LOCAL ANESTHETICS - Professor Dr Ghaleb

• The electrical potential inside the cell is negative and
close to the potential that would be determined by
potassium alone.
This is the resting potential (-70 mV). During the
transmission of an action potential, sodium moves into
the cell through open sodium channels, depolarizing the
Local anesthetics are compounds with the ability to
interrupt the transmission of the action potential in
excitable membranes. They bind to specific receptors on
the Na+ channels and their action at clinically
recommended doses is reversible.
Historical perspective
• The natives of Peru chewed coca leaves and
knew about their cerebral-stimulating effects.
The leaves of erythroxylon coca were taken to
Europe where Niemann isolated cocaine in
Germany in 1860.
Koller in 1884 is credited with the introduction
of cocaine as a topical ophthalmic local
anesthetic in Austria.
Cardiovascular side effects as well as potential
for dependency and abuse were soon
recognized, which led to the search for a better
local anesthetic.
Historical perspective
• 1850’s invention of the syringe and hypodermic hollow needle
• 1884 Halsted, blocks the brachial plexus with a solution of cocaine
under direct vision (surgical exposure).
1897 Braun in Germany relates cocaine toxicity with systemic
absorption and advocates the use of epinephrine.
1898 Bier performs the first planned spinal anesthesia.
1911 Hirschel performs the first percutaneous axillary block
1911 Kulenkampff performs the first percutaneous supraclavicular
Date of introduction in clinical practice of some local anesthetics:
Historical perspective
• 1905 procaine; 1932 tetracaine; 1947
lidocaine; 1955 chloroprocaine (last ester
type local anesthetic introduced that is still
in clinical use); 1957 mepivacaine; 1963
bupivacaine; 1997 ropivacaine; 1999
Chemical structure
• weak bases with a pka above 7.4 and poorly soluble in
Commercially available as acidic solutions (pH 4-7) of
hydrochloride salts, which are hydrosoluble.
A typical local anesthetic is composed of two portions
linked together by a chemical chain. One portion consists
of a benzene ring (lipid soluble “hydrophobic”) and the
other is an amine group that is ionizable and watersoluble (hydrophilic).
The chemical chain can be either ester type (-CO-) or
amide type (-HNC-) defining two different groups of local
anesthetics, esters and amides.
• The injected local anesthetic volume spreads initially by mass
This first step determines how much local anesthetic effectively
reaches the nerve.
Moves across “points of least resistance”, which do not necessarily
lead into the desired nerve(s), stressing the need to bring the
needle in proximity to the target nerve(s).
The local anesthetic solution diffuses through tissues; each layer of
them acting as a physical barrier and in the process part of the
solution gets absorbed into the circulation.
Finally a small percentage of the anesthetic reaches the target
nerve membrane at which point the different physicochemical
properties of the individual anesthetic will dictate the speed,
duration and nature of the interaction with the receptors.
Lipid solubility
Determines both the potency and the duration of
action of the local anesthetics by binding the drug
close to the site of action and thereby decreasing the
rate of metabolism by plasma esterase and liver
In addition the local anesthetic receptor site on Na+
channels is thought to be hydrophobic, so its affinity
for hydrophobic drugs is greater.
Hydrophobicity also increases toxicity, so the
therapeutic index actually is decreased for more
hydrophobic drugs.
Protein binding
Related to duration of action.
In the body, local anesthetics are bound in large part to plasma and
tissue proteins. The bound portion is not pharmacologically active. The
most important binding proteins in plasma are albumin and alpha-1-acid
glycoprotein (AAG)
The fraction of drug bound to protein in plasma correlates with the
duration of action of local anesthetics: bupivacaine > ropivacaine >
mepivacaine > lidocaine > procaine and 2-chloroprocaine.
This suggests that the bond between the local anesthetic molecule and
the sodium channel receptor protein may be similar to that of local
anesthetic binding to plasma protein (similar amino acid sequences).
