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48Inhibitors of Nerve conduction : local Anesthetics

A local anesthetic agent is a drug that, when given either topically or parenterally to a localized
area, produces a state of local anesthesia by reversibly blocking the nerve conductances that
transmit the feeling of pain from this locus to the brain. The term anesthesia is defined as a
loss of sensation with or without loss of consciousness. According to this definition, wide ranges
of drugs with diverse chemical structures are anesthetics. The list includes not only the classic
anesthetic agents, such as the general and local anesthetics, but also many central nervous system
(CNS) sepressants, such as analgesics, barbiturates, benzodiazepines, anticonvulsants, and
muscle relaxants.
What is the difference between a local Anesthetic and other anesthetic Drugs?
Both general and local anesthetic drugs produce anesthesia by blocking nerve conductance in
both sensory and motor neurons. This blockade of nerve conduction leads to a loss of pain
sensation as well as to impairment of motor functions. Generally, however, the anesthesia
produced by local anesthetics is without loss of consciousness or impairment of vital central
functions. It is accepted that a local anesthetic blocks nerve conductance by binding to selective
sites on the sodium channels in the excitable membranes, thereby reducing sodium passage
through the pores and, thus, interfering with the action potentials. Therefore, a local anesthetic
decreases the excitability of nerve membranes without affecting the resting potential. By
contrast, a general anesthetic agent alters physical properties of nerve membranes through rather
nonspecific interactions with the lipid bilayer or the receptor/ionic channel proteins. These, in
trun, reduce membrane excitability through a number of possible mechanisms, including changes
in membrane fluidity, permeability, and receptor/channel functions. Furthermore, local
anesthetics, in contrast to analgesic compounds, do not interact with the pain receptor or inhibit
the release or the biosynthesis of pain mediators.
The discovery of local anesthetics
Similar to many modern drugs, the initial leads for the design of clinically useful local
anesthetics were derived from natural sources. As early as 1532, the anesthetic properties of coca
leaves (Erythroxylon coca Lam) became known to Europeans from the natives of Peru, who
chewed the leaves for a general feeling of well-being and to prevent hunger. Saliva from
chewing the leaves often was used by the natives to relieve painful wounds. The active principle
of the coca leaf, however, was not discovered until 1860 by Niemann, who obtained a crystalline
alkaloid from leaves, to which he gave the name cocaine, and who noted the anesthetic effect on
the tongue. Although Moreno yMaiz in 1868 first asked the question of whether cocaine could be
used as a local anesthetic, it was Von Anrep in 1880 who, after many animal experiments,
recommended that cocaine be used clinically as a local anesthetic. The first report of successful

surgical use of cocaine appeared in 1884 by Koller, an Austrian ophthalmologist. This discovery
led to an explosive development of new anesthetic techniques and local anesthetic agent.
Although the structure of cocaine was not known until 1924, many attempts were made to
prepare new analogues of cocaine without its addicting liability and other therapeutic
shortcomings, such as allergic reactions, tissue irritations, and poor stability in aqueous solution.
Also, cocaine is easily decomposed when the solution is sterilized (Fig. 16.1).
Initially, analogues of ecgonine and benzoic acid, the hydrolysis products of cocaine, were
prepared. When the chemical structure of ecgonine became known, the preparation of active
compounds accelerated. It was soon realized that a variety of benzoyl esters of amino alcohols,
including benzoyltropine, exhibited strong local anesthetic properties without any addicting
liability. Thus, removal of the 2-carbomethoxy group of cocaine also abolished the addicting
liability. This discovery eventually led to the synthesis of procaine. (N,N-diethylaminoethyl ester
of p-aminobenzoic acid [PABA] in 1905, which became the prototype for local anesthetics for
nearly half a century, largely because it did not have the severe local and systemic toxicities.

Local anesthetics are widely used clinically in surgery, dentistry, ophthalmology, and in other
clinical producers in which temporary relief of pain is warranted. Some local anesthetics also can
be used to treat or prevent cardiac arrhythmias because of their action on cardiac sodium
Before using a local anesthetic, clinicians must take into account the physical properties of the
drug, such as its lipid solubility and protein binding as well as the degree of vascularization, the
rate of blood flow at the site of application, and the total dosage administered, because these
factors govern local anesthetic activity and its associated toxicities. For example, increased the
lipid solubility of an anesthetic may produce an increased penetration into a nerve membrane,
but it also can enhance the ability of the drug to pas through a blood vessel wall. This then leads
to reduction in anesthetic potency because of the more rapid removal of the agent from the site,
which thereby increases its systemic toxicity. Another complicating factor affecting local
anesthetic action is didtribution of the drug into adipose tissue, because this reduces local
anesthetic activity. Additionally, if the protein binding affinity of the local anesthetis is to great,
the ability of the drug to reach its target site can be impeded.
Extraneuronal blood vessels near the site of drug application affect the amount of drug that
reaches the nerve trunk to establish anesthesia; thus, a large dosage is required to elicit local
anesthesia, a contributing to toxicity. After the establishment of anesthesia, a contributing factor
to loss of the drug from the nerve may be caused by the intraneuronal blood vessels. Finally, a
reduction in local blood flow also slows systemic uptake of the drug from the injection site and.

