Editorial Views  |   September 2018
Gone Fishing…
Author Notes
  • From the Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
  • Corresponding article on page 459.
    Corresponding article on page 459.×
  • Accepted for publication May 17, 2018.
    Accepted for publication May 17, 2018.×
  • Address correspondence to Dr. Eckenhoff: reckenho@pennmedicine.upenn.edu
Article Information
Editorial Views / Pharmacology
Editorial Views   |   September 2018
Gone Fishing…
Anesthesiology 9 2018, Vol.129, 392-393. doi:10.1097/ALN.0000000000002328
Anesthesiology 9 2018, Vol.129, 392-393. doi:10.1097/ALN.0000000000002328
CURRENTLY used general anesthetics are almost invariably effective, but nagging side effects, both short (e.g., cardiac depression) and long (e.g., neurotoxicity) term, have reawakened the call for new drugs. After all, it has been almost 25 yr since the last inhalational anesthetic (sevoflurane) was introduced and almost 30 yr since the last IV drug (propofol) was released in the United States. There are two general approaches for discovering new drugs. The first is tweaking existing drugs to either enhance the desired effect, or to mitigate some undesired effect. For example, the principle side effect of etomidate was adrenocortical suppression, which was shown to be due to a very high affinity interaction with the 11-β hydroxylase enzyme. This was effectively mitigated by either changing the molecule to remove the interaction, or through addition of an autodestruct moiety (e.g., “softening” the molecule to provide for faster elimination).1,2  Interestingly, neither change to the etomidate molecule significantly diminished hypnotic activity, implying that the desired effect may actually be the pharmacologically less specific one. This also suggests that, while the molecular targets underlying side effects are sometimes known, or at least knowable, the desired effect targets remain enigmatic.