Drugs as lidocaine, tetracaine and bupivacaine have been incorporated
into liposomes to prolong the duration of action and decrease toxicity.
Liposomes are vesicles with two layers of phospholipids, which slow
down the release of the drug effectively prolonging the duration of action
• Protein binding
• This suggests that the bond between the local anesthetic
molecule and the sodium channel receptor protein may
be similar to that of local anesthetic binding to plasma
protein (similar amino acid sequences).
Drugs as lidocaine, tetracaine and bupivacaine have
been incorporated into liposomes to prolong the duration
of action and decrease toxicity. Liposomes are vesicles
with two layers of phospholipids, which slow down the
release of the drug effectively prolonging the duration of
The pka of the local anesthetic determines the ratio of the
ionized (cationic) and the uncharged (base) form of the drug.
The pka for local anesthetics ranges from 7.6 to 9.2.
By definition the pka is the pH at which 50% of the drug is
ionized and 50% is present as a base.
The pka generally correlates with the speed of onset of most
local anesthetics. The closer the pka to the physiologic pH the
faster the onset (e.g., lidocaine with a pka of 7.7 is 25% nonionized at ph 7.4 and has a more rapid onset of action than
bupivacaine with a pka of 8.1 which is only 15% non-ionized).
One important exception is 2-chloroprocaine with a pka of 9.0
and very short onset of action. This fast onset could be related to
its low toxicity, which allows for high concentrations to be used
clinically. It is also claimed to have also better “tissue
Mechanism of action and sodium channels
• The non-charged hydrophobic fraction (B) crosses the
lipidic nerve membrane and initiates the events that lead
to blocking of sodium channels.
Once inside a new equilibrium, dictated by the
compound pka and the intracellular pH, is reached
between the non-charged and charged (BH+) fractions.
Because of the relative more acidic intracellular
environment, the relative proportion of charged fraction
increases. This fraction interacts with the Na+ channel.
Local anesthetics do not ordinarily affect the membrane
resting potential.
Mechanism of action and sodium channels
• The Na+ channel is a protein structure that
communicates the extracellular of the nerve with its
axoplasm and consists of four repeating alpha subunits,
a beta-1 and beta-2 subunits. The alpha subunits are
involved in ion movement and local anesthetic activity.
It is generally accepted that local anesthetics main
action involves interaction with specific binding sites
within the Na+ channel.
The voltage–dependence of channel opening is
hypothesized to reflect conformational changes in
response to changes in transmembrane potential. The
voltage sensors or gates are located in the S4 helix; the
S4 helices are both hydrophobic and positively charged.
Mechanism of action and sodium channels
• The Na+ channels seem to exist in three different states, closed,
open and inactive.
With depolarization the protein molecules of the channel undergo
conformational changes from the closed (resting) state to the ionpermeable state or open state.
The channel goes then through a transitional inactive state where
the proteins leave the channel still closed and ion-impermeable.
With repolarization the proteins revert to their resting configuration.
Local anesthetics may also block in some degree calcium and
potassium channels as well as N-methyl-D-aspartate (NMDA)
Other drugs like tricyclic antidepressants (amitriptyline), meperidine,
volatile anesthetics and ketamine also have sodium channel-blocking
Frequency and voltage dependence of local
anesthetic action
• A resting nerve is much less sensitive to local
anesthetic than one that is being stimulated.
The degree of block also depends on the nerve
resting membrane potential, a more positive
membrane potential causes a greater degree of
These frequency and voltage dependent effects
occur because the local anesthetic in its charged
form gain access to its biding site within the
channel only when the Na+ channel is in an
open state
Pregnancy and local
• Increased sensitivity (more rapid onset, more profound
block) may be present during pregnancy.
Also alterations in protein binding of bupivacaine may
result in increased concentrations of active unbound
drug in the pregnant patient.
