pharmocology of local anesthetics

1. PHARMACOLOGY OF
LOCAL ANAESTHETICS
MODERATOR: DR.CHANDRASHEKAR
DANDI
PRESENTOR: DR.KEERTHY
UNNIKRISHNAN

2. LOCAL ANAESTHETICS
• A local anaesthetic can be defined as a drug which
reversibly prevents transmission of the nerve
impulse in the region to which it is applied , without
affecting consciousness.

3. PROPERTIES OF AN IDEAL LOCAL ANAESTHETIC
Reversible
action
Non-
irritant
No allergic
reaction
No systemic
toxicity
Rapid onset
of action

4. Sufficient
duration of
action
Potent
Stable in
solutions
Not interfere
with healing of
tissue
Have a
vasoconstrictor
action
Not expensive

5. DIFFERENCE BETWEEN LOCAL & GENERAL
ANAESTHESIA
FEATURES GENERAL LOCAL
Site of action CNS Peripheral Nerves
Area of body involved Whole body Restricted areas
Consciousness Lost Unaltered
Preferential use Major surgery Minor surgery
Use in non-
cooperative patient
Possible Not possible
Poor health patient Risky Safer
Care for vital Essential Usually not needed

6. MOLECULAR STRUCTURE
1. Aromatic benzene ring portion: lipophilic moiety
2. Intermediate chain-AMIDE or ESTER-Basis of
classification
3. Amine group: Hydrophilic group,usually a tertiary
amine.

8. CLASSIFICATION ACCORDING TO ROUTE
OF ADMINISTRATION
INJECTABLE:
• Low potency,short duration:Procaine and Chlorprocaine.
• Intermediate
potency:Lidocaine,Prilocaine,Mepivacaine,Cocaine
• High potency&long duration:
Tetracaine,Bupivacaine,Ropivacaine,Etidocaine,Dibucaine.

9. SURFACE:
• Soluble – Cocaine,Lidocaine,Tetracaine&Benoxinate
• Insoluble –
Benzocaine,Butylaminobenzoate&Oxathazine

10. CLASSIFICATION BASED ON CHEMICAL STRUCTURE
ESTER LINKED AMIDE LINKED
Procaine Lidocaine
Chlorprocaine Prilocaine
Tetracaine Mepivacaine
Benzocaine Bupivacaine
Cocaine Levobupivacaine
Ropivacaine
Etidocaine

11. ESTER LINKED AMIDE LINKED
Short acting Longer acting
Metabolized by Plasma
Cholinesterase
Metabolized by liver
enzymes(liver amidase)
Can be used in poor liver
function
Avoided in poor liver function
Hypersensitivity-↑ Hypersensitivity-↓

12. STRUCTURE-ACTIVITY RELATIONSHIPS
• Modifying the chemical structure of a local anaesthetic
alters its pharmacologic effects.
• TETRACAINE-
Substituting a butyl group for the amine group on the
benzene ring of procaine.
Tetracaine is more lipid soluble,10 times more
potent&has a longer duration of action,corresponding
to a four-five fold decrease in the rate of metabolism.

13. • CHLORPROCAINE:
The halogenation of procaine to chlorprocaine results in
a three to four fold rise in the hydrolysis rate of
chlorprocaine by plasma cholinesterase.
• Mepivacaine,bupivacaine & ropivacaine are
characterized as pipecoloxylidides.

14. • The addition of a butyl group to the piperidine nitrogen
of mepivacaine results in bupivacaine,which is 35 times
more lipid soluble & has a potency & duration of action
to four times that of mepivacaine.
• Ropivacaine structurally resembles bupivacaine and
mepivacaine,with a propyl group on the piperidine
nitrogen atom of the molecule.

