The document discusses local anesthetics, covering their introduction, classification, mechanism of action, and metabolism. It details properties of ideal local anesthetics, the historical context of their development, and specific agents like lignocaine and bupivacaine, emphasizing their pharmacokinetics and potential systemic effects. Additionally, it addresses factors influencing anesthetic effectiveness, such as ionization and binding characteristics, and provides clinical applications and considerations for safety and efficacy.

1. Local Anaesthetics
Gaurav joshi
PG 1 Resident
Dept of Anaesthesia
SPMC,Bikaner

2. Outline of discussion
 Introduction
 History
 Properties of Ideal LA
 Classification of LA
 Physiology,biochemistry &Mechanism of action of LA
 Factors affecting LA
 Metabolism
 Individual agents Lignocaine ,Bupivacaine, Levo
bupivacaine, Ropivacine
 Systemic effects and toxicity
 Treatment & prevention of toxicity

3. 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.

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

5. Properties of Ideal local Anaesthetic:
Possess a specific and reversible action.
• They stabilize all excitable membrane including
motor neurones
• CNS is extremely sensitive to its action.
Non-irritant with no permanent damage to
tissues.
No Systemic toxicity
• High therapeutic ratio.
Rapid onset and long duration
Active Topically or by injection

6. 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

7. STRUCTURE:-
• Aromatic Ring – fat soluble (hydrophobic)
• Terminal Amine – water soluble (hydrophillic)
• Ampophoteric character

8. CLASSIFICATION
Local anaesthetics are classified on the basis of
chemical structure and on the duration of
action.

9. BASED ON CHEMICAL STRUCTURE
• Chemically local anaesthetics consists of a benzene
ring separated from tertiary amide either by ester or
amide linkage. Based on this intermediate chain these
are classified as aminoesters and aminoamides.

12. E S T E R S
• Short duration of action
• Less intense analgesia
• Higher risk of
hypersensitivity ESTER
linked LA s are rarely used.
• Hydrolyzed by Plasma
Cholinesterase in blood.
• Rarely used for Infiltration
anesthesia
• But useful for topical ana on
mucous membranes.
A M I D E S
• Produce more intense and
longer lasting ana.
• Bind to alpha1 acid
glycoprotein in plasma
• Not hydrolyzed by Plasma
Cholinesterase, but in liver
• Rarely cause
hypersensitivity reactions-
no cross reactivity with
ESTER L A s.

13. BASED ON DURATION OF ACTION AND
POTENCY
SHORT DURATION, LOW POTENCY
Chloroprocaine(shortest duration) Procaine
INTERMEDIATE DURATION, INTERMEDIATE
POTENCY
Lignocaine Mepivacaine Prilocaine
cocaine

14. LONG DURATION, HIGH POTENCY
•Bupivacaine.
•Levo bupivacaine.
•Tetracaine
•Etidocaine
•Dibucaine(longest duration).
•Ropivacaine
.

15. Physiology, biochemistry &
Mechanism of action of local
anesthetics

16. Physiochemical properties:
• These are very important for local anaesthetic
activity.
• Ionization:
• They are weak base and exist partly in
an unionized and partly in an ionized
form.
• The proportion depend on:
– the pKa or dissociation constant
– The pH of the surrounding medium.
• Both ionizing and unionizing form are
important in producing local
anaesthesia.

17.  pKa is the pH at which the ionized and unionized form of an
agent are present in equal amounts.
The lower the pKa , the more the unionized form, the
greater the lipid solubility.
The higher the pKa , the more the ionized form and the
slower the lipid solubility

18. –Unionized form is able to cross the bi-
lipid nerve membrane.
–The ionized form then blocks
conduction.
–Some of the unionized inside the cell
will become ionized depending upon
the pKa and the intracellular pH (lower
than extracellular)

19. :
–In general the amide type have lower
pKa, and greater proportion of the drug
is present in the lipid-soluble (unionized)
form at the physiological pH
–This produces faster onset of action
–The lower the pKa the faster the onset.

20. Partition coefficient:
–This measures the relative solubility of an
agent in fat and water.
–High numerical value means:
• High lipid-soluble
• less water-soluble.
–More fat solubility, means rapid crossing of
the lipid barrier of the nerve sheath.
–The greater partition coefficient, The faster
the onset

21. Protein binding:
–Local anaesthetic agents bind with:
• α1-acid glycoprotein, which possess high
affinity but low capacity.
• Albumin, with low affinity but high capacity
–The binding is simple, reversible and tend to
increase in proportion to the side chain.
–Lignocaine is 65% bound, Bupivacaine is
95%
–The duration of action is related to the
degree of binding.