During pregnancy, placental transfer is more active for
lipid soluble local anesthetics, whereas higher protein
binding becomes an obstacle to such transfer. In any
case, agents with a pka closer to physiologic pH have a
higher placental transfer. For example the umbilical
vein/maternal vein ratio for mepivacaine is 0.8 (pka 7.6)
while for bupivacaine is 0.3 (pka 8.1).
Pregnancy and local
• In the presence of fetal acidosis, local
anesthetics cross the placenta and
become ionized in higher proportion than
at normal pH. As ionized substances they
cannot cross back to the maternal
circulation (“ion trapping”). 2chloroprocaine with its very short maternal
and fetal half-lives is theoretically an ideal
local anesthetic in the presence of fetal
Fiber size and pattern of blockade
• As a general rule small nerve fibers are more susceptible
to local anesthetics
However other factors like myelinazation and relative
position of the fibers (mantle and core) within a nerve
also play a role.
The smallest nerve fibers are nonmyelinated and are
blocked more readily than larger myelinated fibers.
However myelinated fibers are blocked before
nonmyelinated fibers of the same diameter.
In general autonomic fibers, small nonmyelinated C
fibers (mediating pain), and small myelinated A delta
fibers (mediating pain and temperature) are blocked
before A gamma, A beta and A alpha fibers (carrying
postural, touch, pressure and motor information).
Fiber size and pattern of blockade
• In large nerve trunks motor fibers are usually located in
the outer portion of the bundle and are more accessible
to local anesthetic. Thus motor fibers may be blocked
before sensory fibers in large mixed nerves.
In addition the frequency-dependence of local anesthetic
action favors block of small sensory fibers. They
generate long action potential (5 ms) at high frequency,
whereas motor fibers generate short action potentials
(0.5 ms) at lower frequency. These characteristics of
sensory fibers in general, and of pain fibers in particular,
favor frequency-dependent block.
Modulating local anesthetic action
pH adjustment
• Local anesthetics pass through the nerve membrane in a non•
ionized hydrophobic (lipid soluble) base form.
In the axoplasm they equilibrate into an ionic form that is active
within the sodium channel. The rate-limiting step in this cascade is
penetration of the local anesthetic through the nerve membrane.
All available local anesthetics contain very little drug in the nonionized state. This fraction depends on the pka of the drug and the
ph of the solution.
Changes in ph can produce a shortening of the onset time, being
the limiting factor for ph adjustment the solubility of the base form
of the drug (precipitation).
DiFazio et al (Anesth Analg 1986:65; 760-64) demonstrated more
than 50% decrease in onset of epidural anesthesia when the pH of
commercially available lidocaine with epinephrine was raised from
4.5 to 7.2 by the addition of bicarbonate.
Modulating local anesthetic action
pH adjustment
• Hilgier (Reg Anesth 1985:10; 59-61) reported a marked
improvement in the onset time for brachial plexus anesthesia when
bupivacaine with epinephrine (pH 3.9) was alkalinized to pH 6.4
before injection.
• However, when only small changes in pH can be achieved because
of the limited solubility of the base, only small decreases in onset
time will occur, as when plain bupivacaine is alkalinized. For each
local anesthetic there is a ph at which the amount of base in
solution is maximal (a saturated solution).
• Chloroprocaine plus 1 mL of sodium bicarbonate for 30 mL of
solution raises the pH to 6.8. Adding 1 mL of sodium bicarbonate
per 10 mL of lidocaine or mepivacaine raises the pH of the solution
to 7.2 and adding 0.1 mL of bicarbonate per 10 mL of bupivacaine
raises the pH of the solution to 6.4
Modulating local anesthetic action
pH adjustment
• Carbonation
• Another approach to shortening onset time has
been the use of carbonated local anesthetic
solutions. The solution contains large amounts
of carbon dioxide, which readily diffuses into the
axoplasm of the nerve lowering the ph and
favoring the formation of the cationic active form
of the local anesthetic. Carbonated solutions are
not available in the United States
• Vasoconstrictors to prolong the anesthetic effect and
to decrease absorption.