15. MECHANISM OF ACTION
• LA’s interact with a receptor within the voltage gated inactive Na+
channel and raise the threshold of opening the channel.
• They work best when the axon is firing.
• Na channel exist in 3 states:
1. Resting or nonconducting
2. Open or conducting
3. Inactivated or non conducting

17. • LA’s have a greater affinity for open or inactivated
state.
• Na+ permeability decreased & ultimately stopped in
response to stimulus or impulse.
• Impulse conduction is interrupted when a critical length
of fiber is blocked(2-3 nodes of Ranvier)

18. • As entry of Na+ is essential for AP,two things happen:
1. Rate & rise of AP and depolarization decreases-
slowing of conduction.
2. Finally,local depolarization fails to reach threshold
potential-conduction block.

20. • The effect is concentration-dependent:first,the
impulses are slowed down and then,completely
stopped.
• The binding is reversible.
• The higher the affinity of binding(or the lower the
dissociation),the higher the potency.
• Potassium channel blockage further enhances the
binding of the drug and thereby the anaesthetic
blockade itself.

21. CHEMISTRY OF LOCAL ANAESTHETICS
• Local anaesthetics exist in ionized and unionized
forms.
• Ionization of the drug affects its transportation across
the lipid plasma membrane.
• The ionized form(water-soluble but lipid insoluble) of a
LA is important as it is the most active at the receptor
site.
• However,this form has poor penetration in the neuronal
membrane.

22. MINIMUM EFFECTIVE CONCENTRATION
• The minimum concentration of local anaesthetic 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 anaesthetics.
• The Cm of motor fibers is approximately twice that of sensory
fibres;thus,sensory anaesthesia may not always be accompanied
by skeletal muscle paralysis.

23. LA DRUG AND INFLUENCE OF THE NERVE
DIAMETER AND MYELINATION

24. DIFFERENTIAL CONDUCTION BLOCKADE
Two general rules apply regarding susceptibility of nerve fibers to
LAs:
1. Smaller nerve fibres are more susceptible than large fibers &
are preferentially blocked because a shorter length of axon is
required to be blocked to halt the conduction completely.
2. Myelinated fibres are more easily blocked than non-myelinated
fibres because LA pools near the axonal membrane.This is why
C-fibers,which have a small diameter(but are unmyelinated),are
the most resistant fibers to LA.

25. ORDER OF BLOCK

26. SEQUENCE OF CLINICAL ANAESTHESIA
1. Sympathetic block(vasodilatation).
2. Loss of pain& temperature sensation.
3. Loss of proprioception.
4. Loss of touch & pressure sensation.
5. Loss of motor function.

27. COCAINE
• From leaves of Erythroxylon cocca-is an ester of benzoic
acid.
• CNS stimulant.A low dose produce euphoria.Higher dose
cause convulsion,coma,medullary depressant & death.
• Stimulate vomiting center.
• Block reuptake of catecholamine – enhances sympathetic
nervous system activity.
• CVS:bradycardia due to central vagal stimulation.Larger
dose cause tachycardia,increase TPR & hypertension-
larger may produce myocardial depression,VF & death.

28. • Increases respiratory rate,no effect on depth but high
dose depresses respiratory center.
• May be used as surface anaesthesia.
• As topical LA in ENT(5%).
• Replaced in ophthalmology due to mydriasis,clouding
of cornea,abolished protective eyelid reflexes.
• Only vasoconstrictor and the use of adrenaline is
contraindicated as it sensitizes the myocardium.
• Addiction potential

29. PROCAINE
• Topically ineffective.
• Used for infiltration because of low potency & short
duration.
• Most commonly used for spinal anaesthesia.
• Produces significant vasodilation.
• Adrenaline used to prolong effect.
• Systemic toxicity negligible because rapidly destroyed
in plasma.

30. CHLORPROCAINE
• 2 chloro derivative of procaine.
• More effective,reliable nerve block,low penetration.
• Brief action.
• Hydrolysed rapidly (4times): low toxicity,no harm to fetus.
• Hypotension,motor block more than bupivacaine.
• Epidural:prolong block,neurotoxic.
• Newer contain calcium & EDTA which causes backache
due to tetany of paraspinous muscle.

