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Anesth Analg 2007; 105:1186-1190
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000286231.50178.45
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EDITORIAL

Anesthetic Pharmacology: Reflections of a Section Editor

James G. Bovill, MD, PhD, FCARCSI, FRCA

From the Leiden University Medical Centre, Leiden, The Netherlands.

Address correspondence and reprint requests to Professor James G. Bovill, MD, PhD, FCARCSI, FRCA, Emeritus Professor of Anaesthesiology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Address e-mail to j.g.bovill{at}lumc.nl.


   Introduction
Top
 Introduction
TOPICS OF SPECIAL INTEREST
 NONINVASIVE IMAGING TECHNIQUES
 KETAMINE PHARMACOLOGY
 MECHANISMS OF ANESTHESIA
 NEW DRUG FORMULATIONS
 SUGAMMADEX
 CONCLUSIONS
 REFERENCES
 
In 1999, the Society for Intravenous Anesthesia became an affiliated society of the International Anesthesia Research Society. One of the benefits of affiliation was the creation of a section within Anesthesia & Analgesia (A&A) devoted to IV anesthesia, part of the journal within a journal concept created by the former Editor-in-Chief, Ronald Miller. I had the privilege of being the first Section Editor of this new section. At the time of the affiliation, the Board of Directors of Society for Intravenous Anesthesia were actively considering changing the name of the society to reflect the interests of its members in a much wider area of pharmacology than the narrow field of IV anesthesia. In 2000, the decision was made to change the name to the International Society for Anaesthetic Pharmacology (1), and the section Intravenous Anesthesia was renamed Anesthetic Pharmacology. After 8 years as Section Editor, I have handed over the reins to Marcel Durieux and Tony Gin. They have asked me to write this editorial and to reflect on how the section has developed and changed during its first 8 years.

The number of manuscripts submitted to the section has gradually increased over the years, from <100 in the first year to just over 200 submissions in each of the last 2 years. Consequently, the Editor-in-Chief and the Editorial Board have decided that two Section Editors were needed to deal with this increased workload; Marcel Durieux is now responsible for the basic pharmacology manuscripts, and Tony Gin with those covering clinical pharmacology. Of the almost 600 papers published in this section since its inception in 1999, 43% were reports of clinical studies and 57% dealt with some aspect of basic pharmacology.

Manuscript submissions to the section and to A&A reflect the international character of both the International Anesthesia Research Society and International Society for Anaesthetic Pharmacology. In 2006, there were 207 manuscripts submitted to the section from 40 countries. (In that year A&A received manuscripts from 56 countries.) The United States has each year been the largest contributor to the section, with 36% of published manuscripts, followed by Japan (21%) and Germany (8%). Of particular interest has been the marked increase in the number of manuscripts submitted from Turkey and India. Although their success in having manuscripts accepted for publication has been less than spectacular, I find it encouraging that countries with a less well developed scientific infrastructure and fewer facilities than the big players make the effort to contribute to furthering the scientific basis of our specialty.


   TOPICS OF SPECIAL INTEREST
Top
 Introduction
 TOPICS OF SPECIAL INTEREST
NONINVASIVE IMAGING TECHNIQUES
 KETAMINE PHARMACOLOGY
 MECHANISMS OF ANESTHESIA
 NEW DRUG FORMULATIONS
 SUGAMMADEX
 CONCLUSIONS
 REFERENCES
 
So what topics in anesthetic pharmacology have appeared in this section? The subject material of the clinically orientated papers varied considerably, from straightforward studies investigating ways of reducing pain on injection of propofol or rocuronium to the use of high-technology noninvasive imaging techniques to obtain information about the sites and methods of actions of drugs in the human brain. The two most frequently occurring subjects were ketamine and new formulations of existing drugs. Interests in basic pharmacology were more variable, with investigations into the pharmacology of ketamine again being popular. By far the most popular areas, however, were investigations into the mechanisms of drug action and the influence of anesthetics on inflammatory and immune responses.


   NONINVASIVE IMAGING TECHNIQUES
Top
 Introduction
 TOPICS OF SPECIAL INTEREST
 NONINVASIVE IMAGING TECHNIQUES
KETAMINE PHARMACOLOGY
 MECHANISMS OF ANESTHESIA
 NEW DRUG FORMULATIONS
 SUGAMMADEX
 CONCLUSIONS
 REFERENCES
 
Noninvasive imaging techniques, such as positron emission tomography (PET) and functional magnetic resonance imaging, are increasingly used in the development of new drugs (2) and for expanding knowledge about how existing ones function (3). Although ketamine is primarily a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, it may also act as an agonist at the {gamma}-aminobutyric acid type A (GABAA) receptor (4). Salmi et al. (5) used PET to study cerebral 11C-flumazenil binding in healthy subjects before and during a subanesthetic racemic ketamine infusion. Ketamine did not affect 11C-flumazenil binding to the GABAA receptor in the brain, indicating that this mechanism is of minor importance in the actions of ketamine, at least in subanesthetic concentrations.

