L a agents

LOCAL ANAESTHETIC AGENTS

GUIDED BY

DR. ANAND DALWANI Lecturer

Dept. of Anaesthesia

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.

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

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)

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

ESTERS ESTERS AMIDES AMIDES

1) Combination of aromatic acid 1) Combination of aromatic acid and alcoholand alcohol

1) Combination of organic acid 1) Combination of organic acid and ammonia or amineand ammonia or amine

2) Detoxified in blood stream by 2) Detoxified in blood stream by plasma pseudocholinesteraseplasma pseudocholinesterase

2) Detoxified in liver2) Detoxified in liver

3) Sensitivity reactions are 3) Sensitivity reactions are frequent.frequent.

3) Less frequent3) Less frequent

4) Esters are unstable and 4) Esters are unstable and cannot be autoclavedcannot be autoclaved

4) Stable and can be 4) Stable and can be autoclaved.autoclaved.

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.

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.

(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.

(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.

(D) DIFFERENTIAL CONDUCTION BLOCKADE

Nerve differ in their sensitivity to LA

Nerve Fibre Classification

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.

Reapperance of sensation occurs from below

upwards (reverse direction).

Applied to Tongue

i) Bitter – First

ii) Sweet

iii)Sour

iv)Salty – last

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.

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.

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.

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.

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.

DURATION AND DOSAGES

Plain SolutionPlain Solution Epinephrine – Epinephrine – Containing SolutionContaining Solution

DrugDrug Concentration Concentration (%)(%)

Maximum Maximum Dose Dose (mg)(mg)

Duration Duration (min)(min)

Maximum Maximum Dose (mg)Dose (mg)

Duration Duration (min)(min)

Short DurationShort Duration

ProcaineProcaine

ChloroprocaineChloroprocaine1.0 – 2.01.0 – 2.0

1.0 – 2.01.0 – 2.0400400

80080020-3020-30

15-3015-30600600

100010003030

3030

Moderate DurationModerate Duration

Lidocaine Lidocaine

MepivacaineMepivacaine

PrilocainePrilocaine

0.5 – 1.00.5 – 1.0

0.5 – 1.00.5 – 1.0

0.5 – 1.00.5 – 1.0

300300

300300

500500

30 – 6030 – 60

45 – 9045 – 90

30 – 9030 – 90

500500

500500

600600

120120

120120

120120

Long Duration Long Duration

Bupivacaine Bupivacaine

Etidocaine Etidocaine 0.25 – 0.50.25 – 0.5

0.5 – 1.00.5 – 1.0175175

300300120 – 240120 – 240

120 – 180 120 – 180 225225

400400180180

180180

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.

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

PHARMACODYNAMIC CLASSIFICATION OF LA’S

AGENTAGENT RELATIVE RELATIVE POTENCY POTENCY ONSET ONSET PkaPka DURATION CMDURATION CM

I. LOW POTENCY SHORT DURATION I. LOW POTENCY SHORT DURATION

Procaine Procaine 11 Slow Slow 8.98.9 60 – 9060 – 90

Chlorprocaine Chlorprocaine 1 1 FastFast 8.78.7 30 – 4530 – 45

II. INTERMEDIATE POTENCY AND DURATION II. INTERMEDIATE POTENCY AND DURATION

LignocaineLignocaine 22 Fast Fast 7.97.9 90 – 200 90 – 200

Mepivacaine Mepivacaine 22 Fast Fast 7.67.6 120 – 240 120 – 240

Prilocaine Prilocaine 22 Fast Fast 7.97.9 120 – 240 120 – 240

III. HIGH DURATION AND LONG DURATION III. HIGH DURATION AND LONG DURATION

Tetracaine Tetracaine 8 8 Slow Slow 8.5 8.5 180 – 600 180 – 600

Bupivacaine Bupivacaine 88 IntermediateIntermediate ↓↓ 8.18.1 180 – 600 180 – 600

Etidocaine Etidocaine 66 Fast Fast 7.77.7 180 – 600 180 – 600

Dibucaine Dibucaine 1212 Slow Slow 220 – 600 220 – 600

Ropivacaine Ropivacaine 1010 Fast Fast 8.18.1 300 – 400 300 – 400

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.

a)Site of injection

Greater the vascularity,

greater is the

absorption in absence

of vasoconstrictor.

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.

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.

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.

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.

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

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.

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.

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.

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.

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

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

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.

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%

Spinal Anaesthesia 10-18mg, 1%

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

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.

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

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

S/E – Mild tachycardia,mild hypotension some time twitching of face muscles

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

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

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

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

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

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 250C 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

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

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

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

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

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.

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 1000F significantly increases speed of onset and extent of spread

The mech similar to alkalinisation and carbonation

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

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

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

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

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.

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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