31. LIGNOCAINE
• Effective by all routes.
• Faster onset,more intense,longer lasting.
• Good alternative for those allergic to ester type.
• Quicker CNS effects than others.
• Overdose(muscle twitching,cardiac arrhythmia,fall in
BP,coma & respiratory arrest).
• Antiarrhythmic.
• Available as injections,topical solution,jelly & ointment
etc.

32. PREPARATIONS OF LIGNOCAINE

33. MEPIVACAINE
• Same potency,onset as lignocaine.
• Good penetration.
• Very potent vasoconstriction,no need for adding
vasoconstrictor.
• Higher fetal blood concentration due to ion trapping of
this drug due to lower pH of fetal blood & the pKa of
mepivacaine.

34. PRILOCAINE
• Same potency,onset as lignocaine.
• Good penetration.
• More motor blockade.
• Rapid metabolism& tissue uptake.
• Less protein bound.
• 600mg(8mg/kg) increases methHb levels from 1-5%.
• Treatment IV methylene blue(1-2 mg/kg).

35. ETIDOCAINE
• Quick onset,longer duration of action.
• High motor blockade useful for surgery requiring
intense muscle relaxation.
• Toxicity similar to bupivacaine.
• Crosses placenta.
• Rapid elimination.
• Used as 1 or 1.5%.

36. BUPIVACAINE
• This is a single use ampule 4ml vial of sterile 0.5% heavy
hydrochloride salt of 1-butyl 2,6 pipecoloxylidide.
• A long acting,high potency,slow onset amide group of LA.
• Administration in spinal anaesthesia.
• 0.5%: each ml contains 5mg bupivacaine hydrochloride and
80mg dextrose monohydrate.
• A clear,colourless & particle-free solution containing racemic (S-
and r- enantiomers).
• Molecular wt 288.4.The pH has been adjusted to 4.0 to 6.0.With a
specific gravity of 1.026 at 20℃.
• Introduced in 1963 by Eckenstam.

38. • Unique analgesia without significant motor
blockade(popular drug for analgesia during labour).
• High lipid solubility,high distribution in tissues&less in
blood(benefit to fetus).
• More cardiotoxic than other LA(prolong QT interval).

39. CONTRAINDICATIONS OF BUPIVACAINE
• Hypersensitivity to the drug or its components,amide
anaesthetics.
• Obstetric paracervical block or 0.75% concentration.
• Intravenous regional anaesthesia,intra-articular
continuous infusion.
• Liver,kidney,cardiac function impairment.
• Heart block.
• Debilitated or acutely ill patients.

40. EUTECTIC MIXTURE OF LA(EMLA)
• A 5% lidocaine-prilocaine cream at 25℃(2.5% lidocaine &
2.5% prilocaine) is EMLA.
• The melting point of the combined drug is lower.
• It acts by diffusing through intact skin to block neuronal
transmission from dermal receptors.
• Occlusive dressing prior to procedure.
• IV cannulation,split skin graft harvesting,superficial
procedure.
• Up to 5mm.
• Last for 1-2 hour.

42. BENZOCAINE
• Low aqueous solubility-Not absorbed from mucosa
or broken skin.
• Long lasting anaesthesia without systemic toxicity.
• Lozenges for stomatitis,sore throat.
• Dusting powder on wounds/ulcerated surfaces.
• Suppositories for anorectal lesions.

43. PHARMACODYNAMICS
• Potency correlates directly with lipid solubility and
molecular weight.
-More potent agents have greater affinity to Na channels.
• Onset of action depends on lipid solubility and relative
concentration of nonionized form.
-Closer the pKa to physiologic pH,greater the nonionized
fraction.

