Mechanism of action Lignocaine Bupivacaine Ropivacaine LAST Toxicity Prilocaine

1. Local anaesthetics
Dr Tess Jose
PG resident
Anaesthesia

2. COMMERCIAL PREPARATION
• Local anaesthetics are weak bases. They are poorly
soluble in water; so for commercial purpose they are
prepared as water soluble salt of an acid which is
stable in solution form.
• Acid + Base = salt + water
• Usually, acid used is hydrochloride.
• An acidic pH of the local anaesthetic solution is
important if epinephrine is used as an adjuvant as this
catecholamine is unstable at alkaline pH
• Onset of action and efficacy of LA can be improved by
reformulating them as carbonated solutions.
Carbonated solutions have a higher pH than
hydrochloride salt solutions.

3. STRUCTURE – ACTIVITY RELATIONSHIP
• 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).
• 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.

4. • Branching the intermediate chain results into more
fat soluble compound, e.g. etidocaine.
• Bulkier the moiety in terminal amino group, more is
the potency of the drug, e.g. bupivacaine.
• The amine portion of LA can accept one proton
(H+) and exist in charged form.

5. • 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.
• Higher the concentration of H+ ions more the equation moves
from right to left and more drug exists in nondiffusable
cationic form. On the other hand alkaline pH favours the
equation to move towards right and more drug exists in base
form.

6. Classification Based on chemical linkage

7. Classification based on duration of action

8. MECHANISM OF ACTION
• Local anesthetics are Na+ channel blockers.
• On the inner portion of Na+ channel specific
receptor for local anesthetics is present.
•

9. • Local anesthetics gain entry to their site of action via
two mechanisms.
• Unionized base form penetrate cell membrane of the
neuron easily due to its lipophilic character.
• Ionized cationic form reach the Na+ channel directly
through external orifice.
• One must remember that only cationic form binds
with Na+ channel. Therefore base form should
convert into cationic form before binding with Na+
channel

10. PROPERTIES OF LOCAL ANAESTHETICS
• Lipid Solubility:- Determines – Potency
• Structure of a cell membrane consists of two layers of lipid
(lipid bilayer) with large number of protein molecules
embedded in it.
• Lipid soluble agents are able to travel these barriers more
easily as compared to agents with poor lipid solubility.
• That is why highly lipid soluble local anesthetics produce
conduction blockade at lower concentration than less
soluble local anesthetics. [More molecules cross lipid
barrier to reach their site of action i.e. Na+ channels].

11. • Dissociation Constant (Pka) Determines – Onset of Action
• Pka is defined as the pH at which half (50 percent) of the
drug is in ionized form and half (50 percent) is in unionized
form.
• All the local anesthetics have Pka more than 7.4.
• Any medium having a pH less than 7.4 will therefore be
acidic for the drug. Acidic medium more drug well exist in
cationic nondiffusible form
• Local inflammation (tissue acidosis) increases the cationic
form of LA and thus reduces efficacy.

12. • Protein Binding Determines – Duration of Action
• Protein binding affects the duration of action in two
ways.
• a. Sodium channel is a protein spanning the lipid
bilayer cell membrane. Affinity of LA for protein
determines its affinity for sodium channel. Greater
the protein binding characteristics, longer the
drug binding with sodium channel and longer will
be its wash out time.

13. • Frequency Dependent Blockade Determines –
Sensory Motor Dissociation
• A resting nerve is less prone to blockade by local
anesthetic as compared to the nerve which is being
repetitively stimulated. This results into what is
called as frequency dependent block.

14. • . Vasodilation

15. .Differential Conduction Blockade

16. Order of block
• type B > C > A δ > α > β fibers.
• Autonomic(Preganglionic)> sensory> motor
Sensory blockade
• Temperature (cold before heat ) >pain >touch deep
pressure

17. • 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.

18. • 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 the periphery of the nerve.

19. FATE OF LOCAL ANAESTHETIC

20. Absorption
• :The systemic absorption of local anaesthetics is
determined by :
• 1. Site of injection: Absorption depends upon
vascularity of the area.
• Intravenous > Tracheal > Intercostal > Paracervical
> Caudal > Lumbar epidural > Brachial plexus >
subarachnoid > Subcutaneous.

