inhalational anesthetics is low, providing an obvious challenge for improvement, although the conflicting data on specific versus global anesthetic effects will make it difficult to plan de novo new chemical entitity approaches. An issue in the mechanistic studies is that much of the data has been derived in artificial membrane systems and as such is sufficiently reductionistic to question its value. Similarly, the stereospecific effects that have been reported for various anesthetics are, at best, modest. A recent review51 has concluded that anesthesiology has evolved in two phases over the past 60 years. The first phase, from 1954 to 1978, was characterized by the introduction of new anesthetics and new surgical techniques; the second, from 1979 to 2004, had a greater emphasis on clinical excellence, outcome, and quality of patient care both in the operating room and elsewhere in the hospital, and research. Analgesic Side Effects

Opioid drugs are the current mainstay of perioperative pain control, and are widely used during general anesthesia to suppress responses to surgical stimuli. Opioids have serious side effects; respiratory depression is the most dangerous. Side effects commonly limit the effective use of analgesic drugs. Development of opioid or nonopioid analgesics with superior side-effect profiles could dramatically alter the treatment of acute and chronic pain. Local Anesthetic Side Effects

Local anesthetics are relatively safe drugs in clinical practice; however there are unmet needs for less cardiotoxic, long-acting local anesthetics and for a local anesthetic with onset and duration similar to lidocaine for spinal anesthesia but without the risk for transient radicular irritation. Rapid-Offset Intravenous Anesthetics

Improved pharmacokinetic properties can result in significant improvement in the utility of anesthetic drugs, even in the absence of significant changes in pharmacodynamic properties. Propofol (Figure 2) and remifentanil (Figure 4) are examples of intravenous anesthetic drugs (a hypnotic drug and an opioid, respectively) that are mainly distinguished by being more rapidly cleared than similar, alternative drugs. Generally, there is a considerable advantage to anesthetic drugs with rapid offset that promote rapid recovery from anesthesia. This has been a significant theme in the development of inhaled and intravenous anesthetics for a number of years. Development of an intravenous hypnotic drug that would have a significantly faster offset than propofol, comparable to the offset of remifentanil, would be a significant advance. Long-Lasting Side Effects of Inhaled Anesthetics

Pharmacologic dogma suggests that the effects of inhaled anesthetics are fully reversible. However, decrements in mental performance have been noticed following anesthesia, especially in the elderly, that can persist for long periods of time. This has not been well understood. Recently, in vitro and animal studies have suggested that inhalational agents may produce lasting changes in brain chemistry, raising concerns about the safety of inhaled anesthetics. Intravenous anesthetics may not produce similar effects, raising the possibility that total intravenous anesthesia (usually consisting of continuous intravenous infusion of a hypnotic and an opioid drug, e.g., propofol and remifentanil) may be superior to inhaled anesthetics for general anesthesia. Much more investigative work is needed in this area. If inhaled anesthetics prove to have significant long-lasting side effects, and if intravenous anesthetic drugs do not have these effects, there will be a profound effect on the direction of development of new anesthetic agents.

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