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

www.indiandent...
Introduction.
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LA are drugs that produce reversible
depression of nerve impulse and
conduction when applied to ner...
IDEAL PROPERTIES
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Physiochemical properties
Easy to produce and economical
Stability during storage
Easy aa...
IDEAL PROPERTIES cont.
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Pharmacokinetics
Ease of administration
Rapid onset
Duration appropriate to use
Clear...
IDEAL PROPERTIES cont.
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Pharmacodynamics

High therapeutics ratio
No hypersensitivity reaction
Absence of ...
Chemistry and Structure Activity
Relationship
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All typical LA contain h.philic and h.phobic
domain that are separ...
Cont.

Hydrophobic
group

Aromatic
residue

Intermediate
alkyl

Intermediate
alkyl

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Hydrophil...
Cont.
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Intermediate chain = either ester or amide
Determines many of the properties of the agent
Classification...
Cont.
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



Length of two terminal group are also
equally important
Eg. Add butyl group to mepivacain 
bupivacain
...
Mode of action

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
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All has similar MOA
Most LA bind to Na channels in the inactivated state,
preventing subsequen...
Cont.





Some LA act by
Penetrating the mb, causing mb expansion and
channel distortion (analogous to the critical
vo...
Differential sensitivity of nerve fibre
class

Aα
Aβ
Aχ
Aδ
B
C

mylination

Functions

diamete
r

Conductio
n

heavy

12-2...
Factors influence
potency,speed of onset and
duration of action
 POTENCY
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
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1. Lipophilic nature = lipid solubilit...
Cont.
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
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2. Partition coefficient /
vasodilatation
? Lidocaine > potent than mepivicaine in
vitro
vasodilatation...
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2. SPEED OF ONSET
1. Unionized fraction / pKa & pH
Weak bases tend to be relatively ionized at high
concent...
Cont.
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
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2. Fick’s Law of diffusion
D ∝ A.Pc.(P1-P2)
/MW.T

www.indiandentalacademy.com
Cont.
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
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3. Lipid solubility
Its effect on onset is poorly understood
?high lipid solubility  inc rate of diff and
s...
Cont.
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4. Barrier eg. Nerve root
Epineurium
Perineurium
Endoneurium
! Subarachnoid block rapid onset because
ner...
Cont.
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Sensitivity ∝ 1/size
Autonomic > sensory >
Small, unmyelinated
medium, < myelin
Order of blockage :

motor...
Cont.


Duration of blockage

Protein binding regulate the duration of
anaesthetic activity
 Due to protein binding of L...
Factors affecting anaesthetic activity
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∀
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Dosage
↑ mass injected (vol x conc.)
Red onset time
Inc duration
Inc de...
Cont.


Addition of vasoconstictor



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

www.indiandentala...
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

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PHARMACOKINETICS
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Plasma concentration : depends on
 absorption kinetics
 systemic disposition kinetics
Di...
Absorption of LA
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Site of injection ( intercostal > caudal >
brachial plexus etc )
Dosage (blood level of LA rel...
Systemic disposition kinetics
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•

Ultimate plasma conc. Of LA is determined by
rate of tissue distribution and r...
Cont.
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Placental transfer
Protein binding ( lidocaine > bupivacaine X
placental )
Acidosis in fetus ( ion ...
Metabolism of LA

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A. ESTERS
Rapid hydrolysis by plasma cholinesterase
Water soluble metabolites excreted in ...
Cont.
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B. AMIDE
Enzymatic degradation in liver by microsomal
enzymes (prilocaine > lidnocaine > mepivacaine
...
Cont.
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
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Metabolite of prilocaine (o-toluidine ) which
accumulate after large dose (>10mg/kg) convert
hemoglobin t...
cont
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Renal
Poor water solubility of LA – limit renal
excretion of unchange drug to < 5% of
injected dose (except c...
Side effects
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
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Toxicity often directly proportionate to its
potency
Mixture of LA roughly give additive to...
CVS
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Affect both myocardium and peripheral
vascular smooth muscle
Primary site is myocardium once absorbed
Ef...
Cont.
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At Tx conc lidocaine cause no ECG change
↑ to toxic level, prolonged conduction  ↑PR
and QRS inter...
Cont
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Most LA cause biphasic peripheral
arteriolar response, with initial
vasoconstriction then vasodilatation
As d...
RESPIRATORY
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Depress hypoxic drive
Apnoea can result from phrenic and IC nerve
paralysis or depression of medu...
NEUROLOGICAL


