2. DEFINITION
LA are drugs which block, generation and conduction of nerve impulse
at all parts of neurons where they come in contact.
Drugs which upon topical application or local injection causes reversible
loss of pain, in the restricted region of body without causing permanent
damage to the tissue.
Applied to mixed nerves causes interruption of sensory and motor
impulse resulting in loss of autonomic control and muscular paralysis.
HISTORY
First LA, isolated from leaves of erythroxylum coca – was cocaine–
naturally occuring alkaloid by Neiman. Anaesthetic action was
demonstrated by Karl Koller in 1984 in ophthalmic surgery.
1st effective and widely used LA was procaine produced by Einhorn in
1905 from Benzoic acid and diethyl amino ethanol, introduced in clinical
practice by Braun.
3. Dibucaine - 1st
amide, produced by Mischer in 1929 and was
used clinically by Mc Elwain in same year.
Inspired by this, Lofgren synthesised Lignocaine in 1948 was
used clinically by T. Gordh in 1949.
Various potent LA are found in subsequent year like –
ESTER Tetracaine in 1932
2 – chloroprocaine – 1955
AMIDES Mepivacaine – 1956
Bupivacaine – 1951
Prilocaine – 1959
Etidocaine - 1971
4. CHEMISTRY
WEAK BASES
Basic structure consists of tertiary amine and aromatic ring
attached by intermediate chain ester ( - C - O) or amide ( - NHC -)
classified as aminoester or aminoamide
Dia. 14.1 (Miller)
Aromatic gr. Intermediate Bond Tertiary amine
(Lipophilic) (Hydrophilic)
Lidocaine
(aminoamide)
Procaine
(ester)
5. Lipophilicity is concerned with anaesthetic activity.
Lengthening the connecting hydrocarbons chain or ↑ no. of
carbon atoms on tertiary amine or aromatic ring often result in
LA with different lipid solubility, potency, rate of metabolism and
duration of action.
Difference between Esters and Amides
ESTERSESTERS AMIDESAMIDES
1) Combination of aromatic acid1) Combination of aromatic acid
and alcoholand alcohol
1) Combination of organic acid1) Combination of organic acid
and ammonia or amineand ammonia or amine
2) Detoxified in blood stream by2) Detoxified in blood stream by
plasma pseudocholinesteraseplasma pseudocholinesterase
2) Detoxified in liver2) Detoxified in liver
3) Sensitivity reactions are3) Sensitivity reactions are
frequent.frequent.
3) Less frequent3) Less frequent
4) Esters are unstable and4) Esters are unstable and
cannot be autoclavedcannot be autoclaved
4) Stable and can be4) Stable and can be
autoclaved.autoclaved.
6. RACEMIC MIXTURES OR PURE ISOMER
LA like mepivacaine, bupivacaine ,ropivacaine,
levobupivacaine – pipecolic acid derivative of xylidides –
amide gr.
Are chiral drugs – as they posses an assymetrical carbon
atom – have left (S) or right (R) handed configuration.
Mepivacaine and bupivacaine – are available in racemic
mixtures
S – enantiomers of bupivacaine i.e. ropivacaine and
levobupivacains produce less neurotoxicity and
cardiotoxicity – due to decreased potency at sodium ion
channel.
7. MECHANISM OF ACTION
LA prevents transmission of nerve impulses by inhibiting passage
of Na+
ions through ion – selective Na+
channels in nerve
membranes.
do not alter resting memb- potential or threshold potential. LA slows
the rate of depolarization so that threshold potential is not reached
and action potential is not propagated.
8. (A) SODIUM CHANNEL
Exist in activated – open, inactivated – closed and rested
closed states during various phases of action potential.
In the resting memb, Na+
channels are distributed in
equvilibrium between rested closed and inactivated closed.
LA binds selectively to inactivated – closed Na+
channels and
stabilizes these channels in this configuration and prevent
their change to rested – closed and activated – open states in
response to nerve impulse.
9.
10. (B) FREQUENCY DEPENDENT BLOCKADE
Na+
channel recover from LA induced conduction blockade between
AP and develop additional conduction blockade each time Na+
channels open during an action potential.
Therefore, LA gain access to receptor only when Na+
channel
present in activated open state.
Selective conduction blockade of nerve fibres by LA – related to
nerves character, frequency and diameter.
Calcium ion channels may also be blocked by .
(C) MINIMUM CONCENTRATION (CM)
The mini. conc. of LA required to produce conduction blockade of
nerve impulses termed the Cm.
