Local anesthetics NIYAZ PV

LOCAL ANESTHETICS
PRESENTER : Dr. NIYAZ.PV
(PG Dept.Of ANESTHESIOLOGY)
SANTHIRAM MEDICAL COLLEGE & GENERAL
HOSPITAL NANDYAL A.P

Includes;
Definition
History
Introduction
Physiology
Structure
Classification of LA’s
MOA
Properties
TOXICITY

DEFINITION
I. “LOCAL ANESTHESIA HAS BEEN DEFINED AS LOSS OF SENSATION IN
A CIRCUMSCRIBED AREA OF THE BODY CAUSED BY A DEPRESSION
OF EXCITATION IN NERVE ENDINGS OR AN INHIBITION OF THE
CONDUCTION PROCESS IN PERIPHERAL NERVES.” (GRUNE &
STRATON 1976)
II. “LOCAL ANESTHETICS ARE THE DRUGS HAVE A LITTLE OR NO
IRRITATING EFFECTS WHEN INJECTED IN TO THE TISSUES & THAT
WILL TEMPORARILY INTERRUPT CONDUCTION WHEN ABSORBED IN
TO THE NERVES.” (MONHIEMS)
III. “LOCAL ANESTHESIA HAS BEEN DEFINED
AS DIRECT ADMINISTRATION OF ANESTHETIC
AGENT TO TISSUE TO INCLUDE THE ABSENCE
OF SENSATION IN SMALL AREA OF
THE BODY.”(MOSBY’S DICTIONARY)

HISTORY
KARL KOLLER:
• Austrian ophthalmologist
• Introduced cocaine as the 1st
LA in 1884 for use in ophthalmology
SIR WILLIAM STEWART HALSTED:
• Recognized the ability of the injected
cocaine to interrupt nerve conduction
• Leading to the introduction of peripheral
nerve block anesthesia & Spinal Anesthesia.
ALFRED EINHORN:
• Introduced Procaine as first synthetic amide
LA in 1905 .

(Contd..)
LOFGREN:
• Introduced LIDOCAINE as an Amide LA in 1943.

IDEAL PROPERTIES OF LA
• Reversible action
• Non-irritant
• No allergic reaction
• No systemic toxicity
• Rapid onset of action
• Potent
• Stable in solutions
• Not interfere with healing of tissues
• Not expensive

INTRODUCTION
• LA are used to provide analgesia & anesthesia for
various surgical & non-surgical procedures
• The first LA introduced into medical practice was
cocaine , a naturally occurring ester of benzoic acid
that is present in the leaves of Eythrwylon coca , a
tree growing in Andes mountains.

USES
These drugs are also used for :
1. Acute and chronic pain management
2. To reduce peri-operative stress
3. To improve peri-operative outcomes
4. To treat dysrhythmias

• LA produce reversible conduction blockade of
impulses along central & peripheral nerve
pathways.
• With progressive increase in concentrations of LA ,
the transmission of Autonomic ,somatic Sensory &
somatic Motor impulses is interrupted , producing
Autonomic nervous system blockade , Sensory
anesthesia & skeletal muscle paralysis in the area
innervated by the affected nerve.
• If given in sufficiently high dose , local anesthetics
may block additional excitable tissue such as brain
and myocardium leading to Convulsions , cardiac
Arrest & Death

ACTION POTENTIAL:
• At rest an electrical potential of
approx. -70mV exists on the inside
of nerve membrane.
• Impulse generation along a nerve
alters membrane potential by rapid
movement of Na+ inwards & K+ ions
outwards through highly selective
ion channels.
• Once the membrane potential rises to a threshold of
-55mV an ACTION POTENTIAL is generated, due to the
opening of voltage-activated Na+ channels.
• The action potential peaks at +40mV .
• There is rapid Na+ channel inactivation and efflux of K+
ions repolarizes the nerve back in to resting state.

• Local anaesthetic consists of an aromatic part linked
with tertiary amine via an intermediate chain.
• The aromatic part is fat soluble (lipophilic) while amine
group is water soluble (hydrophilic).
STRUCTURAL ACTIVITY RELATIONSHIP

Chemistry
Hydrophilic
amine
Lipophilic
aromatic residue
AMIDE
ESTER
A l k y l C h a i n

• The intermediate chain contains either an ester (-CO-) or
amide (NHC-)linkage, on the basis of which local anaesthetics
are classified as amides and esters.
• The amine portion of LA can accept one proton (H+) and exist
in charged form. In solution, local anaesthetic therefore exists as
cationic and base form, the amount of each being determined
by the pH of the solution.

