about local anaesthetics and their history,pharmacology and clinical application

1. LOCAL
ANAESTHETICS
Presenter :
Dr BALA MURALI KRISHNA
ANAESTHETIST

2. INTRODUCTION
• Local anesthetics are drugs that produce a reversible
conduction blockade of impulses along central and
peripheral nerve pathways
• In addition to blockade of impulses, local anesthetics
can inhibit various receptors, enhance release of
glutamate, and depress the activity of certain
intracellular signaling pathways.
• When local anesthetics are given systemically , the
functions of cardiac, skeletal, and smooth muscle, as
well as transmission of impulses in the central and
peripheral nervous systems and within the specialized
conducting system of the heart, can all be altered.

3. HISTORY
• 1884- cocaine, 1st LA introduced by Karl Koller
& first used in opthalmology.
• HALSTED- used it to block nerve conduction.
• 1905- 1st synthetic LA – procaine itroduced by
Einhorn.
• 1943-Lidocaine, 1st amide LA – LoFGREN.

4. BASIC STRUCTURE
• Local Anesthetic Molecule contains a tertiary
amine attached to a substituted aromatic ring by
an intermediate chain that almost always
contains either an ester or amide linkage
• The aromatic ring system gives a lipophilic
character to its portion of the molecule, whereas
the tertiary amine is relatively hydrophilic, since it
is partially protonated and bears some positive
charge in the physiologic pH range

9. STRUCTURAL DIFFERENCE

10. MODIFICATION OF CHEMICAL
STRUCTURE
• Modifying the chemical structure of a local anesthetic
alters its pharmacologic effects .
• TETRACAINE - Substituting a butyl group for the amine
group on the benzene ring of procaine . tetracaine is
more lipid soluble, ten times more potent, and has a
longer duration of action, corresponding to a four- to
fivefold decrease in the rate of metabolism.
• CHLORPROCAINE - The halogenation of procaine to
chloroprocaine results in a three- to fourfold increase
in the hydrolysis rate of chloroprocaine by plasma
cholinesterase.

11. • Mepivacaine, bupivacaine, and ropivacaine are
characterized as pipecoloxylidides .
• The addition of a butyl group to the piperidine
nitrogen of mepivacaine results in bupivacaine,
which is 35 times more lipid soluble and has a
potency and duration of action three to four
times that of mepivacaine.
• Ropivacaine structurally resembles bupivacaine
and mepivacaine, with a propyl group on the
piperidine nitrogen atom of the molecule.

12. RACEMIC MIXTURES OR PURE
ISOMERS
• The pipecoloxylidide local
anesthetics(mepivacaine, bupivacaine,
ropivacaine, levobupivacaine) are chiral drugs,
because their molecules possess an
asymmetric carbon atom.
• Mepivacaine, bupivacaine, ropivacaine, and
levobupivacaine have been developed as a
pure S enantiomers.

13. • Ropivacaine is a single (S)-stereoisomer that
differs from levobupivacaine in the
substitution of a propyl for the butyl group on
the piperidine ring
• These S enantiomers are considered to
produce less neurotoxicity and cardiotoxicity
than racemic mixtures or the R enantiomers of
local anesthetics, perhaps reflecting
decreased potency at sodium ion channels

14. STRUCTURE-ACTIVITY RELATIONSHIPS
• The intrinsic potency and duration of action of local
anesthetics are clearly dependent on certain features
of the molecule like
Lipophilic versus Hydrophilic Balance --
• depends on the size of alkyl substituents on or near
the tertiary amine and on the aromatic ring
• Compounds with a more hydrophobic nature(
octanol/buffer partitioning) are obtained by increasing
the size of the alkyl substituents.These agents are more
potent and produce longer-lasting blocks than their
less hydrophobic congeners do

16. • Hydrogen Ion Concentration –
• Average pKa of local anesthetics is lower than in
solution in a apolar or neutral environment
• This is chemically equivalent to saying that the
membrane concentrates the base form of the
local anesthetic more than it concentrates the
protonated cation form
• The pH of the medium containing the local
anesthetic influences drug activity by altering the
relative percentage of the base and protonated
forms