↑ tissue pH or high frequency nerve stimulation ↓ Cm.
Cm of motor fibres is twice than sensory fibres.
12. Sequence of blockade of nerve fibres –
Order of sensitivity to blockade –
1. Vasomotor and sympathetic efferent
2. Temperature – cold
3. Warm.
4. Slow pain
5. Fast pain
6. Cutaneous discrimination
7. Touch
8. Pressure
9. Motor fibres
10.Muscle, tendon joint sensation
11.Deep pressure.
13. Reapperance of sensation occurs from below
upwards (reverse direction).
Applied to Tongue
i) Bitter – First
ii) Sweet
iii)Sour
iv)Salty – last
14. CLINICAL PHARMACOLOGY
Concern with potency, speed of onset, duration of action and
differential sensory and motor blockade.
All LA are synthetic compound except cocaine.
Contain nitrogen, basic in reaction and bitter in the taste
forms salts which are solids with inorganic acids like
hydrochloric acid (HCl) and sulphuric acid. Salts are acid in
reaction and when treated with alkalies form free base.
Free base is insoluble in water and soluble in lipids and lipid
solvents.
Lowers surface tension.
No cross tolerance or cross sensitization between esters and
amides.
15. I. ONSET OF ACTION OF LA’S
Depends upon
a) Dissociation constant of LA
b) Site of administration
c) Dose administered.
a) Dissociation constant (pKa)
It is the pH at which drug is present in 50% undissociated
(unionized) and 50% in dissociated (ionized) form.
pKa of commonly used LA is between 7.6 – 8.9.
Diffusion across nerve membrane related to unionized form
i.e. base form, hence no. of molecules of unionized form
determines the speed of onset.
16. The physiochemical principles stats that the amount
present in the unionized base form is inversely
propotional to the pKa of the agent at a given pH of the
medium i.e. less pKa more is unionized form.
Eg – Mepivacaine, etidocaine, lignocaine and prilocaine
have pKa values ranging from 7.6 to 7.9 (pH of body
fluids ≈ 7.4) – when these drugs are injected into tissue,
65% will be ionized and 35% nonionized – hence uptake
is rapid and onset is fast.
In contrast, tetracaine, chlorprocaine, procaine they have
pKa values from 8.6 to 8.9 – ionized extensively in tissue
at pH 7.4 – upto 95% or more – hence uptake is slow
and onset of block delayed.
17. b) Onset of action – also depends on site of
administration of LA
Most rapid onset – following
1. Subcutaneous
2. Subarachnoid administration
Slowest onset – after brachial plexus block
Rapidity of onset of SAB because of deposition of LA in
the vicinity of the nerve roots at spinal cord level and also
due to lack of sheaths around the nerves.
In brachial plexus block, deposited away from the nerve
roots and the longer time for diffusion to the nerves is
required.
18. c) Dose administered
Amt. of durg administered affect the onset duration and
quality of anaesthesia.
↑ in the dose within the clinical range enhances the quality
of anaesthesia.
Dosage can be ↑ed by administrating larger volume or
more concentrated solution.
Volume influences the spread of anaesthesia.
e.g. 30 ml of 1% lignocaine administered into epidural
space produces level of anaesthesia 4.3 dermatomes
higher than that achieved when 10ml of 3% lidocaine is
given.
20. II. DURATION OF ACTION OF LA –depends on
a) Protein binding
b) Site of administration
a) Protein binding of LA
High protein binding associated with prolonged duration of
action.
On basis of it, LA classified into 3 categories –
i. Short duration and low potency
ii. Intermediate duration and potency
iii. Long duration and high potency.
21. b) Site of administration
Duration of action decreased at highly vascular site
because of rapid absorption from site.
Addition of vasoconstrictor (Like adrenaline)
increases duration of action.
