Local anaesthetic lecture Class - Final.ppt

Local anaesthesia medicine lecture class

1. Local Vs General AnaesthesiaLocal Vs General Anaesthesia
General Local
Site of action CNS Peripheral nerves
Area Whole body Restricted areas
Consciousness Lost Unaltered
Preferntial use Major surgery Minor surgery
Use in non-coperative
patients
Possible Not possible
Poor health patient Risky Safer
Care for vital functionsEssential Not needed

2. Another Classification ?Another Classification ?
•Local anesthetics are classified by their
chemistry into two classes.
What are they?
Answer
–Esters
–Amides
Short acting
Metabolized in the plasma and tissue
fluids
Excreted in urine

3. Chemistry of LAChemistry of LA
Esters
–Short acting
–Metabolized in the
plasma and tissue
fluids
–Excreted in urine
Amides
–Longer acting
–Metabolized by liver
enzymes
–Excreted in urine

4. Chemistry of LAs – contd.Chemistry of LAs – contd.
ESTER LINKAGE
AMIDE LINKAGE (2 EYES!!)
PROCAINE
procaine (Novocaine)
tetracaine (Pontocaine)
benzocaine
cocaine
LIDOCAINE
lidocaine (Xylocaine)
mepivacaine (Carbocaine)
bupivacaine (Marcaine)
etidocaine (Duranest)
ropivacaine (Naropin)

5. C
Chemistry of LA – contd. (LAs are Chemistry of LA – contd. (LAs are
Weak Bases)Weak Bases)
C O
O
R N
R
R
NH
O
R N
R
R
Aromatic portion Amine portion
Intermediate chain
ESTER
AMIDE
LIPOPHILIC
HYDROPHILIC

6. Chemistry of LAs (Clinical Chemistry of LAs (Clinical
significance) – contd.significance) – contd.
•Cross sensitivity (allergy)
–Occurs with drugs in the same chemical class
–Esters are metabolized to common metabolite PABA
–Allergy rarely occurs with amide linkage class
•Biotransformation/duration of action
–ESTERS are rapidly metabolized in the plasma by a
cholinesterase
–AMIDES are more slowly destroyed by liver
microsomal P450 enzymes.

7. Chemistry – contd.Chemistry – contd.
•Hydrophobicity: increases potency and
duration of action
-Partitioning of Drug at site of action
-Decrease in metabolism by esterases
and liver enzymes
-More receptor affinity as Na+ channel is
hydrophobic
-Increases toxicity

8. Mechanism of action of LAs:Mechanism of action of LAs:
•Prevent generation and conduction of Nerve
impulses by acting at the cell membrane:
-Decrease the entry of Na+ ions during action
potential
-Increase in LA conc. decreases the maximum
depolarization causing slowing of conduction
-Finally depolarization fails to reach threshold
potential

9. Mechanism of LA – contd.Mechanism of LA – contd.
•Effect of progressive increase of LA conc.
+30-
0 -
-30-
-60-
-90-
------------------------------------------------------
a
b

c

d

10. Mechanism of LA – contd.Mechanism of LA – contd.
•Specific (No effect on RMP)
–bind to specific receptors at the INTRACELLULAR
end of the voltage gated sodium channel
–prevent axonal conduction by a functional blockade
•LA have greatest affinity for sodium channel in
inactivated state and slows its reversion to the
resting state.

11. + +
- -
+ +
--
- -
+ + + +
- -
Na
+

+ ++ +
- - - -
Resting
(Closed**)
Open
(brief)
inactivated
Very slow
repolarization in
presence of LA
LA receptor
LA have highest
affinity for the
inactivated form
Refractory period
Mechanism of LA – contd.Mechanism of LA – contd.

12. The Sodium ChannelThe Sodium Channel

13. Voltage gated Sodium ChannelVoltage gated Sodium Channel

14. Mechanism of LA – contd.Mechanism of LA – contd.
•Degree of blockade is frequency
dependent:
-Greater blockade at higher frequency of
stimulation
-Higher concentration of Ca++ reduces
inactivation of Na+ channel
-Blockade is not due to hyperpolarization
(RMP is unaltered as K+ channels are not
blocked)

