic records and alerts clinicians to documentation errors by alphanumeric page and e-mail. The softwares efficacy was determined retrospectively by comparing billing performance before and after its implementation. Staff satisfaction with the software was assessed by survey. Results:After implementation of this software, the percentage of anesthetic records that could never be billed declined from 1.31% to 0.04%, and the median time to correct documentation errors decreased from 33 days to 3 days. The average time to release an anesthetic record to the billing service decreased from 3.0 ± 0.1 days to 1.1 ± 0.2 days. More than 90% of staff found the system to be helpful and easier to use than the previous manual process for error detection and notification. Conclusion:This system allowed the authors to reduce the median time to correct documentation errors and the number of anesthetic records that were never billed by at least an order of magnitude. The authors estimate that these improvements increased their departments revenue by approximately

Methoxycarbonyl-etomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression.

400,000 per year.

Azo-propofols: photochromic potentiators of GABA(A) receptors.

Background:Etomidate is a rapidly acting sedative-hypnotic that provides hemodynamic stability. It causes prolonged suppression of adrenocortical steroid synthesis; therefore, its clinical utility and safety are limited. The authors describe the results of studies to define the pharmacology of (R)-3-methoxy-3-oxopropyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-etomidate), the first etomidate analogue designed to be susceptible to ultra-rapid metabolism. Methods:The &ggr;-aminobutyric acid type A receptor activities of MOC-etomidate and etomidate were compared by using electrophysiological techniques in human &agr;1&bgr;2&ggr;2l receptors. MOC-etomidate’s hypnotic concentration was determined in tadpoles by using a loss of righting reflex assay. Its in vitro metabolic half-life was measured in human liver S9 fraction, and the resulting metabolite was provisionally identified by using high-performance liquid chromatography/mass spectrometry techniques. The hypnotic and hemodynamic actions of MOC-etomidate, etomidate, and propofol were defined in rats. The abilities of MOC-etomidate and etomidate to inhibit corticosterone production were assessed in rats. Results:MOC-etomidate potently enhanced &ggr;-aminobutyric acid type A receptor function and produced loss of righting reflex in tadpoles. Metabolism in human liver S9 fraction was first-order, with an in vitro half-life of 4.4 min versus more than 40 min for etomidate. MOC-etomidate’s only detectable metabolite was a carboxylic acid. In rats, MOC-etomidate produced rapid loss of righting reflex that was extremely brief and caused minimal hemodynamic changes. Unlike etomidate, MOC-etomidate produced no adrenocortical suppression 30 min after administration. Conclusions:MOC-etomidate is an etomidate analogue that retains etomidate’s important favorable pharmacological properties. However, it is rapidly metabolized, ultra–short-acting, and does not produce prolonged adrenocortical suppression after bolus administration.

Differential modulation of human N-methyl-D-aspartate receptors by structurally diverse general anesthetics

Shine and rise! GABA(A) receptors are ligand-gated chloride ion channels that respond to γ-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter of the mammalian central nervous system. Azobenzene derivatives of propofol, such as compound 1 (see scheme), increase GABA-induced currents in the dark form and lose this property upon light exposure and thus function as photochromic potentiators. Compound 1 can be employed as a light-dependent general anesthetic in translucent tadpoles.

Is a New Paradigm Needed to Explain How Inhaled Anesthetics Produce Immobility

N-Methyl-d-aspartate (NMDA) receptors have a presumed role in excitatory synaptic transmission and nociceptive pathways. Although previous studies have found that inhaled anesthetics inhibit NMDA receptor-mediated currents at clinically relevant concentrations, the use of different experimental protocols, receptor subtypes, and/or tissue sources confounds quantitative comparisons of the NMDA receptor inhibitory potencies of inhaled anesthetics. In the present study, we sought to fill this void by defining, using the two-electrode voltage-clamp technique, the extent to which diverse clinical and aromatic inhaled anesthetics inhibit the NR1/NR2B subtype of the human NMDA receptor expressed in Xenopus laevis oocytes. At 1 minimum alveolar anesthetic concentration (MAC), anesthetic compounds reversibly inhibited NMDA receptor currents by 12 ± 6% to 74 ± 6%. These results demonstrate that equianesthetic concentrations of inhaled anesthetics can differ considerably in the extent to which they inhibit NMDA receptors. Such differences may be useful for defining the role that this receptor plays in producing the in vivo actions of general anesthetics.

Carboetomidate: a pyrrole analog of etomidate designed not to suppress adrenocortical function.

A paradox arises from present information concerning the mechanism(s) by which inhaled anesthetics produce immobility in the face of noxious stimulation. Several findings, such as additivity, suggest a common site at which inhaled anesthetics act to produce immobility. However, two decades of focused investigation have not identified a ligand- or voltage-gated channel that alone is sufficient to mediate immobility. Indeed, most putative targets provide minimal or no mediation. For example, opioid, 5-HT3, &ggr;-aminobutyric acid type A and glutamate receptors, and potassium and calcium channels appear to be irrelevant or play only minor roles. Furthermore, no combination of actions on ligand- or voltage-gated channels seems sufficient. A few plausible targets (e.g., sodium channels) merit further study, but there remains the possibility that immobilization results from a nonspecific mechanism.