e.g. Bupivacaine – Epidural – 4 hour
Brachial plexus block – 10 hours
22. PHARMACODYNAMIC CLASSIFICATION OF LA’S
AGENTAGENT
RELATIVERELATIVE
POTENCYPOTENCY
ONSETONSET PkaPka DURATION CMDURATION CM
I. LOW POTENCY SHORT DURATIONI. LOW POTENCY SHORT DURATION
ProcaineProcaine 11 SlowSlow 8.98.9 60 – 9060 – 90
ChlorprocaineChlorprocaine 11 FastFast 8.78.7 30 – 4530 – 45
II. INTERMEDIATE POTENCY AND DURATIONII. INTERMEDIATE POTENCY AND DURATION
LignocaineLignocaine 22 FastFast 7.97.9 90 – 20090 – 200
MepivacaineMepivacaine 22 FastFast 7.67.6 120 – 240120 – 240
PrilocainePrilocaine 22 FastFast 7.97.9 120 – 240120 – 240
III. HIGH DURATION AND LONG DURATIONIII. HIGH DURATION AND LONG DURATION
TetracaineTetracaine 88 SlowSlow 8.58.5 180 – 600180 – 600
BupivacaineBupivacaine 88 IntermediateIntermediate ↓↓ 8.18.1 180 – 600180 – 600
EtidocaineEtidocaine 66 FastFast 7.77.7 180 – 600180 – 600
DibucaineDibucaine 1212 SlowSlow 220 – 600220 – 600
RopivacaineRopivacaine 1010 FastFast 8.18.1 300 – 400300 – 400
23. PHARMAKOKINETICS OF LA
Described under
Absorption
Distribution
Metabolism
Excretion
ABSORPTION OF LA
Depends upon
a) Site of injection
b) Total dosage and concentration
c) Specific pharmacological characteristic of agent.
d) Effect of vasoconstrictor.
25. b) Total dosage and concentration
Total dosage α rate of absorption and peak plasma levels.
Conc. of drug may influence the rate of absorption.
c) Specific LA agent
Except cocaine and ropivacaine, all LA have intrinsic
vasodialator activity and degree of this action influences the
absorption rate.
Act directly on vascular smooth muscles and occurs in
innervated as well as denervated blood vessels and is Ca++
dependant.
Order of absorption of various
LA Lignocaine > Mepivacaine > Bupivacaine > etidocaine >
prilocaine > procaine.
Lignocaine reduces vascular resistance and dilates
capacitance vessels.
26. d) Role of vasoconstrictor
Vasoconstriction decreases rate of absorption of LA’s.
Epinephrine is used most commonly in conc. Of 1 : 2,00,000
or 5 µg/ml
Absorption of lignocaine, mepivacaine and procaine is
reduced by approx 30% reguardless of site of injection.
Absorption of prilocaine, bupivacaine and etidocaine after
peripheral nerve blocks are reduced but epinephrine has little
influence on the absorption of these drugs from the epidural
space. This might be because of strong affinity for the neural
receptors.
27. DISTRIBUTION
After vascular absorption from various injection sites, distributed to all
body organs and throughout the total body water.
Great percentage of administered dose is distributed to large skeletal
mass, although the conc. is low, the amount is significant.
Uptake and tissue conc. i.e. amt/gm of tissue is greater in lungs, kidneys.
Various phases of distribution in body after vascular absorption.
i. Pi phase – Peak plasma levels are reached rapidly with lower lipid
solubility, vice versa.
ii. Alpha phase – initial rapid disappearance from plasma due to
distribution to rich vascular tissues having high perfusion rates
(brain, heart and kidney)
iii. Beta phase – slower secondary phase related to distribution to
slowly perfused tissue including skeletal muscles and fat.
iv. Gamma phase – In this phase, metabolism and excretion of the
agent occurs.
28. METABOLISM
Esters
Hydrolysis in plasma occur by alkaline breakdown -accelerated
by plasma pseudocholinesterase. Benzoic acid and PABA are
principle break Down product and diethyl aminoethanol is
secondary product.
Amides
Enzymatic degradation in liver
Oxidative dealkylation converts tertiary amine into secondary
amine.
Secondary amine is clevated by Hydrolysis by amidases and
oxidases.
29. EXCRETION
Via kidney
Renal clearance is inversely proportional to protein binding and
pH of urine i.e. acidified urine more excretion.
PHYSIOLOGICAL EFFECTS OF LAS
1. EFFECT ON CIRCULATION
Stimulatory effect by central action ↑CO, ↑ HR, BP, ↓PR.
Contraction of smooth muscles - ↑ venous rectum
↑ C.O.
Intra arterial injection - ↑ smooth muscle tone
Delayed conduction in heart
↑ pulmonary vascualr resistance
↓ splanchnic vascular resistance
30. 2) EFFECT ON RESPIRATION
Blood- gas tension are not influenced
N ↑ response to hypercapnia resultant in respiratory
stimulation.
But LAS depress common hypoxia.
3) ANTITHROMBIC EFFECT
Inhibits platelet aggregation - Ca+
influx blocked
- Intracelluler stores are mobilized
↑ antithrombin III
4) ON SMOOTH MUSCLES
Low concentration – direct stimulatory effect in blood vessels, GIT
musculature.