Ketamine is a potent analgesic that allows sensory input to reach the primary cortical areas but depresses nociceptive processing in association areas. Sprenger et al. (6) used functional magnetic resonance imaging to investigate the effect of subanesthetic doses of S(+)-ketamine on activation of brain regions during experimental, painful heat stimuli in healthy volunteers. They found that ketamine caused a dose-dependent suppression of activity in the secondary somatosensory cortex, insula, and anterior cingulate cortex, confirming that S(+)-ketamine attenuates the overall perception of painful stimuli by disrupting sensory input before it reaches the somatosensory association areas.

Veselis et al. (7) analyzed PET images to test whether different brain regions were affected by propofol and thiopental at similar drug effects in volunteers. The neuroanatomical locations of drug effects were identified by changes in regional cerebral blood flow imaged with 15O water. They found that, despite very similar behavioral states, these drugs decreased regional cerebral blood flow in distinctly different regions of the brain; propofol in the anterior brain regions and thiopental primarily in the cerebellar and posterior brain regions. These differences may help to identify the loci involved in the nonsedative effects of propofol, such as amnesia.


   KETAMINE PHARMACOLOGY
Top
 Introduction
 TOPICS OF SPECIAL INTEREST
 NONINVASIVE IMAGING TECHNIQUES
 KETAMINE PHARMACOLOGY
MECHANISMS OF ANESTHESIA
 NEW DRUG FORMULATIONS
 SUGAMMADEX
 CONCLUSIONS
 REFERENCES
 
Ketamine, one of the older anesthetic drugs still available for clinical use, fell into disfavor because of an unacceptable incidence of severe emergence delirium. In recent years, however, interest in ketamine has revived due to an improved understanding of the drug's pharmacology and the availability of the S(+) stereoisomer of ketamine. Although the side effect profiles of S(+)- and racemic ketamine are similar, patient acceptability is higher with the S(+) isomer (8). Ketamine is increasingly being used as an adjunct to conventional anesthetics, and as a perioperative analgesic (9,10), in the management of patients with chronic and neuropathic pain (11) and in the anesthetic management of patients with sepsis.

Induction of anesthesia with ketamine decreases the extent of hypothermia, probably because ketamine-induced vasoconstriction minimizes redistribution of body heat from the core to the periphery (12). Subanesthetic doses of ketamine significantly improved depression (13) and improved the postoperative depressive state in depressive patients undergoing orthopedic surgery (14). Although it has long been considered contraindicated in patients with brain injury because of the risk of increasing intracranial pressure, it is now accepted that ketamine may safely be used in neurologically impaired patients, provided their ventilation is well controlled. Indeed, the cardiovascular stimulation induced by ketamine may improve cerebral perfusion, potentially making it a preferred choice for sedation of patients after brain injury (15). Ketamine, and particularly the S(+)-isomer, also has neuroprotective properties, due to inhibition of NMDA receptor activation (16).

Ketamine has been recommended as the anesthetic of choice in patients with septic shock, both for its cardiovascular stimulating effects and its antiinflammatory properties. The latter are due to suppression of the excessive production of proinflammatory cytokines (17) and attenuation of neutrophil activation (18). However, suppression of antiinflammatory and immune responses may also have a down-side, as postoperative immunosuppression by anesthetics may compromise resistance to infection and tumor metastasis. Natural killer cell activity plays an important function in controlling tumor development, and this activity is suppressed by several anesthetics, including ketamine and opioids. Melamed et al. (19) investigated the effects of four IV anesthetics, ketamine, thiopental, halothane, and propofol on tumor retention and lung metastases in rats injected with mammary adenocarcinoma cells. All anesthetics apart from propofol significantly reduced natural killer cell activity and increased tumor retention and lung metastases. Ketamine had the largest effects, increasing tumor retention and lung metastases more than 2.5-fold. These findings, if confirmed, have potentially important implications in the choice of an anesthetic for patients with cancer.