22. Vasodilatory ability:
–Most Local anaesthetics possess a
vasodilatory action on blood vessels
except Cocaine.
–It influence the duration of action of
the agent.
–Prilocaine is 50% bound to proteins
but has a longer duration than
Lignocaine (65%) since it possess no
strong vasodilatory effect.
–Affect the duration of action of the
agent

23. Mechanism of Action
• conduction of nerve impulses is
mediated by action potential (AP)
generation along axon
• Cationic form of anesthetic binds
at inner surface of Na+channel –
preventing Na+influx (rising
phase of membrane potential)
which initiates AP → blockade of
nerve impulses (e.g., those
mediating pain)

24. Na +Na +

26. Mechanism – Other Targets
• Voltage dependent K+ channels
• Ca2+ Channels (L type)
• Possibly G-protein coupled receptors

29. Differential sensory/motor blockade:-
Sensory > motor at lower conc. of ropivacaine & bupivacaine
Useful when selecting an agent for ambulatory labour
analgesia or post op analgesia.
 For the same diameter, myelinated nerves will be blocked
before unmyelinated nerves
 Nerves that fire frequently are preferentially blocked over
nerves that fire infrequently.

30. Cm – Minimum Concentration
• Cm is the minimum concentration of a LA to
produce a conduction blockade
• Analogous to MAC for inhaled Anesthetics
• Factors Affecting Cm
– Nerve Fiber diameter (increases)
– Increased tissue pH (decreases)
– Increased rates of nerve firing (decreases)
– Length of nerve exposed to LA (longer better
block)
• Unique to each LA
• Cm for motor neuron roughly 2X sensory
neuron

31. Fate & Metabolism:
Metabolism of Ester drugs:
• Metabolized in plasma by
peudocholinesterase enzyme, and some in the
liver.
Cocaine is only exception (liver mostly)
• People, who lack the enzyme, are at risk of an
overdose by the ester type local anaesthetic
• Para-aminobenzoic acid (PABA) is the major
metabolite of ester with no anaesthetic effect
– It is the agent responsible for ester allergies.

32. Amide Drugs:
• metabolized in the liver, except Prilocaine
which undergo some biotransformation in the
kidney and lungs.
• Some of the metabolites possess local
anaesthetic and sedative properties.
• Normal local anaesthetic dose in patient with
impaired liver function will result in relative
overdosage.
• Old age patient shows reduction in liver
function
»Reduce dose

33. Individual LA
Lignocaine
Bupivacaine
Levo bupivacine
Ropivacine

34. LIGNOCAINE
(XYLOCAINE, LIDOCAINE)
It is the most commonly used local anaesthetic
First synthesized by Lofgren and first used by Gordh.
Solution is very stable, not even decomposed by boiling.
Contains preservative methyl paraben.
pKa =7.8

35. It is also a class 1b antiarrhythmic drug.
Rapid onset of action and intermediate duration
of efficacy.

36. CONCENTRATION USED
: 4% and 10%
: 1% and 2%
: 2%
:0. 5%(heavy)
: 1-2%
: 0.5%
• Surface (topical) analgesia
• Nerve blocks
• Urethral procedures(as jelly)
• Spinal
• Epidural
• Intravenous regional analgesia
(bier`s block)
Inflitration block
: 1-2%

37. DURATION OF EFFECT
• Without adrenaline
• With adrenaline
DOSE :
Without adrenaline
With adrenaline
: 45 to 60 minutes
: 2-3 hours
:
4.5 mg/kg(max 300 mg)
:7mg/kg(max 500 mg)

38. Pharmacokinetics
• The onset of action of about 45 to 90 sec
• t1/2 of lidocaine is biphasic and around 90–120 min in most
patients
• metabolized(dealkylated) in the liver(95% )to
active metabolites mono ethyl glycine xylidide (MEGX)
• MEGX has a longer half-life than lidocaine, but less potent sodium
channel blocker.
• bound to the protein alpha1 acid glycoprotein.
• The oral bioavailability is 35% and the topical bioavailability is 3%.
• Lidocaine is excreted in the urine (90% as metabolites and 10% as
unchanged drug

39. • Systemic toxicity is much less than bupivicaine. CNS involvement
occurs at much lesser dose than CVS involvement.
• Lignocaine releases calcium from sacro-plasmic reticulum so
should not be used in patients with history of malignant
hyperthermia.
• Can cause cauda equina syndrome after continuous spinal.
Other uses…
• Used for treating ventricular tachycardia. Preservative free
lignocaine (xylocard 2%) is used intravenously in dose of 2 mg /kg.
• Intravenous xylocard is used to blunting cardiovascular response to
laryngoscopy and intubation.