Epinephrine is also used to detect intravascular injection
(test dose).
Vasoconstrictors may also improve the quality and
density of the block especially with spinal and epidural
anesthesia. This has been demonstrated with tetracaine,
lidocaine and bupivacaine. The mechanism is unclear.
Epinephrine may simply increase the amount of local
anesthetic available by reducing absorption. It could
have also some anesthetic effect by means of its alpha
2-agonist actions.
Subarachnoid epinephrine potentially delays the time for
urination, which may delay discharge.
• Epinephrine used other than intrathecally is absorbed systemically and may
produce adverse cardiovascular effects.
• In small doses the beta-adrenergic effects predominate with increased
cardiac output and heart rate. Dose larger than 0.25 mg (250 ug) may be
associated with arrhythmias or other undesirable cardiac effects.
• Lately concerns have been raised about potential neural ischemia caused by
epinephrine acting on epineural vessels and vaso nervorum. This potential
risk has to be balanced against lower risk of systemic toxicity, marker for
intravascular injection and prolongation of action.
• Neal in 2003
adding 5 ug/mL (1:200,000 dilution) prolongs the duration of lidocaine for
peripheral nerve blocks from 186 minutes to 264 minutes.
Adding only 2.5 ug/mL (1:400,000 dilution) prolongs the block to 240 minutes
(almost the same prolongation) without apparent effect on nerve blood
Patients with micro angiopathy (e.g., diabetics) who could be at increase risk
for neural ischemia secondary to vasoconstriction potentially could benefit
from the use of more diluted epinephrine (1:400,000).
• Opioids
• The addition of short-acting opioids such as
fentanyl and sufentanil to spinal anesthetics
appears to intensify the block and prolong the
duration of anesthesia similar to epinephrine
without affecting urination. They also prolong
analgesia beyond the duration of local
anesthetics. When used epidurally they usually
produced pruritus. Their usefulness in peripheral
nerve blocks is not clear
• Clonidine
• Alpha 2-agonists have analgesic effects when injected on nerves or
in the subarachnoid space. Side effects (hypotension, bradycardia)
limit its use but small doses (50-75 ucg) have shown to significantly
prolong analgesia in spinal, epidural, intravenous regional, and
peripheral nerve blocks both when injected with the local
anesthetics and when given orally.
It breaks down collagen bonds potentially facilitating the spread of
local anesthetic through tissue planes. The evidence however shows
at least in the epidural space to decrease the quality of anesthesia.
Its use seems limited to retrobulbar blocks.
Dextran and other high-molecular-weight compounds have been
advocated to increase the duration of local anesthetics. The
evidence is lacking.
• Ester local anesthetics
• They are hydrolyzed at the ester linkage by plasma
pseudocholinesterase (also hydrolyses acetylcholine and
succinylcholine). The hydrolysis of 2-chloroprocaine is about four
times faster than procaine, which in turn is hydrolyzed about four
times faster than tetracaine. In individuals with atypical plasma
pseudocholinesterase the half-life of these drugs is prolonged and
potentially could lead to plasma accumulation.
• The hydrolysis of all ester anesthetics leads to the formation of
para-aminobenzoic acid (PABA), which is associated with a low
potential for allergic reactions. Allergic reactions may also develop
from the use of multiple dose vials of amide local anesthetics that
contain PABA as a preservative.
• Amide local anesthetics
• They are transported into the liver before their biotransformation. The two
major factors controlling the clearance of amide local anesthetics by the
liver are: hepatic blood flow and hepatic function.
The metabolism of local anesthetics as well as that of many other drugs
occurs in the liver by the cytochrome P-450 enzymes. Because the liver has
a large capacity for metabolizing drugs it is unlikely that drug interaction
would affect the metabolism of local anesthetics.