High concentration – vasodilatation, relaxation of smooth muscles
of GIT.
31. CLINICAL IMPLICATION
Intraperitoneally or I.V. LA may induce faster return of
propulsive motility in the colon in the post op period.
1. ANTIINFLAMMATORY EFFECT
Potent anti-inflammatory action.
Inhibition of peritonitis when instilled in peritoneum.
MECHANISM-
a) Inhibition of PG synthesis.
b) Inhibition of migration of granulocytes into the inflammatory
area.
c) Inhibition of granulocytes release of lysosomal enzymes and
the production of tissue toxic oxygen free radical.
32. Analgesic effects – IV lignocaine is effective
a) Chronic painful diabetic neuropathy
b) Adiposa dolorosa (Dercum’s disease)
c) Chr. Pain of differentation type.
e.g. post operative pain, burn pain.
d) Sub cut. Inj of lignocaine for malignant pain.
4) PREGNANCY
• Spread and depth of anaesthesia (epidural and spinal) are reported to
be greater hence dose required less
Factors
a) Dilated epidural vein ↓ed epidural and subarchnoid space.
b) Alteration of harmones in pregnancy ↑ progesterone level in CSF
cause more rapid onset and ↑sensitivity to LA induced conduction
blockade.
33. VARIOUS LA AGENTS (INDIVIDUALS LAS)
I) COCAINE
1st
LA used for ocular anaesthesia in 1984
Obtained from leaves erythroxylum coca.
Benzoic acid esters of base ecognine.
Used for topical application
Rapid absorption from nasopharyngeal membrane
Vasoconstrictor causes shrinkage of mucous membrane and
↓bleeding after topical application.
Instilled into nostrils, enlargement of nasal passage occur
used for nasotracheal intubation.
34. DOSE: 1 – 2 mg/kg,. Max – 200mg
CAUSES: ↑ myocardial O2 demands
↓ coronary artery diameter
↓ coronary sinus bld flow
action is α - agonistic
TOXICITY : CNS – Stimulant – seizures
CVS - ↑HR, BP – Arrythmias, IHD
Hyperpyrexia
Anxiety
Tactile hallucination-cocaine bugs
coma, and death
35. II. PROCAINE
PABA ester of diethylamino ethanol.
Synthesized by Einhorn in 1905
Duration of action 30-60 min
Uses 1. 0.5 and 1% solution – Infiltration
2. 1.5 and 2% sol – Nerve blocks
Drug interactions:
Procaine and curare are additive at autonomic ganglia –
ganglion blockade ↓ BP ↑ HR
Procaine- sulphonamide antagonism
PABA the degradation product is sulphonamide antagonist
36. III. CHLORPROCAINE:
Analogue of procaine,
Introduced by Folder in 1952
2-4 times more potent than procaine
approaches the ideal for N. block anaes.
Because: 1. Rapid onset of action
2. Slow incidence of failure
3. Lack of systemic reaction.
4. Adequate duration of action with
5. Low potential for toxicity
Uses: 3% high recommended dose 800 – 1000mg with
adrenaline
Clinical uses: Peripheral N. blocks, obst. Epidural.
37. IN 1980
Neurotoxicity observed fallowing epidural anaesthesia
Cauda equina syndrome.
Anterior spinal artery syndrome.
due to toxicity of 0.2% Na bisulplate used as
antioxidant
IV. TETRACAINE
Synthetic derivative of PABA
Ist prepared by Eisleb in 1928 and used by klers in 1930
8 times more potent and toxic than procaine
Total permissible dose
Infiltration – 40-60mg – 0.05 – 0.15%
Nerve blockade 40-60mg
Topical Anaestnesia 20-40mg, 1% and 2%
38. V. DIBUCAINE
Ist amide LA
Prepared by Miescher and introduced in 1929 by MC Elwain
Synthetic quinoline derivatives, parent alkaloid related to
quinine
The base is readily ppted by alkalies so should be stored in
alkaline free gases container
Most potent, most toxic and longest acting
16 times more toxic and 22 times more potent than procaine
Mainly used as surface anaesthesia on less delicate mucous
membrane like anal canal concentration 0.1% and 1%
Occasionaly for spinal anaesthesia 0.5% hyperbaric
39. VI. LIGNOCAINE
Introduced in 1948 by Lofgren
An amide formed from reaction of dietheyl amino acetic acid and xylene
Molecular wt. of base is 234 and that of HCL salt is 270
Physiochemical properties
1. Freely soluble in water, very stable
2. Sterilized by boiling or autoclaving
3. Non irritating to tissue even at conc of 85%
4. 1.5 times more potent and 3 times more toxic than procaine
Causes maximum vasodilatation so rapid absorption without
vasoconstrictor.
