LOCAL ANAESTHETICS

INTRODUCTION
DEFINITION:-

drugs that produce reversible conduction blockade of nerve impulses along central and peripheral pathways after regional anaesthesia.

HISTORY:-

Cocaine 1884 Procaine 1905 Tetracaine 1930 Lidocaine 1948 Chlorprocaine 1955

Mepivacaine - 1957 Prilocaine - 1960 Bupivacaine - 1963 Etidocaine - 1971 Ropivacaine - 1992

STRUCTURE ACTIVITY RELATIONSHIP

Aromatic ring linkage chain Amine portion R1 O R N R2

O
C

(Ester linkage)

O NH C R N

R1
R2

(Amide linkage)

CLASSIFICATION
It is done on the basis of the type of linkage between aromatic and amine portions
ESTERS ester linkage Metabolized by plasma pseudocholinesterases chances of allergic reaction systemic toxicity Slow onset AMIDES amide linkage metabolized by liver cytochromes chances of allergic reaction more systemic toxicity moderate to fast onset

Classes: The rule of i

Am

ides

Esters

Lidocaine Bupivacaine Levobupivacaine Ropivacaine Mepivacaine Etidocaine Prilocaine

Procaine
Chloroprocaine Tetracaine Benzocaine Cocaine

Mechanism of Action
Blocks Local

the sodium channel

ranging effects on the nervous system

Wide

anesthetics blocks the channel from the intracellular side

Must

enter the neuron to work increased lipophilicity is associated with increased potency Increased un-ionized fraction increases potency
The un-ionized molecule crosses the cell membrane Adding bicarbonate increases the un ionized fraction

Tetrodotoxin

outside

binds the sodium channel from the

Sodium Channels
Voltage gated ion channel 4 segments, each with 6 transmembrane helices Central pore

http://courses.washington.edu/conj/membrane/nachan.htm

Sodium Channels

A small machine with:

Ion

selector (very specific for Na) Voltage sensor

1 in each unit
Gate

Outside
+++++ Selectivity Filter Voltage sensor

connected to voltage sensor

Opens when voltage rises, letting Na+ enter cell.

70-90 mV at rest
-----

Gate

Inactivation

gate

Inside
Inactivation gate

Closes when voltage gets to +30 mV, ending Na+ flux.

http://courses.washington.edu/conj/membrane/nachan.htm

Na channel conformations 3 channel forms: resting,

open, & inactivated (1952)
Na+

ions pass only through open channels No Na+ current through channels bound by LA GR Strichartz Brigham and Womens Hospital LA binding favored by: Harvard Medical School Depolarization Open or inactivated Na channels Frequent impulses (use-dependence)

Site of Action

Local Anesthetic

MECHANISM OF ACTION
Permeates axonal memb in unionized form Reaches voltage gated Na channel by hydrophobic approach from within the axonal memb Bind to -subunit of Na channel in ionized state Stabilizes channel in inactive state & prevents rapid entry of Na ions Reduces the amplitude of action potential which eventually fails to attain threshold potential

Action potential not propogated reversible conduction blockade

Frequency dependent block (phasic inhibition):Rapidly firing Na channels are more susceptible to blockade by LA

Nerves
Small

diameter nerves are more easily blocked than large diameter nerves For the same diameter, myelinated nerves will be blocked before unmyelinated nerves.
Why

preganglionic nerves are blocked before the smaller unmyelinated C fibers (pain nerves) in spinal anesthesia.

Nerves

that fire frequently are preferentially blocked over nerves that fire infrequently.

Nerve Sensitivity
1.

2.
3. 4. 5. 6.

Autonomic Pain Temperature Touch Proprioception Skeletal muscle tone

Properties that govern clinical effect

Potency

Lipophilicity
Ionization

(all are weak bases) Rate of metabolism

Rate of Onset

Potency
Correlates

closely with lipophilicity, with more lipophilic local anesthetics being more potent dose, either by increasing volume or increasing concentration, accelerates the rate of onset bicarb accelerates the rate of onset the rate at which the drug washes away

Dose
Increased

Un-ionized fraction
Adding

Epinephrine
Reduces

PKa. LAs having PKa closer to physiologic Ph 7.4 have fast onset.

