LOCAL ANESTHETICS

VMED5223
Veterinary Pharmacology
10-2007
Masami Yoshimura
myoshimura@vetmed.lsu.edu
Room2423
 Local Anesthesia
n Loss of sensation
n No loss of consciousness
n Block of action potential initiation or
conduction in nerves
n Voltage-gated Na+ channels
n Synthetic analogues of cocaine
 History
n Coca leaves used by Andean natives for its
stimulatory and euphoric actions.
n 1860-Albert Niemann isolated cocaine.
n 1884-Sigmund Freud used it to wean a
morphine addict.
n 1884-Karl Kollar used it as a topical ocular
anesthetic.
n 1884-William Stewart Halsted injected cocaine
into a sensory nerve trunk to create surgical
anesthesia.
n 1905-procaine (trade name “Novocaine”)
 Chemical Structure
n aromatic portion
n hydrophobic
n intermediate alkyl chain
n ester
n amide
n amine portion
n hydrophilic
n Tertiary, secondary amine
 General Structure of Local Anesthetics

Intermediary
chain
Amine
Aromatic Ring

Lidocaine
Amide

Procaine
Ester
Structures of some common local anesthetics
 Ester

n Cocaine
n Procaine (Novocain)
n Tetracaine
n Chloroprocaine
 Amide

n Lidocaine (Xylocaine)
n Mepivacaine
n Etidocaine
n Prilocaine
n Bupivacaine
n Ropivacaine
Resting Potential Generation

http://eee.uci.edu/clients/anson/b36/lect2.ppt #11
 Membrane & Channel Changes during
an Action Potential

http://www.liralab.it/IIT_school/files/Courses/Neuroscienze%202005_2006/Pietro%20Baldelli/LEZ-seconda.pdf #9
Propagation of Action Potential

http://eee.uci.edu/clients/anson/b36/lect2.ppt #21
 Voltage-gated Na+
Channels
n Made up of 4 domains
n Channels are usually
closed

Figure not available anymore

 Depolarization Opens Na+ Channels

Figure not available anymore

n Positively charged portion of the channel is usually

attracted to the negative interior of the cell
n Depolarization weakens that attraction
n The pore changes shape, and opens (Voltage-
gated)
 Figure not available anymore
Link is for a figure similar to the one shown

http://sitemaker.umich.edu/lisom.lab/files/sodium-channel-1999-copy.jpg
 •The route for local anesthetic
access to the binding site is
via the intracellular pore
entrance
Figure not available anymore

•Local anesthetics reach their

binding site primarily when
the channel is open.
Table 1. Relative size of nerves and susceptibility to local anesthetic block.

Fiber Diameter
Conduction Sensitivity
type Function (μm) Myelination vel (m/s)to block
A-
motor, proprioception 12 – 22 heavy 70 - 120 +
A- touch, pressure 5 – 12 heavy 30 - 70 ++
A- muscle tone (spindles) 3–6 moderate 15 - 35 ++
A- pain, temperature, touch 1–4 moderate 5 - 25 +++
B preganglionic sympathetic <3 light 3 - 15 ++++
C postganglionic sympathetic 0.3 - 1.3 none 0.1 - 2 ++++
(pain, temperature, touch)

In General the smaller fibers with higher firing

rates (type B and C fibers) are blocked before
larger (type A) fibers.
Order of Sensory Function Block
n 1. pain
n 2. cold

n 3. warmth
n 4. touch

n 5. deep pressure
n 6. motor

Recovery in reverse order

 Anesthetic Potency
n more lipophilic agents are more potent
as local anesthetics.
 Anesthetic Onset
n Lower pKa and higher lipophilicity are
associated with more rapid onset.
 Effect of pH

n charged (cationic) form binds to receptor

site
n uncharged form penetrates membrane
n effect of drug can be changed by altering
extracellular or intracellular pH
 Anesthetic Duration
n The higher the protein binding, the
longer the duration of anesthetic
action.
 Termination
n Esters are hydrolyzed in plasma by
pseudo-cholinesterase. (pregnancy)
One of the by-products of metabolism is
paraaminobenzoic acid (PABA), the
common cause of allergic reactions seen
with these agents.
n Amides are metabolized in the liver.
n Excretion by kidney
 Application
n Topical anesthesia
n Infiltration anesthesia
n Peripheral nerve block anesthesia
n Intravenous anesthesia
n Epidural anesthesia
n Spinal (Subarachnoid) anesthesia
n Co-utilization of a vasoconstrictor
Epidual & Spinal anesthesia

http://www.noblood.org/wiki/images/9/9d/Epidural_blood_patch.gif
 Toxicity
n Hypersensitivity. Para-aminobenzoic
acid (PABA) is a breakdown product of
the esters responsible for allergic
reactions.
n Central Nervous System Toxicities.
CNS excitement
CNS depression.
n Excitement: Tremors, shivering, and
convulsions characterize the CNS excitement.
n Depression: respiratory depression

respiratory arrest.
 Toxicity cont
n Cardiovascular Toxicities. depression of
the cardiovascular system.
n Myocardium can carry an action potential
n Arteriolar dilation
n Hypotension and a certain type of abnormal
heartbeat
n Cardiac and respiratory arrest.
 Signs of toxicity
n Signs of toxicity occur on a continuum. From
early to late stages of toxicity, these signs are:
circum-oral and tongue numbness,
lightheadedness, tinnitus, visual disturbances,
muscular twitching, convulsions,
unconsciousness, coma, respiratory arrest,
then cardiovascular collapse.
 Tetrodotoxin
Tetrodotoxin (TTX) is an especially potent neurotoxin, specifically blocking voltage-
gated sodium channels on the surface of nerve membranes. A single milligram or
less of TTX - an amount that can be placed on the head of a pin, is enough to kill an
adult. TTX is most commonly associated with puffer fish (Fugu, considered a
delicacy by many in Japan). From 1974 through 1983 there were 646 reported cases
of fugu poisoning in Japan, with 179 fatalities.

http://www.thingsasian.com/goto_article/article.2909.html
Fugu restaurant in Kyoto

http://www.phototravels.net/japan/pcd2452/fugu-restaurant-40.html
Tetrodotoxin Poisoning Associated With Eating Puffer Fish Transported from Japan--
California, 1996
On April 29, 1996, three cases of tetrodotoxin poisoning occurred among chefs in California
who shared contaminated fugu (puffer fish) brought from Japan by a co-worker as a
prepackaged, ready-to-eat product.
Case Reports
Case 1. A 23-year-old man ate a piece of fugu “the size of a quarter” (approximately 1/4 oz).
Approximately 10-15 minutes later, he had onset of tingling in his mouth and lips followed by
dizziness, fatigue, headache, a constricting feeling in his throat, difficulty speaking, tightness in
his upper chest, facial flushing, shaking, nausea, and vomiting. His legs weakened, and he
collapsed.
Case 2. A 32-year-old man ate three bites of fugu (approximately 1 1/2 oz) over 2-3 minutes.
While eating his third bite, he noticed tingling in his tongue and right side of his mouth followed
by a “light feeling,” anxiety, and “thoughts of dying.” He felt weak and collapsed.
Case 3. A 39-year-old man ate approximately 1/4 oz of fugu after eating a full meal.
Approximately 20 minutes after eating the fugu, he had onset of dizziness and mild chest
tightness.
Diagnosis and Treatment
A presumptive diagnosis of tetrodotoxin poisoning in all three men was based on clinical
presentation in the ED and the history of recent consumption of fugu. All were treated with
intravenous hydration, gastric lavage, and activated charcoal. Symptoms gradually resolved, and
the men were discharged the following day with no residual symptoms.