DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Local Anesthetics
William A. Catterall and
Kenneth Mackie
Local anesthetics bind reversibly to a specific receptor
site within the pore of the Na + channels in nerves and
block ion movement through this pore. When applied
locally to nerve tissue in appropriate concentrations,
local anesthetics can act on any part of the nervous system
and on every type of nerve fiber, reversibly blocking
the action potentials responsible for nerve
conduction. Thus, a local anesthetic in contact with a
nerve trunk can cause both sensory and motor paralysis
in the area innervated. These effects of clinically
relevant concentrations of local anesthetics are
reversible with recovery of nerve function and no evidence
of damage to nerve fibers or cells in most clinical
applications.
History. The first local anesthetic, cocaine, was serendipitously discovered
to have anesthetic properties in the late 19th century.
Cocaine occurs in abundance in the leaves of the coca shrub
(Erythroxylon coca). For centuries, Andean natives have chewed an
alkali extract of these leaves for its stimulatory and euphoric actions.
Cocaine was first isolated in 1860 by Albert Niemann. He, like many
chemists of that era, tasted his newly isolated compound and noted
that it caused a numbing of the tongue. Sigmund Freud studied
cocaine’s physiological actions, and Carl Koller introduced cocaine
into clinical practice in 1884 as a topical anesthetic for ophthalmological
surgery. Shortly thereafter, Halstead popularized its use in
infiltration and conduction block anesthesia.
Chemistry and Structure-Activity Relationship. Cocaine is an
ester of benzoic acid and the complex alcohol 2-carbomethoxy, 3-
hydroxy-tropane (Figure 20–1). Because of its toxicity and addictive
properties (Chapter 24), a search for synthetic substitutes for
cocaine began in 1892 with the work of Einhorn and colleagues,
resulting in the synthesis of procaine, which became the prototype
for local anesthetics for nearly half a century. The most widely used
agents today are procaine, lidocaine, bupivacaine, and tetracaine.
The typical local anesthetics contain hydrophilic and
hydrophobic moieties that are separated by an intermediate ester or
amide linkage (Figure 20–1). A broad range of compounds containing
these minimal structural features can satisfy the requirements
for action as local anesthetics. The hydrophilic group usually is a
tertiary amine but also may be a secondary amine; the hydrophobic
moiety must be aromatic. The nature of the linking group determines
some of the pharmacological properties of these agents. For example,
local anesthetics with an ester link are hydrolyzed readily by
plasma esterases.
The structure-activity relationship and the physicochemical
properties of local anesthetics have been reviewed by Courtney and
Strichartz (1987). Hydrophobicity increases both the potency and
the duration of action of the local anesthetics; association of the
drug at hydrophobic sites enhances the partitioning of the drug to its
sites of action and decreases the rate of metabolism by plasma
esterases and hepatic enzymes. In addition, the receptor site for
these drugs on Na + channels is thought to be hydrophobic (see
Mechanism of Action), so that receptor affinity for anesthetic agents
is greater for more hydrophobic drugs. Hydrophobicity also
increases toxicity, so that the therapeutic index is decreased for
more hydrophobic drugs.
Molecular size influences the rate of dissociation of local
anesthetics from their receptor sites. Smaller drug molecules can
escape from the receptor site more rapidly. This characteristic is
important in rapidly firing cells, in which local anesthetics bind during
action potentials and dissociate during the period of membrane
repolarization. Rapid binding of local anesthetics during action
potentials causes the frequency- and voltage-dependence of their
action.
Mechanism of Action. Local anesthetics act at the cell
membrane to prevent the generation and the conduction
of nerve impulses. Conduction block can be
demonstrated in squid giant axons from which the axoplasm
has been removed.
Local anesthetics block conduction by decreasing
or preventing the large transient increase in the permeability
of excitable membranes to Na + that normally
is produced by a slight depolarization of the membrane
(Chapters 8, 11, and 14) (Strichartz and Ritchie, 1987).
This action of local anesthetics is due to their direct
interaction with voltage-gated Na + channels. As the
anesthetic action progressively develops in a nerve, the
threshold for electrical excitability gradually increases,
the rate of rise of the action potential declines, impulse