Broad spectrum LA.
40. Onset of action : 2-3 min duration of action 90 – 200 min
Concn used Max recommended dose
0.5 – 2% infiltration-nerve blocks 200mg
500mg with adrenaline
5% in 7.5% Glucose intra thecally 100mg
4% for topical 200mg
Viscouse 2% 300mg
Recommended dose 200 – 400
Total dose should not exceed 4-5 mg | kg
Uses: 1. Surface anaesthesia
2. Infiltration
3. Nerve blocks
4. Epidural, spinal
5. Intra venous regional anaesthesia
41. 1. Cardiac action : Class IB antiarrythmic agent used for ventricular
tachycardta and digitalis toxicity
Dose I.V. 50-100mg bolus. (1-2 mg/kg) followed by 1-3 mg/min for
infusion
Therapeutic plasma concn – 2-3µg/ml
Peak level attended = Initial dose administered x 0.3
2. Skeletal muscles: Extrusion of Ca++ from sarcoplasmic reticulum
VII. MEPIVACAINE
- Ist prepared by Dhuner and used clinically by Ekenstar in 1956.
- Pharmacological properties similar to lignocaine
- More toxic to neonate thus not used in obstetrical anaesthesia-as
they have lower bld pH (7.25) and mepivacaine 7.6-forms more
active drug in neonate
Concentration used – 0.5-2%
Maximum dose – 5mg/kg
42. VIII. BUPIVACAINE
Introduced by Ekenstam in 1957
Molecular wt. Of salt 325 and that base form 288
Base is sparingly soluble but HCL salt is readily soluble in
water.
Highly stable and can withstand repeated autoclaving
4 times more potent than lignocaine and 8 times than of
procaine
Duration 2-3 times longer than lignocaine
Onset of action 7-8 min intermediate
Duration of action 180-600min
Produce excellent and prolonged duration of sensory
anaesthesia than motor blockade
43. Used for : Infiltration, Nerve blocks caudal blocks epidural blocks
SAB
DOSAGE
I. Infiltration 0.25% 70-90ml with epinsptione
II. Never block 0.5% 35ml plain
(For large. N) 45ml with epinephra
(For small N) 45ml with epinepnrine
I. Caudal 0.25% 30ml obstetric anaes and perianal anaes
0.5% 30ml lower limb surg
I. Epidural 0.25% 20ml – obstetric and perineal surgery
0.75% 20ml – abd surgery
I. SAB 0.5% heavy 3-4ml lower limb, abdominal surgery
44. Not used for I.V. anaesthesia because of cardiotoxicity
Sev. Ventricular arrythmias and myocardial depression
Lignocaine and bupivacaine both block cardiac Na++
channels rapidly during systole
Bupivacaine dissociates more slowly than lignocaine during
diastole
It also block Ca++ channel
Central action on medulla
Cardiac toxicity is difficult to treat and severity is enhanced
by acidosis, hypercarbia and hypoxemia
45. IX. ETIDOCAINE
Introduced in 1972
Onset of action like lignocaine
Duration of action longer like bupivacaine
Produces preferential motor blockade
Cardiac toxicity similar to bupivacaine
Useful for surgeries requiring intense skeletal muscle
relaxation
Concn used : 1-1.5%
High dose – 4mg.kg
Max dose – 300mg
46. X. PRILOCAINE
Intermediate action and potency
Pharmacologic similar to lignocaine but causes less vasodilation so can
be used without vasoconstriction
More volume of distribution in body so causes less CNS toxicity so can
be used I.V.R.A.
S/E.: Methemoglobinaemia as consequence of metabolism of aromatic
ring to o-toludine. Haem of Hb is in Fe+++ (oxidised form) -dose
dependent seen after 8 mg/kg
T/t : I.V methylene blue 1-2 mg/kg
Limited use in obst. Practice because of risk of methemoglobinemia in
newborn.
Fetal Hb has low resistance to oxidant stresses
Neonatal enzyme are immature to convert
Fe+++ Fe++ state
Used concn – 0.5-2%
Max. reco. Dose. = 400mg
47. XI. EMLA PATCH
Eutectic mixture of La
Mixture having its melting point less than melting point of individual
components.