Acidic
LAH+ LA + [H+]
cationic(water sol. Alkaline Base(fat soluble
non-diffusible form) diffusible form)
• That is why carbonated solutions of local
anesthetics show faster onset and increased
efficacy as compared to hydrochloride solutions.

CLASSIFICATION
 BASED ON CHEMICAL LINKAGE:
• Local anaesthetics are classified into esters and amides .
ESTERS
• Amide linkage
• Stable in solution
• Amides have low Pka values
• They are metabolized in liver via
enzymatic degradation
• Rare
• Metabolism is slow, high chance
of systemic toxicity
• Ester linkage
• Unstable in solution
• Ester drugs have high Pka values
• They are metabolized by
plasmacholinesterases,except
COCAINE undergo hepatic
metabolism
• More chance of allergic reactions
• Metabolism is fast, so less chance
of developing systemic toxicity
AMIDES

Amides and Esters
Amides Esters
Bupivacaine Benzocaine
Etidocaine Chloroprocaine
Levobupivacaine Cocaine
Lidocaine Procaine
Mepivacaine Tetracaine
Prilocaine
Ropivacaine

 BASED ON POTENCY AND DURATION:
1. SHORT ACTING(15-30min)
Procaine
Chloroprocaine
2. INTERMEDIATE ACTING(1-3hrs)
Lidocaine
Prilocaine
Mepivacaine
3. LONG ACTING(2-4hrs)
Bupivacaine
Ropivacaine
Dibucaine

MECHSNISM OF ACTION
• As you know entry of Na+ is essential for Action
Potential.
• Local anesthetics bind to specific sites in voltage-
gated Na+ channels.
• They block Na+ current, thereby reducing excitability
of neuronal, cardiac or central nervous system tissue.
• Local anesthetics prevent transmission of nerve
impulses (conduction blockade) by inhibiting
passage of sodium ions through ion-selective sodium
channels in nerve membranes.
• Failure of sodium ion channel permeability to
increase slows the rate of depolarization such that
threshold potential is not reached and thus an action
potential is not propagated.
• Local anesthetics do not alter the resting
transmembrane potential or threshold potential.

 CHARACTERISTICS OF BLOCKADE:
 No effect on resting membrane potential.
 Does not affect repolarization.
 Concentration dependent.
 Reversible blockade.
 Frequency – dependent blockade.

BASE FORM(B) CATIONIC FORM(BH+)
• Penetrates lipid barrier
BH+ acts from inner
side of Na+ channel
Local anesthetic binds
to
Receptor in inner portion of
sodium channel
Prevent inward flow of
Na+ ions
REVERSIBLE CONDUCTION
BLOCKADE
Enter the channel directly
When Na+ channel is in
activated state during
action potential
Therefore LA selectively
block nerves that fire more
frequently
FREQUENCY DEPENDENT
BLOCKADE

SODIUM CHANNEL
• The sodium channel is a dynamic
transmembrane protein consisting of the
large sodium-conducting pore (α subunit) and
varying numbers of adjacent smaller β
subunits.
• The large polypeptide that forms the α
subunit is further divided into four subunits
(DI to DIV).
• H is the α subunit that allows ion conduction
and binds to local anesthetics.
• Binding affinities of local anesthetics to the
sodium ion channels are stereospecific and

• Sodium channels exist in :
 activated-open
inactivated-closed and
rested-closed states
during various phases of the action potential.
• Voltage gated Na+ channels undergo fast and
slow inactivation processes and this is critical for
membrane excitability.

• In the resting nerve membrane, sodium channels
are distributed in equilibrium between the rested-
closed and inactivated-closed states.
• 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.
• LA’s bind to specific sites located on the inner
portion of sodium channels (internal gate or
gate) as well as obstructing sodium channels near
their external openings to maintain these
channels in inactivated-closed states.
h

MINIMUM EFFECTIVE CONCENTRATION (Cm)
• The minimum concentration of LA necessary to
produce conduction blockade of nerve impulse.
• Nerve fiber diameter influences Cm, with larger
nerve fibers requiring higher conc. of LA for
production of conduction blockade.
• An increased tissue pH or high frequency of nerve
stimulation decreases Cm.
• Each LA has a unique Cm.
• The Cm of motor fibers is approx. twice that of
sensory fibers thus sensory anesthesia may always
be accompanied by skeletal muscle paralysis.

