Exposición en inglés de anestésicos locales

1. Local Anesthetics
Dr. Hiwa K. Saaed,
PhD Pharmacology & Toxicology
College of Pharmacy/ University of Sulaimani
2017-2018
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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”
Amides
Lidocaine
Bupivacaine
Levobupivacaine
Ropivacaine
Mepivacaine
Etidocaine
Prilocaine
Esters
Procaine
Chloroprocaine
Tetracaine
Benzocaine
Cocaine
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7. Clinical pharmacology of LAs
Procaine
chlorprocaine
Lidocaine,
mepivacaine
prilocaine
tetracaine,
bupivacaine,
etidocaine
ropivacaine.
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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
(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
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Local anesthetics reversibly bind to the voltage-gated Na+ channel, block
Na+ influx, and thus block action potential and nerve conduction.
Schematic diagram of the sodium channel in an excitable membrane (eg, an axon) and the
pathways by which a local anesthetic molecule (Drug) may reach its receptor. Sodium ions
are not able to pass through the channel when the drug is bound to the receptor. The local
anesthetic diffuses within the membrane in its uncharged form. In the aqueous extracellular
and intracellular spaces, the charged form (Drug+) is also present. (Katzung & Trevor
Pharmacology exam & Board review 10th edition)

15. Membrane Potential and neurotransmission
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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.

16. 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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17. Effects of Ca+2 & K+ on LAs
• Elevated extracellular Ca+2 [↑ surface potential on the
membrane potential → resting state (which favors the
low-affinity rested state)] partially 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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18. 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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19. 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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20. 20
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

21. 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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22. 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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23. 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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24. Clinical pharmacology of LAs
Local anesthetics can provide highly effective analgesia in
well-defined regions of the body. The usual routes of
administration include:
– topical application (eg, nasal mucosa, wound [incision site]
margins)
– injection in the vicinity of peripheral nerve endings (perineural
infiltration) and major nerve trunks (blocks),
– injection into the epidural or subarachnoid spaces surrounding
the spinal cord.
– Intravenous regional anesthesia (so-called Bier block) is used for
short surgical procedures (< 60 minutes) involving the upper
and/or lower extremities.
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25. 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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26. Toxicity and side effects
A. CNS:
-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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27. 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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28. 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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29. 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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