Contains lignocaine 2.5% + pricocaine 2.5% mixed at 250
C to form oil in
water emulsion (25mg and 25mg 1gm)
Used for surface anaesthesia
Indication
Skin biopsy / grafting
Venepucture in childrens
Arterial puncture
Removal of excessive granulation
E.g. genital warts
Surgical debridement of leg ulcer
Circumcision
48. Application time on intact skin should be 1-3 hrs and on
mucous membrane 5-10min
Should not be used in children < 3 months (Fetal Hb) and in
childrens 3-12 months who undergo medical treatment with
drugs inducing methemoglobin formation (e.g sulpha drugs)
Application time:
1. Minor procedure (Needle insertion) 2gm Minimum 60min to
max 5hrs
2. Superficial skin grafting 1.5-3gm Minimum 2hrs to max 5hrs
49. XII. ROPIVACAINE
Recently developed LA
A pipecolic acid derivaties of xylide with propyl group on
piperidine nitrogen atom of molecule
Long acting but less cardiotoxic, short duration
Highly protein bound and lower solubility
Lipid solubility is intermediate between lignocaine and
bupivacaine.
Metabolisim of ropivacaine is 3 hydrory ropivacaine
Concn – 0.5% 0.75%, and 1%
Onset of motor blockade require 25min for all concentration
50. DOSE USED:
1. Extradural analgesia in labour 10ml of 0.5% followed by top up
0.25% 10ml
2. Extradural anaesthesia in LSCS 0.5% 30ml bolus
3. Peripheral N. block – 0.5% - 33ml -onset of sensory block < 4min
and it last for 14hr
4. Ropivacaine is not recommended for SAB as safety is yet to be
confirmed:
TAC:
For topical anaesthesia
Paediatric surgery (TAC – 0.5%)
Recommended dose 3-4ml for adult 0.05ml/kg for children
Ineffective through intact skin
Absorbed from mucosal surface leading to toxic reacition
Applied to laceration that require suturing
51. DIBUCAINE NUMBER (DN)
1. Used for distinguish between normal and atypical plasma
pseudocholinesterases
2. Potent inhibitor of normal plasma cholinesterase but reacts poorly with
atypical ones
3. In testing procedures
1. Benzylcholine is used as substrate
2. Specifically hydrolysed by normal and atypical ch E but not true RBC
CHE
4. DN is % inhibition of hydrolysis of benzyl choline by dibucaine added to
plasma mixtures or % of CHE inhibited by dibucaine
Normal plasma che – 70-80% of benzylcholine is intact
Homozygous atypical < 20% of benzylcholine is intact
Heterozygous atypical plasma CHE 40-70% of benzyl choline is intact
52. POTENTIATION OF LA ACTION
I. ALTERATION OF PHYSIOCHEMICAL PROPERTIES OF LA
A. pH adjustment to alkalanity
Increasing pH of LA with functional range increases amount
of free base in soln with early onset. soln can be made
alkaline by
a. Carbonation of solution with CO2 gas
Gassing LA soln with 10-20% CO2 results in ↑ ed block by
ten folds
Dissolution of CO2 in soln influence the LA in following way.
53. i. When ampoule is opened some CO2 diffuses out ,this
effervances raises pH and its base form
ii. On. Inj around N. CO2 diffuse through neural membrane –
enter interior of N –decrases pH –enhance neural blocked
b. Using carbonate salts of LAS
Commonly used salts are hydrochloride salt
Instead carbonate salts are used
Effect it similar to that with CO2 addition
B. Altering LA pka by warming of LAS
Warming soln to 1000
F significantly increases speed of
onset and extent of spread
The mech similar to alkalinisation and carbonation
54. II. IMPROVING INTENSITY AND DURATION OF BLOCKED
DONE BY
a. Opioid addition – Synergistic effect
b. Monoamine neurotransmitter addition
c. Vasoconstrictor
i. Epinephrine (1:200,000 or 5ug/ml) – MC used
- Contrraindition – in plastic surgery esp in local infiltration of skin
flaps
- Blocks of digits, foot, penis
- In obstetric regional anaesthesia
- In clinical conditions like severe HT, dysarrythmias, toxemia
ii. Fely pressine (synth – analogue of vasopressin) – action more on
venous microcirculation so absorption is delayed
ιιι. α2 adrenergic agents like clonidine
55. d. Potassium addition
Alteration of Na++, k+ ion balance around nerve
↑ level of K out side nerve causes ↓in resting potential
resulting in conduction blockade
miscellaneous
Dyes
Propylene glycol
Vegetable oils
hyaluronidase
56. Types of regional anaes produced by LAS
1. TOPICAL APPLICATON
Surface application of LA to skin or mucous membrane
Method – Spray
– Spreading of an ointment
– Instillation with syringe into urethra
Nebulised lidocaine is used to produce surface anaesthesia
of upper and lower respiratory tract before fiberoptic
laryngoscopy / broncnoscopy e.g. EMLA, TAC
57. 2. INFILTRATION ANAESTHESIA
Inj LA into tissue to be cut
Nerve ending likely to be disturbed by surg manipulation- are
infiltrated with LA
Duration varies, epinephrine prolong duration
Dose depends upon extent of area to be anaesthetised and
expected duration of surgery.