40. Ropivacaine
long-acting amide and first produced as a pure
enantiomer.
• It is less lipophilic than bupivacaine and is less
likely to penetrate large myelinated motor
fibres, resulting in a relatively reduced motor
blockade.
• Thus, has a greater degree of motor sensory
differentiation.

41. • Enantiomers exist in two different spatial
configurations,
• dextrorotatory (R+) &levorotatory (S-)
• R(+) and S(-) enantiomers have different
affinity for different ion channels of sodium,
potassium, and calcium;
• this results in a significant reduction in CNS
and cardiac toxicity of the S(-)enantiomer as
compared with the R(+)enantiomer.

42. PHARMACOKINETICS
• plasma concentration of depends on:-
- total dose administered
- route of administration
- haemodynamic and circulatory condition of
the patient
- vascularity of the administration site.
• When it was administered intravenously,its
pharmacokinetics were linear and dose
proportional up to 80 mg.

43. • The absorption of ropivacaine 150 mg from the
epidural space is complete and biphasic.
• The t1/2 of the initial phase 14 minutes,
• followed by a slower phase with a mean absorption
t1/2 of 4.2 hours.
• bound mainly to α1-acid glycoprotein.(94%)
• rapidly crosses the placenta .
• metabolised in the liver
• Excreated by kidney

44. Usage
• Infilteration - .2 – 0.5 % 200 mg
• PNB .5-1% 250 mg
• Epidural 0.5-1% 200 mg
• Labour pain 0.2 % 20-40 mg
• Caudal block 0.2% 2mg/kg

45. BUPIVACAINE
 Commonly used drug .
 It is a homologue of mepivacaine and is chemically related to
lidocaine
 The onset of action is rapid
 The duration of anesthesia is longer
 4 times more potent than lignocaine and mepivicaine.
 Available in 0.25% and .5 % solution & solution is very stable.
 It is highly toxic on the heart in overdose so it should not be
used in beir`s block
 Metabolised in liver
• Elimination half life is 3.5 hrs

46. • The very unique property of bupivacaine which make it local
anaesthetic of choice for post op pain relief and painless labour is it
wide sensory and motor blockade (means motor block will occur only
at higher concentrations making it LA of choice for labor analgesia)
• The drug crosses placenta barrier only a limited extent and its effect
on the baby is usually minimal.
• It is not used in topical anaesthesia.
• Injectable solution is 0.25% ,.5 % , 0.75 %.
• Bupivicaine has no severe interactions with other drugs
• Long acting local anaesthetic

47. CONCENTRATION USED
• For nerve block
• Epidural
: 0.5%
:0.125 -0.5 %(depending
whether used for sensory block
or motor block)
• Spinal : 0.5 % (heavy)

48. DURATION OF EFFECT
• Without adrenaline
• With adrenaline
: 2-3 hours
: 3-5 hours
Addition of adrenaline has no effect on motor
blockade, it prolongs only duration of sensory
block.
DOSE
Without adrenaline
With adrenaline
:2.5mg/kg(max 175mg)
:3mg/kg (max 225mg)

49. Bupivacaine metabolism
•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

50. Pharmacokinetics
 Rate of systemic absorption is dependent upon
 - dose and concentration of drug administered,
 -route of administration,
 -vascularity of the administration site,
 -the presence or absence of epinephrine in the preparation.
 Onset of action: 1-17 min
 Duration of action: 2-9 hr
 Time to peak plasma concentration (for peripheral, epidural or caudal
block): 30-45 min
 Protein binding: about 95%
 Metabolism: hepatic
 Excretion: renal (6% unchanged)

51. • Its far more cardiotoxic than lignocaine,it R component
contibutes more than S component
• It may cause dangerous and prolonged ventricular
dysrhythmias like tachycardia, extrasystole, cardiac
arrest
• Its high tissue binding and high protein binding makes
resuscitation after cardiac arrest proloned and very
difficult.
• Absolutely contraindicated in biers block (IVRA)
Toxicity

52. LEVOBUPIVICAINE
• Recently introduced drug.
• it is the (S)-(–)-enantiomer of bupivacaine,
produces less vasodilation.
• Not used in topical anaesthesia.
• Less cardiotoxic than bupivicaine but higher than lignocaine.
• Neurotoxicity of levobupivicaine is also lesser than
bupivicaine.
• It is also contraindated in bier`s block and in severe
hypotension patients.
• Elimination half life is 2-2.6 hours