• Despite an unchanged Cm, less LA is needed for
Subarachnoid Anesthesia than for Epidural
Anesthesia, reflecting greater access of LA to
unprotected nerves in the subarachnoid space.
• For a conduction block to occur it is necessary to
expose at least 2 and preferably 3 successive nodes
of Ranvier to an adequate conc. of LA.

PHARMACOLOGICAL PROPERTIES OF LA
INVITRO
o Lipid solubility
o Dissociation constant
o Protein binding
o Frequency dependent
blockade
INVIVO
o Vasodilation
o Tissue penetrance
o Differential conduction
blockade
o Mantle effect
o Concentration effect

 INVITRO PROPERTIES:
1. LIPID SOLUBILITY: Determines –POTENCY
 Lipid solubility is measured in terms of partition
coefficient.
 Increase in lipid solubility, faster the onset of action.
 Highly lipid soluble LA produce conduction blockade at
low conc than less soluble LA.


2. DISSOCIATION CONSTANT: [pKa]
 pKa expresses the relationship between ionized and non-ionized
forms of local anesthetic.
 pKa is the pH at which the ionized and non-ionized forms are
equal.

pKa
Non-Ionized Form Ionized Form
pKa= pH at which ionized and non-ionized forms of local anesthetics are
equal.

(Contd..) DISSOCIATION CONSTANT: [Pka]- >7.4
 Determines - ONSET OF ACTION
 Lower Pka-faster acting [ex:lidocaine;mepivacaine]
 Higher Pka-slow acting [ex:bupivacaine; procaine; tetracaine]
 LA with Pka close to physiological pH will have high
concentration of unionized form that can cross the
membrane easily.

ESTER
Pka
Cocaine 8.6
Benzocaine 8.1
Procaine 8.9
Chloroprocaine 8.7
Tetracaine 8.5
AMIDE
Pka
Lidocaine 7.7
Mepivacaine 7.6
prilocaine 7.7
Etidocaine 7.7
Bupivacaine 8.1
ropivacaine 8.1

3. PROTEIN BINDING:
• Determines - DURATION OF ACTION.
• Affinity of LA for protein determines its affinity for Na+
channel.
• Greater the protein binding characteristics, longer the
drug binding with Na+ channel and longer will be its
washout time.
4. FREQUENCY DEPENDENT BLOCKADE:
• Determines - SENSORY MOTOR DISSOCIATION
• A resting nerve is less prone to blockade by LA as
compared to the nerve which is being repetitively
stimulated.

 IN VIVO PROPERTIES:
1.VASODILATION:
LA

2.TISSUE PENETRANCE: Besides Pka, tissue penetrance plays a
major role in deciding the speed of onset of LA.
Ex:chlorprocaine has high Pka-8.7,its onset of action should
be very slow.
3.DIFFERENTIAL CONDUCTION BLOCKADE:
 Different types of fibres are present in our body
 Type-A fibres (A delta,alpha,beta)
Type-B fibres
Type-C fibres

• Clinically,
autonomic and pain fibres - most sensitive.
motor fibres -least sensitive to blockade.
• Order of sensitivity of blockade:
autonomic >sensory >motor.
• Sequence of sensitivity of sensory blockade:
Temp>pain>touch>pressure>Vibration & proprioception.

• Sensitivity to blockade depends on
1.Type of fibre
2. Myelination
3. Critical length of the axon that must be exposed to LA for
blockade.
• As a general rule thick (large diameter) fibres are less sensitive
than small diameter fibres.
• Nonmyelinated are more sensitive than myelinated fibers.

4. MANTLE EFFECT:
 Mantle effect occurs due to specific pattern of arrangement of
nerve.

• Mostly, fibres that innervate the proximal part of the body are
present on the outer surface of the nerve .
• while distal body parts are innervated by nerve fibres near the
core of the nerve.
• Outer surface of the nerve is exposed to highest concentration
of LA.
• That is why proximal limb is first to get anaesthetized after
peripheral nerve block. This is followed by anaesthesia of the
distal part.
• Regression of the block occurs in opposite fashion, because
concentration of the local anaesthetic, first decreases in the
core and then in periphery of nerve.

