The object of the course is to teach students an approach to the study of pharmacologic agents. It is not intended to be a review of the pharmacopoeia. The focus is on the basic principles of biophysics, biochemistry, and physiology as to the mechanisms of drug action, biodistribution and metabolis...
Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology
Instructor: Prof. Gary Strichartz
HST-151 1
LOCAL ANESTHETICS
1. Objective: The aim of this lecture is to describe the mechanisms of local anesthesia
as well as some relevant clinical pharmacology of local anesthetics.
II. Definition: Local anesthesia is the selective numbing of a particular, circumscribed
region of the body by a controlled, reversible procedure. Drugs called local anesthetics
(LA) are usually employed for these procedures, although directly applied pressure,
cooling, or even heating will also produce numbness. The general strategy is to inhibit
the propagation or generation of impulses in nerves from a defined anatomical region.
III. Chemistry: Knowledge of the structure of local anesthetic drugs is essential for an
understanding of their mechanism of action, potencies and pharmacokinetics. The
general structure of a local anesthetic is:
Structures and properties of drugs used clinically are listed in Table 1, along with one
experimental derivative, QX-314.
The aromatic group sometimes contains a para-amino group (-NH2) at R3 (procaine) and
additional alkyl groups attached to this amino (tetracaine), or at R1, R2 (lidocaine, and
other amides).
Amide or ester bonds connect the aromatic moiety to a tertiary (3o-) amine which can
have alkyl groups of lengths from -CH3 to -C4H9 attached to it. The absolute potency of
LA increases with increasing alkyl length substituents on both aromatic and 3o-amine
groups. Physico-chemical analysis reveals a monotonic increase of absolute potency with
increasing hydrophobicity for all compounds. Since the mechanisms of action are
complex (see below), the exact relationships between structure, pKa, and membrane
distribution are still not known.
IV. Mechanism of Action: LAs block nerve impulses by interfering with the sodium
permeability increase (PNa) which subserves the depolarizing phase of action potentials.
The mechanistic details depend on the LA molecule being used.
A. Active species: (3o)-amine local anesthetics (pKa = 7.8-10) exist as equilibrium
mixtures of protonated cation and neutral base at physiological pH.
, HST-151 2
The ionization reactions at neutral pH are quite rapid (-10-3 sec).
1. Which form of the LA module blocks PNa?
2. Where does it act: inside or outside the cell or on the
membrane?
Evidence to answer these questions comes from:
1. Quaternary (4o)-amine derivatives (permanent cations, e.g., QX-314
which do not permeate the membrane, block sodium channels (PNa), but only when
applied in the cytoplasm.
2. The observed impulse-blocking potency of benzocaine and of
lidocaine derivatives where -OH replaces -NR2 (both permanently neutral
molecules). These drugs act identically whether applied externally or
cytoplasmically.
Conclusion: Both neutral and protonated species of LA can inhibit Na channels
and block impulses. In general, however, the protonated form appears to be more potent.
B. Molecular Mechanisms:
1. The block of sodium current (INa) or of impulses by 4o-amine LAs
increases in extent with repetitive opening of sodium channels ("use-dependent" block)
(Figure 2). Use-dependent block is reversed when stimulation stops.
2. With benzocaine (and some alcohols) and with 3o-amine anesthetics at
alkaline pH, resting nerve block reveals more "inactivated" sodium channels (Fig. 3) but
use-dependent block is very weak. 3o-amine LAs show much more use-dependent
block at neutral or slightly acid pH than at alkaline pH (external). Internal pH has
surprisingly little effect.
3. Inhibition of ionic Na+ current by benzocaine is paralleled by a
proportional reduction of "gating current", the movement of charge which results directly
from conformational changes of Na channels during activation (Figure 4).
The sodium channel itself appears to be a receptor for local anesthetics.
Intentional mutation of part of the channel's inner pore region changes resting and use-
dependent pharmacology of various local anesthetic molecules. In addition, in normal
channels the membrane potential changes the channel conformations, which in turn have
different anesthetic affinities. This is collectively referred to as the "modulated receptor
hypothesis" (Figure 5). In addition, there is a non-receptor mediated action of local
anesthetic agents, which may occur through a disruption of normal membrane structure.
4. Calcium ions may antagonize the blocking action of some local
anesthetics, but this probably is mediated through changes in channel structure and
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