17. PERIPHERAL NERVE

18. ACTION POTENTIAL

19. IMPULSE IN PERIPHERAL NERVE

21. PERIPHERAL NERVES

22. MECHANISM OF ACTION
• Local anesthetics prevent the transmission of
nerve impulses (conduction blockade) by
inhibiting the passage of sodium ions through
ion-selective sodium channels in nerve
membranes.
• Local anesthetic bases are poorly to sparingly
soluble in water, but are soluble in relatively
hydrophobic organic solvents. Therefore, as a
matter of chemistry (and to optimize shelf life),
most of these drugs are formulated as
hydrochloride salts

23. • The hydrophobic local anesthetics, having higher
intrinsic potencies , are therefore used in lower
concentrations and their diffusion-controlled rate
of onset is correspondingly reduced
• On sheath-free nerves, the rate of inhibition by
tertiary amine anesthetics is greater at alkaline
than at neutral external pH because membrane
permeation, favored by the base over the cationic
species, determines the rate of access to the
binding site.

24. • Local anaesthetic acts by causing the failure of sodium
ion channel permeability to increase slows the rate of
depolarization so that the threshold potential is not
reached and thus an action potential is not propagated.
• Local anesthetics do not alter the RMP or threshold
potential.
• There appears to be a single binding site for local
anesthetics on the Na+ channel, with a tonic affinity at
rest and increased phasic affinity occurring because of
depolarization called toic inhibition and phasic
inhibition respectively

25. SODIUM CHANNELS

26. SODIUM CHANNELS
• The protein that forms sodium ion channels is
a single polypeptide designated the α-subunit,
and each channel consists of four subunits (DI-
DIV).
• Sodium channels exist in activated-open,
inactivated-closed, and rested-closed states
during various phases of the action potential.

27. • By selectively binding to sodium channels in
inactivated-closed states, local anesthetic
molecules stabilize these channels in this
configuration and prevent their change to the
rested-closed and activated-open states in
response to nerve impulses.
• Sodium channels in the inactivated-closed state
are not permeable to sodium, and thus
conduction of nerve impulses in the form of
propagated action potentials cannot occur.

28. LA ORDER OF ACTION
• Solutions of local anesthetic are deposited
near the nerve
• penetration of the nerve sheath by the
remaining free drug molecules.
• Local anesthetic molecules then permeate
the nerve’s axon membranes and
accumulate within the axoplasm.

29. • Binding of local anesthetic to sites on voltage-gated Na+
channels prevents opening of the channels by inhibiting the
conformational changes that underlie channel
activation.(TONIC INHIBITION )
• During onset of and recovery from local anesthesia, impulse
blockade is incomplete, and partially blocked fibers are
further inhibited by repetitive stimulation, which produces an
additional, use-dependent binding to Na+ channels.(PHASIC
INHIBITION)
• The recovery from blockade is by the relatively slow diffusion
of local anesthetic molecules into and out of the whole nerve,
not by their much faster binding and dissociation from ion
channels.

30. MINIMUM CONCENTRATION
• The minimum concentration of local anesthetic
necessary to produce the conduction blockade of
nerve impulses is termed the Cm. The Cm is
analogous to the minimum alveolar
concentration (MAC) for inhaled anesthetics.
• The Cm of motor fibers is approximately twice
that of sensory fibers; thus, sensory anesthesia
may not always be accompanied by skeletal
muscle paralysis.

31. • A minimal length of myelinated nerve fiber( 2
NODES OF RANVIER ) must be exposed to an
adequate concentration of local anesthetic for
the conduction blockade of nerve impulses to
occur in peripheral nerves.

32. DIFFERENTIAL BLOCKADE
• Small-diameter axons, such as C fibers, are often stated
to be more susceptible . However, when careful
measurements are made of single-impulse annihilation
in individual nerve fibers, exactly the opposite
differential susceptibility is noted
• The length of drug-exposed nerve in the intrathecal
space, imposed by anatomic restrictions, can perhaps
explain clinically documented differential spinal or
epidural blockade, with longer drug-exposed regions
yielding block by lower concentrations of local
anesthetic.