5.CONCENTRATION EFFECT:
 Increasing the concentration of LA may increase its speed
of onset, this is called as concentration effect.

PHARMACOKINETICS
• LA’s are weak Bases that have pKa values
somewhat above physiologic pH.
• As a result , <50% of the LA exists in a lipid
soluble nonionized form at physiologic pH.
• LA’s with pKa’s nearest to physiologic pH have
the most rapid onset of action, reflecting the
presence of an optimal ratio of ionized to
Nonionized drug fraction.

Pharmacokinetic Phases of Local
Anesthetics
Uptake
• Site of
injection
• Absorption
Distribution
• Lipid
solubility
• Protein
binding
Elimination
• Metabolism
• Elimination

i. ABSORPTION:
Site of injection
Dose and volume
Addition of a vasoconstrictor

SITE OF INJECTION
• Has a great impact on the blood levels of local
anesthetics.
• The more vascular the tissue the greater the
uptake and subsequent blood concentrations.
• From the greatest amount of uptake to the
least:
IV> tracheal> intercostal> caudal> Para
cervical> epidural> brachial> sciatic>
subcutaneous

Dose and volume
 As the dose of local anesthetic is increased, the
probability and duration of satisfactory
increase, and the time to onset of block is
shortened.
 The dose of local anesthetic can be increased by
administering either a larger volume or a more
concentrated solution.
 For example, increasing the concentration of
epidurally administered bupivacaine from 0.125%
to 0.5%, while maintaining the same volume of
injectate (10 mL), resulted in more rapid onset, an
improved incidence of satisfactory analgesia, and a
longer duration of sensory analgesia.

 The volume of anesthetic solution probably
influences the spread of anesthesia.
 For example, 30 mL of 1% lidocaine
administered into the epidural space produces
a level of anesthesia that is 4.3 dermatomes
higher than that achieved when 10 mL of 3%
lidocaine is given.
• In selecting the volume and concentration for
a specific block in a particular patient, we
must balance the risk of adverse effects from
overdosing.

Addition of a vasoconstrictor:
• Vasoconstrictor is a substance used to keep
the anesthetic solution in place at a longer
period and prolongs the action of the drug
• vasoconstrictor delays the absorption which
slows down the absorption into the
bloodstream
• Vasoconstrictor used ---the natural hormone
called epinephrine (adrenaline).

 DISTRIBUTION:

Distribution depends on organ uptake, which is determined by
the following factors.
1. Tissue perfusion: The highly perfused organs (brain, lung,
liver, kidney, and heart) are responsible for the initial rapid
uptake followed by a slower redistribution to moderately
perfused tissues (muscle and gut).
• In particular, lung extracts significant amounts of LA
consequently, the threshold for systemic toxicity involves
much lower doses following arterial injections than venous
injections.

2.Tissue/blood partition coefficient: Increasing lipid
solubility is associated with greater plasma protein binding
and also greater tissue uptake, but inversely related to
plasma conc of drug.
3.Tissue mass: Muscle provides the greatest reservoir for
distribution of LA agents in the bloodstream because of its
large mass.

iii. Metabolism and Elimination:

1. ESTERS :
Chloroprocaine Tetracaine

• Extensive hydrolysis in the plasma by
Pseudocholinesterase enzymes (plasma
cholinesterase or butyrylcholinesterase).
• Hydrolysis is rapid and results in water soluble
metabolites that are excreted in the urine.
• Cocaine is the exception. It is partially
metabolized in the liver (N-methylation) in
addition to ester hydrolysis.
• Patients with Pseudocholinesterase deficiency
are at risk for toxicity due to the slowed
metabolism and risk of accumulation.
• Procaine and benzocaine are metabolized to
p-aminobenzoic acid (PABA) which is
associated with allergic reactions.

Amide Local Anesthetics
Mepivacaine
Prilocaine
Bupivacaine Ropivacaine
LevoBupivacaine

• Primary metabolism is by the microsomal P-
450 enzymes in the liver (N-dealkylation and
hydroxylation) and to a lesser extent by other
tissues.
• Rate of metabolism among amides varies
according to the individual local anesthetic.
• Rate of metabolism: Prilocaine> lidocaine>
Mepivacaine> ropivacaine> bupivacaine.
• Prilocaine metabolites include o-toluidine
derivatives which can accumulate after large
doses (>10 mg/kg) and result in
methemoglobinemia.

