1. Local Anesthetic
Pharmacology
Dr. Hiwa K. Saaed,
PhD Pharmacology & Toxicology
College of Pharmacy/ University of Sulaimani
2016-2017

2. Local anesthetics (LAs)
LAs are drugs that:
 block nerve conduction of sensory impulses and, in higher
concentrations, motor impulses from the periphery to the
CNS.
 used to prevent or relieve pain in specific regions of the body
without loss of consciousness
 Reversibly block impulse conduction along nerve axons &
other excitable membranes that utilize sodium channels as the
primary means of action potential generation
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3. Delivery techniques include:
• topical administration,
• infiltration,
• peripheral nerve blocks,
• neuraxial (spinal, epidural, or
caudal) blocks.
Small, unmyelinated nerve fibers
for pain, temperature, and
autonomic activity are most
sensitive.
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Local anesthetics (LAs)

4. History of local anesthetics
3000 B.C.: cocaine
1905: procaine
1932: Tetracaine
1943: Lidocaine
1957: Mepivacaine
1960: Prilocaine
1963: Bupivacaine
1972: Etidocaine
1996: Ropivacaine
1999: Levobupivacaine
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• The first local anesthetic introduced
into medical practice Cocaine, was
isolated from coca leaves by Albert
Niemann in Germany in the 1860s.
• The very first clinical use of Cocaine
was in 1884 by Sigmund Freud who
used it to wean a patient from
morphine addiction.
• Freud and his colleague Karl Kollar
first noticed its anesthetic effect and
introduced it to clinical ophthalmology
as a topical ocular anesthetic.

5. Chemistry of LAs
Structurally, local anesthetics consists of three
parts :
1. A lipophilic ‘hydrophobic’ aromatic group.
2. An intermediate chain (ester or amide).
3. A hydrophilic an ionizable group (usually a
tertiary amine group).
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Esters usually have
a shorter duration
of action because
ester links are more
prone to hydrolysis
than amide link

6. Classes: The rule of “i”
Lidocaine
Bupivacaine
Levobupivacaine
Ropivacaine
Mepivacaine
Etidocaine
Prilocaine
Procaine
Chloroprocaine
Tetracaine
Benzocaine
Cocaine
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7. Clinical pharmacology of LAs
• Procaine
• chlorprocaine
• Lidocaine,
• mepivacaine
• prilocaine
• tetracaine,
• bupivacaine,
• etidocaine
• ropivacaine.
The choice of LA for a specific procedure is usually based on the
duration of procedure required
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8. Local anesthetics
• Local anesthetics are weak bases.
• The pKa for most local anesthetics is in the range of 8-9
(Except benzocaine).
• the larger percentage in body fluids at physiologic pH will
be the charged, cationic form.
• The ratio between the cationic and uncharged forms of
these drugs is determined by the Henderson-Hasselbalch
equation:
Log cation (charged)/ uncharged= pKa - pH
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9. Effect of pH:
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Effectiveness of Local anesthetics are affected by pH of the
application site; altering extracellular or intracellular pH
• Charged (cationic) form binds to receptor site
• uncharged form penetrates membrane ,

10. Local anesthetics; Effect of lipophilicity
• LAs bind to receptor near the intracellular end of the channel.
It is not readily accessible from the external side of the cell
membrane.
• The uncharged form is more lipophilic and thus more rapidly
diffuses through the membrane.
• However, the charged form has higher affinity for the receptor
site of the sodium channel, because it cannot readily exit from
closed channels.
• Therefore, LA are much less effective when they are injected
into infected tissues because a larger % of the LA is ionized in
an environment with a low extracellular pH and can not
diffused across the membrane.
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11. Systemic absorption
Local anaesthetics can also affect sodium channels in other parts
of the body, such as the conduction system of the heart. This
can lead to an abnormal heartbeat; thus, systemic distribution
of local anaesthetics is best kept to a minimum.
Local anesthetics are removed from depot site mainly by
absorption into blood. Systemic absorption is determined by
several factors, including:
– Dosage
– Site of injection
– Local blood flow: highly or poorly perfused
– Use vasoconstrictors (e.g., epinephrine)
– Drug tissue binding
– Physicochemical properties of the drug itself
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12. Effect of epinephrine on local anesthetics
Addition of vasoconstrictor drugs such as epinephrine
• reduces absorption of local anesthetics by decreasing blood
flow (imp. For intermediate & short duration of action), thus
prolonging anesthetic effect and reducing systemic toxicity.
• Epinephrine also reduce sensory neuron firing via α2
receptors, which inhibit release of substance-P (neurokinin-1).
Clonidine (α2 agonist) augment LA effect
Epinephrine is included in many local anesthetic preparations.
Know your patient’s health status!
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13. Pharmacokinetics
Distribution
• Amide are widely distributed & sequestered in fat.
• Ester short plasma t1/2
; No enough time for distribution
Metabolism and excretion
• Amide: in the liver by CYP450
• Ester: in plasma butyrylcholinesterase
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14. LAs mechanism of action
Local anesthetics reversibly bind to the voltage-gated Na+ channel, block
Na+ influx, and thus block action potential and nerve conduction.
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The excitable membrane of neuronal axons
maintains a transmembrane potential of -90
to -60 mv.
The transmembrane ionic gradients are
maintained by the Na+/K+ ATPase (Na+
pump).
During excitation the Na+ channels open, a
fast inward Na+ current quickly depolarizes
the membrane toward the Na+ equilibrium
potential +40mv.
Membrane Potential and neurotransmission