Drugs such as general anesthetics, norepinephrine, cimetidine, propranolol
and calcium channel blockers (e.g., diltiazem) can decrease hepatic blood
flow and increase the elimination half-life of amides. Similarly decreases in
hepatic function caused by a lowering of body temperature, immaturity of
the hepatic enzyme system in the fetus, or liver damage (e.g., cirrhosis)
lead to a decreased rate of hepatic metabolism of the amides. Renal
clearance of unchanged local anesthetics is a minor route of elimination
(lidocaine is only 3% to 5% recovered unchanged in the urine of adults
while for bupivacaine is 10% to 16%).
• Systemic local anesthesia toxicity is related to plasma levels. Plasma
concentration depends on:
• The total dose
• The net absorption, which depends on: vasoactivity of the drug, site
vascularity and use of a vasoconstrictor.
• Biotransformation and elimination of the drug from the circulation
• Peak local anesthetic blood levels are directly related to the dose
administered at any given site. Generally the administration of a
100-mg dose of lidocaine in the epidural or caudal space results in
approximately a 1 ucg/mL peak blood level in an average adult. The
same dose injected into less vascular areas (e.g., brachial plexus
axillary approach or subcutaneous infiltration) produces a peak
blood level of app 0.5 ucg/mL. The same dose injected intercostal
produces a 1.5 ucg/mL plasma level.
• Systemic local anesthesia toxicity
• Peak blood levels may also be affected by the rate of
biotransformation and elimination. In general this is the
case only for very actively metabolized drugs such as 2chloroprocaine, which has a plasma half-life of about 45
seconds to1 minute.
For amide local anesthetics like lidocaine peak plasma
level after regional anesthesia primarily result from
absorption. Lidocaine biotransformation half-life is
approximately 90 minutes. Local anesthetics interfere
with the functions of all organs in which transmission of
impulses occurs, among others the CNS and
cardiovascular systems.
• Central nervous system
• Toxic levels are usually produced by inadvertent intravascular
It can also result from the slow absorption following peripheral
A sequence of symptoms can include:
Numbness of the tongue
Respiratory arrest
• Cardiovascular system
– The cardiovascular manifestations usually follow the
CNS effects (therapeutic index). The exception is
bupivacaine, which can produce cardiac toxicity at
subconvulsant concentrations.
– Rhythm and conduction are rarely affected by
lidocaine, mepivacaine and tetracaine but
bupivacaine and etidocaine can produce
ventricular arrhythmias.
– EKG shows a prolongation of PR and widening of the
– Higher incidence in pregnancy
– CV toxicity is increased under hypoxia and acidosis.
Treatment of systemic toxicity
• ABC (Airway, Breathing and Circulation) is the mainstay
of treatment.
Administration of O2 by mask or bag and mask is often
all that is necessary to treat seizures. If seizures
interfere with ventilation benzodiazepines, thiopental or
propofol can be used. The use of succinylcholine
effectively facilitates ventilation and by abolishing
muscular activity decreases the severity of acidosis.
However neuronal seizure activity is not inhibited and
thus cerebral metabolism and oxygen requirements
remain increased.
Treatment of systemic toxicity
• Little information is available regarding the treatment of
cardiovascular toxicity of local anesthetics in humans. Animal data
suggest that (1) high doses of epinephrine may be necessary to
support heart rate and blood pressure; (2) atropine may be useful
for bradycardia; (3) DC cardioversion is often successful; and (4)
ventricular arrhythmias are probably better treated with amiodarone
than with lidocaine. Amiodarone is used as for ACLS, 150 mg over
10 min, followed by 1 mg/min for 6 hrs then 0.5 mg/min.
Supplementary infusion of 150 mg as necessary up to 2 g. For
pulseless VT or VF, initial administration is 300 mg rapid infusion in
20-30 mL of saline or dextrose in water. Vasopressin (40 U IV, single
dose, one time only) is more frequently used now before
epinephrine (1 mg IV every 3-5 minutes). The best treatment for
toxic reactions is prevention
Maximum dose
• Regional anesthesiologists perform peripheral nerve blocks with an amount
of local anesthetic that usually exceeds the maximum recommended doses.