53.  Metabolised in liver excreated 70% by renal and 24 % in
faecal
 Dose is 2.5 mg/kg(without adrenaline).
 Duration of action is similar to bupivicaine.
 Lipid soluble & highly protein bound(97%)
 Onset of action – 8to 17 min
 Duration of action 3 to 4 hr.
 Rest pharmacology is similar to bupivicaine

54. Additives and modifiers
of LA activity
• Increasing dose: ↓latency of onset; ↑duration, ↑block
success, ↑[LA]
• Vasoconstrictors: ↑duration, ↑block success, ↓[LA]
• α2 agonists: ↑duration,↑[LA]
• Opioids: ↑duration; permit ↓LA dose
• Alkalinization (usually NaHCO3): ↓latency of onset,
↑potency
• Pregnancy: ↑dermatomal spread, ↑LA potency, ↑free
blood ( doses should be decreased in patients in all
stages of pregnancy.)

55. USES :-_ TOPICAL
ANAESTHESIA:-

56. • EMLA:- Eutectic mixture of local anaesthetics
– 2.5% lox + 2.5% prilocaine
– Diffuse through intact skin to block neuronal
transmission from dermal receptors
– Dose- 1-2 gm per 10 cm² area under occlusive dressing
– Used for skin graft harvesting, i.v.cannulation,
cauterising genital warts, circumcision
– To be applied 45-60 min prior to procedure
– Low frequency USG speeds the onset
– Side effects:- skin reactions like pruritus, edema,
erythema and rash may cause methemoglobinemia in
children<3 mth or patients on oxidising drugs like
sulphonamides, paracetamol, phenytoin, NTG.

57. PERIPHERAL NERVE BLOCKS:-
– LA injected in the vicinity of peripheral nerve or plexus
– LA diffuse from mantle to core across a conc gradient
– Proximal anatomic structures are first to be anaesthetized
and first to regain sensation
– Sequence of onset & recovery in a mixed nerve depends
more on the anatomic location of the fibres

58. SPINAL ANAESTHESIA
• LA is injected into the subarachnoid space. Injection
is made heavy by adding dextrose or light by adding
saline.
• Lignocaine, Bupivacaine the two agents most
commonly used regularly in anesthesia practice.

59. EPIDURAL ANAESTHESIA:
When the anesthetic in injected outside the dura, the
technique is known as Epidural anesthesia.

60. I V R A (Bier’s Block)
• Intravenous regional anesthesia
• Agent of choice- Lignocaine (Xylocaine )
• 20 to 40 ml of 0.5 % Lidocaine is used
• Used for only for Upper Limb orthopedic
surgeries and others on Up. Limb.

61. OTHER USES:-
- Analgesia: lidocaine as continuous infusion to maintain a
plasma conc 1-2 ug/ml. effective in post op pain & stump
pain.
-Cough suppressant: i.v. lignocaine in perioperative period
-Anti arrythmic: i.v. lignocaine (class I B drug) used in a dose
of 1.5mg/Kg
-Anti epileptic: suppression of grand mal seizures
-Bronchodilation

62. Side Effects - Allergy
• Rare Events
• <1% of all adverse reactions
• Often systemic toxicity is attributed to allergy
• Esters are more likely to cause allergy
– PABA
• Allergy is usually due to preservatives
– methyl paraben (structurally similar to PABA)
– Sodium metabisulphite
• Antibodies are made to preservatives not LA
• Known allergies to Ester LA do not preclude use of Amide LA
• Allergy determination
– History
– Skin testing
– Intradermal testing

63. Local Toxicity
Neurotoxicity
 Range of symptoms: patch numbness to muscle weakness
 Often blamed on positioning during delivery
Transient Radicular Irritation
Severe pain lower back, buttocks, posterior thigh
Develops within 24 hours of dosing
May require opiods
Recovery usually in one week
Lidocaine and Mepivicaine implicated – dose
dependent
Less problems with bupivicaine, ropivicaine,
tetracaine

64. Cauda Equina Syndrome
 When diffuse injury across the lumbosacral plexus producing various
degree of sensory anesthesia
 Bowel and bladder sphincter dysfunction
 Paraplegia
 It is associated with use of hyperbaric 5%Lidocaine for continous spinal
anaesthesia
Anterior Spinal Artery Syndrome
 Consist of lower extremity paresis with a variable sensory deficit that is
usually diagnosed as the neuronal blockade resolves
 Etiology is uncertain,thrombosis or spasm of anterior spinal artery is
possible
 Difficult to distinguish from epidural hematoma / abscess
 Risk Factors
 Advanced age
 Peripheral Vascular Disease