Ketamine, of course, is not the only anesthetic that influences inflammatory and immune processes. Local anesthetics attenuate ischemic-reperfusion injury and the accompanying inflammatory responses, possibly by attenuating cytokine-induced cell injury (20–22). They impair immune function (23,24). Similar properties have been described for propofol (25,26) and volatile anesthetics (27).


   MECHANISMS OF ANESTHESIA
Top
 Introduction
 TOPICS OF SPECIAL INTEREST
 NONINVASIVE IMAGING TECHNIQUES
 KETAMINE PHARMACOLOGY
 MECHANISMS OF ANESTHESIA
NEW DRUG FORMULATIONS
 SUGAMMADEX
 CONCLUSIONS
 REFERENCES
 
How the chemically diverse compounds that possess anesthetic activity actually produce the state of anesthesia has long intrigued anesthesiologists and pharmacologists. Theories about how anesthetics work have been as diverse as anesthetic compounds themselves. An early suggestion, made in 1847 by von Bibra and Harless, was that anesthetics dissolve and remove lipids in the brain (28). Happily, this idea proved to be false, or the anesthetic revolution might have been short-lived. Today, more than 160 years since the discovery of anesthesia, research into the mechanisms of anesthesia continues unabated. More than one-quarter of the more than 200 manuscripts submitted annually to the Anesthetic Pharmacology section report research into some aspect of the mechanism of anesthesia.

One topic of continued attention has been the mechanisms underlying MAC or, more correctly, the ability of anesthetics to cause immobility after noxious stimulation. There is now a consensus that most IV anesthetics act primarily at the GABAA receptor, and that this receptor is also important for the amnesic effects of volatile anesthetics. However, the mechanism whereby volatile anesthetics produce immobility remains unclear. The volatile anesthetics interact with a diverse number of receptors and ion channels (29), but only a few can be considered as potential candidates, including the glycine (30,31), 5-HT2A (32), and NMDA receptors (33) in the spinal cord.

One approach to understanding why compounds acts as anesthetics is to focus on the molecules themselves, rather than their interactions with putative sites of action. Sophisticated computer models have been used to identify key areas in molecules that correlate best with known anesthetic activities (34,35). Using this approach, Sewell and Sear investigated the molecular basis for the immobilizing activity of nonhalogenated (36) and halogenated (37) volatile anesthetics. Their results confirm earlier findings that electrostatic interactions are important molecular properties in determining whether a compound has anesthetic activity (38). These models can correctly predict anesthetic activity for 89–98% of compounds tested. Perhaps even more important, identification of areas of a molecule where substitution could enhance potency might point the way towards even better anesthetics.

One of the factors that led to the virtual demise of purely lipid-based theories of anesthesia was the discovery of inhaled compounds with potencies that did not correlate with their lipophilicity, and thus disobeyed the Meyer-Overton rule. Polar alcohols, for example, are more potent than predicted from their lipophilicity, whereas some compounds, known as transitional compounds, are less potent. At the other extreme are compounds known as nonimmobilizers that have no anesthetic effect, despite a lipophilicity, that according to the Meyer-Overton rule, should make them potent anesthetics (29). For example, 1,2-dichlorohexafluorobutane (also called F6 or 2N) has an oil or gas partition coefficient similar to that of sevoflurane but is not anesthetic at any concentration. However, despite their lack of anesthetic effect, experiments with the nonimmobilizers have provided valuable insights into how inhaled anesthetics might produce anesthesia (39,40).


   NEW DRUG FORMULATIONS
Top
 Introduction
 TOPICS OF SPECIAL INTEREST
 NONINVASIVE IMAGING TECHNIQUES
 KETAMINE PHARMACOLOGY
 MECHANISMS OF ANESTHESIA
 NEW DRUG FORMULATIONS
SUGAMMADEX
 CONCLUSIONS
 REFERENCES
 
Although the efficacy and safety of drugs for anesthesia have improved dramatically, none of the currently available drugs fully meet the specifications of the ideal anesthetic. However, most are close enough to that ideal to make it difficult to improve upon them without very considerable effort and expense. The alternative is to manipulate available drugs or their formulations to improve their pharmacological and clinical characteristics. The success of remifentanil and its esterase metabolism has encouraged attempts at developing compounds with recovery profiles faster than propofol (41). Some of the disadvantages of propofol, such as pain on injection, risk of bacterial contamination, and hyperlipidemia when used for sedation in the intensive care unit, result from the conventional lipid emulsion formulation. Some of these problems are ameliorated by formulating the drug in medium-triglyceride emulsions currently on the market (42,43). Other approaches have been to avoid the problems caused by a lipid formulation by developing a water-soluble prodrug of propofol (44,45), aqueous formulations of inclusion complexes of propofol in cyclodextrin (46), or combining propofol with biocompatible surfactants to form stable microemulsions (47). One disadvantage of these drugs is a slower onset and recovery, particularly for the prodrugs that need to be enzymatically converted to propofol. The advantage of modifying a drug in such a way as to slow its onset of action is not obvious when almost the entire focus of anesthetic drug development has been to achieve the opposite effect (48), although this may be less of a problem when using propofol for sedation, as opposed to anesthesia.