15. Influencing factor of LA actionInfluencing factor of LA action
Lipid solubility
•All local anesthetics have weak bases. Increasing the lipid solubility leads to faster
nerve penetration, block sodium channels, and speed up the onset of action.
•The more tightly local anesthetics bind to the protein, the longer the duration of onset
action.
•Local anesthetics have two forms, ionized and nonionized. The nonionized form can
cross the nerve membranes and block the sodium channels.
•So, the more nonionized presented, the faster the onset action.
Influence of pH
•Usually at range of pKa: 7.6 – 8.9
•Lower pKa (7.6 – 7.8) – faster acting (lidocaine, mepivacaine)
•Higher pKa (8.1 – 8.9) – slower acting (procaine, tetracaine, bupivacaine)
Vasoconstrictors
•Cocaine itself vasoconstrictor
•Adrenaline
–Potential adverse effects of vasoconstrictors
•DON’T use in areas of toes, fingers, ear lobes, penis (ischemia)
•May produce tissue necrosis
•May produce systemic toxicity (cardiovasc)

16. Influencing factor of LA action - Influencing factor of LA action -
contd.contd.
•Inflammation tends to produce lower pH in tissues
therefore
•LA are more ionized
•don’t penetrate very well
•decreased ability of LA to produce effects
•Alkalinized to hasten onset of neural block
–Limit to how much can alkalinize before ppt LA
–Limited increase of % in unionized form (~10%
increase)

17. Functions lost with LAFunctions lost with LA
Answer
–Pain perception
–Temperature
–Touch sensation
–Proprioception
–Skeletal muscle tone

18. Differential sensitivity of Nerve Differential sensitivity of Nerve
fibres to LAfibres to LA
•The order of blockade:
Pain – temperature – postural, touch and
pressure and vibration – motor fibres.
Tongue: bitter – sweet – sour and salt
•Small unmyelinated fibres – C fibres
•Small myelinated A-delta fibres
•Large myelinated A-alpha, A-beta and A-
delta fibres

19. Undesired effects of LA Undesired effects of LA
(toxicities)(toxicities)
•Extensions of pharmacological action
•Primarily related to blocking sodium channels
•Intensity is dependent on blood levels
•Toxic levels of LA in blood will not occur if
absorption (into systemic blood) is slow or
metabolism is rapid

20. Undesired effects of LA – contd.Undesired effects of LA – contd.
•CNS Stimulation:
•(More sensitive than cardiac)
–Dose-related spectrum of effects
and All effects are due to
depression of neurons
•First an apparent CNS
stimulation (convulsions
most serious)
•Followed by CNS depression
(death due to respir
depression)
•Premonitory signs include:
ringing in ears, metalic taste,
numbness around lips
–Cocaine - euphoria (unique in its
ability to stimulate CNS)
–Lidocaine - sedation even at non-
toxic doses

21. Undesired effects of LA – contd.Undesired effects of LA – contd.
•Cardiovascular System
–ARRHYTHMIAS: direct
effect (More resistant than
CNS)
•Decrease cardioexcitability
and contractility
•Decreased conduction rate
•Increased refractory rate
(bupivicaine)
• Note: cocaine is
exception......it stimulates
heart
•ALL can cause arrhythmias
if conc. is high enough

22. Undesired effects of LA – contd.Undesired effects of LA – contd.
•Cardiovascular System
–HYPOTENSION: Arteriolar dilation is a result of:
•Direct effect (procaine and lidocaine have most effect)
•Block of postganglionic sympathetic fiber function
•CNS depression
•Avoid by adding vasoconstrictor to the preparation
•cocaine is exception: produces vasoconstriction, blocks
catecholamine reuptake

23. •Methemoglobinemia
–Some LA metabolites have significant oxidizing
properties
–This may cause a significant conversion of
hemoglobin to methemoglobin and compromize ability
to carry oxygen
–May be a problem if cardiopulmonary reserve is
limited
–Treat with oxygen and methylene blue (converts
methemoglobin to hemoglobin)
•prilocaine benzocaine lidocaine have been implicated
Undesired effects of LA – contd.Undesired effects of LA – contd.

24. Undesired effects of LA – contd.Undesired effects of LA – contd.
•Hypersensitivity:
Common with ester-linked LA
Rashes, angio-edema, dermatitis and rare
anaphylaxis
Sometimes typical asthmatic attack

25. Undesired effects of LA – contd.Undesired effects of LA – contd.
•NEUROTOXICITY
–LA can cause concentration-dependent nerve
damage to central and peripheral NS
–Mechanism(s) not clear
–Permanent neurological injury is rare
–May account for transient neurological
symptoms after spinal anesthesia
•Cauda equina syndrome