33. • BUT this does not explain the functionally
differential loss from peripheral nerve block.
• Other factors can include actual spread of the
drug along the nerve or its selective ability to
inhibit Na+ channels over K+ channels, which
in itself can produce a differential block
because these channels are present in
different proportions in different types of
nerves

34. • Preganglionic sympathetic nervous system B >
small C fibers > A delta >A alpha.
• In an anxious patient, however, any sensation
may be misinterpreted as failure of the local
anesthetic

35. FACTORS affecting LA action
1.DOSAGE –
• Increasing the concentration -- rapid onset,
and longer duration .
• Increasing volume of -- spread of anesthesia
• Selecting a dose should balance between risk
of adverse effects from overdosing or
underdosage resulting in failure

36. Dosage

37. 2.Use of Vasoconstrictors
• The duration of action of a local anesthetic is
proportional to the time the drug is in contact
with nerve fibers.
• Epinephrine (1:200,000 or 5 µg/mL) may be
added to local anesthetic solutions to produce
vasoconstriction, which limits systemic
absorption and maintains the drug
concentration in the vicinity of the nerve
fibers to be anesthetized .

38. • Epinephrine action is influenced by –
1) the local anesthetic selected ,
2) the level of sensory blockade required if a spinal or epidural
anesthetic is chosen.
• BENEFITS –
1) Additional analgesic effect (alpha 2 agonism)
2) Decreased possibility of systemic toxicity
• NO CHANGE – In onset –time
• SIDE-EFFECTS
1)Increased chances of cardiac irritability in presence of inhalational agents
2) systemic hypertension in vulnerable patients

39. • 3.SITE OF INJECTION :
• These differences in the onset and duration of
anesthesia and analgesia are due in part to
the particular anatomy of the area of
injection, which will influence the rate of
diffusion and vascular absorption and, in turn,
affect the amount of local anesthetic used for
various types of regional anesthesia

40. • 4.CARBONATION AND PH ADJUSTMENT :
The addition of sodium bicarbonate to a
solution of local anesthetic applied to an
isolated nerve accelerates the onset and
decreases the minimum concentration required
for conduction blockade

41. • 5.MIXING OF LOCAL ANAESTHETICS
-- used in an effort to compensate for the short
duration of action of certain rapidly acting
anesthetics
--Do not to use maximum doses of two local
anesthetics in combination in the mistaken
belief that their toxicities are independent

42. • 6.PREGNANCY
• The effects of pregnancy on local anesthetic
potency may reflect a combined effect of
mechanical factors associated with pregnancy
(i.e., dilated epidural veins) and direct effects of
hormones, especially progesterone, on the
susceptibility of nerves to conduction blockade
by local anesthetics
• The dosage of local anesthetics probably should
be decreased in patients in all stages of
pregnancy

43. PHARMACOKINETICS

44. Absorption and Distribution
Influenced by the site of injection
and dosage, use of epinephrine,
and pharmacologic characteristics
of the drug.
Lung Extraction - The lungs are
capable of extracting local
anesthetics such as lidocaine,
bupivacaine, and prilocaine from
the circulation.

45. • Placental transfer - Plasma protein binding influences
the rate and degree of diffusion of local anesthetics
across the placenta.
• Bupivacaine, which is highly protein bound
(approximately 95%), has an umbilical vein-maternal
arterial concentration ratio of about 0.32.
• Ester local anesthetics cross the placenta in very less
amounts due to rapid metabolism.
• Acidosis in the fetus, which may occur during
prolonged labor, can result in accumulation of local
anesthetic molecules in the fetus (ion trapping).

46. METABOLISM
• Clearance values and elimination half-
times for amide local anesthetics
probably represent mainly hepatic
metabolism, because renal excretion of
unchanged drug is minimal.
• Pharmacokinetic studies of ester local
anesthetics are limited because of a
short elimination half-time due to their
rapid hydrolysis in the plasma and liver.

47. Metabolism of Amide Local Anesthetics
• Amide local anesthetics undergo varying
rates of metabolism through microsomal
enzymes located primarily in the liver.
• Prilocaine -- rapid metabolism;
• lidocaine and mepivacaine -- intermediate;
• etidocaine, bupivacaine, and ropivacaine
undergo the slowest metabolism.

48. Lidocaine
• Metabolic pathway -- oxidative dealkylation in the
liver
• Metabolites -- mono ethylglycinexylidide, followed
by hydrolysis of this metabolite to xylidide.
• Monoethylglycinexylidide -- 80% of the activity of
lidocaine and has prolonged elimination half-time for
protecting against cardiac dysrhythmias in an animal
model.
• Hepatic disease or decreases in hepatic blood flow
during anesthesia, can decrease the metabolism rate
of lidocaine.