Henderson Hasselbalch equation

The basis for understanding this equation is knowing the pKa of the agents, remembering that pKa equals the pH where the ionized and non-ionized forms are at equilibrium. In other words, 50% of each form is present. Local anaesthetics are weak bases. For bases, the pKa - pH relationship is described by the Henderson Hasselbalch equation, as follows: pKa - pH= log_ionized
non-ionized

Duration of Action
Rate
Rate Dose Potency

of systemic absorption
of elimination
for esters, which are metabolized locally

Tissue

vascularity Use of epinephrine

Particularly

General

groups:

Short:

Procaine, chloroprocaine Intermediate: lidocaine, mepivicaine, prilocaine Long acting: Tetracaine, bupivacaine, etidocaine, ropivacaine, levobupivacaine

Potency, pKa, Lipophilicity

Drug
Low Potency Procaine Intermediate potency Mepivacaine Prilocaine Chloroprocaine Lidocaine High potency Tetracaine Bupivacaine Etidocaine Ropivacaine Levobupivacaine

pKa
8.9 7.7 8.0 9.1 7.8 8.4 8.1 7.9 8.1 8.1

Octanol/H2O
100 130 129 810 366 5822 3420 7320 3420

Additives and modifiers of LA activity

Increasing

dose: latency of onset; duration, block success, [LA] Vasoconstrictors: duration, block success, [LA] 2 agonists: duration,[LA] Opioids: duration; permit LA dose Alkalinization (usually NaHCO3): latency of onset, potency Pregnancy: dermatomal spread, LA potency, free blood [LA]

Addition of Bicarbonate
Lidocaine:

1 cc bicarb / 10 cc drug Mepivacaine: 1 cc bicarb / 10 cc drug Bupivacaine: 0.1 cc/10 cc

Hard

to not get precipitation

Levobupivacaine:

same as bupivacaine

 Differential

sensory/motor blockade:-

Sensory > motor at lower conc. of ropivacaine & bupivacaine Useful when selecting an agent for ambulatory labour analgesia or post op analgesia.

 EFFECT

OF PREGNANCY ON LA ACTION:-

sensitivity of nerves to conduction blockade due to progesterone effect conc of unbound drug in plasma due to alterations in protein binding dose required for SA/EA due to reduction in size of potential spaces as a result of engorged epidural veins.

Systemic Absorption
Dose

Vascularity
Intercostal > Caudal > Epidural > Brachial > Infiltration

pH
Slower

absorption if solution is alkaline, because more is bound into the tissues. absorption for more lipophilic drugs, again because more is bound in the tissues local blood flow, decreasing absorption

Lipophilicity
Slower

Epinephrine
Decreases

Metabolism
Amides

Esters
Ester hydrolysis in the plasma by pseudocholinesterase Almost no potential for accumulation Toxicity is either from direct IV injection
tetracaine,

Primarily hepatic Plasma concentration may accumulate with repeated doses Toxicity is dose related, and may be delayed by minutes or even hours from time of dose.

cocaine

or persistent effects of exposure

benzocaine,

cocaine

Some points about individual LA

Procaine (Novocaine)
Ester Linkage N

O
O Cl

Rapid onset, rapid offset. Neurotoxic, so not used in spinal anesthesia

 Procaine:

The only indication for its use in dentistry is in patients with proven allergy to the amide group. Used intra-arterially, as part of the recognized regimen, to treat the arteriospasm which might occur during intravenous sedation. It has an excellent vasodilatory properties.

Chloroprocaine
Ester Linkage N

(Nesacaine)

O
O Cl

Rapid onset, rapid offset. Neurotoxic, so not used in spinal anesthesia

Benzocaine

(Hurricaine)

Ester Linkage O N O

Only used topically. Associated with methemoglobinemia, particular as an mucosal spray.

 Benzocaine:

Used mainly as topical, due to its poor water solubility, and because of its low toxicity, it is used in concentration up to 20%.
Hydrolyzed rapidly by plasma esterase to aminobenzoic acid accounting for its low toxicity. p-

Tetracaine (Pontocaine)
O O N

Ester Linkage

Slow diffusion in tissues. Often found in topical preparations.

Cocaine
N O O O

O
Ester Linkage
Causes vasoconstriction (as do ropivacaine, bupivacaine, and levobupivacaine). No reason to use. Use 4% lidocaine mixed with 1 ampule (10 mg) phenylephrine instead.

 Cocaine:

The first local anaesthetic agent, rarely used because of the problems of misuse. It is unique in it is ability to produce intense vasoconstriction. Half life 30 minutes. Dosage:
Used

as topical 4 10% solution Maximum dose is 1.5 mg/kg 100mg max. Used intranasally .