21. Presence of additives
A.Vasoconstrictors
• a. Adrenaline (0.1 mg adrenaline is added to 20 ml LA to
give a 5 µg/ml concentration).
• b. Phenylephrine (0.1 mg adrenaline = 1 mg phenylephrine)
• c. Felypressin : It is Synthetic derivative of vasopressin and
can be safely used with inhalational agents as it has little
effect on cardiac rhythm
• Prolongs the duration of action of local anesthetic by
reducing its systemic uptake; as a result more drug is
available to cross neuronal cell membrane and produce
blockade.

22. • B.Clonidine and Dexmedetomidine :
• Increases the duration and quality of block
• Causes analgesia via action on α2 receptors.
• Clonidine prolongs the action of local anesthetics
by about 2 hours
• Dexmedetomidine is a much more specific α-2
agonist, and prolongs both motor and sensory
block by long-acting local anesthetics by
approximately 4 hours.

23. • C.Buprenorphine. The partial μ-opiate receptor
agonist
• two mechanisms : blockade of κ- and δ-opioid
receptors, and blockade of voltage-gated sodium
channel-blocking properties.
• Blockade by long-acting local anesthetics is
prolonged by about 6 hours, but at the price of a
high incidence of nausea and vomiting

24. D.alkalinisation

25. Metabolism
• Esters—Ester local anesthetics are predominantly
metabolized by pseudocholinesterase (also termed
butyrylcholinesterase). Ester hydrolysis is rapid, and the
water-soluble metabolites are excreted in the urine.
Procaine and benzocaine are metabolized to p-
aminobenzoic acid (PABA), which has been associated
with rare anaphylactic reactions.
• Amides—Amide local anesthetics are metabolized (N-
dealkylation and hydroxylation) by microsomal P-450
enzymes in the liver. Decreases in hepatic function or in
liver blood flow will reduce the rate of amide metabolism

26. Local Anaesthetic Systemic Toxicity ( LAST)
• Symptoms
• CNS more sensitive to LA toxicity than CVS.
• Prodromal (EARLY) symptoms: Perioral paresthesia,
metallic taste, and tinnitus.
• Neurological symptoms: Seizures , agitation , or
loss of consciousness .
• CVS toxicity:Heart conduction anomalies, cardiac
contractility, systemic vascular
resistance,progressing to cardiac arrest

28. Cocaine
• Cocaine was the first local anesthetic used by Carl
Koller for anesthetizing cornea.
• It is extracted from the leaves of Erythroxylum coca.
• Cocaine is not preferred because it is a very potent
vasoconstrictor, stimulates sympathetic system and can
cause CNS excitement leading to euphoria, agitation,
violence, convulsions, apnea and death.
• It is the only ester which is not metabolized
bypseudocholinesrerase.
• It is metabolized in liver.

29. Procaine
• Ist synthetic LA
• LA of choice in malignant hyperpyrexia.
• PABA is released on hydrolysis can antagonised
sulfonamides and PAS.
Chloroprocaine
• Shortest LA.
• Intradural injection can lead to paraplegia due to
sodium metabisulfate which is preservative.

30. • Amethocaine (Tetracaine)
• Only agent which is completely hydrolysed in body
and not excreted.
• It is very toxic due to slow metabolism and may
cause cardiac asystole and VF
• it's absorption from tracheobronchial spray is very
fast. therefore used for laryngeal block.

31. Lignocaine (Xylocaine, Lidocaine)
• It is the most commonly used local anesthetic.
• 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.

32. • Preparation
• A colourless solution in a concentration of 2%
solution of lignocaine hydrochloride. Preservative
free solutions may be used for IV administration.
A 2% gel containing 21.4 mg/ml of Lignocaine
hydrochloride
A 10% spray (10mg per spray)
A 4% aqueous solution for topical application,
For IV use only: Lignocaine 2% preservative free
(does not contain Methylparaben)
Lignocaine 5% Patch for topical application

33. • CVS
• In low concentrations, Lignocaine causes stabilisation of
excitable membranes by blockade of inactivated sodium
channels. Causes a rise in the threshold potential and
shortening of the duration of the action potential and effective
refractory period-class Ib anti arrhythmic
• Have minimal haemodynamic effects when used in therapeutic
doses
• At toxic doses, it decreases the SVR and myocardial
contractility, leading to circulatory collapse
• Respiratory System
• The drug causes tachypnoea and bronchodilation and may
cause respiratory depression when used in toxic doses.