49. Prilocaine
• Prilocaine is metabolized to orthotoluidine.
• Orthotoluidine can cause methemoglobinemia.
• When the dose of prilocaine is >600 mg,
sufficient methaemoglobin may be present (3 to
5 g/dL) to cause the patient to appear cyanotic,
and oxygen-carrying capacity is decreased.

50. Mepivacaine
• Mepivacaine has pharmacologic properties
similar to those of lidocaine, although the
duration of action of mepivacaine is somewhat
longer.
• In contrast to lidocaine, mepivacaine lacks
vasodilator activity and is an alternate selection
when the addition of epinephrine to the local
anesthetic solution is not recommended.

51. Bupivacaine
• The possible pathways for bupivacaine
metabolism include aromatic hydroxylation,
N-dealkylation, amide hydrolysis, and
conjugation.
• The urinary excretion of bupivacaine and its
dealkylation and hydroxylation metabolites
account for >40% of the total anesthetic dose

52. Ropivacaine
• Ropivacaine is metabolized to 2,6-
pipecoloxylidide and 3-hydroxyropivacaine
through hepatic cytochrome P-450 enzymes.
• Only a very small fraction of ropivacaine is
excreted unchanged in the urine (about 1%)
• Ropivacaine is highly bound to α1-acid
glycoprotein.

53. Dibucaine
• Dibucaine is metabolized in the liver and is the
most slowly eliminated of all the amide
derivatives
• Dibucaine number

54. Metabolism of ESTER Local Anesthetics
• Ester local anesthetics undergo hydrolysis
through the cholinesterase enzyme, principally in
the plasma and to a lesser extent in the liver.
• The rate of hydrolysis varies, with chloroprocaine
being most rapid, procaine being intermediate,
and tetracaine being the slowest.
• The resulting metabolites are pharmacologically
inactive.

55. • The exception to the hydrolysis of ester local
anesthetics in the plasma is cocaine, which
undergoes significant metabolism in the liver.
• Systemic toxicity is inversely proportional to the
rate of hydrolysis.
• Patients with atypical plasma cholinesterase
may be at increased risk for developing excess
systemic concentrations of an ester local
anesthetic due to absent or limited plasma
hydrolysis.

56. Benzocaine
• Benzocaine is ideally suited for the topical
anesthesia of mucous membranes prior to
tracheal intubation, endoscopy, transesophageal
echocardiography, and bronchoscopy.
• The onset of topical anesthesia is rapid and lasts
30 to 60 minutes.
• A brief spray of 20% benzocaine delivers the
recommended dose of 200 to 300 mg.

57. • Cetacaine® is a combination of 14%
benzocaine, 2% tetracaine, and 2% butamben.
• Methemoglobinemia is a rare but potentially
life-threatening complication following the
topical application of benzocaine, especially
when the dose exceeds 200 to 300 mg.

58. Renal Elimination
• The poor water solubility of local anesthetics
usually limits the renal excretion of unchanged
drug to <5% (exception is cocaine, of which 10%
to 12% of unchanged drug can be recovered in
urine).
• Water-soluble metabolites of local anesthetics,
such as para-aminobenzoic acid resulting from
metabolism of ester local anesthetics, are readily
excreted in urine.

59. USES OF LOCAL ANAESTHETICS
• Regional anesthesia
• Anti-inflammatory effects
• Bronchodilation
• Tumescent liposuction

60. REGIONAL ANAESTHESIA
Regional anesthesia is classified according to the
following six sites of placement of the local
anesthetic solution:
(a) topical or surface anesthesia,
(b) local infiltration,
(c) peripheral nerve block,
(d) intervenous regional anesthesia (Bier block),
(e) epidural anesthesia, and
(f) spinal (subarachnoid) anesthesia.

61. TOPICAL ANAESTHESIA
• Local anesthetics are used to produce topical
anesthesia by placement on the mucous
membranes of the nose, mouth,
tracheobronchial tree, esophagus, or
genitourinary tract.
• Nebulized lidocaine is used to produce surface
anesthesia of the upper and lower respiratory
tract before fiber optic laryngoscopy and/or
bronchoscopy.