Lidocaine (Xylocaine)

O
N N

Amide Linkage

Lidocaine
amide

type anesthetic the most commonly used local anesthetic rapid onset and a duration of 60-75 minutes extended when solutions with epinephrine are used for up to 2 hours metabolized in the liver and excreted by the kidneys.

(Marcaine, Sensoricaine)

Bupivacaine

N N O

N O

S Bupivacaine
levobupivacaine, Equipotent, but less cardiotoxic than bupivacaine

R Bupivacaine

BUPIVACAINE
No

topical effect Slow onset and long duration of action Provide analgesia without significant motor blockage High lipid solubility ,high distribution in tissues d/t protein binding so less in blood Available as 0.25% and 0.50% solution

Ropivacaine (Naropin)

N N O *
S bupivacaine

Only available as pure S isomer Causes vasoconstriction Less motor block than bupivacaine Otherwise, equipotent anesthesia, but less cardiotoxic

N O

(Carbocaine, Polocaine)

Mepivacaine

N N O

 Mepivacaine:

Possess the least vasodilating effect. Metabolized in the liver and has t0.5 of 120 minutes. Its main indication is when local anaesthetic without vasoconstrictor is needed. 3% plain is more effective than lignocaine. Onset & duration:
Rapid

onset but slightly shorter duration.

Etidocaine (Duranest)

N N O

rapid onset, long effect. Causes profound motor block.

Prilocaine
Only amide missing a methyl group here.

N O

 Prilocaine:

A very potent local anaesthetic and is less toxic than Lignocaine. It produces less vasodilatation than lignocaine Rate of clearance is higher than other amidetypes, suggesting extra-hepatic metabolism with relatively low blood concentration. Its metabolite o-toluidine lead to methaemoglobinaemia (more than 600 mg in adults)

Meperidine
N Ester Linkage

(Demerol)
Called pethidine Probably the strangest drug in anesthesia
opioid,

atropinic, local anesthetic blocks seretonin reuptake

leading to fatal interactions with MAO inhibitors
toxic

metabolite
inotrope

Normeperidine
Negative

USES OF LOCAL ANAESTHETICS

1. 2. 3. 4.

5.
6.

Topical anaesthesia Local infiltration Peripheral nerve block I.V. regional anaesthesia Spinal anaesthesia Epidural anaesthesia

 TOPICAL

ANAESTHESIA:-

LA placed on mucous membrane or skin Cocaine is commonly used for rhinolaryngologic procedures due to vasoconstricting effect Lox-oxymetazoline combination is equally effective Nebulized lox used for surface anaesthesia for fiberoptic laryngoscopy/bronchoscopy May cause bronchoconstriction in asthmatics Rapid absorption of LA from these mucosal sites and blood conc achieved are similar to i.v. route Synera: lox+tetracaine with heating element for intact skin anaesthesia TAC: tetracaine+ adrenaline+ cocaine anaesthesia through cut skin in children LET: lox+ epi+ tetracaine (subs of TAC)

 EMLA:-

Eutectic mixture of local anaesthetics

2.5% lox + 2.5% prilocaine Diffuse through intact skin to block neuronal transmission from dermal receptors Dose- 1-2 gm per 10 cm area under occlusive dressing Used for skin graft harvesting, i.v.cannulation, cauterising genital warts, circumcision To be applied 45-60 min prior to procedure Low frequency USG speeds the onset Side effects:- skin reactions like pruritus, edema, erythema and rash may cause methemoglobinemia in children<3 mth or patients on oxidising drugs like sulphonamides, paracetamol, phenytoin, NTG.

 LOCAL

INFILTRATION:-

Extravascular placement of anaesthetic in the area to be anaesthetized Choice of agent depends on the desired duration

Lignocaine is the most commonly used agent

Duration may be significantly increased by adding 1:200000 epinephrine

 PERIPHERAL

NERVE BLOCKS:-

LA injected in the vicinity of peripheral nerve or plexus LA diffuse from mantle to core across a conc gradient Proximal anatomic structures are first to be anaesthetized and first to regain sensation Sequence of onset & recovery in a mixed nerve depends more on the anatomic location of the fibres Dose required is lesser if USG guided blocks are used as the LA is placed in the immediate perineural area Long acting amide LA like bupivacaine and ropivacaine are preffered as they provide analgesia for upto 12 hrs. Ropivacaine may prove to be a better choice Shorter duration of motor block Less cardiovascular side effects

 I.V.

