saxitoxin (7.2)). The interaction of the local anesthetic with the receptor protein is
seemingly via a three-point binding interaction between the local anesthetic pharma-
cophore and the Na+channel protein. The three points of contact include a lipophilic/
pi electron stacking pocket for the aromatic ring, a hydrogen-bonding surface for the
amide or ester group, and an anionic zone for coulombic electrostatic interaction with
the cationic terminus of the local anesthetic.
Since local anesthetics contain a tertiary amine ionizable group, they are weak bases.
In vivo local anesthetics can thus coexist either as an uncharged base or as a cation. The
ratio of molecular forms is important to bioactivity and may be calculated using the
Henderson–Hasselbalch equation. Since the pKaof most local anesthetic molecules is in
the 8.0–9.0 range, they tend to exist predominantly in the cationic form. This charged
form is optimal for the pharmacodynamic interaction of the local anesthetic with its recep-
tor, since this interaction involves an electrostatic interaction. However, the charged form
is less than optimal for the pharmacokinetic delivery of the local anesthetic molecule
through the lipid membrane to its intracellular binding site. Therefore, having local anes-
thetics exist in a mixture of charged and uncharged forms is best suited for the combined
task of drug delivery (favored by the neutral form) and subsequent drug binding (favored
by the charged form). By increasing the proportion of the drug that exists in the uncharged
form at a physiological pH of 7.3–7.4, it is possible to design a local anesthetic with a
faster time to onset of action. This is because the neutral form can more rapidly penetrate
biological membranes and thus be more quickly bioavailable to its intracellular receptor
site, although it will bind to the receptor with lower affinity. Infected tissues have a more
acidic pH, and thus local anesthetics that are injected into such regions will have a lower
fraction in the neutral form; accordingly, local anesthetics are less effective under such
circumstances because they are less likely to reach their intracellular receptor site.
Since local anesthetics possess an ionizable tertiary amine group, they tend to exist at
least in part, in a highly polar charged ionic form at physiological pH. This prevents them
from diffusing across apolar lipid barriers such as the blood–brain barrier. This is an
immense benefit when attempting to design a drug with reduced CNS toxicity—an
important consideration when one recalls the large number of Na+channel proteins
which exist within the brain and which could, in principle, be blocked by local anesthetic
molecules! However, the inability to cross the blood–brain barrier precludes the use of
local anesthetics in the therapeutic treatment of abnormalities of electrical transmission
within the CNS (i.e., seizures). The heart, on the other hand, is an electrically active
organ that is not protected by the blood–brain barrier. Since the heart is a systemic organ
external to the brain, local anesthetic molecules (or analogs thereof) can be used in the
therapeutic treatment of abnormalities of electrical transmission within the heart’s con-
duction system (i.e., arrhythmias). Conversely, local anesthetic molecules can also produce
cardiac side effects by virtue of binding to Na+channels within the heart.
Clinically, local anesthetics may be used in a variety of pharmaceutical forms and
administered in many ways, tailored to the desired clinical indication:
- Topical anesthesia—direct application to the skin, or a mucous membrane, of the
local anesthetic in the form of a spray, cream, or gel - Infiltration anesthesia—relatively nonspecific injection of the local anesthetic into
the skin and deeper tissues of the area to be anesthetized
418 MEDICINAL CHEMISTRY