Pt. experience pain immediately after subcut inj of LA sol that
is due to acidic nature of drugs
It can be prevented by addition of Na bicarbonate and
improvement of action
3. FIELD BLOCK
Inj. LA into tissue around periphery of area in which surgeon
is going to operate
58. 4. CONDUCTION ANAESTHESIA
Deposition of LA soln along course of nerve or nerve supplying a
region of body.
e.g. Nerve block of trunk
Epidural block – N – N root in epidural space.
SAB – Nerve root in Subarachnoid space
5. INTRAVENOUS REGIONAL ANAESTHESIA
I.V. admin of La into torniquet occluded limb (i.e. Bier block)
LA diffuses from peripheral vascular bed to non vascular tissue e.g.
Axon, nerve ending
I.V. anaesthesia used for surgical procedure of upper limb and
shorter proced by foot.
Lidocaine is most frequently used without preservative
3mg/kg lidocaine with out epinephrine used for upper extremity
procedure.
50-100ml of 0.25% ltdocaine used for lower limb surgery.
59. C. TOXICITY OF LAS
1. Physical status :
Hyper purexia - ↑ absorption
Debility – affect metabolism
Shock
Starvation
Old age
Vit. C deficiency
2. Types and site of procedure are:
Highly vascular area - ↑ absorption
60. 3. Detoxification potentials
Slow metabolism – greater chancer of toxicity
↓ plasma pseudoche - ↓ metabolism of espe– in
Liver disease
Sever anemia
Malnutrition
Renal dysfunction failure to eliminate breakdown product or
unchanged drugs.
4. Nutrition
Hypoproteinemia – More free drug
Vit C deficiency - ↓ ability to handle LA
61. A. CENTRAL NERVOUS SYSTEM
1. STIMULATION:
a. Cerebral cortex
Convulsions (incidence 1:1300 to 4:1000)
b. Medullary vagal centres
↑respiratory and cardiovascular activity with or without activity of vomiting
centre
2. DEPRESSION:
a. Cerebral cortex:
Psychomoter inpairment
↓ co-ordinating skills
↓ Reaction capacity
Unconsciounsness
b. Medulla
i. Vasomotor – Syncope
ii. Respiratory – depression to arrest
62. B. CARDIO VASCULAR SYSTEM
1. Cardiac
Bradycardia – Procaine
Tachycartia – cocaine
2. Vascular
Vasodilatation - ↓ C.O., hypotension
C. ALLERGIC RESPONSES
1. Cutaneous
Rashes urticaria
2. Respiratory
Bronchospasm, laryngospasm
D. Miscellaneous Reactions
1. Psychogenic
2. Other Drugs – vasopressor and additives
63. CNS TOXICITY
Site of action subcortical level
Hippocampous
Limbic system sp. Amygdala
Relative CNS toxicity of LAS in decreasing order
Bupivacaine > Tetracaine > Etidocaine > Prilocaine >
Lignocaine > Mepivacaine > procaine chlorprocaine
64. S/S OF CNS TOXICITY
Symptomatology is progressive
Mild : Light headedness – Most common
perioral numbness
Tinnitus
Drowsiness
Disorientation
Moderate : Restlessness
Headache
Blurring of vision
Nausea and vomiting
Severe : Muscle twitching
Tremours of face and extrimities
Unconsciousness
Generalised convulsions
Respiratory arrest
65. PROPHYLAXIS OF CNS TOXICITY
1. Least amount and lowest conc. of LA necessary should be given
2. Precautions to minimise absorption and high blood levels should
be taken
Ex. Vasoconstrictors
No intravasuclar injection
3. Threshold of reaction of CNS is raised
Ex. By sedation with diazepam
4. Test should be done to recognise IV placement of needles
Ex. In epidural and plexus blocks
Injection of small dose of epinephrine 15µg in 3.0ml of
anaesthetic solution is recommended
Tachycardia occurs on IV injection
66. 5. Injection should be done slowly
Rate < 10ml / min esp for epidural procedures is
preferable
6. In IVRA, injections should be done slowly and the
tourniquet should not be released until at least 20 min
have elapsed from the time of completing injection.