44. • Duration of action correlated with lipid solubility
-More lipid soluble,longer duration of action
-More protein bound,longer duration(to alpha-1-acid
glycoprotein) and slower elimination.
• Concentration can overcome potency if concentration
is high enough for degree of clinical blockade,but
doesnot affect duration of action(risk toxicity).

45. PHARMACOKINETICS
• ABSORPTION
• DISTRIBUTION
• METABOLISM
• CLEARANCE
• PLACENTAL TRANSFER

46. • Absorption is determined by:
-Absorption site
-Dose
-Rate of injection
-Pharmacological properties of LA
-With or without addition of adrenaline.
• Systemic absorption is proportional to vascularity.
• Vessel rich tissues result in higher systemic
concentrations.

47. • Plasma concentration after injection at various sites is:
intrapleural › intercostal › lumbar › epidural › brachial
plexus › subcutaneous › sciatic › femoral.
• First-pass pulmonary metabolism limits the concentration
of local anaesthetic which reaches the systemic circulation.
• Mucus membranes are weak barriers and lead to rapid
onset of action.
• Skin is opposite and requires high concentration of lipid
soluble LA.

48. DISTRIBUTION
• Tissue distribution of local anaesthetics is proportional
to the lipid solubility of the drug and blood supply.
• Local anaesthetics are distributed rapidly to
brain,heart,liver and lungs but more slowly to muscle
and fat which have a lower blood supply.
• The patient’s age,cardiovascular status and hepatic
function influence tissue blood flow.

49. METABOLISM
AMIDE
• Metabolized by the liver(slower than esters)
• Carboxylesterases and P450 system N-dealkylation.
• Hepatic disease may slow clearance and lead to
toxicity.
• Allergic reactions are rare.

50. ESTERS
• Hydrolysed rapidly in plasma by pseudocholinesterase
to the metabolite para-aminobenzoic acid(PABA),which
can generate an allergic reaction.

51. CLEARANCE
• Clearance of amide local anaesthetics is dependent on
hepatic metabolism.
• Metabolites may accumulate in renal failure.
• Metabolism is fastest in the rank order:
Prilocaine › lidocaine › bupivacaine

52. PLACENTAL TRANSFER
• Protein binding determines the rate and degree of
diffusion of local anaesthetics across the placenta.
• Bupivacaine-highly protein bound,umbilical vein-
maternal arterial concentration ratio of about 0.32.
• Ester local anaesthetics cross the placenta in very less
amounts – rapid metabolism.
• Acidosis in the fetus due to prolonged labour result in
accumulation of LA molecules in the fetus(ion
trapping).

53. LOCAL ANAESTHETIC ADDITIVES
• EPINEPHRINE
-Prolongs blockade time,enhances intensity of block,and
decreases systemic LA absorption.
-Alpha 2 direct analgesic effect.
-Higher concentrations may lead to clinically concerning
HTN,tachycardia,and possible tissue/nerve damage
secondary to arterial constriction and reduced blood flow.
-Avoid the use of epinephrine in digital nerve,penile blocks
and around the sciatic nerve.

54. • ALKALINIZATION OF LA SOLUTIONS
-Shortens the onset of neural blockade.
-Enhances the depth of sensory and motor blockade.
-Increases the percentage of LA existing in the lipid-
soluble form that is available to diffuse across lipid cellular
barriers.
-Adding sodium bicarbonate will speed the onset of
peripheral nerve block and epidural block by 3-5 minutes.

55. • ALPHA 2 AGONISTS(CLONIDINE)
-inhibitory effects on A and C pain fibres.
-Duration of action improved upto 2 hours.
-Effective in epidural/caudal/spinal anaesthesia.

56. CLINICAL USES OF LA
• Local infiltration
• Topical anaesthesia
• Peripheral nerve blocks
• Spinal,epidural & caudal anaesthesia
• Arrhythmic therapy
• Pain management
• To suppress sympathetic response during
endotracheal intubation.