The common recommendations for maximum doses as suggested by the
literature “are not evidence based” (14) and have proven to be “poor
approximation of safety” (15).
Many practitioners have called to review these guidelines to better reflect
the reality of clinical practice. The American Society of Regional Anesthesia
convened a “Conference in Local Anesthetic Toxicity” with a panel of experts
in 2001 to discuss the subject. Many papers related to that conference have
been published.
In a review article by Rosenberg et al (14) the authors propose that the
safe ranges should be block specific and related to patient’s age (e.g.,
epidural), organ dysfunction (especially for repeated doses) and pregnancy.
They suggest also adding epinephrine 2.5 to 5 µg/ml when not
The fact is that most of the systemic toxicity occurs with unintentional direct
intravascular injection
• Prilocaine and benzocaine can oxidize the ferric form of the
hemoglobin to the ferrous form, creating methemoglobin. When this
exceeds 4 g/dL cyanosis can occur. Depending on the degree
Methemoglobinemia can lead to tissue hypoxia. The oxyHb curve
shifts to the left (P50 < 27 mmHg). MetHb has a larger absorbance
than Hb and 02Hb at 940 nm but simulates Hb at 660 nm.
Therefore at high SaO2 levels (more than 85%) the reading
underestimates the true value of it or overestimates the O2Hb. At
low SaO2 (<85%) the value is falsely high. In the presence of high
MetHb concentrations the SaO2 approaches 85% independent of
the actual arterial oxygenation.
• Methemoglobinemia is easily treated by the administration of
methylene blue (1-5mg/kg) or less successfully of ascorbic acid (2
• True allergy to local anesthetics is rare. It is
relatively more frequent with esters, which are
metabolized to para-amino-benzoic acid (PABA).
PABA is frequently used in the pharmaceutical
and cosmetic industries. Allergy to amide local
anesthetics is exceedingly rare. There is no cross
allergy between esters and amides. However
use of methylparaben as a preservative in
multidose vials of lidocaine can elicit allergy in
patients allergic to PABA
• Ester
pka 8.9
slow onset
very short half life (20 sec)
protein binding 5%
• duration: short
• Ester
pka 9.0
rapid onset
short duration (it has 30 minutes 2-segment regression
in epidural)
• serious neurological deficits have occurred after massive
intrathecal injection planned for spinal possible
associated with the antioxidant bisulfite.
The next preservative used ethylenediamine tetraacetic
acid (EDTA) was associated with severe muscle spasm
after epidural in ambulatory patients.
The present solution is prepared without preservative
and no back spasms have been reported
• Ester
pka 8.6
slow onset
short plasma half life (2.5 to 4 min) and
long duration of action
• ester
pka 8.5
slow onset
short duration
interferes with the reuptake of cathecolamines
resulting in hypertension, tachycardia,
arrhythmia and myocardial ischemia.
Can potentiate cathecolamine-induced
arrhythmia by halothane, theophylline or
• ester (only secondary amine). It limits its
ability to pass through membranes.
pka 3.5
slow onset
short duration
Topical anesthetic
excessive use is associated with
• Lidocaine
pka 7.7
intermediate onset and duration
half-life 45-60 min
• Mepivacaine
pka 7.6
intermediate onset and duration
• Bupivacaine
pka 8.1
Slow onset, long duration
Cardiac arrest associated with bupivacaine
is difficult to treat possibly due to its high
protein binding and high lipid solubility
• Ropivacaine
pka 8.2
chemical analog of mepivacaine and
Prepared as L enantiomer
Onset and duration as well as potency
similar to bupivacaine
Cardiac toxicity higher than mepivacaine
but lower than bupivacaine
• Levobupivacaine
L enantiomer of bupivacaine
similar to ropivacaine
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