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
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
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Earliest signs are circumoral and tongue numbness,
tinnitus, nystagmus and dizziness
Follo...
Cont.
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

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Factors affecting the occurance of
CNS toxicity:
Relative toxicity  approx LA potency
Rate of injection...
IMMUNOLOGICAL
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True allergy to LA are uncommon
Ester are more likely – ester derivative
para aminobenzoic acid i...
MUSCULOSKELETAL
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Direct inj into skeletal muscle  LA are
myotoxic
Histopathologically cause myofibril
hypercontracti...
HEMATOLOGICAL
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Lidocaine demonstrate redn coagulation
(prevent thrombosis and platelet
aggregation) and enhance fibri...
Cont
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Plasma lignocaine concentration ( µ g/ml)  

CVS collapse------------------------26...
Drug interaction
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Non depolarising muscle relaxant blockade is
potentiated by LA
Concurrent administration of...
Contraindication
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Allergy/hypersensitivity to LA / sol. Additives
Adrenalin is contraindicated for
Ta...
Precautions
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Resuscitation equipment and drugs should be available
Reliable iv access
Injection sh...
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...
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
Pote...
Ropivacaine
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Chemical analogue of bupivacaine
The molecule is designed to modify the spesific
cardiotoxicity...
Cocaine
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From leaves of erytroxylon coca – is an ester of benzoic
acid
CNS stimulant. At low dose produce ...
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 ...
Uses of LA
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Surface anaesthesia
Infiltration anaesthesia
Nerve block anaesthesia (peripheral,plexus)
Intraveno...
Thank you
For more details please visit
www.indiandentalacademy.com

www.indiandentalacademy.com
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Local anaesthetis /certified fixed orthodontic courses by Indian dental academy

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The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.

Indian dental academy provides dental crown & Bridge,rotary endodontics,fixed orthodontics,
Dental implants courses.for details pls visit www.indiandentalacademy.com ,or call
0091-9248678078

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Local anaesthetis /certified fixed orthodontic courses by Indian dental academy