26. Pharmacokinetic of LAPharmacokinetic of LA
•Absorption:
-Surface anesthetics from mucus membrane and abraded
areas
-Depends on Blood flow to the area, total dose and
specific drug characteristics
-Procaine has poor penetration in mucus membrane
-Procaine is negligibly bound to plasma protein but
amides are bound to alpha 1 acid glycoprotein
•Distribution:
- Widely distributed in the body: (lipophilic)
-Enters brain, heart, liver and kidney
-Followed by muscle and other viscera

27. Pharmacokinetic of LA – contd.Pharmacokinetic of LA – contd.
•METABOLISM
–Ester type LA
•Hydrolysis by cholinesterase in plasma to PABA derivatives
–pseudo cholinesterase or butrylcholinesterase
•Generally, short acting and low systemic toxicity
•Prolonged effects seen with genetically determined deficiency or
altered esterase (cholinesterase inhibitors)
- Amide type LA
•Bound to alpha1 acid glycoprotein
•Hydrolyzed by liver microsomal enzymes (P450)
•Longer acting & more systemic toxicity than esters
•High first pass metabolism on oral ingestion

28. Individual LA - EstersIndividual LA - Esters
Cocaine:
•Natural alkaloid from Erythroxylon coca
•Medical use limited to surface or topical
anesthesia (corneal or nasopharyngeal)
•Avoid adrenaline because cocaine already has
vasoconstrictor properties. (EXCEPTION!!!)
•A toxic action on heart may induce rapid and
lethal cardiac failure
•A marked pyrexia is associated with cocaine
overdose
•Not used presently

29. Esters – contd.Esters – contd.
Procaine (Novocaine)
–Topically ineffective
–Used for infiltration because of low potency and short
duration but most commonly used for spinal
anesthesia
–Short local duration ......produces significant
vasodilation. Adrenaline used to prolong effect
–Systemic toxicity negligible because rapidly destroyed
in plasma
–Procaine penicillin

30. Individual LA - AmidesIndividual LA - Amides
LIDOCAINE (Xylocaine) Most widely used LA
–Effective by all routes.
–Faster onset (3 Vs 15 min), more intense, longer lasting, than
procaine.
–Good alternative for those allergic to ester type
–More potent than procaine but about equal toxicity
–Quicker CNS effects than others (drowsiness, mental clouding,
altered taste and tinnitus)
–Overdose (muscle twitching, cardiac arrhythmia, fall in BP, coma
and respiratory arrest)
–Antiarrhythmic
–Available as Injections, topical solution, jelly and ointment etc.

31. Individual LA (Amides) – contd.Individual LA (Amides) – contd.
Bupivacaine (Marcaine)
–No topical effect
–Slower onset and one of longer duration agents
–Used for infiltration, spinal, nerve block and epidural
–Unique property analgesia without significant motor
blockade (popular drug for analgesia during labor)
–High lipid solubility, high distribution in tissues and
less in blood (benefit to fetus)
–More cardio toxic than other LA (prolong QT interval)
–Available as 0.25%, 0.5% inj.

32. ConclusionConclusion
Anesthetic pKa Onset Duration
(with
Adrenaline)
in minutes
Max Dose
(with
adrenaline)
Procaine 9.1 Slow 45 - 90 8mg/kg –
10mg/kg
Lidocaine7.9 Rapid 120 - 2404.5mg/kg –
7mg/kg
Bupivacaine8.1 Slow 4 hours – 8
hours
2.5mg/kg –
3mg/kg

33. Individual LA (Amides) – contd.Individual LA (Amides) – contd.
EMLA = eutectic mixture of local anesthetics
–Eutectic = two solid substances mixed
together in equal quantities by weight form a
eutectic mixture
–the melting point of the mixture is lower than
the melting points of the individual
components
•EMLA = lidocaine and prilocaine becomes
an oily mixture

34. Individual LA (Amides) – contd.Individual LA (Amides) – contd.
lidocaine/prilocaine combination is indicated for
dermal anaesthesia
–Specifically it is applied to prevent pain associated
with intravenous catheter insertion, blood sampling,
superficial surgical procedures; and topical
anaesthesia of leg ulcers for cleansing or
debridement
–it can also be used to numb the skin before tattooing.
–EMLA cream is also used in the treatment of
premature ejaculation

35. Individual LA (Amides) – contd.Individual LA (Amides) – contd.
TAC:
•tetracaine 0.5%, adrenaline1 in 2000 and
cocaine 10%
•topical anesthetic mixture found to be effective
for nonmucosal skin lacerations to the face and
scalp
•applied directly to the wound using a cotton-
tipped applicator with firm pressure that is
maintained for 20 to 40 minutes
•maximum dose for children-0.05ml/Kg
•toxicity due to cocaine