15. Membrane Potential and neurotransmission
• As a result of depolarization:
– the Na+ channels close
(inactivate)
– & K+ channels open→
outward flow of K+
repolarizes the membrane
toward the K+ equilibrium
potential about
-95mv
• As a result of repolarization the
Na+ channels returns to the
rested state.
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16. Effects of Ca+2 & K+ on LAs
• Elevated extracellular Ca+2 [↑membrane potential →
resting state (low affinity)] particularly antagonized the
action of LA.
• Increase of extracellular K+ depolarizes the membrane
potential & favors the inactivated state → enhance the
effect of LA
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17. Actions on Nerves
• Since LAs are capable of blocking all nerves,
• Their actions are not usually limited to the desired loss of
sensation.
• Although motor paralysis may at times be desired, it may
also limit the ability of the patient to cooperate, e.g., during
obstetric delivery.
• During spinal anesthesia, motor paralysis may impair
respiratory activity & AN blockade may lead to hypotension
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18. Effect of fiber diameter
• Local anesthetics preferably block small, unmylinated fibers
that conduct pain, temperature, and autonomic nerves.
• for the same diameter, myelinated nerves will be blocked
before unmyelinated nerves.
– The smaller B preganglionic autonomic & C (pain) fiber are
blocked 1st.
– The small type A delta (sensations) are blocked next.
– Motor function is blocked last.
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19. 19
Relative size and susceptibility to block of types of nerve fibers
1. pain, 2. cold, 3. warmth, 4. touch, 5. deep pressure & 6. motor
Recovery is in reverse order

20. Time & voltage-dependent fashion
The effect of a drug is more marked in rapidly firing axons than
in resting fibers. Because LAs block the channel in a time &
voltage-dependent fashion.
– Channels in the rested state (-ve mps) have a low affinity for LAs
– Channels in the activated (open state) and inactivated (+ve mps) have a
high affinity for Las.
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21. Effect of firing frequency
(state dependent mechanism)
• Nerves with higher firing frequency, more positive
membrane potential, & with longer depolarization
(duration) are more sensitive to local anesthetic block
• Sensory fibers especially pain fibers, have a high firing
rate & relatively long action potential duration (up to 5 ms)
• Motor fibers fire at a slower rate & have a shorter AP
(<0.5 ms)
• In nerve bundles, fibers that are located circumferentially
are affected first by local anesthetics
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22. Effect on other excitable membranes
• LAs have weak NM blocking-little clinical
importance.
• Cardiac cell membrane;
– antiarrhythmia at concentration lower than those
required to produce nerve block
– Arrhythmogenic: and all can cause arrhythmias in high
enough concentration.
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23. Clinical pharmacology of LAs
• The onset of LAs is sometimes accelerated by the use of
solutions saturated with CO2 (carbonated) → intracellular
acidosis → intracellular accumulation of the cationic form of
LA.
• Repeated injection of LAs during epidural anesthesia →
tachyphylaxis because of extracellular acidosis.
• Pregnancy appears to increase susceptibility to LAs
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24. Toxicity and side effects
A. CNS: at
low dose: sleepiness, light headedness, visual and
auditory disturbances, restlessness, circumoral &
tongue numbness.
high dose (stimulatory effects): nystagmus, muscular
twitching, finally tonic-clonic convulsions, followed
by CNS depression→ death may occur.
• Convulsion because of cortical inhibitory pathways →
unopposed activity of excitatory components.
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25. Convulsion prevention
Convulsion prevented by:
• administering smallest dose of LA
• premedication with BDZ (diazepam)
↓LA toxicity by:
• Prevent hypoxemia (hypercapnia) & acidosis by
hyperventilation →↑blood pH → ↓ E.C K+ →
hyperpolarization → resting state → ↓LA toxicity
Seizure Rx:
• thiopental 1-2mg/kg
• Diazepam 0.1 mg/kg
• succinylcholine for muscular manifestation.
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26. Toxicity and side effects
B. PNS (neurotoxicity)
C. Cardiovascular system (CVS): direct & indirect effect
Direct: all LAs are vasodilators (except cocaine) and also
decrease the strength of cardiac contraction→ both effects →
hypotension
Indirect: ANS, cocaine blockade of NE reuptake →
• vasoconstriction → ischemia → ulceration of mucous
membrane & damage nasal septum .
• HTN
• Precipitate cardiac arrhythmia
NB. Bupivacaine is more cardiotoxic → CV collapse, after
accidental I.V
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27. Toxicity and side effects
D. Blood: prilocaine (large dose; 10mg/kg) → accumulation
of metabolite an oxidating agent, convert Hb to metHb →
cyanotic
• RX: methylene blue or ascorbic acid I.V to rapidly convert
metHb → Hb.
E. Allergy: the ester type LA are metabolized to PABA
derivative responsible for allergic reaction in a small % of
population.
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