MECHANISM OF ACTION OF LOCAL ANESTHETICS (PHARMACODYNAMICS)
Active Form
Local anesthetic bases are poorly to sparingly soluble in water
but are soluble in relatively hydrophobic organic solvents. Therefore, as a matter
of convenience, most of these drugs are marketed as the hydrochloride salts. The
pKa
of the drug and tissue pH determine
the amount of drug that exists in solution as free base or as positively charged
cation when injected into living tissue (see earlier). Furthermore, uptake of the
drug by the tissue, largely as a result of lipophilic adsorption, will also alter
its activity, both by shifting the effective pKa
downward and thereby favoring the neutral base form and by limiting diffusion of
the anesthetic away from the site of injection. Moderately hydrophobic local anesthetics
will act more rapidly than either hydrophilic or highly hydrophobic ones when delivered
at the same concentration for the following reasons. Moderately hydrophilic local
anesthetics, such as lidocaine, are less bound to tissues than very hydrophobic drugs
(e.g., tetracaine), but are still more membrane permeant than very hydrophilic ones
(e.g., chloroprocaine). Highly hydrophobic local anesthetics also have higher intrinsic
potencies (see Table 14-2
);
therefore, they are used in lower concentrations, and their rate of onset is correspondingly
reduced.
Which form of the local anesthetic, charged cation or neutral
base, is actually responsible for impulse blockade? More alkaline solutions of local
anesthetics more effectively block nerve conduction.[14]
In a desheathed nerve and in an isolated single axon, the rate of inhibition by
tertiary amine anesthetics is greater at alkaline than at neutral external pH[15]
[16]
because membrane penetration and transport,
highly favored by base over cation species, are essential for controlling the rate
of access to the binding site. Direct control of axoplasmic pH[17]
(or internal perfusion with permanently charged quaternary amine homologs) shows
that the dominant potency is derived from the cationic species acting from the cytoplasmic
surface.[18]
[19]
The uncharged base also has intrinsic pharmacologic activity, however, and in addition
to molecules with tertiary amine moieties, those having hydroxyl (alcohols) or alkyl
groups (e.g., benzocaine) can also inhibit Na+
channels and block impulses.
[16]
[20]
[21]
[22]
To obtain a clear picture of the fundamental blocking mechanism,
knowledge of the channel-binding kinetics of the drug is necessary, but it is almost
impossible to measure the rate of binding of local anesthetics to the receptor after
their addition to a bathing solution. Drug diffusion through the unstirred layer
of solution next to the membrane and through the membrane itself present steps that
limit the rate of access to the receptor site.[16]
[23]
However, once the drug has equilibrated with
membranes and solutions, it is possible to perturb the channels by depolarizing the
membrane and follow the "phasic" inhibition by local anesthetics to clarify the details
of the binding reaction, as described later.