34. • CNS
• This leads to a biphasic CNS response
• Initial CNS excitation due to the inhibition of inhibitory
interneurons in the cortex (manifested as dizziness, visual
and auditory disturbances, and seizure activity).
• Later, CNS depression with increasing doses as it inhibits
both the facilitatory and inhibitory pathways (manifested as
drowsiness, disorientation, and coma).
• Other: Lignocaine has some amount of anticholinergic and
antihistaminergic activity.

35. • CC/CNS Ratio
• The cardiovascular collapse/CNS (CC/CNS) ratio is
"the ratio of drug dose required to cause
catastrophic cardiovascular collapse to the drug
dose required to produce seizures."
• The lower the number the more cardiotoxic the
drug .
• bupivacaine it is 3 and for lidocaine it is 7
• BUPIVACAINE> LIGNOCAINE

36. • Additional Uses
• Dose to prevent stress response to laryngoscopy-1.0 to 1.5mg/kg
IV
• Antiarrhythmic for ventricular dysrhythmias:
Cardiac Arrest from VT/VF: First dose of 1 to 1.5 mg/kg IV/10,
Second dose 0.5 to 0.75 mg/kg IV/IO (AHA ACLS Guidelines 2020)
 Refractory VF: additional 0.5 to 0.75 mg/kg IV push, repeat in 5
to 10 minutes; maximum 3 doses or total of 3mg/kg
Stable VT, wide-complex tachycardia of uncertain type: 0.5 to 0.75
mg/kg and up to 1 to 1.5mg/kg. Repeat 0.5 to 0.75 mg/kg every
5-10 minutes with maximum total dose of 3 mg/kg.
Maintenance infusion: 1 to 4 mg/min (30-50 mcg/kg/min)

37. • Analgesia: low-dose infusion of Lignocaine to maintain a
plasma concentration of 1 to 2 mcg/ml causes analgesia,
however its use is restricted due to high chances of systemic
toxicity.
• Bronchodilator: Inhaled lignocaine attenuates histamine-
induced bronchospasm and induces airway anaesthesia.
• Anti-inflammatory effect: Modulates inflammatory responses
and may be useful in mitigating peri operative inflammatory
injury.
• Suppression of grand Mal seizure: Effective in suppressing
seizures through initial depression of hyper-excitable cortical
neurons.

38. • Adverse Effects
• CNS- more neurotoxic than cardiotoxic, biphasic
response
• Early- Excitation with seizures, Late- CNS depression,
decreased consciousness, respiratory arrest, coma
• CVS-Bradycardia, Hypotension, Conduction blocks,
cardiac arrest (CC/CNS ratio: 7.1)
• Respiratory depression/arrest
• Allergy
• Local Anaesthesia Systemic Toxicity (LAST)

39. • TNS- Transient Neurological Symptoms defined as
back pain with radiation or dysesthesia in the
buttocks, thighs, hips and calves, occurring within
24 h after recovery from otherwise uneventful
Spinal anaesthesia, and TRI- Transient radicular
irritation were seen in several patients after
5%Lignocaine, hence it is no longer used.

40. • Dose dependent effects of lignocaine:
• 1-5 microgram/ml - Analgesia
• 5-10 microgram/ml - Circumoral numbness,
tinnitus, muscle twitching, hypotension,
• Myocardial depression
• 10-15 microgram/ml - Seizures, unconsciousness
15-25 microgram/ml - Apnoea, coma
• >25 microgram/ml - Cardiovascular depression

41. Bupivacaine hydrochloride
Chemical Structure
It is an aminoamide local anaesthetic. Chemically designated
as 2-piperidinecarboxamide-1-butyl-N- (2,6-dimethylphenyl)-
monohydrochloride monohydrate.
R and S enantiomers present in which the S enantiomer is
less cardiotoxic and neurotoxic than the R enantiomer
perhaps reflecting decreased potency at sodium ion channel.

42. • availability:
• It is available in the following forms: Preservative-
free solutions: 0.5% solution, made hyperbaric by
the addition of 8% dextrose – 4 ml ampoule for
intrathecal use.
• With preservative (methylparaben): 0.25%, 0.5%
solutions for use as local anaesthetic – intradermal,
subcutaneous injections, epidural anaesthesia and
nerve blocks.