65. Local Anesthetic Systemic Toxicity
(LAST ) it can occur after administration of an excessive dose, with
rapid absorption,or an accidental intravenous injection.
 The management of this toxicity can be challenging,
 In the case of cardiac toxicity, prolonged resuscitation efforts
may be necessary .
 Systemic toxicity is typicaly manifested as central nervous
system (CNS) toxicity or cardiovascular toxicity .
 dose causing CNS symptoms is typically lower than the dose
and concentration result in cardiovascular toxicity.
 This is because the CNS is more susceptible to local anesthetic
toxicity than the cardiovascular system.

66. -symptoms appear 1-5 minutes after the injection, (30 sec to 60
min)
- Initially, patients experience symptoms of central nervous
system (CNS) excitement are:
- Circum oral and/or tongue numbness
-Metallic taste
-Lightheadedness
-Dizziness
-Visual and auditory disturbances (difficulty focusing and
tinnitus)
-Disorientation
-Drowsiness

67. With higher doses,initial CNS excitation is often followed by a
rapid CNS depression,features of:
- Muscle twitching
-Convulsions
-Unconsciousness
-Coma
-Respiratory depression and arrest
-Cardiovascular depression and collapse
Acid-base status plays an important role.
-Acidosis and hypercarbia amplify the CNS effects by overdosing( decrease the
plasma protein
binding) and exacerbate cardiotoxicity.
-Hypercarbia enhances cerebral blood flow; so more drug reach to the
cerebral circulation

68.  signs and symptoms of CVS toxicity are:
-Chest pain
-Shortness of breath
-Palpitations
-Lightheadedness
-Diaphoresis
-Hypotension
-Syncope
-arrythemia
-cardiac arrest

69. Prevention
 Monitor electrocardiogram, blood pressure, and arterial
oxygen saturation.
 Keep talking to the patient– both during and after drug
administration
 Be conservative with local anesthetic (LA) dose in patients
with advanced age, poor cardiac function, conduction
abnormalities, or abnormally low plasma protein concentration.
 Gentle aspiration of the syringes before every injection.
 Monitor the patient after high-dose blocks for 30 minutes.
 Be prepared: A plan for managing systemic local anesthetic
toxicity should be established in facilities where local anesthetics
are used.
 Current recommendations are to have 20% lipid emulsion
stocked close to sites where local anesthetics are used.
 Consider infusing lipid emulsion early to help prevent cardiac
toxicity.
 USG guided nerve block– if available

70. Treatment of Systemic LA Toxicity
• Get help and call for 20% lipid emulsion.
• Perform airway management. Hyperventilate with 100%
oxygen.
• Abolish the seizures
• Perform cardiopulmonary resuscitation
• Epinephrine-controversial; may have to use higher doses
then recommended in ACLS.
• Consider using vasopressin to support circulation
• Alert the nearest facility having cardiopulmonary bypass
capability.

71. Perform lipid emulsion treatment
(for a 70-kg adult patient):
- Bolus 1.5 mL/kg intravenously over 1 minute (about 100
mL)
-Continuous infusion 0.25 mL/kg per minute (about 500
mL over 30 minutes)
-Repeat bolus every 5 minutes for persistent
cardiovascular collapse.
-Double the infusion rate if blood pressure returns but
remains low.
-Continue infusion for a minimum of 30 minutes.

72. LipidRescue
• It is lipid emulsion to treat severe, systemic
drug toxicity or poisoning.
• It was originally developed to treat local
anesthetic toxicity, also occur in other
situations where patients receive local
anesthetic injections.
• It also effective antidote for poisoning or
overdose caused by a wide array of other
(non-local anesthetic) lipophilic agents.

73. Proposed Mechanisms
• lipids reversing toxicity by increasing clearance from
cardiac tissue.
• This nonspecific, observed extraction of local
anesthetics from aqueous plasma or cardiac tissues
is termed a “lipid sink.”
• Another proposed mechanism is that lipids
counteract local anesthetic inhibition of myocardial
fatty acid oxidation, thereby enabling energy
production and reversing cardiac depression

74. LOCAL ANAESTHETIC FAILURE
technical failure to deliver the drug
insufficient dosage
Incorrect technique
injecting LA in a site of inflammation
genetic cause