Although the primary route of administration of volatile anesthetics is through the lungs, attempts have been made to give these drugs directly IV, thereby bypassing the anesthesia circuitry and the lung's functional residual capacity. Although direct IV administration of liquid volatile anesthetics is usually lethal, favorable results have been reported when the liquid anesthetic is administered as an emulsion (49,50). A recent paper published in the Anesthetic Pharmacology section demonstrated that anesthesia could be successfully induced in rats by IV emulsified isoflurane, with a safety index and safety factor comparable to propofol (51). Recovery of anesthesia in the rats was faster than with propofol.


   SUGAMMADEX
Top
 Introduction
 TOPICS OF SPECIAL INTEREST
 NONINVASIVE IMAGING TECHNIQUES
 KETAMINE PHARMACOLOGY
 MECHANISMS OF ANESTHESIA
 NEW DRUG FORMULATIONS
 SUGAMMADEX
CONCLUSIONS
 REFERENCES
 
One drug currently undergoing phase III clinical trials, sugammadex, has the potential to revolutionize one aspect of anesthesia: the management of neuromuscular block (52). Sugammadex is a modified {gamma}-cyclodextrin that was engineered to reverse the effects of aminosteroid muscle relaxants, specifically rocuronium. It rapidly removes rocuronium molecules from the plasma by encapsulating them within its inner structure, forming a water-soluble complex that is renally excreted. Sugammadex will facilitate the use of rocuronium for rapid sequence induction of anesthesia by providing a faster onset-offset profile than that seen with succinylcholine. Why ever give succinylcholine if you can give high doses of rocuronium and then reverse it more quickly than the succinylcholine would wear off? (53). The Anesthetic Pharmacology section of the March 2007 issue of A&A is devoted to this revolutionary drug, one which I am certain we will hear much more about in the future.


   CONCLUSIONS
Top
 Introduction
 TOPICS OF SPECIAL INTEREST
 NONINVASIVE IMAGING TECHNIQUES
 KETAMINE PHARMACOLOGY
 MECHANISMS OF ANESTHESIA
 NEW DRUG FORMULATIONS
 SUGAMMADEX
 CONCLUSIONS
REFERENCES
 
The pharmacological basis of anesthesia has changed dramatically during the 40 years I have worked in the specialty. When I started my training in 1967, pancuronium was not yet available, tubocurarine and gallamine were the standard muscle relaxants, and halothane was still a relatively new inhaled anesthetic. Today we have a wide variety of drugs to modify or manipulate unconsciousness, or to treat patients in the pain clinic or in the intensive care unit. Many of the drugs we use are extremely potent and among some of the most potentially dangerous drugs in medicine. However, despite the progress that has been made, many questions remain to be answered about the clinical and basic pharmacology of anesthetic drugs; enough to keep those interested in this branch of pharmacology busy providing material for the Anesthetic Pharmacology section for many years to come.

Being a Section Editor has been a demanding but very rewarding task. It has given me new and deeper insights into several areas of pharmacology that previously lay only at the edge of my knowledge. For this I am indebted to the authors who submitted manuscripts, and the many reviewers who have given of their time and expertise to assess the manuscripts. To both groups I offer my gratitude and thanks. The positive feedback I have had from authors, including many who have had their manuscripts rejected, has been a particular source of satisfaction. Finally, I would like to wish my successors, Marcel Durieux and Tony Gin, every success in the exciting tasks ahead of them.


   Footnotes
 
Accepted for publication August 2, 2007.


   REFERENCES
Top
 Introduction
 TOPICS OF SPECIAL INTEREST
 NONINVASIVE IMAGING TECHNIQUES
 KETAMINE PHARMACOLOGY
 MECHANISMS OF ANESTHESIA
 NEW DRUG FORMULATIONS
 SUGAMMADEX
 CONCLUSIONS
 REFERENCES
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2007 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press