43. • Pharmacology: It is an amino-amide type of local anaesthetic.
It has a pKa of 8.2.
• Uses, dose and route: It is a sodium channel blocker and
stabilizes the membrane
As a local anaesthetic, to block various nerves and plexuses
To produce central neuraxis block
 Labour analgesia
• Onset and Duration: Depends on the site of injection, dose
and concentration of the drug, additives to the solution and
certain tissue characteristics.
• Elimination: It is metabolized by liver

44. • Pharmacokinetics
• Onset: Slow, 5-20 min
• Duration of action: 240-480 min
• Toxic plasma concentration>3 µg/ml
• pka: 8.1
• Protein Binding: 95%
• Absorption: Depends on the site of injection with its
tissue blood perfusion, dosage and volume, addition of
vasoconstrictor agent etc.
• Elimination Half Life: 210 min

45. • Absorption
• Absorption of Bupivacaine is related to various factors
such as:
• Site of injection: Intercostal > Intrathecal > Caudal >
Epidural > Brachial plexus >Subcutaneous
• Dose: Absorption of the drug is faster with a larger
dose administered.
• Use of Adrenaline: Reduces the absorption of
Bupivacaine into the systemic circulation by 10-20%
(20-30% for other local anaesthetics)

46. • Distribution
• Amide local anaesthetics are more widely
distributed than ester local anaesthetics.
• The drug does not cross the placenta in significant
amounts.
• Some amount of pulmonary excretion also takes
place which limits the concentration of drug
reaching the systemic circulation.

47. • Metabolism
• Occurs by aromatic hydroxylation, N-dealkylation,
amide hydrolysis and conjugation in the liver to
inactive metabolite pipecoloxylidide.
• Only the N dealkylated metabolite N des butyl
bupivacaine has been measured in blood or urine
after spinal or epidural anaesthesia.
• Excretion: 5% is excreted in the urine as
pipecoloxylidide, and 16% is excreted unchanged.

48. • Bupivacaine is markedly cardiotoxic, and acts both by inhibiting
the cardiac sodium channels and by direct interaction withthe
myocardial proteins, leading to slowing of myocardial
conductance causing profound cardiovascular depression.
• The ratio of the dosage required for irreversible cardiovascular
collapse (CC) and the dosage that will produce CNS toxicity
(CC/CNS ratio) is lower than lignocaine.
• Ventricular arrythmias and fatal ventricular fibrillation - rapid IV
administration.
• Bupivacaine has inherent vasodilatory properties.
• At toxic doses, it also decreases the SVR and myocardial
contractility, leading to myocardial collapse.

49. • CNS
• The peripheral effect of Bupivacaine is reversible
neuronal blockade. This leads to a biphasic CNS response
• Initial CNS excitation due to the inhibition of inhibitory
interneurons in the cortex (manifested as dizziness, visual
and auditory disturbances, and seizure activity)
• Later, CNS depression with increasing doses as it inhibits
both the facilitatory and inhibitory pathways (manifested
as drowsiness, disorientation, and coma)

50. • Adverse Effects
• Allergic reactions to amide local anaesthetics are
extremely rare.
• Bupivacaine is more cardiotoxic than neurotoxic.
• LAST

51. • Contraindications
• Intravenous regional anaesthesia (Bier's Block)
• Allergy to Bupivacaine

52. Levobupivacaine
• Chemical structure
• S-enantiomer of Bupivacaine, Levobupivacaine contains
a single enantiomer of bupivacaine hydrochloride
which is chemically described as (S)-1-butyl-2-
piperidylformo-2, 6-xylidide hydrochloride
• Presentation
• It is non-pyrogenic, colourless solution (PH 4.0-6.5)
• Levobupivacaine is preservative free and is available in
10 ml and 30 ml single dose vials.

