Is anesthesiology going soft?: trends in fragile pharmacology.

IS anesthesiology going soft? If the study by Cotten et al. in this issue of ANESTHESIOLOGY can be viewed as a lead indicator, the answer is clearly yes. The “soft drug” approach, a strategy wherein novel active compounds are specifically designed to be vulnerable to rapid biotransformation into inactive metabolites, can be employed to develop drugs that meet the unique demands of anesthesia practice. In essence, a soft drug is metabolically fragile and thus rapidly eliminated, enabling anesthesiologists to manipulate the drug concentration up and down as needed. Cotten et al. describe a soft drug development effort aimed at producing a short-acting etomidate-like molecule, methoxycarbonyl-etomidate (MOC-etomidate). A key goal of this effort was to preserve etomidate’s desirable hemodynamic profile but eliminate the well-documented suppression of adrenal corticosteroid synthesis associated with etomidate administration. In summary, using a variety of sophisticated in vitro and in vivo methods, Cotten et al. were able to demonstrate that MOC-etomidate is active at the -aminobutyric acid-A receptor, that it is rapidly metabolized by nonspecific esterase activity, that it has an etomidate-like hemodynamic profile, and that it is indeed devoid of adrenal corticosteroid suppressive effects. Although this body of work must be regarded as preliminary in that it represents only the preclinical beginning of what is typically a long, expensive, and scientifically challenging development pathway that is vulnerable to failure at many points along the way, the results reported by Cotten et al. are intriguing and have exciting, albeit unproven, clinical potential in man. Although the terminology is new, soft drug success stories in anesthesiology date back many years. Perhaps the modern prototype example is the short-acting opioid remifentanil. Approved by the US Food and Drug Administration in 1996, remifentanil has emerged as a useful adjunct in the provision of general anesthesia, especially when total intravenous anesthesia techniques are used. Looking back, the historical soft drug prototype is succinylcholine, a short-acting muscle relaxant metabolized in the plasma by butyrylcholinesterase. An older drug to which the newer soft drug label obviously applies, succinylcholine has been a work horse in the production of neuromuscular blockade for decades despite the pharmacogenetic issues that complicate its use. Other soft drugs commonly used in anesthesia practice include esmolol, a short-acting -adrenergic blocker that shares the metabolic pathway of remifentanil. MOC-etomidate is the latest example of a novel soft drug under investigation within anesthesiology and is only part of a larger, noticeable trend. Other recently published soft drug development programs include THRX-918661, a rapidly acting, putative propranadid relative, and CNS-7557, an esterase metabolized, shortacting benzodiazepine. As Cotten et al. point out, a common theme observed within this series of soft drug molecules is the ester structure, although the ester structure alone is not enough to confer reliably a short-acting pharmacokinetic profile; the ester must also be “sterically” available for rapid hydrolysis. Why has drug development in anesthesiology gravitated toward soft drugs? The answer is obvious. The pharmacology of anesthesia practice is unique compared to other disciplines within medicine. Most settings in clinical medicine do not require immediate onset and rapid offset of pharmacologic effect. When an internist prescribes an antihypertensive, for example, the fact that a few days may be required for establishment of a therapeutic effect is of little consequence. Similarly, when terminating therapy, the necessity to wait a few days to achieve complete dissipation of drug effect is usually of no clinical importance. Anesthesiologists, in contrast, must respond to the dynamic needs of patients under anesthesia where the optimal degree of central nervous system depression may widely and frequently fluctuate, requiring continuous adjustment of drug concentrations. In addition, the anesthesiologist must respond to the practical realities of modern medical practice in terms of operating room efficiency and the outpatient revolution, meaning that the anesthesiologist must rapidly anesthetize the patient and then quickly reanimate the patient when the surgeons have finished their work, enabling the patient to transition quickly through the recovery process in preparation for going home. As a result, the profound physiologic alterations of the anesthetized state (and their reversal) must be produced on demand. To achieve this degree of pharmacologic control, anesthesiologists increasingly rely on drugs with rapid onset and predictable offset of effect to ensure This Editorial View accompanies the following article: Cotten JF, Husain SS, Forman SA, Miller KW, Kelly EW, Nguyen HH, Raines DE: Methoxycarbonyl-etomidate: A novel rapidly metabolized and ultra-short acting etomidate analogue that does not produce prolonged adrenocortical suppression. ANESTHESIOLOGY 2009; 111:240–9.