62. • Local anesthetics are absorbed into the
systemic circulation after topical application to
mucous membranes.
• Systemic absorption of tetracaine, and to a
lesser extent lidocaine, after placement on the
tracheobronchial mucosa produces plasma
concentrations similar to those present after
an intravenous injection of the local
anesthetic.

63. Eutectic Mixtures of Local Anesthetics
• An eutectic mixture of local anesthetics (EMLA) is
effective in relieving the pain of venipuncture,
arterial cannulation, lumbar puncture, and
myringotomy in children and adults.
• EMLA cream is not recommended for use on
mucous membranes because lidocaine and
prilocaine is absorbed faster through mucous
membranes than through intact skin.
.

65. LOCAL INFILTRATION ANAESTHESIA
• Local infiltration anesthesia involves the
extravascular placement of local anesthetic in the
area to be anesthetized (placement of an
intravascular cannula).
• Lidocaine is the local anesthetic most often
selected for infiltration anesthesia.
• Epinephrine-containing drugs should not be
injected intra cutaneously or into tissues supplied
by end arteries (fingers, ears, nose) because the
resulting vasoconstriction can produce ischemia
and even gangrene.

66. • The choice of a specific drug for infiltration anesthesia
largely depends on the desired duration of action.
• The dose depends on the extent of the area to be
anesthetized and the expected duration of the surgical
procedure.
• When large surface areas have to be anesthetized,
large volumes of dilute anesthetic solutions should be
used.
• These considerations are particularly important when
performing infiltration anesthesia in infants and
smaller children

68. Peripheral Nerve Block Anesthesia
• Peripheral nerve block anesthesia is achieved
through the injection of local anesthetic
solutions into tissues surrounding individual
peripheral nerves or nerve plexuses, such as the
brachial plexus.
• When local anesthetic solutions are deposited in
the vicinity of a peripheral nerve, they diffuse
from the outer surface (mantle) toward the
center (core) of the nerve along a concentration
gradient.

69. • Consequently, nerve fibers located in the
mantle of the mixed nerve are anesthetized
first.
• These mantle fibers usually are distributed to
more proximal anatomical structures, in
contrast to distal structures innervated by
nerve fibers near the core of the nerve.

70. • This explains the initial development of
anesthesia proximally, with subsequent distal
spread.
• Conversely, the recovery of sensation occurs in
a reverse direction; nerve fibers in the mantle
that are exposed to extra neural fluid are the
first to lose local anesthetic

71. • The rapidity of onset of sensory anesthesia after
the injection of a local anesthetic solution into
tissues around a peripheral nerve depends on the
pK level of the drug (amount of local anesthetic
that exists in the active nonionized form at the pH
level of the tissue).
• Onset time lidocaine –14 min and bupivacaine –
23 min
• The duration of action is prolonged by one-third
by adding epinephrine to the local anesthetic
solution.

72. • The addition of opioids to local anesthetic
solutions placed in the epidural or intrathecal
space results in synergistic analgesia.
• Combining local anesthetics and opioids for
peripheral nerve blocks appears to be
ineffective in altering the characteristics or
results of the block.

75. Intravenous Regional Anesthesia(Bier Block)
• The intravenous injection of a local anesthetic
solution into an extremity isolated from the rest
of the systemic circulation by a tourniquet
produces a rapid onset of anesthesia and skeletal
muscle relaxation.
• The duration of anesthesia is independent of
the specific local anesthetic and is determined
by how long the tourniquet is kept inflated.

76. • Lidocaine has been the drug used most
frequently for intravenous regional anesthesia.
• Prilocaine, mepivacaine, chloroprocaine,
procaine, bupivacaine, and etidocaine have also
been used successfully.
• aminoester-linked compounds because of their
rapid hydrolysis in bloodmight be assumed to be
safer but side effects like thrombophlebitis has
been reported with chloroprocaine.
.

77. • 3 mg/kg (40 mL of a 0.5% solution) of
preservative-free lidocaine without epinephrine
is used for upper extremity procedures. For
surgical procedures on the lower limbs, 50 to 100
mL of a 0.25% lidocaine solution can be used
• Bupivacaine is not recommended for intravenous
regional anesthesia, considering its greater
likelihood than other local anesthetics for
producing cardiotoxicity when the tourniquet is
deflated at the conclusion of the anesthetic

78. • The mechanism by which local anesthetics
produce intravenous regional anesthesia is
unknown but probably reflects the action of
the drug on nerve endings as well as nerve
trunks.
• Normal sensation and skeletal muscle tone
return promptly on release of the tourniquet,
which allows blood flow to dilute the
concentration of local anesthetic.