36. EMLA applicationEMLA application

37. CLINICAL APPLICATIONS (TECHNIQUES) CLINICAL APPLICATIONS (TECHNIQUES)
OF LOCAL ANAESTHESIAOF LOCAL ANAESTHESIA
•SURFACE ANESTHESIA (Topical)
–Mucous membranes and abraded skin
–Nose, mouth, bronchial tree, cornea and
urinary tracts
•Lidocaine, tetracaine

38. Sites of LA administrationSites of LA administration

39. Clinical applications of LA – contd.Clinical applications of LA – contd.
•INFILTRATION ANESTHESIA
–Direct injection into tissues to reach nerve
branches and terminals
–Used in minor surgery = incisions, hydrocele,
herniorrhaphy, etc.
–Immediate onset with variable duration
–Motor function not lost
–Most LA’s used

40. Clinical applications of LA – contd.Clinical applications of LA – contd.
Field block:
•Injection of LA subcutaneously
•Aim is to anaesthetize the region distal to the
site of injection
•Anaesthesia starts 2-3 cm distal to site of
injection
•All nerves coming to the field are blocked
•Examples – forearm, anterior abdominal wall,
scalp and lower extremity
•Knowledge of neuroanatomy is required

41. Clinical applications of LA – contd.Clinical applications of LA – contd.
Nerve Block:
-LA is injected around the nerve trunks or plexuses
-Area of anaesthesia is large in comparison to the amount of drug used
-Lasts longer than the field or infiltration methods
-Flooding technique for plexus block
Examples:
-Trigeminal nerve blocks (face)
-Ophthalmic nerve block (eyelids and scalp)
-Supraorbital nerve block (forehead)
-Maxillary nerve block (upper jaw)
-Sphenopalatine nerve block (nose and palate)
-Cervical epidural, thoracic epidural, and lumbar epidural block (neck and back)
-Cervical plexus block and cervical paravertebral block (shoulder and upper neck)
-Brachial plexus block, elbow block, and wrist block (shoulder/arm/hand, elbow, and
wrist)
-Subarachnoid block and
 
coeliac 
plexus block (abdomen)

42. Clinical applications of LA – contd.Clinical applications of LA – contd.
Spinal anaesthesia:
•Site of injection – Subarachnoid space between L2-3 or L3-4
•Site of action – nerve root in the cauda equina
•Level of anaesthesia – vol. & speed of injection; baricity of drug
soln. with CSF and posture of patient
•Order of anaesthesia – sympathetic > motor
•Uses – lower limbs, pelvis, lower abdomen, prostatectomy fracture
setting and obstetric procedures
•Problems - Spinal headache, hypotension, bradycardia and
respiratory depression, cauda equina syndrome and nausea-
vomiting
•
Drugs - Lidocaine, tetracaine

43. Clinical applications of LA – contd.Clinical applications of LA – contd.
EPIDURAL AND CAUDAL ANESTHESIA
Site of injection – sacral hiatus (caudal) or lumber,
thoracic or cervical region
Catheters are used for continuous infusion
Used like spinal and also painless childbirth.
Unwanted effects similar to that of spinal except less
likely because longitudinal spread is reduced.
Lidocaine, bupivacaine, ropivacaine

44. Clinical applications of LA – contd.Clinical applications of LA – contd.
Regional anaesthesia (Intravenous)
-Injection of LA in a vein of a torniquet
occluded limb
-Mostly limited to upper limb
-Orthopaedic procedures

45. THINGS TO REMEMBER THINGS TO REMEMBER
(Precautions)(Precautions)
•Aspirate lightly before injection
•Make injections slowly and not to exceed
maximum safe dose
•Avoid ß Blockers (Propranolol)
•Have drugs available to manage adverse effects
•Avoid vasoconstrictors in IHD, Cardiac
arrhythmia, thyrotoxicosis, ß Blockers and TCA
•Don’t take food or liquids < 60 minutes after oral
topical application .... gag, swallow, cough
reflexes may be not working

46. Newer Techniques of LANewer Techniques of LA
Iontophoresis: Lidocaine-soaked sponges

47. Newer Techniques of LANewer Techniques of LA
Liposomes: Liposomal Bupivacaine Formulation

48. B + H
+
BH
+
(active form)
B + H
+
BH
+
B + H
+
BH
+
axoplasm
B
Specific
action
Non-specific action
pH = 7.4
pH = 6.9
pH = 7.4
Most LA are
in this form
at pH 7.4
Nerve sheathT
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k Y
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