67. T/T OF CNS TOXICITY
1. 100% O2 administration in very early stages ↑ PaO2 raises
threshold for seizure
If toxicity is progressive and convulsions start
2. Provide an adequate airway by endo tracheal incubation
3. Institute artificial controlled ventilation with 100% O2.
4. If convulsions do not stop with in 15 seconds
anticonvulsants should be administered
a. IV diazepam – 0.25 mg/kg
b. IV short acting barbiturate like thiopentone 3-5 mg/kg
5. In CNS depression is seen, all the above misuses are taken
except for anticonvulsant use
68. CVS TOXICITY
Generally cardiovascular system is resistant to effects of LA as
compared to CNS
Ex. Dose of lignocain causing CVS toxicity is three times greater
than that causing CNS toxicity
Negative chronotropism - ↑ PR interval, ↑ QRS duration
AV blocks
Negative inotropism - ↓ cardiac output
↓ B.P.
Ultimately may lead to circulatory failure
69. T/T
1. Establishment of airway
2. Oxygen therapy
3. IV infusion
4. Vasopressors
5. Antiarrythmic agents like bretyllium
6. Cardiac resuscitation (Massage, defibrillation)
CC/CNS ration
for bupivacaine and etidocaine found to be lower than lidocaine
CC/CNS dose ratio – for lido caine – 7.1 ± 1.1
for bupivacaine – 3.7 ± 0.5
CC/CNS blood ratio - for lido caine – 3.6 ± 0.3
for bupivacaine – 1.6 to 1.7
70. ALLERGIC REACTIONS
Usually rare
Drugs are non-protein, non-antigenic and do not induce
an antibody response
Drug metabolite may act as hapten and may combine
with protein or polysaccharide to produce antigen
May be immediate or delayed
71. 1. IMMEDIATE:
i. Mucocutaneous Urticaria
Skin rashes
Conjunctivitis Rhinttis
Angioneurotic edema
Edema of larynx, pharynx
ii. Respiratory Bronchospasm
Edema of bronchial mucosa
ANAPHYLACTOID REACTIONS
Due to massive release of histamine
2. DELAYED REACTIONS
Urticaria and rashes several hours after injection
Subcutaneous edema over injection site spreading to adjacent area
Edema of face and neck
Swelling of pharynx, tongue and floor of month
72. SKIN TESTING (INTRADERMAL TESTING)
0.02 to 0.04ml of drug injected intradermally
Response noted in 15-20 minutes
Around an injection site
Pseudopodia may occurs
Quantitiative grading is as fallows
≤ 4mm – Negative
5mm - +
5 – 8 mm - ++
8 – 12 mm - +++
≥ 12 mm - ++++
Of pseudopodes appear, the rating is higher for any area of
erythema
73. REACTIONS TO PRESERVATIVES IN LA SOLUTIONS
Additives and preservatives used in LA solution
1. Antioxidants: Bisulphites
Sulpher dioxides
Na or K sulphite
Na or K metabisulphite
Urticaria, angioedema, bronchospasm
2. Buffers: Sodium pyrosulphite
Acidification prevents oxidation of added epinephrine
↓ pH affects the pKa LA and hence penetration and activity
so higher dose may be required leading to toxicity
74. 3. Bacteriostatics : Parabens
Methylparabens
May act as haptens leading to allergic
TACHYPHYLAXIS AND LA
Repeated inj of the same dose of LA leads to ↓ efficacy
Influenced by dosing interval
Short dosing intervals that do not permit pain to occur may not
associated tachyphylaxis
75. ADVANTAGES AND DISADVANTAGES OF LAS
ADVANTAGES
1. Practical, Cheap, Safer
2. Can be used when pt is not NBM
3. Pt breathes spontaneously and normally
4. Pharyngeal and lanyngeal reflexes are preserved
5. Needs little equipments
6. Pt can co-operate
DISADVANTAGES
1. Less reliable than GA
2. Dose is limited, so the area to be anaesthetized is limited.
3. Difficulty may be encountered if pt fatty
4. Can not be given through infected tissues
5. Not suitable for children and uncooperative patient