• Excretion of amides occurs in the kidneys.
Less than 5% of the unchanged medication is
excreted by the kidneys.

Patient Alterations to Pharmacokinetics
Age: elderly and newborns. Newborns have an
immature hepatic enzyme system whereas the
elderly have decreased hepatic blood flow.
Disease: any disease process that impairs blood
flow to the liver or the livers ability to produce
enzymes.
Pregnancy: Pregnant Pt’s show increased
sensitivity for LA’s probably due to prolonged
increase in Progesterone levels.
Poor Nutrition: Cachexic Pt’s have low α1 Acid
Glycoprotein levels and so more drug is
available to cross BBB.

 VASOCONSTRICTORS: Adrenaline
phenylephrine
 Vasoconstrictors increases the duration of action by decreasing
the systemic absorption.
o ADRENALINE:
 Concentration of 1:2,00,000 or 5mcg/ml is used.
 Addition of adrenaline to lignocaine increases both sensory and
motor blockade.
 Addition of adrenaline to bupivacaine increases only sensory
blockade.
ADJUVANTS OF LA

 ADVANTAGES:
 Prolongs the duration of action of LA by reducing its
systemic absorption.
 Improves the depth of anaesthesia .
 Slow and reduced systemic absorption –lowers the risk of
toxicity.
 DISADVANTAGES:
 Large doses of adrenaline (>0.25mg total dose) are
associated with cardiac rhythm disturbances.
 CONTRAINDICATIONS:
 Ring block of fingers, toe, penis.
 Local infiltration of skin flap.
 Severe HTN, Hyperthyroidism.

o PHENYLEPHRINE:
 Concentration used :1:20,000.
 Does not cause tachycardia.
 SODIUM BICARBONATE(ALKALINIZATION): 1ml of 8.4% to
Local anaesthetic + NaHCO3 10ml of LA
Increases the pH of the solution
More drug exists in unionized
diffusible form
Rapid onset of anaesthesia

 ADVANTAGES:
 Enhances the onset of action.
 Increases the duration of action.
 Improves the quality of block.
 Decreases the pain on injection.
 CLONIDINE:
 Causes analgesia via action on alpha2 receptors.
 It increases the duration and quality of block
 Dose is 1mg/kg for caudal or epidural block
 LIMITATIONS:
 It causes vasodilation and hypotension.
 High cost.

• OTHERS:
 Hyaluronidase
 Dextran
 Compounding: [ ex:LIDOCAINE+BUPIVACAINE]
 Opioids like fentanyl
 Dexmeditomidine
 Preservative free ketamine.

 RESPIRATORY SYSTEM:
• Lignocaine depresses hypoxic drive. Direct depression of
medullary centre can occur at high dose.
 IMMUNOLOGIC: Allergic reactions are very common with esters
but rare with amides.
• The reaction with amides is because of preservative
(methylparaben).
 LOCAL TOXICITY:(NEUROTOXICITY)
• Neurotoxicity from placement of LA containing solutions into
the epidural or subarachnoid space can lead to various
complications.

1) TRANSIENT NEUROLOGICAL SYMPTOMS:
• Manifests as moderate to severe pain in lower back,
buttocks and posterior thighs that appear with in 6-36hrs
after complete recovery from spinal anaesthesia.
• In TNS sensory and motor neurological examination is
not abnormal and full recovery from symptoms usually
occurs with in 1-7 days.
• Spinal anaesthesia with lidocaine was associated with
significantly higher incidence of TNS when compared to
bupivacaine, Prilocaine or procaine.

2) CAUDA EQUINA SYNDROME:
• CES occurs when diffuse injury across the lumbosacral
plexus.
• produces varying degrees of sensory anaesthesia, bowel and
bladder sphincter dysfunction and paraplegia.
• CES is associated with the use of hyperbaric 5% lidocaine
and also with micro catheters during continuous spinal
anaesthesia.
• There will be inhomogeneous distribution of LA solution, with
pooling of high concentrations of LA solution on certain
dependent or stretched(lithotomy position) nerves.
3)ANTERIOR SPINAL ARTERY SYNDROME:

 METHEMOGLOBINEMIA:
• Due to administration certain drugs that cause oxidation of
Hb to methHb. [ex:prilocaine,benzocaine, and lidocaine]
• MethHb cannot bind O2 or CO2,resulting in loss of Hb
molecules transport function.
• Central cyanosis usually occurs when methHb concentration
exceeds 15%.
• Treatment: 1% methylene blue, 1-2mg/kg IV over 5min.
 MALIGNANT HYPERTHERMIA: Lignocaine can cause malignant
hyperthermia in susceptible individuals.

