Local anaesthetis /certified fixed orthodontic courses by Indian dental academy

LOCAL
ANAESTHETICS
INDIAN DENTAL ACADEMY
Leader in continuing dental education
www.indiandentalacademy.com


Introduction.
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LA are drugs that produce reversible
depression of nerve impulse and
conduction when applied to nerve fibres
The ester group of LA were first used in
1884 – cocaine for topical use in
opthalmology
Amino amide LA were manufactured in
1943 – lidnocaine, since then many newer
safer LA has been produced

IDEAL PROPERTIES
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Physiochemical properties
Easy to produce and economical
Stability during storage
Easy aaccessibility; appropriate packaging and
labelling
Formulation (where possible, additive free)
Soluble in water
Sterilisable by heat without decomposition

IDEAL PROPERTIES cont.
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Pharmacokinetics
Ease of administration
Rapid onset
Duration appropriate to use
Clearance independent of hepatic and renal
function
No active or toxic metabolites


IDEAL PROPERTIES cont.
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Pharmacodynamics

High therapeutics ratio
No hypersensitivity reaction
Absence of toxicity on : local tissue, liver, brain and other
tissue
Nervous depression, especially of sensory fibres
Administration should be effective by topical application,
injection near a nerve trunk or infiltration
Specificity – only nerve tissue should be affected


Chemistry and Structure Activity
Relationship
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All typical LA contain h.philic and h.phobic
domain that are separated by intermediate alkyl
chain
The h.philic grp usually tertiary amine
The h.phobic grp usually an aromatic residue
Intermediate bond is either of the ester or amide
type – determines many of the properties of the
agent


Cont.

Hydrophobic
group

Aromatic
residue

Intermediate
alkyl

Intermediate
alkyl


Hydrophilic
group

Tertiary
amine

Cont.
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Intermediate chain = either ester or amide
Determines many of the properties of the agent
Classification of LA
Changes to any part of the molecule lead to
alteration in activity and tocxicity
Increase length of intermed. Alkyl group will
increase potency up to critical length  increase
further will increase toxicity


Cont.
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Length of two terminal group are also
equally important
Eg. Add butyl group to mepivacain 
bupivacain
Inc. lipid solubility
Greater potency
Longer duration of action

Mode of action
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All has similar MOA
Most LA bind to Na channels in the inactivated state,
preventing subsequent channel activation and the large
transient Na influx associated with mb depn.
Marked depression of rate of depn
Failed to reach TP  no propogation of AP  neural
blockage
LA act in their cationic form but most reach their site of
action by penetrating the nerve sheath and axonal mb as
unionized species


Cont.
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Some LA act by
Penetrating the mb, causing mb expansion and
channel distortion (analogous to the critical
volume hypothesis)
Partial penetration by LA of the axonal mb could
increase the transmembrane potential and inhibit
depn. (surface charge theory)


Differential sensitivity of nerve fibre
class

Aα
Aβ
Aχ
Aδ
B
C

mylination

Functions

diamete
r

Conductio
n

heavy

12-20

velocity
70-120

Moderate

5-12

30-70

Touch and pressure

Moderately

3-6

15-30

Motor to muscle spindle

lightly

2-5

12-30

Pain, temperature, touch

lightly

1-3

3-15

Preganglionic autonomic

None

0.4-1.2

0.7-1.3

none

0.3-1.3

0.7-1.3

Pain & reflex response

Motor and propioception

Postganglionic sympathetics


Factors influence
potency,speed of onset and
duration of action
 POTENCY
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1. Lipophilic nature = lipid solubility
Inc. lipid solubility = inc potency
(penetrare mb more easily)
less molecule required for nerve blockage
Inc alkyl substitution to aromatic ring and
amine  inc lipophilic nature


Cont.
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2. Partition coefficient /
vasodilatation
? Lidocaine > potent than mepivicaine in
vitro
vasodilatation
Bupivacaine > Etidocaine in vivo
inc fat uptake