Thus minimizes any potential toxicity, but it increases the amount of drug available to the nerve
and, thus, the duration of anesthesia.
Matthias C. Lu
University of Illinois at Chicago
Professor, Assistant Head for Curricular Affairs
Departement of Medicinal Chemistry and Pharmacognosy

Although the untrinsic potency of procaine was low and its duration of action relatively short
compared with that of cocaine, it was found that these deficiencies could be remedied when
procaine was combined with a vasoconstrictor, such as epinephrine. Apparently, a
vasoconstrictor agent reduces the local blood supply and, thereby, prolongs the residences time
of the local anesthetic.
Fig 16.1. structure of cocaine and its hydrolysis products.
Following the introduction of procaine, hundreds of structurally related analogues were prepared
and their local anesthetic properties examined. Most of these compounds were prepared for the
purposes of enhancing the intrinsic potency and the duration of action of procaine. Among these
compounds, tetracaine remains the most potent, long-acting ester-type local anesthetic agents
used in spinal anesthesia.
Benzocaine, an effective topical anesthetic agent, was synthesized by Ritsert in 1890 and was
found to have good anesthetizing properties and low toxicity. Benzocaine, however, has limited
water solubility except at low PH values because of the lack of a basic aliphatic amino group,
thereby disallowing the preparation of pharmaceutically acceptable parenteral solutions.
The next major turning point in the development of clinically useful local anesthetic activity of
another natural alkaloidal product, isogramine, in 1925 by von Euler and Erdtman. This
observation led to the synthesis of lidocaine (Xylocaine) by Lofgren in 1946; lidocaine was the
first nonirritating, amide-type local anesthetic agent with good local anesthetic properties yet less
prone to allergenic reactions than procaine analogues. A further practical advantage of lidocaine
was its stability in aqueous solution because of the more stable amide functionally. Structurally,

lidocaine can be viewed as an open-chain analogues of isogramine and, thus, is a bio-isoteric

analogue of isogramine.
In the years since 1948, extensive progress has been achieved primarily in the fields of
neurophysiology and neuropharmacology rather than that of synthetic medicinal chemistry. Most
of this research has significantly increased our understanding of how nerve conduction occurs
and how compounds interact with the neuronal membranes to produce local anesthesia. It should
be noted, however, that although a number of current clinically useful local anesthetic agents
have been introduced into the market, an ideal local anesthetic drug has, unfortunately, not been
Characretistics for an ideal local anesthetic
An ideal local anesthetic ahould produce reversible blockade of sensory nerve fibers with a
minimal effect on the motor fibers. It also should possess a rapid onset and have a sufficient
procedures without any systemic toxicity.
This goal, however, can be attained only through further structure-activity relationship studies,
particularly with regard to their selective actions on the voltage-gated sodium channels.
Additional leads for the design of ideal local anesthetics also could come from a more systematic
metabolic and toxicity study of currently available agents. To understand the chemical aspects of
local anesthetics and, thus, to provide a proper background for practical uses of these
compounds, it is necessary to have a working knowledge of basic neuroanatomy and
electrophysiology of the nervous system.
As can be seen in Figure 16.2 the sensory fibers (afferent neurons) course together in bundles
with the motor fibers (efferent neurons) from the periphery to the spinal cord. The cell bodies of
the sensory fibers are found at the point at which the nerve enters the vertebta, and they are seen
as enlargements on the nerve bundles. The cell bodies of motor fibers are found within the spinal
cord. The bundles of sensory and motor fibers aoutside the spinal cord are wrapped in a
connective tissue sheath the epineurium. Groups of fibers are found within this nerve in small
bundles, each of which is surrounded by connective tissue known as perineurium and, in even
smaller tubes of connective tissue, called endoneurium.
Fig. 16.2. diagram showing the various parts of a peripheral nerve.

Figures 16.2 and 16.3 also show that each nerve axon has its own membranous covering, often
called the nerve membrane, tightly surrounded by a myelin sheath called a Schwann cell
covering. The mycellin is not continuous along the fiber. The interruptions are the nodes of
Ranvier, which are great importance for nerve functioning.
Electrophysiology of Nerve Membrane
Resting Potential
Most nerves have resting membrane potentials of approximatelu -70 to -90 mV as a result of a
slight imbalance of electrolytes across the nerve membranes (.i.e., between the cytoplasm and the
extracellular fluid) (3). The origin of this membrane potential has been of great interest to
neurophysiologists. The main electrolytes in nerve axons and cell bodies are sodium, potassium,
calcium, magnesium, and chloride.
At resting potential, the nerve membrane was believed to be impermeable to sodium because of
the low sodium ion concertration in the excitable cell. Potassium ions may flow in and out of the
cell with ease, indicating that the membrane is highly permeable to potassium ions. A high
potassium ion concertrarion is retained intracellularly by the attractive forces provided by the
negative charges on the protein molecules. Thus, the predominant intracellular cation is
potassium (110 to 170 mmol/L), and the predominant extracellular ions are sodium (140
mmol/L) and chloride (110 mmol/L).
Fig. 16.3. Single myelinated nerve fiber.
It would appear that changes in the intracellular or extracellular concertration of potassium ions
markedly alter the resting membrane potential. For this reason, neurophysiologists treatedan
excable cell as if it were an electrochemical, or Nernst, cell. The resting potential for one
permeant species could therefore be explained by the familiar Nernst equation :