LOCAL ANESTHETIC SYSTEMIC TOXICITY (LAST)
DEFINITION:
• Local anesthetic systemic toxicity (LAST) is due to
an excess plasma concentration of the drug.
• Plasma concentrations of local anesthetics are
determined by :
the rate of drug entrance into the systemic
circulation relative to their redistribution to inactive
tissue sites and clearance by metabolism.
INCIDENCE:
2.5 to 20 per 10,000 peripheral nerve blocks
And about 1.2 to 11 per 10,000 epidurals

CAUSES & RISK FACTORS FOR LAST
DRUG
Potency (Lipophilicity)
Dose (Volume & Conc.)
Rate of injection
Streoselectivity (Racemic mixture / pure enantiomer)
Intrinsic vasoconstrictor action
Addition of vasoconstrictor (Epinephrine/Phenylephrine)
SITE OF BLOCKADE
Decreasing toxicity from Head to Foot
Intercostal>Caudal & Epidural>Brachial Plexus>femoral & Sciatic
Nerve block
PATIENT RISK FACTORS
Extremes of age
Pregnancy
Respiratory / Metabolic Acidosis
Hypoxia
Hyper K+
Drug interaction (Class I Antiarrhythmic , β 𝑏𝑙𝑜𝑐𝑘𝑒𝑟𝑠 , Ca 2 +
channel blockers)
Genetic predisposition
Cardiac Renal & Hepatic Disease

SIGNS & SYMPTOMS
CENTRAL NERVOUS SYSTEM:
• CNS toxicity correlate directly with the potency of LA’s.
• At low plasma conc. Mild subjective symptoms appear
such as : Light headiness, dizziness , disorientation &
drowsiness.
• Earliest indications are : Circumoral and tongue numbness
& metallic taste in mouth.
• With increase in plasma conc. Excitatory symptoms like
shivering nystagmus muscular twiching & tremors of facial
muscle & distal part of extrimities, eventually GTCS may
occur.
• If sedative drugs have been coadministrated, CNS
depression can occur without a preceding excitatory
phase, can lead to masking of valuable initial signs and
direct progression to CVS toxicity.

• In case of LAST it is of utmost importance to promptly
assist ventilation & circulation as needed to prevent
hypercapnia , acidosis & hypoxemia because it further
potentiates CNS toxicity.

LA OVERDOSE
Blockade of amygdaloid
complex
Blockade of inhibitory
pathways
Blockade of facilitatory
pathways
CNS DEPRESSION
convulsions
coma and death

 CARDIOVASCULAR SYSTEM:
• Cardiotoxicity is primarily by a dose dependent blockage of
sod.channels (cardiac Myocyte Specific Voltage Gated
Sod.channels), which decreases the rate of depolarisation in the
conducting tissues of Purkinje fibers & ventricular muscles thus
leads to prolonged PR interval & QRS complex.
• At High conc. LA’s depress spontaneous pacemaker activity & leads
to Sinus Bradycardia & Arrest, have also shown to antagonize the
intracellular Ca2+ & K+ currents.
• And also action on the brain stem leading to impaired Arterial
baroreceptor reflex attenuates the HR response to changes in
systemic BP.
• LA’s also have BIPHASIC EFFECT on blood vessels causing
direct vaso constriction at low plasma levels and
vasodilatation at high plasma levels

CC/CNS RATIO
• Ratio of doses required for irreversible cardio vascular
collapse (CC)and for cns toxicity is the CC/CNS ratio
• This ratio is much lower for Bupivacaine (3.7 +/- 0.5)
than for Lignocaine (7.1 +/- 1.1) , so fatal ventricular
arrhythmia is more common with Bupivacaine than with
Lignocaine.
• Pregnant pts have a lower CC/CNS ratio for Bupivacaine
(2.7 +/-0.4)and hence are more prone for its cardiotoxic
effects.

