Chapter 16 Case Study Answer
Conduct a thorough and mechanistic SAR analysis of the 3 therapeutic options in the case.
Compound 1 is 2-(methylamino)-2-(2-chlorophenyl) cyclohexanone and as such has one
chiral center and can exist as a racemic mixture. Compound 1 acts as a general anesthetic by
binding to the NMDA (N-methyl-D-aspartate) receptor, a nonspecific ion channel receptor. The
NMDA receptor is located throughout the brain and binds L-glutamate, NMDA, and aspartate.
Compound 1 binds to the phencyclidine (PCP) binding site on the receptor blocking the flow of
cations into the cell thereby inhibiting ion-dependent excitatory synaptic transmission. The S(+)
enantiomer is 2–3 times more potent as an anesthetic than the R(-) enantiomer indicating that
binding to the NMDA receptor is stereoselective. Compound 1 is metabolized by Ndemethylation to form the main metabolite which retains 1/3 the anesthetic activity. CYP450
isoforms CYP3A4 (major) and CYP2B6 (minor) are responsible for the N-demethylation. Minor
oxidative products have also been identified.
Compound 2 is a simple chemical, nitrous oxide (dinitrogen oxide). Exactly how nitrous
oxide works as a general anesthetic is not precisely known. It can interact with any number of
ligand-gated ion channels but its modulation of the NMDA receptor may be its major mechanism
of action.
Compound 3 is a halogenated alkylether. Chemically it is a 1,1,1,3,3,3-hexafluoro-2(fluoromethoxy) propane. Halogenated hydrocarbons and ethers are classified as volatile
anesthetics. They work by interacting with ion channels in the brain. Most attention has been
paid to their modulation of the chloride channel. Both the -aminobutyric acid (GABAA) receptor
and the glycineA receptors are ligand-gated chloride ion channels that mediate inhibitory
responses in the brain. Volatile anesthetics such as compound 3 can inhibit the breakdown of
GABA and prolong its inhibitory effects. Additionally, volatile anesthetics such as compound 3
may also enhance the binding of GABA to its receptor as well as potentiating other inhibitory
receptors such as the glycineA receptor. Five to 8% of administered compound 3 is metabolized
to hexafluoroisopropanol, CO2 and F- by CYP2E1. In addition, under the influence of CO2
absorbers (soda lime and Baralyme) compound 3 can decompose to a potentially toxic alkene,
“Compound A” (2-(fluoromethoxy)-1,1,3,3,3,-pentafluoro-1-propene).
Apply the chemical understanding gained from the SAR analysis to this patient’s specific
needs to make a therapeutic recommendation.
BB needs emergency surgery for acute appendicitis. The use of general anesthesia in the
pregnant patient must always consider that there are two patients receiving anesthesia, the
mother and the fetus. Fortunately, use of volatile anesthetics in the second trimester (after
organogenesis has occurred) is most safe, even though no volatile anesthetic has been shown to
be teratogenic in therapeutic doses.
Compound 1 is ketamine, an injectable, rapidly acting anesthetic. It is available as the
hydrochloride salt and has a short duration of action (10–25 minutes). Ketamine would not be a
good choice for BB’s surgery for a number of reasons. First, it does not relax skeletal muscle and
should not be used alone for surgery that requires skeletal muscle relaxation. Second, recovery
from ketamine anesthesia is accompanied by confusing visual and auditory illusions ("emergence
delirium"). Additionally, the N-demethylated metabolite (norketamine) has significant activity
at the NDMA receptor and may be responsible for ketamine’s long lasting effects.
Compound 2 is nitrous oxide and is often called “laughing gas.” It is commonly used in
dental surgery where it can induce rapid and short-termed anesthesia and where full surgical
anesthesia is not required. To achieve full anesthesia, the patient would have to breathe pure NO2
to the exclusion of oxygen. This fact alone makes NO2 unacceptable for use in the pregnant
patient where depriving the fetus of oxygen will have serious consequences. Nitrous oxide has
also been reported to induce spontaneous abortions, however these reports have not been
substantiated by newer studies.
Compound 3 is sevoflurane, a nonflammable and nonirritating volatile anesthetic. It has a
relatively high potency with a rapid induction and recovery. Although it does not have skeletal
muscle relaxant effects, it would be the best choice for this surgery among those given. It can be
administered to maintain anesthesia as 1.5% exhaled and an air-to-oxygen ratio of 50% which is
important to maintain an adequate supply of oxygen to the mother and fetus. Sevoflurane is not
teratogenic in doses used for short term anesthesia maintenance. Although there is the formation
of fluoride ion which is nephrotoxic, there is no evidence that at therapeutic doses there is any
risk of kidney damage. As noted above, sevoflurane breaks down to a toxic “Compound A”
when exposed to CO2 absorbers; therefore it is recommended that its use be limited to <2 MAC
(minimal alveolar concentration) hours.