Nonhalogenated Alkane Anesthetics Fail to Potentiate Agonist Actions on Two Ligand-gated Ion Channels

Background:Etomidate is a sedative hypnotic that is often used in critically ill patients because it provides superior hemodynamic stability. However, it also binds with high affinity to 11&bgr;-hydroxylase, potently suppressing the synthesis of steroids by the adrenal gland that are necessary for survival. The authors report the results of studies to define the pharmacology of (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), a pyrrole analog of etomidate specifically designed not to bind with high affinity to 11&bgr;-hydroxylase. Methods:The hypnotic potency of carboetomidate was defined in tadpoles and rats using loss of righting reflex assays. Its ability to enhance wild-type &agr;1&bgr;2&ggr;2l and etomidate-insensitive mutant &agr;1&bgr;2M286W&ggr;2l human &ggr;-aminobutyric acid type A receptor activities was assessed using electrophysiologic techniques. Its potency for inhibiting in vitro cortisol synthesis was defined using a human adrenocortical cell assay. Its effects on in vivo hemodynamic and adrenocortical function were defined in rats. Results:Carboetomidate was a potent hypnotic in tadpoles and rats. It increased currents mediated by wild-type but not etomidate-insensitive mutant &ggr;-aminobutyric acid type A receptors. Carboetomidate was a three orders of magnitude less-potent inhibitor of in vitro cortisol synthesis by adrenocortical cells than was etomidate. In rats, carboetomidate caused minimal hemodynamic changes and did not suppress adrenocortical function at hypnotic doses. Conclusions:Carboetomidate is an etomidate analog that retains many beneficial properties of etomidate, but it is dramatically less potent as an inhibitor of adrenocortical steroid synthesis. Carboetomidate is a promising new sedative hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable.

Neural mechanisms of anesthesia

Background Although ether, alcohol, and halogenated alkane anesthetics potentiate agonist actions or increase the apparent agonist affinity of ligand-gated ion channels at clinically relevant concentrations, the effects of nonhalogenated alkane anesthetics on ligand-gated ion channels have not been studied. The current study assessed the abilities of two representative nonhalogenated alkane anesthetics (cyclopropane and butane) to potentiate agonist actions or increase the apparent agonist affinity of two representative ligand-gated ion channels: the nicotinic acetylcholine receptor and &ggr;-aminobutyric acid type A (GABAA) receptor. Methods Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana, and human GABAA receptors (&agr;1&bgr;2&ggr;2L) were expressed in human embryonic kidney 293 cells. The Torpedo nicotinic acetylcholine receptors apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the apparent rates of desensitization induced by a range of acetylcholine concentrations. The GABAA receptor’s apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the peak currents induced by a range of GABA concentrations. Results Neither cyclopropane nor butane potentiated agonist actions or increased the apparent agonist affinity (reduced the apparent agonist dissociation constant) of the Torpedo nicotinic acetylcholine receptor or GABAA receptor. At clinically relevant concentrations, cyclopropane and butane reduced the apparent rate of Torpedo nicotinic acetylcholine receptor desensitization induced by low concentrations of agonist. Conclusions Our results suggest that the in vivo central nervous system depressant effects of nonhalogenated alkane anesthetics do not result from their abilities to potentiate agonist actions on ligand-gated ion channels. Other targets or mechanisms more likely account for the anesthetic activities of nonhalogenated alkane anesthetics.

Gamma-aminobutyric acidA receptors do not mediate the immobility produced by isoflurane

I. Introduction The Development of Concepts of Mechanisms of Anesthesia Donald Caton and Joseph F. Antognini II. Anesthesia, Consciousness, and Memory Mechanisms of Consciousness with Emphasis on the Cerebral Cortical Component G. Bryan Young Anesthesia Meets Memory: Tools for Critical Appraisal Robert A. Veselis III. Sleep, Coma, and Anesthesia-Similarities and Differences Sleep and Anesthesia John Keifer Possible Relationships of Anesthetic Coma and Pathological Disorders of Consciousness Nicholas D. Schiff and Fred Plum IV. Neural Mechanisms Cerebral Cortex-Anesthetic Action on the Electroencephalogram: Cellular and Synaptic Mechanisms and Clinical Monitoring Heath Lukatch and Scott Greenwald Cerebral Mechanisms of Analgesia and Anesthesia in Humans Elucidated by In Vivo Brain Imaging Ferenc Gyulai and Leonard Firestone Thalamus Anthony Angel The Hippocampus M. Bruce MacIver Anesthetic Effects on the Reticular Formation, Brainstem and Central Nervous System Arousal Joseph F. Antognini and Earl Carstens Anesthesia, the Spinal Cord and Motor Responses to Noxious Stimulation Joseph F. Antognini and Earl Carstens Spinal Cord-Dorsal Horn J. G. Collins Spinal Cord: Anesthetic Actions on Motor Neurons Joan J. Kendig Simple Genetic Models for Anesthetic Action Philip G. Morgan and Margaret Sedensky Genetic Dissection of Anesthetic Action Gregg E. Homanics and Leonard L. Firestone V. Cellular and Molecular Mechanisms General Anesthetic Effects on GABAA Receptors Robert A. Pearce Nicotinic Acetylcholine Receptors and Anesthetics Stuart A. Forman, Pamela Flood, and Douglas Raines Actions of General Anesthetic on Voltage-Gated Ion Channels Norbert Topf, Esperanza Recio-Pinto, Thomas J. J. Blanck, and Hugh C. Hemmings, Jr Glutamate Receptors: Physiology and Anesthetic Pharmacology Misha Perouansky and Joseph F. Antognini General Anesthetic Effects on Glycine Receptors Stephen Daniels Presynaptic Actions of General Anesthetics Misha Perouansky and Hugh C. Hemmings, Jr The Meyer-Overton Relationship and Its Exceptions Warren S. Sandberg and Keith W. Miller Protein Models Jonas S. Johansson and Roderic G. Eckenhoff The Opioid Receptors Gary J. Brenner, Jianren Mao, and Carl Rosow Local Anesthetics Ging Kuo Wang Neuromuscular Blocking Agents and General Anesthesia Gerald A. Gronert and Timothy Tautz VI. Future Research The Future of Anesthetic Mechanisms Research Joseph F. Antognini, Douglas E. Raines, and Earl Carstens Index