53. • Pharmacokinetics
• Absorption: The plasma concentration of
levobupivacaine following therapeutic administration
depends on dose and also on route of administration.
• Distribution: Plasma protein bound >97%, Vd: 55 L;
T½: 156 minutes
• Metabolism: CYP3A4 isoform and CYP1A2 isoform
mediate the metabolism oflevobupivacaine to
desbutyl levobupivacaine and 3-hydroxy
levobupivacaine
• Elimination: 95% being recovered in urine and
faeces in 48 hours

54. • Pharmacodynamics
• CVS
• • Toxic blood concentrations depress cardiac
conduction and excitability which may lead to
arrhythmias and cardiac arrest, sometimes
resulting in death.
• In addition, myocardial contractility is depressed
and peripheral vasodilation occurs, leading to
decreased cardiac output and arterial blood
pressure.
• However, levobupivacaine has less cardiac and CNS
toxicities than bupivacaine.

55. • CNS:
• Apparent central nervous system stimulation is
usually manifested as restlessness, tremors, and
shivering, progressing to convulsions.
• Ultimately central nervous system depression may
progress to coma and cardio-respiratory arrest.

56. Adverse effects
• Hypotension (31%),
• Nausea (21%)
• Post-operative pain (18%)
• Fever (17%)
• Vomiting (14%)
• Levobupivacaine is toxic to cartilage and intra-
articular infusion can lead to post-arthroscopic
glenohumeral chondrolysis.

57. Ropivacaine
• Chemical
• An amino amide which is member of the
pipecoloxylidide group of local anaesthetics
• Presentation:
• As a clear, colourless solution containing racemic
ropivacaine hydrochloride monohydrate (S- and R-
enantiomers) in concentrations of 0.2/0.75/1.0% .
• A pure S-ropivacaine preparation is also available.
• S-ropivacaine is more potent and less cardiotoxic than
R-ropivacaine .

58. • Pharmacokinetics
• Onset: Slow, approx. 15 min
• Duration of action: 240-480 min (After infiltration)
• Protein Binding: 94% (mainly to a1 acid
glycoprotein)
• pka is 8.1 and it is 15% unionised at pH 7.4
• Elimination Half Life: 108 min

59. • Distribution: Ropivacaine is 94% protein-bound in
the plasma, predominantly to a acid glycoprotein.
Vd is 52-66 L.
• Metabolism: Hepatic (CYP1A2 mediated),
metabolised to 2, 6-pipecoloxylidide and 3-
hydroxyropivacaine by cytochrome P450 enzymes.
• Excretion: Renal (86%)

60. Pharmacodynamics
• CVS
• Ropivacaine is less cardiotoxic than bupivacaine;
• In toxic concentrations, the drug decreases the
peripheral vascular resistance and myocardial
contractility, producing hypotension and possibly
cardiovascular collapse.
• The maximum recommended dose of ropivacaine is 3
mg/kg.
• Ropivacaine has a biphasic vascular effect, causing
vasoconstriction at low, but not at high,
concentrations.

61. • CNS
• The peripheral effect of Ropivacaine is reversible
neuronal blockade.
• This leads to a biphasic CNS response:
Initial CNS excitation due to the inhibition of inhibitory
interneurons in the cortex (manifested as dizziness, visual
and auditory disturbances, and seizure activity)
Later, CNS depression with increasing doses as it inhibits
both the facilitatory and inhibitory pathways (manifested
as drowsiness, disorientation, and coma)

63. PRILOCAINE
• It is an amide local anaesthetic derived from
toluidine.
• Salient Features
• 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 6 mg/kg.

65. EMLA (Eutectic mixture of local anaesthetic)
• It contains 2.5 % lidocaine with 2.5 % prilocaine in
an emulsion form.
• The term eutectic refers to lowering of melting
point of two solids when they are mixed together

66. • Salient Features
• • It is a white cream used for anesthesia of intact skin
(topical anesthesia).
• It is not recommended over mucous membranes or
open wounds as the fast rate of absorption can lead
to systemic toxicity.
• Method of application:- Usually 1-2 gms of cream is
applied over 10 cm2 area under an occlusive
dressing. Dressing is opened after 1-2 hrs, anesthesia
achieved lasts for around 2-4 hrs.

67. • Uses
• Topical anesthesia before venipuncture, arterial
cannulation, lumbar puncture, circumcision.
• IV cannulation in children.
• Split-skin grafting as anesthesia achieved is around
5 mm deep.

69. References
• Millers 9 E
• Stoeltings
• Katzung pharmacology
• Comparative Pharmacology for Anaesthetist -vipin
dhama
• AFMC notes on 100 Anaesthesia drugs.