  1. 1. LOCAL ANAESTHETICS INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com www.indiandentalacademy.com
  2. 2. Introduction.    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 www.indiandentalacademy.com
  3. 3. IDEAL PROPERTIES        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 www.indiandentalacademy.com
  4. 4. IDEAL PROPERTIES cont.       Pharmacokinetics Ease of administration Rapid onset Duration appropriate to use Clearance independent of hepatic and renal function No active or toxic metabolites www.indiandentalacademy.com
  5. 5. IDEAL PROPERTIES cont.        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 www.indiandentalacademy.com
  6. 6. Chemistry and Structure Activity Relationship     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 www.indiandentalacademy.com
  7. 7. Cont. Hydrophobic group Aromatic residue Intermediate alkyl Intermediate alkyl www.indiandentalacademy.com Hydrophilic group Tertiary amine
  8. 8. Cont.      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 www.indiandentalacademy.com
  9. 9. Cont.      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 www.indiandentalacademy.com
  10. 10. Mode of action      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 www.indiandentalacademy.com
  11. 11. Cont.    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) www.indiandentalacademy.com
  12. 12. 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 www.indiandentalacademy.com
  13. 13. Factors influence potency,speed of onset and duration of action  POTENCY     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 www.indiandentalacademy.com
  14. 14. Cont.      2. Partition coefficient / vasodilatation ? Lidocaine > potent than mepivicaine in vitro vasodilatation Bupivacaine > Etidocaine in vivo inc fat uptake www.indiandentalacademy.com
  15. 15.       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 www.indiandentalacademy.com
  16. 16. Cont.    2. Fick’s Law of diffusion D ∝ A.Pc.(P1-P2) /MW.T www.indiandentalacademy.com
  17. 17. Cont.    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 www.indiandentalacademy.com
  18. 18. Cont.      4. Barrier eg. Nerve root Epineurium Perineurium Endoneurium ! Subarachnoid block rapid onset because nerve rootlets are almost completely bare of fibrous www.indiandentalacademy.com
  19. 19. Cont.     Sensitivity ∝ 1/size Autonomic > sensory > Small, unmyelinated medium, < myelin Order of blockage : motor large, myelinated B – C, Ad – Ag – Ab - Aa www.indiandentalacademy.com
  20. 20. Cont.  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  www.indiandentalacademy.com
  21. 21. Factors affecting anaesthetic activity  ∀    Dosage ↑ mass injected (vol x conc.) Red onset time Inc duration Inc depth www.indiandentalacademy.com
  22. 22. Cont.  Addition of vasoconstictor  Red LA absorption    inc depth inc duration red toxicity www.indiandentalacademy.com
  23. 23. cont  Site of injection  Carbonation  Mixture of LA  Chloroprocaine & bupivacaine www.indiandentalacademy.com
  24. 24. PHARMACOKINETICS        Plasma concentration : depends on  absorption kinetics  systemic disposition kinetics Distribution Elimination  metabolism  excretion www.indiandentalacademy.com
  25. 25. Absorption of LA     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 www.indiandentalacademy.com
  26. 26. Systemic disposition kinetics      • 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 www.indiandentalacademy.com
  27. 27. Cont.        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 www.indiandentalacademy.com
  28. 28. Metabolism of LA       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 www.indiandentalacademy.com
  29. 29. Cont.       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 www.indiandentalacademy.com
  30. 30. Cont.     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+ ) www.indiandentalacademy.com
  31. 31. cont    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 www.indiandentalacademy.com
  32. 32. Side effects        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 www.indiandentalacademy.com
  33. 33. CVS      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 www.indiandentalacademy.com
  34. 34. Cont.        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 www.indiandentalacademy.com
  35. 35. Cont    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 www.indiandentalacademy.com
  36. 36. RESPIRATORY      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 www.indiandentalacademy.com
  37. 37. NEUROLOGICAL          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 www.indiandentalacademy.com
  38. 38. Cont.      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 www.indiandentalacademy.com
  39. 39. IMMUNOLOGICAL     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 www.indiandentalacademy.com
  40. 40. MUSCULOSKELETAL   Direct inj into skeletal muscle  LA are myotoxic Histopathologically cause myofibril hypercontraction  lytic degeneration  oedema  necrosis www.indiandentalacademy.com
  41. 41. HEMATOLOGICAL   Lidocaine demonstrate redn coagulation (prevent thrombosis and platelet aggregation) and enhance fibrinolysis Lower incident of embolic event in patient receiving epidural anaesthesia www.indiandentalacademy.com
  42. 42. Cont                 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 www.indiandentalacademy.com
  43. 43. Drug interaction      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 www.indiandentalacademy.com
  44. 44. Contraindication           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 www.indiandentalacademy.com
  45. 45. Precautions             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 www.indiandentalacademy.com
  46. 46. 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 www.indiandentalacademy.com
  47. 47. Bupivacaine               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 www.indiandentalacademy.com
  48. 48. Ropivacaine       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 www.indiandentalacademy.com
  49. 49. Cocaine       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 www.indiandentalacademy.com
  50. 50. cont    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 www.indiandentalacademy.com
  51. 51. Uses of LA       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 www.indiandentalacademy.com
  52. 52. Thank you For more details please visit www.indiandentalacademy.com www.indiandentalacademy.com

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