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
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
3. Delivery techniques include:
• topical administration,
• peripheral nerve blocks,
• neuraxial (spinal, epidural, or
Small, unmyelinated nerve fibers
for pain, temperature, and
autonomic activity are most
Local anesthetics (LAs)
4. History of local anesthetics
3000 B.C.: cocaine
• 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
• 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
1. A lipophilic ‘hydrophobic’ aromatic group.
2. An intermediate chain (ester or amide).
3. A hydrophilic an ionizable group (usually a
tertiary amine group).
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”
7. Clinical pharmacology of LAs
The choice of LA for a specific procedure is usually based on the
duration of procedure required
8. Local anesthetics
• Local anesthetics are weak bases.
• The pKa for most local anesthetics is in the range of 8-9
• 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
Log cation (charged)/ uncharged= pKa - pH
9. Effect of pH:
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
• 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
• 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.
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:
– Site of injection
– Local blood flow: highly or poorly perfused
– Use vasoconstrictors (e.g., epinephrine)
– Drug tissue binding
– Physicochemical properties of the drug itself
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!
• 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
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.
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+
During excitation the Na+ channels open, a
fast inward Na+ current quickly depolarizes
the membrane toward the Na+ equilibrium
Membrane Potential and neurotransmission
15. Membrane Potential and neurotransmission
• As a result of depolarization:
– the Na+ channels close
– & K+ channels open→
outward flow of K+
repolarizes the membrane
toward the K+ equilibrium
• As a result of repolarization the
Na+ channels returns to the
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
17. Actions on Nerves
• Since LAs are capable of blocking all nerves,
• Their actions are not usually limited to the desired loss of
• Although motor paralysis may at times be desired, it may
also limit the ability of the patient to cooperate, e.g., during
• During spinal anesthesia, motor paralysis may impair
respiratory activity & AN blockade may lead to hypotension
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
– The small type A delta (sensations) are blocked next.
– Motor function is blocked last.
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 &
– 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.
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
• In nerve bundles, fibers that are located circumferentially
are affected first by local anesthetics
22. Effect on other excitable membranes
• LAs have weak NM blocking-little clinical
• Cardiac cell membrane;
– antiarrhythmia at concentration lower than those
required to produce nerve block
– Arrhythmogenic: and all can cause arrhythmias in high
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
• Repeated injection of LAs during epidural anesthesia →
tachyphylaxis because of extracellular acidosis.
• Pregnancy appears to increase susceptibility to LAs
24. Toxicity and side effects
A. CNS: at
low dose: sleepiness, light headedness, visual and
auditory disturbances, restlessness, circumoral &
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.
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
• thiopental 1-2mg/kg
• Diazepam 0.1 mg/kg
• succinylcholine for muscular manifestation.
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 →
Indirect: ANS, cocaine blockade of NE reuptake →
• vasoconstriction → ischemia → ulceration of mucous
membrane & damage nasal septum .
• Precipitate cardiac arrhythmia
NB. Bupivacaine is more cardiotoxic → CV collapse, after
27. Toxicity and side effects
D. Blood: prilocaine (large dose; 10mg/kg) → accumulation
of metabolite an oxidating agent, convert Hb to metHb →
• 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