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2. SPEED OF ONSET
1. Unionized fraction / pKa & pH
Weak bases tend to be relatively ionized at high
concentration H+
The uncharged form diffuse more readily across
nerve mb  determine the onset of LA
Mechanism of ion trapping?
Onset of blockage ∝ pKa


Cont.
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2. Fick’s Law of diffusion
D ∝ A.Pc.(P1-P2)
/MW.T


Cont.
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3. Lipid solubility
Its effect on onset is poorly understood
?high lipid solubility  inc rate of diff and
shorten onset time BUT it also inc
solubility in the surrounding tissue


Cont.
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4. Barrier eg. Nerve root
Epineurium
Perineurium
Endoneurium
! Subarachnoid block rapid onset because
nerve rootlets are almost completely bare
of fibrous

Cont.
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Sensitivity ∝ 1/size
Autonomic > sensory >
Small, unmyelinated
medium, < myelin
Order of blockage :

motor
large, myelinated

B – C, Ad – Ag – Ab - Aa


Cont.
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Duration of blockage

Protein binding regulate the duration of
anaesthetic activity
 Due to protein binding of LA to protein receptor
in the Na channel of nerve mb
Highly protein bound will remain for a long time
Procain  6% protein bound
Ropi, bupi, etidocaine  94-96% prot. bound



Factors affecting anaesthetic activity
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∀
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Dosage
↑ mass injected (vol x conc.)
Red onset time
Inc duration
Inc depth


Cont.
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Addition of vasoconstictor

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Red LA absorption
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inc depth
inc duration
red toxicity


cont
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Site of injection

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Carbonation

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Mixture of LA
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Chloroprocaine & bupivacaine


PHARMACOKINETICS
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Plasma concentration : depends on
 absorption kinetics
 systemic disposition kinetics
Distribution
Elimination
 metabolism
 excretion

Absorption of LA
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Site of injection ( intercostal > caudal >
brachial plexus etc )
Dosage (blood level of LA related to total
dose of drug rather than spesific volume
or concentration of solution
Addition of vasoconstrictor
Disease process


Systemic disposition kinetics
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Ultimate plasma conc. Of LA is determined by
rate of tissue distribution and rate of clearance
(metabolism and excretion ) of the drug
Distribution depends on
Tissue perfusion ( alpha and beta phase)
Tissue/blood partision coefficient
Tissue mass
Lung extract significant amount of LA


Cont.
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Placental transfer
Protein binding ( lidocaine > bupivacaine X
placental )
Acidosis in fetus ( ion trapping )
Ester LA – rapid hydrolysis not available to cross
placental in significant amount
Clearance
Mainly hepatic metabolism
Minimal renal excretion

Metabolism of LA
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A. ESTERS
Rapid hydrolysis by plasma cholinesterase
Water soluble metabolites excreted in the urine
(p-aminobenzoic, diethylaminoethanol
Abnormal pseudocholinesterase  inc risk of
toxic side effect
CSF lack of esterase enzyme
Exception Cocain - partially metabolized in liver
and partially excreted in urine unchanged


Cont.
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B. AMIDE
Enzymatic degradation in liver by microsomal
enzymes (prilocaine > lidnocaine > mepivacaine
> bupivacaine and etidocaine )
Much slower than ester hydrolysis
N-dealkylation, aromatic and amide hydrolysis
Decrease hepatic function or hepatic blood flow
reduce metabolic rate  pred systemic toxicity
Very little drug excreted unchanged by kidney


Cont.
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Metabolite of prilocaine (o-toluidine ) which
accumulate after large dose (>10mg/kg) convert
hemoglobin to methemoglobin
Prilocaine epidural labour
Benzocaine also may cause
methemoglobinemia
Tx iv methylene blue @ 1-2 mg/kg of 1% over 5
minutes  reduce methemoglobin ( Fe3+ ) to
hemoglobin ( Fe2+ )


cont
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Renal
Poor water solubility of LA – limit renal
excretion of unchange drug to < 5% of
injected dose (except cocain 10-12%
urine)
Water soluble metabolites paraaminobenzoic acid readily excreted in the
urine


