esters typically have a shorter duration of action. This observation enables the drug
designer to engineer, with insight, a compound that will be either a short-duration or
long-duration local anesthetic.
The receptor for local anesthetic molecules is the voltage-gated Na+channel protein.
Local anesthetics act as blockers of the Na+channel. This blockade is described as
voltage dependent. The Na+channel protein undergoes significant changes in its shape
(conformation) as it opens and closes during the process of temporarily permitting Na+
ions to enter a cell (a process driven by changes in the transmembrane voltage gradient).
Three dominant conformations have been described: activated (open), inactivated
(closed and temporarily unable to open), and resting (closed but waiting to open). Local
anesthetics tend to bind with greater affinity to the activated conformation in preference
to the resting conformation of the channel protein; they therefore more effectively block
actively firing nerve axons than resting fibres. The local anesthetic receptor is located
near the intracellular end of the Na+channel protein (this binding site is distinct from
the extracellular binding site for such biological toxins as tetrodotoxin (7.1) and
ENDOGENOUS CELLULAR STRUCTURES 417