Bupivacaine has most potent
cardiotoxic effects due to
• It has an inherently greater affinity for binding
resting and inactivated Na+ channels .It has the
most prominent effect on the rapid phase of
depolarisation in purkinje fibres and ventricular
muscles
• All LAs bind Na+ channels during systole and
dissociates during diastole. Dissociation of
Bupivacaine during diastole occurs more slowly
,particularly at high heart rates .This prevents a
complete recovery and leads to its accumulation.

Contd…
• Bupivacaine also leads to more pronounced inhibition on
cardiac sarcolemmal Ca2+ and Na+ current and Ca2+
release from the SR.This may explain the increased
myocardial depression and AV block with Bupivacaine.
• LevoBupivacaine (S.enantiomer of Bupivacaine)exhibits
30 to 40 % Less cardiac toxicity than Bupivacaine in equal
doses because these are much less potent in blocking
inactivated Na channels.

MANAGEMENT OF LAST
“an ounce of prevention is worth a
pound of cure” (BENZAMIN FRANKLIN )

MANAGEMENT OF LAST
• If signs and symptoms of LAST occur,
 IMMEDIIATE MANAGEMENT:
 Stop injecting LA.
 Call for help.
 Maintain the airway and , if necessary secure it with a
endotracheal tube.
 Give 100% O2 and ensure adequate lung ventilation.
 Confirm or establish IV access.
 Control seizures: BZD’s,thiopental or propofol in small doses
 Assess cardiovascular status throughout.
 consider drawing blood for analysis.

• If cardiac arrest occurs: recommend ACLS with the following
modifications:
 If epinephrine is used , small initial doses(10-100mcg
boluses in the adult) are preffered.
 vasopressin is not recommended.
 Avoid Ca++ channel blockers and beta blockers.
 If ventricular arrythmias develop , AMIODARONE is
preffered.
 LIPID EMULSION THERAPY:
 1.5ml/kg 20% lipid emulsion bolus.
 0.25ml/kg per min of infusion , continued for at least 10min
after circulatory stability is attained.

 If circulatory stability is not attained, consider rebolus and
increasing infusion to 0.5ml/kg per min.
 Approx. 10ml/kg lipid emulsion for 30min is
recommended as the upper limit for initial dosing.
 Propofol is not substitute for lipid emulsion.
 If any failure to respond to lipid emulsion and
vasopressor therapy then go for cardiopulmonary bypass.

USES OF LOCAL ANAESTHETICS
• Topical(surface anaesthesia)
• Infiltration anaesthesia
• Nerve blocks
• Intravenous regional anaesthesia (BIER’S BLOCK)
• Central neuraxial blocks –spinal and epidural anesthesia.
 EMLA[Eutectic mixture of local Anaesthetics]:
o This is unique topical preparation which can anaesthetize
intact skin.
o It is a mixture of 2.5%lidocaine and 2.5%prilocaine.
o It acts slowly and the cream must held in contact with skin
for at least 1hr with the help of adhesive covering.
o Depth of penetration is usually 3-5mm.
o Duration of action is 1-2hrs.

• EMLA is used to make venipuncture painless especially in
children and for procedures like skin grafting and
circumcision.
• EMLA should not be used on cut surfaces and mucous
membranes.
 BIER’S BLOCK: [IVRA]
 It can be used for short procedures(<90min) involving the
limb extremities.
 An IV cannula is placed as far distally as possible in the
extremity to be operated.
 A double tourniquet is placed proximally in the same limb

and inflated approx. 150mmHg more than the systolic
pressure.
 LA(commonly lignocaine or Prilocaine) is then injected
through the cannula.
 This technique provides reliable anaesthesia within 5min.
 Post procedure the tourniquet is deflated slowly , and care
is taken to monitor for features of LA toxicity.
 Bupivacaine should not be used as it is more cardiotoxic.

 DISADVANTAGES:
• It can be used for only short procedures
• Premature release of tourniquet might lead to local
anaesthetic toxicity.
• It does not provide post op analgesia.

INDIVIDUAL AGENTS
 COCAINE: Cocaine was used for anaesthetizing cornea.
• It is the only naturally occurring LA obtained from the
leaves of erythroxylin coca.
• Cocaine is the only ester which is not metabolized by
plasma esterase(it is metabolized in liver).
• The only indication for cocaine is in ocular anaesthesia.
• It should never be used with adrenaline due to its
sympathomimetic property.