Side effects
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Toxicity often directly proportionate to its
potency
Mixture of LA roughly give additive toxic
effect
In addition to blocking transmission in the
nerve axon, LA affect all tissue where
conduction of impulse occur, therefore in
The CNS
Autonomic ganglia
The NMJ
All form of muscle fibre, esp cardiac

CVS
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Affect both myocardium and peripheral
vascular smooth muscle
Primary site is myocardium once absorbed
Effects : ↓conduction, contractility and
excitability
CVS effect are seen at ↑ dose, when CNS
effects are already evident
Inadvertent iv adm may lead to suddent
death
!VF, it is more likely if soln contain
adrenalin

Cont.
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At Tx conc lidocaine cause no ECG change
↑ to toxic level, prolonged conduction  ↑PR
and QRS interval
Very ↑suppress SAN  sinus brady/arrest
and also ↓AVN  AV block ± dissociation
Cardiac toxicity of bupivacaine ppt VF
Bupivacaine markedly depress dV/dt
Slow rate of recovery  arrhytmias
Produce direct pulm vasoconstrictive effect


Cont
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Most LA cause biphasic peripheral
arteriolar response, with initial
vasoconstriction then vasodilatation
As dose ↑ action change to inhibition/Vdil
Cocaine produce vasoconstriction at most
doses, inhibit noradrenalin uptake by
tissue binding site


RESPIRATORY
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Depress hypoxic drive
Apnoea can result from phrenic and IC nerve
paralysis or depression of medulla RC
LA relax bronchial smooth muscle
Iv lidocaine 1.5 g/kg red reflex b/constriction
upon intubation
Occationally direct LA aerosol  b/spasm


NEUROLOGICAL
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Earliest signs are circumoral and tongue numbness,
tinnitus, nystagmus and dizziness
Following absorption, all nitrogenous LA cause CNS
excitation
Restlessness, tremor, eventually tonic-clonic fits
CNS stimulation then followed by depression
Death usually d/t subsequent respiratory depression
Both stimulation and depression are thought to be d/t
neuronal depression
↓ in inhibitory p/w in ARAS being responsible for the
excitatory effects
Ventilatory support may be req. later
Convultion can be controlled by barbiturate eg
diazepam

Cont.
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Factors affecting the occurance of
CNS toxicity:
Relative toxicity  approx LA potency
Rate of injection  r[plasma] achieved
pCO2  inversely related to fit threshold
pH ↓pH  ↓fit threshold


IMMUNOLOGICAL
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True allergy to LA are uncommon
Ester are more likely – ester derivative
para aminobenzoic acid is a known
allergen
Amide often contain methylparaben as
additive – structure similar to PABA
LA may inhibit neutrophil fx and
theoritically may retard wound healing

MUSCULOSKELETAL
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Direct inj into skeletal muscle  LA are
myotoxic
Histopathologically cause myofibril
hypercontraction  lytic degeneration 
oedema  necrosis


HEMATOLOGICAL
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Lidocaine demonstrate redn coagulation
(prevent thrombosis and platelet
aggregation) and enhance fibrinolysis
Lower incident of embolic event in patient
receiving epidural anaesthesia


Cont
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Plasma lignocaine concentration ( µ g/ml)

CVS collapse------------------------26 -

Respiratory arrest------------------20 -

Coma--------------------------------15 --
Unconsciousness------------------12 --Convulsions------------------------10 --Muscular twitching--------------- -8 ---Visual disturbance-----------------6 ---4
positive inotrophy
Light headedness,tinnitus-------- 2 -- } anticonvulsant
Circumoral&tongue numbness 0
antiarrhytmic