79. Epidural Anesthesia
• Local anesthetic solutions placed in the epidural or
sacral caudal space produce epidural anesthesia
by diffusion across the dura to act on nerve roots
and by passage into the paravertebral area
through the intervertebral foramina.

81. • Bupivacaine is now being replaced by
levobupivacaine and ropivacaine because these
are associated with less risk for cardiac and CNS
toxicity and are also less likely to result in
unwanted postoperative motor blockade.
• Unlike spinal anaesthesia , larger dose required to
produce epidural anesthesia, leading to a
substantial systemic absorption of the local
anesthetic

82. Spinal Anesthesia
• Spinal anesthesia is produced by the injection of
local anesthetic solutions into the lumbar
subarachnoid space.
• Local anesthetic solutions placed into lumbar
cerebrospinal fluid act on superficial layers of
the spinal cord, but the principal site of action is
the preganglionic fibers as they leave the spinal
cord in the anterior rami.

83. • Differential blockade is seen with sympathetic
at the highest and motor blockade at the
lowest .
• Dosages of local anesthetics used for spinal
anesthesia vary according to the
• (a) height of the patient, which determines
the volume of the subarachnoid space,
• (b) segmental level of anesthesia desired, and
• (c) duration of anesthesia desired

84. • The total dose of local anesthetic and specific
gravity of the solution administered for spinal
anesthesia is more important than the
concentration of drug or the volume of the
solution injected.
• The addition of glucose to local anesthetic
solutions increases the specific gravity of local
anesthetic solutions above that of
cerebrospinal fluid (hyperbaric).

85. • The addition of distilled water lowers the
specific gravity of local anesthetic solutions
below that of cerebrospinal fluid (hypobaric).
• Tetracaine, lidocaine, bupivacaine,
ropivacaine, and levobupivacaine are the local
anesthetics most likely to be administered for
spinal anesthesia.

87. • Although lidocaine has long been used for
spinal anesthesia as a 5% solution, recent
studies of local anesthetic neurotoxicity have
led some to question this practice.
• Tetracaine is available both as crystals and as a
1% solution, which may be diluted with 10%
glucose to obtain a 0.5% hyperbaric solution.

88. • Hypobaric solutions of tetracaine (tetracaine in
sterile water) can be used for specific operative
situations, such as anorectal or hip surgery.
• Isobaric tetracaine obtained by mixing 1%
tetracaine with cerebrospinal fluid or normal
saline is useful for lower limb surgical procedures
• The addition of vasoconstrictors can prolong the
duration of spinal anesthesia

89. ANTI-INFLAMMATORY EFFECTS
• Local anesthetics modulate inflammatory
responses and may be useful in mitigating
perioperative inflammatory injury.
• The beneficial effects attributed to epidural
anesthesia (pain relief, decreased thrombosis
from hypercoagulability) may reflect the anti-
inflammatory effects of local anesthetics.

90. • Local anesthetics may modulate inflammatory
responses by inhibiting inflammatory
mediator signaling. In addition, local
anesthetics inhibit neutrophil accumulation at
sites of inflammation and impair free radical
and mediator release

91. TUMESCENT LIPOSUCTION
• The tumescent technique for liposuction
characterizes the subcutaneous infiltration of
large volumes (5 or more liters) of solution
containing highly diluted lidocaine (0.05% to
0.10%) with epinephrine (1:100,000).
• When highly diluted lidocaine solutions are
administered for tumescent liposuction, the
dose of lidocaine may range from 35 mg/kg to
55 mg/kg (“mega-dose lidocaine”).

92. • Despite the popularity and presumed safety of
tumescent liposuction, reports exist of
increased mortality associated with this
technique, due to lidocaine toxicity or local
anesthetic-induced depression of cardiac
conduction and contractility

93. Systemic LA for neuropathic pain
• A broad variety of local anesthetics ,
antiarrhythmics, anticonvulsants, and other Na+
channel blockers are administered intravenously ,
orally, or both to relieve a number of forms of
neuropathic pain
• When the signs of neuropathic pain are reversed
by lidocaine infusion, normal nociception and
other sensory modalities are unaffected,
suggesting that the neurophysiologic correlate of
the disease has an unusually high susceptibility to
these drugs.