57. OTHER USES OF LOCAL ANAESTHETICS
ANTI-INFLAMMATORY EFFECTS:
• LAs modulate inflammatory responses and may be useful
in mitigating perioperative inflammatory injury.
• The beneficial effects attributed to epidural
anaesthesia(pain relief,decreased thrombosis from
hypercoagulability) may reflect the anti-inflammatory
effects of local anaesthetics.

58. • LAs may modulate inflammatory responses by
inhibiting inflammatory mediator signaling.
• In addition,LAs inhibit neutrophil accumulation and
impair free radical and mediator release.

59. TUMESCENT LIPOSUCTION:
• Tumescent technique for liposuction characterizes the
subcutaneous infiltration of large volumes(5 L or more)
of solution containing highly diluted lidocaine(0.05% to
0.10%) with epinephrine(1:100,000).
• The taut stretching of overlying blanched skin by the
large volume of solution and epinephrine-induced
vasoconstriction is the origin of the term tumescent
technique.

60. • The result is sufficient LA for the liposuction,virtually
bloodless aspirates and prolonged postoperative
analgesia.
• When highly diluted lidocaine solutions are
administered for tumescent liposuction,the dose of
lidocaine may range from 35mg/kg to 55mg/kg(mega-
dose lidocaine).
• Tumescent liposuction is commonly used in aesthetic
contouring of thigh,abdomen,hip and its use is
increasing in reconstructive plastic surgery procedures.

61. • There are reports of increased mortality associated
with this technique.
• Cause of death may include lidocaine toxicity or local
anaesthetic-induced depression of cardiac conduction
and contractility.

62. ADVERSE EFFECTS OF LOCAL
ANAESTHETICS
1.Allergic reactions
• Allergic reactions to local anaesthetics 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 anaesthetic.

63. • The ester local anaesthetics that produce metabolites
related to para-aminobenzoic acid are more likely to
evoke an allergic reaction.
• Cross-Sensitivity:Cross-sensitivity between local
anaesthetics reflects the common metabolite para-
aminobenzoic acid.
• A similar cross-sensitivity,however,doesnot exist
between classes of local anaesthetics.

64. • Documentation of Allergy to a local
anaesthetic 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
anaesthetic-induced allergic reaction.

65. • Conversely,hypotension associated with syncope or
tachycardia when an epinephrine-containing local
anaesthetic 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 anaesthetic
solutions to eliminate the possibility that the allergic
reaction was caused by a substance other than the
local anaesthetic.

66. MUSCULOSKELETAL
• Direct injection into skeletal muscle – LA are myotoxic.
• Histopathologically cause myofibril hypercontraction.
• Lytic degeneration.
• Oedema.
• Necrosis.

67. METHAEMOGLOBINEMIA
• Methaemoglobinemia is a rare but potentially life-
threathening 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
anaesthetics(prilocaine,benzocaine,lidocaine),nitroglycerin,
phenytoin& sulfonamides.

68. • The presence of methaemoglobinemia 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).

69. LOCAL ANAESTHETIC SYSTEMIC
TOXICITY(LAST)
• Systemic toxicity of a local anaesthetic is due to an
excess plasma concentration of the drug.
• Most common mechanism is accidental direct
intravascular injection of local anaesthetic and less
often systemic absorption of LA.
• Systemic toxicity first effects CNS and then CVS.

70. CENTRAL NERVOUS SYSTEM
• Low plasma concentrations of local anaesthetics 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.

71. • 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
anaesthetics,due to variations in cerebral blood flow
& resultant delivery of drugs to the brain.

72. TRANSIENT NEUROLOGIC SYMPTOMS
• Manifest as moderate to severe pain the lower back,buttocks
& posterior thighs that appears within 6 to 36 hours after
complete recovery from uneventful single-shot spinal
anaesthesia.
• Relief of pain with trigger point injections and NSAIDS
suggests a musculoskeletal component.
• Sensory & motor neurological examination is not abnormal.
• Full recovery from transient neurologic symptoms usually
occurs within 1 to 7 days.