Drug interaction
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Non depolarising muscle relaxant blockade is
potentiated by LA
Concurrent administration of succinylcholine and
an ester LA may potentiate the effect of both
drugs (pseudocholinesterase dependant)
Dibucaine inhibit pseudocholinesterase
Cimetidine and propanolol red liver blood flow
and lidocaine clearance
Opiods and a2 agonist potentiate LA pain relief

Contraindication
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Allergy/hypersensitivity to LA / sol. Additives
Adrenalin is contraindicated for
Tachycardia! (thyrotoxicosis,CCF,IHD)
Anesthesia around end arteries
Iv regional anaesthesia
Epidural/spinal anaesthesia in the presence of
significant
Hypotention/hypovolaemia
Coagulopathy
Presence of local tissue sepsis
Patient refusal


Precautions
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Resuscitation equipment and drugs should be available
Reliable iv access
Injection should follow aspiration TRO iv inj
Lowest effective dose possible
Careful in pt with
Pre-existing CNS & cardiac disorder
Cardiac glycoside toxicity
Hepatic or renal impairment
Pred to malignant hyperthermia
Porphria
Fetal bradycardia after Xcess maternal adm with subsequent
hypoxia and acidosis
Retrobulbar block have been a/w respiratory areest


lidocaine
pKa 7.85
Plain aq solution 1, 1.5, 2% @ pH 5-7
Solution with adrenalin @ pH 3-4.5
Ralative potency 2
T1/2ß adult 1.8 hr, neonate 2hr
Xtremely stable
Max dose : plain 3mg/kg, adrenalin 7mg/kg
E.A. of 400mg/70kg @ [blood] = 2-4ug/ml
Toxicity begin @5 ug/ml
Relatively quickly absorbed from GIT
Metab in liver (dealkylation)  excreted urine
Toxic dose lead to death by VF or cardiac arrest
Suitable for surface, infiltration,nerve block, caudal, epidural and SA


Bupivacaine
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pKa 8.1
Plain aq soln .25, .375, .5% @ pH 4.5-6
If with adrenalin pH 3.5-5.5
Potency 8
Protein binding 95%
> lipid solubility than lidocaine
T1/2ß adult 3.5hr, neonate 8.1-14hr
Amide link LA
Prod prolonged anaesthesia with slower onset
Add adrenalin - ↓toxicity, h/e no change in duration
Post op analgesia : IC 7hr, EA 3-4hr
Epid/caudal peak [plasma] 30-45 min
Lower foetal/maternal ratio cf lidnocaine (! Protein binding)
Max dose : plain/with adrenalin 2 mg/kg


Ropivacaine
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Chemical analogue of bupivacaine
The molecule is designed to modify the spesific
cardiotoxicity associated with bupivacaine
pKa 8.2 and pH solution 5.5-6.0
Equally potent as bupivacaine
Its quality of clinical block appear to be very
similar in onset, duration and quality that of
bupivacaine
No spesific toxicity has been detected


Cocaine
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From leaves of erytroxylon coca – is an ester of benzoic
acid
CNS stimulant. At low dose produce euphoria. Higher
dose cause convulsion, coma, medullary depressant and
death
Stimulate vomiting centre
Block reuptake of catecholamine  enhance SNS
activity
Small dose may cause bradycardia d/t central vagal
stimulation
Larger dose cause tachycardia, inc TPR and
hypertention  larger may produce myocardial
depression, VF and death

cont
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May be used as surface anaesthesia
As topical LA in ENT (5%)
Cocain itself constrict blood vessel and the
use of adrenalin is contraindicated as it
sensitises the myocardium


Uses of LA
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Surface anaesthesia
Infiltration anaesthesia
Nerve block anaesthesia (peripheral,plexus)
Intravenous regional anaesthesia
Spinal/subarachnoid anaesthesia
Other uses (antiarrhytmic, reduction in ICP,
Blunting of CVS responses to intubation and
extubation


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