94. • Laboratory studies suggest that ectopic
impulse activity arising at a site of injury or
elsewhere, such as the dorsal root ganglion,
contributes to the neuropathic pain and that
such impulses are particularly sensitive to use-
dependent Na+ channel blockers
• The mechanism of this remarkable action
remains unknown

95. SIDE EFFECTS

96. Local Anaesthetic Systemic Toxicity
(LAST)
• Systemic toxicity from a local anesthetic is due
to an excess plasma concentration of the drug.
• Most common mechanism is Accidental direct
intravascular injection of local anesthetic and
less often systemic absorption of LA
• Systemic toxicity first effects CNS and then
CVS

97. • Central Nervous System
• Low plasma concentrations of local anesthetics
produce numbness of the tongue and circumoral
tissues, presumably reflecting the delivery of
drug to these highly vascular tissues.
• As the plasma concentrations continue to
increase, inhibitory pathways are blocked and
glutamate release leads to excitatory symptoms
like twitching and seizures
• Finally CNS depression is seen leading to
respiratory arrest.

98. • Seizures are classically followed by CNS
depression, which may be accompanied by
hypotension and apnea.
• An inverse relationship exists between the
PaCO2 level and seizure thresholds of local
anesthetics, due to variations in cerebral
blood flow and the resultant delivery of drugs
to the brain.

99. • CARDIOVASCULAR SYSTEM
• DIRECT EFFECTS -- The primary cardiac
electrophysiologic effect of local anesthetics is a
decrease in the rate of depolarization in the fast
conducting tissues of Purkinje fibers and ventricular
muscle.
• This reduction in rate is believed to be due to a
decrease in the availability of fast sodium channels in
cardiac membranes.
• Action potential duration and the effective refractory
period are also decreased by local anesthetics

100. • Electrophysiologic studies have shown that high
blood levels of local anesthetics will prolong
conduction time.
• Extremely high concentrations of local
anesthetics depress spontaneous pacemaker
activity in the sinus node, thereby resulting in
sinus bradycardia and sinus arrest
• Local anesthetics may depress myocardial
contractility by affecting calcium influx and
triggered release from the sarcoplasmic
reticulum, as well as by inhibiting cardiac
sarcolemmal Ca2+ currents and Na+ currents.

101. • MANAGEMENT OF LAST
• The AAGBI Safety Guideline on LAST,
published in 2010, recommends the following
steps:
1.recognition (see types of toxicity above),
2.immediate management,
3.treatment,
4.follow-up.

105. • The lipid resuscitation story began in 1998 by
Weinberg and colleagues
• POSSIBLE MOA—
• 1.Lipid sink hypothesis
• 2. Enhanced fatty acid metabolism
• 3. cytoprotective effect by activation of Akt
(protein kinase B)
• 4. ILE exerts a cardiotonic effect by positive
inotropy

106. OTHER SIDE EFFECTS
1.Allergic Reactions
• Allergic reactions to local anesthetics are
rare(less than 1%)
• The majority of adverse responses that are
often attributed to an allergic reaction are
instead manifestations of excess plasma
concentrations of the local anesthetic.
• The ester local anesthetics that produce
metabolites related to para-aminobenzoic acid
are more likely to evoke an allergic reaction.

107. • Cross-Sensitivity -- Cross-sensitivity between
local anesthetics reflects the common
metabolite para-aminobenzoic acid.
• A similar cross-sensitivity, however, does not
exist between classes of local anesthetics.

108. • Documentation of Allergy
• The documentation of allergy to a local
anesthetic is based on the clinical history and
perhaps the use of intradermal testing.
• The occurrence of rash, urticaria, and
laryngeal edema, with or without hypotension
and bronchospasm, is highly suggestive of a
local anesthetic-induced allergic reaction.

109. • Conversely, hypotension associated with syncope
or tachycardia when an epinephrine-containing
local anesthetic solution is administered suggests
an accidental intravascular injection of drug.
• The use of an intradermal test requires the
injection of preservative-free preparations of
local anesthetic solutions to eliminate the
possibility that the allergic reaction was caused
by a substance other than the local anesthetic.