73. • The incidence of transient neurologic symptoms is
greatest following intrathecal injection of lidocaine(as
high as 30%).

74. CARDIOVASCULAR SYSTEM SIDE EFFECTS
• The cardiovascular system is more resistant than the
CNS to the toxic effects of high plasma concentrations
of local anaesthetics.
• Plasma lidocaine concentrations of 5 to 10
microgram/ml & equivalent plasma concentrations of
other local anaesthetics may produce profound
hypotension due to a relaxation of arteriolar vascular
smooth muscle & direct myocardial depression.

75. SELECTIVE CARDIAC TOXICITY
• The accidental intravenous injection of bupivacaine may
result in precipitous hypotension,cardiac dysrhythmias and
AV heart block.
• Pregnancy may increase sensitivity to the cardiotoxic
effects of bupivacaine,but not ropivacaine
• All LA’s depress the maximal depolarization rate of the
cardiac action potential(Vmax).

76. • Bupivacaine depresses Vmax considerably more than
lidocaine,whereas ropivacaine is intermediate in its
depressant effect on Vmax.
• Bupivacaine depresses the rapid phase of
depolarization(Vmax) in purkinje fibers & 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 & subsequent cardiac toxicity.

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

78. DIAGNOSIS OF LAST
• LAST can occur immediately at the time of
injection(usually accidental intravascular injection) or
upto an hour after it(due to delayed tissue absorption).
• Continue monitoring for 30-45 min after injection of
large volumes or toxic doses of LAs.
• Monitor patients with any signs of LAST for 2-6 hrs
because cardiovascular depression due to LAs can
persist or recur after treatment.

79. AMERICAN SOCIETY OF REGIONAL
ANAESTHESIA&PAIN MEDICINE
RECOMMENDATIONS FOR MANAGING LAST
1) If signs & symptoms of LAST occur,prompt and
effective airway management is crucial to preventing
hypoxia & acidosis,which are known to potentiate
LAST.
2) If seizures occur,they should be rapidly halted with
benzodiazepines.If benzodiazepenes are not readily
available,small doses of propofol or thiopental are
acceptable.

80. 3)Although propofol can stop seizures,large doses
further depress cardiac function;propofol should be
avoided when there are signs of CV compromise.If
seizures persist despite benzodiazepines,small doses of
succinylcholine or similar neuromuscular blocker should
be considered to minimize acidosis & hypoxemia.

81. 4)If cardiac arrest occurs,we recommend standard
Advanced Cardiac Life Support with the following
modifications:
-If epinephrine is used,small initial doses(10-100µg
boluses in the adult).
-Vasopressin is not recommended.
-Avoid calcium channel blockers & β-adrenergic receptor
blockers.
-If ventricular arrhythmias develop,amiodarone is
preferred.

82. 5)Lipid emulsion therapy:
-Consider administering at the first signs of LAST,after airway
management.
-Dosing:
*1.5mL/kg 20% lipid emulsion bolus.
*0.25mL/kg per minute of infusion,continued for at least 10
minutes after circulatory stability is attained.
*If circulatory stability is not attained,consider rebolus and
increasing infusion to 0.5mL/kg per minute.
*Approximately 10mL/kg lipid emulsion for 30 minutes is
recommended as the upper limit for initial dosing.

83. 6)Propofol is not a substitute for lipid emulsion.
7)Failure to respond to lipid emulsion and vasopressor
therapy should prompt institution of cardiopulmonary
bypass(CPB).Because there can be considerable lag in
beginning CPB,it is reasonable to notify the closest
facility capable of providing it when CV compromise is
first identified during an episode of LAST.

84. REFERENCES
• Millers’s anaesthesia.
• Stoelting’s Pharmacology& Physiology in Anaesthetic
Practice.
• Morgan&Mikhail’s Clinical Anesthesiology.