• Cocaine is unique among drugs of abuse –it does not
produce tolerance
• In periphery cocaine blocks the uptake of adrenaline and
noradrenaline in adrenergic nerve ending causes
sympathomimetic effect.
• The peripheral sympathomimetic action of cocaine
produces following effects:
1) Mydriasis
2) Rise in BP
3) Local vasoconstriction
4) Tachycardia

 PROCAINE: short acting and low potency.
• It should be stored in cool place to prevent hydrolysis.
• Metabolized by pseudocholinesterase.
• It inhibits the bacteriostatic action of Sulphonamides and
para amino salicylic acid.
• LA of choice in patients for the treatment of malignant
hyperthermia.
 CHLORPROCAINE:
• Shortest acting (15-30min)
• Most acidic(pH=3.3)
• It is C/I for spinal anaesthesia because it causes
neurotoxicity.

 BENZOCAINE: It is used in topical anaesthesia.
• 5% benzocaine is used for anal fissuers,proctoscopy.
• It is also used as lozenges for stomatitis,sorethroat.
• It has low water solubility.

 LIGNOCAINE:(xylocaine, lidocaine)
• It is most commonly used LA.
• First synthesized by Lofgren and first used by Gordh.
• Solution is very stable .
• Contains preservative methylparaben; PKa =7.8
• Concentration used:
 Surface(topical) analgesia : 4% and 10%

 Nerve blocks :1 to 2%
 Urethral procedures (as jelly) :2%
 Spinal :5%
 Epidural :1 to 2%
 IVRA :0.5%
 Infiltration block :1 to 2%
o METABOLISM: Metabolized in liver, excreted by kidney.
o DURATION OF EFFECT: with out Adrenaline :45-60 min
with Adrenaline :2-3 hrs
o MAXIMUM SAFE DOSE : without adrenaline :4.5mg/kg[max 300mg]
with adrenaline :7mg/kg [max 500mg]
• systemic toxicity is much less than bupivacaine.
• Lignocaine releases Ca++ from sarcoplasmic reticulum so
should not be used in pts with h/o malignant hyperthermia.

o OTHER USES:
1) Used for treating ventricular tachycardia.
2) Preservative free lignocaine [available as xylocard 2%] is
used intravenously in dose of 2mg/kg.
3) IV xylocard is used for blunting cardiovascular response
to laryngoscopy and intubation.
 MEPIVACAINE: Mepivacaine is similar to lignocaine except
duration of action slightly longer than lignocaine.

 BUPIVACANE: 2nd most commonly used LA after
lignocaine.
• It is most cardiotoxic LA.
• Long acting
• LevoBupivacaine(S- enantiomer of bupivacaine) is less
cardiotoxic and less prone to cause seizures.
• Concentrations used:
 Nerve block :0.5%
 Epidural :0.25-0.5%
 Spinal :0.5%
• Maximum safe dose is :without adrenaline-2mg/kg
with adrenaline -3mg/kg

 PRILOCAINE:
• It is an amide LA derived from toluidine.
• Many properties [potency , speed of onset , protein binding]
are similar to lignocaine.
• CNS and cardiovascular toxicity is less than that of lignocaine.
• Maximum dose should not be more than 6mg/kg.
• Methemoglobinemia occurs at high dose [>6mg/kg] and this is
because of accumulation of its metabolite ortho toluidine
which can convert Hb to methHb.

ROPIVACAINE:
• Amide LA , commercial preparation is pure S-isomer.
• Structure similar to bupivacaine except for substitution of
a propyl group for the butyl group on the piperdine
ring.
• Safer and alternative to bupivacaine due to less cardiac
and cns toxicity.
• Onset, potency, duration of action similar to bupivacaine.
• Lipid solubility is little less than bupivacaine so high
therapeutic index.

TUMESCENT ANESTHESIA
Used by plastic surgeons during liposuction procedures; involves the
subcutaneous injection of large volumes of dilute local anesthetic in
combination with epinephrine and other drugs.
Total doses of lidocaine ranging from 35 to 55 mg/kg produce safe
plasma concentrations, which can peak more than 8 to 12 hours after
infusion

Several case series of cardiac arrest and death during plastic
surgery procedures happened in which multiple risk factors,
including high local anesthetic concentrations and concomitant
use of sedatives, contributed to the patients’ instability and
deterioration

Local anesthetics NIYAZ PV

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