110. • 2. Transient Neurologic Symptoms
• Transient neurologic symptoms manifest as moderate
to severe pain in the lower back, buttocks, and
posterior thighs that appears within 6 to 36 hours after
complete recovery from uneventful single-shot spinal
anesthesia.
• Sensory and motor neurologic examination is not
abnormal and relief of pain with trigger point
injections and nonsteroidal anti-inflammatory drugs
suggests a musculoskeletal component.
• Full recovery from transient neurologic symptoms
usually occurs within 1 to 7 days.

111. • The incidence of transient neurologic
symptoms is not altered by decreasing spinal
lidocaine concentrations from 2% to 1% or
0.5% and are similar to the incidence of
symptoms described with 5% lidocaine.
• Spinal anesthesia produced with 0.5%
bupivacaine or 0.5% tetracaine is associated
with a lower incidence of transient neurologic
symptoms compared with lidocaine

112. Cardiovascular system side effects
• The cardiovascular system is more resistant
than the CNS to the toxic effects of high
plasma concentrations of local anesthetics.
• plasma lidocaine concentrations of 5 to 10
µg/mL and equivalent plasma concentrations
of other local anesthetics may produce
profound hypotension due to a relaxation of
arteriolar vascular smooth muscle and direct
myocardial depression.

113. Selective Cardiac Toxicity
• The accidental intravenous injection of bupivacaine
may result in precipitous hypotension, cardiac
dysrhythmias, and atrioventricular heart block.
• Pregnancy may increase sensitivity to the cardiotoxic
effects of bupivacaine, but not ropivacaine. All local
anesthetics depress the maximal depolarization rate of
the cardiac action potential (Vmax).
• bupivacaine depresses Vmax considerably more than
lidocaine, whereas ropivacaine is intermediate in its
depressant effect on Vmax.

114. • Bupivacaine depresses the rapid phase of
depolarization (Vmax) in Purkinje fibers and
ventricular muscle more than lidocaine does.
• During diastole, highly lipid soluble
bupivacaine dissociates from sodium ion
channels at a slow rate when compared with
lidocaine, thus accounting for the drug's
persistent depressant effect on Vmax and
subsequent cardiac toxicity

115. • At normal heart rates, diastolic time is
sufficiently long for lidocaine dissociation, but
bupivacaine block intensifies and depresses
electrical conduction, causing reentrant-type
ventricular dysrhythmias.
• Ropivacaine is a pure S-enantiomer that is less
lipid soluble and less cardiotoxic than
bupivacaine but more cardiotoxic than
lidocaine

116. Indirect Cardiovascular Effects
• High levels of spinal or epidural blockade can
produce severe hypotension and bradycardia
• These events frequently occurred in conjunction
with high dermatomal levels of blockade, liberal
use of sedatives, and often involving delays in
recognition of the problem, delays in instituting
airway support , and delays in administration of
direct acting combined α- and β-adrenergic
agonists, such as epinephrine

117. Methaemoglobinemia
• Methemoglobinemia is a rare but potentially life-
threatening complication (decreased oxygen
carrying capacity) that may follow the
administration of certain drugs or chemicals that
cause the oxidation of hemoglobin to
methemoglobin more rapidly than
methemoglobin is reduced to hemoglobin.
• Known oxidant substances include topical local
anesthetics (prilocaine, benzocaine, Cetacaine®,
lidocaine), nitroglycerin, phenytoin, and
sulfonamides.

118. • The presence of methemoglobinemia is
suggested by a difference between the calculated
and measured arterial oxygen saturation.
• The diagnosis is confirmed by qualitative
measurements of methemoglobin by co-
oximetry.
• Methemoglobinemia is readily reversed through
the administration of methylene blue, 1 to 2
mg/kg IV, over 5 minutes (total dose should not
exceed 7 to 8 mg/kg).

119. NEW METHODS
• PROLONG DURATION
1.liposomal encapsulation
2.Biodegradable polymer microspheres
3. Site 1 sodium channel blocker : neosaxitoxin

120. LOCAL ANAESTHETIC FAILURE
• 1.technical failure to deliver the drug
• 2.insufficient dosage
• 3.Incorrect technique
• 4..injecting LA in a site of inflammation
• 5..genetic cause

121. Thank you

122. REFERENCES
• 1.MILLER
• 2.STOELTING
• 3.BJA JOURNAL