REGIONAL ANAESTHESIA (IVRA):-

LA injected i.v. in a torniquet occluded limb LA diffuses from vascular bed to non vascular tissues like

axons &nerve endings leading to conduction blockade

Occluding torniquet is gradually released Prilocaine attains lower blood conc as compared to lignocaine when administered in equal doses Dose of lignocaine- 3 mg/Kg (40 ml of 0.5% solution)

Chlorprocaine, bupivacaine & ropivacaine not recommended

for IVRA

 SPINAL

ANAESTHESIA:-

LA injected in the lumbar subarachnoid space Site of action: preganglionic fibres as they leave the spinal cord in the anterior rami Differential zones of autonomic, sensory & motor block Total dose of LA more imp than the volume/conc. Hyperbaric solutions produce more dense block Duration depends mainly on systemic absorption for both ester & amide LA Dose of lox to be limited to 60 mg to prevent TNS Side effects: Hypotension Bradycardia Cardiac arrest Respiratory depression & apnea

 EPIDURAL

ANAESTHESIA:-

LA placed in epidural/sacral caudal space LA diffuses in paravertebral area and across the dura to act

on nerve roots & spinal cord

Delayed onset as compared to SA Zone of differential motor blockade extends four segments

below the sensory level

Addition of epinephrine may lead to 1/3 reduction in systemic absorption

Long acting amide LA in lower conc may be used for post op analgesia and labour analgesia without producing significant motor paralysis

OTHER USES:Analgesia: lidocaine as continuous infusion to

1.

maintain a plasma conc 1-2 ug/ml. effective in post

op pain & stump pain.
2.

Cough suppressant: i.v. lignocaine in perioperative period Anti arrythmic: i.v. lignocaine (class I B drug) used

3.

in a dose of 1.5mg/Kg
4. 5.

Anti epileptic: suppression of grand mal seizures Bronchodilation

Antiinflammatory Effects: following mechanisms

Inhibit PAF Inhibit G protein Inhibit neutrophil accumulation Impair free radical & mediator release Inhibit superoxide anion production

DOSES OF COMMONLY USED DRUGS

Infiltration
Conc dose

Drug

PNB
Conc dose

Spinal
Conc dose

Epidural
Conc dose

Lox
Bup Rop

0.5- 300/ 1-1.5 1.0% 500 0.25 175/ 0.25225 0.5 0.2- 200 0.50.5 1.0

300/ 500 175/ 225 250

1.5-5 100 0.5- 20 0.75 0.5- 150.75 20

1.5-2 300/ 500 0.5- 175/ 0.75 225 0.5- 200 1.0

TOXICITY OF LOCAL ANAESTETICS

ALLERGIC <1% More

REACTIONS:-

of ADR due to LA are due to to allergic reactions

common with esters as compared to amides due to formation of PABA related compounds

When
Cross

using amides, the allergy is mostly to methylparaben which is added as a preservative

sensitivity occurs between esters but not bet agents of different classes testing:- intradermal testing by using preservative free preprations

Allergy

 SYSTEMIC

TOXICITY:i.v. injection

due to higher plasma conc of the LA

Accidental Tissue

absorption- depends on

Dose administered

Vascularity of the tissue

Use of epinephrine Lipid solubility of the drug

Acute toxicity
Risk

of seizure and/or cardiovascular collapse is increased by:

Cold

temperature (slows metabolism) Metabolic or respiratory acidosis Hypoxia

Acute Toxicity
With

most drugs, CNS toxicity proceeds cardiac toxicity, providing a warning of impending disaster.
Key

response: maintain oxygenation and normal CO2!

With

bupivacaine, CNS toxicity rapidly progresses to cardiovascular collapse. Pregnancy enhances the risk of cardiac toxicity.

 CNS

toxicity:Bupivacaine: 4.5-5.5ug/ml

Toxic conc for lignocaine: 5-10ug/ml

Rate of increase of serum conc is more important than the absolute concentration reached
Symptoms- numbness of tongue & circumoral tissues

restlessness, vertigo, tinnitus

muscle twitching & tonic clonic seizures CNS depression with hypotension and apnea

coma & cardiac arrest

raised serotonin, mexiletine treatment

Factors reducing seizure threshold: PaCO2, hyperkalemia,

 TREATMENT:-

Hyperventilation Controlled mechanical ventilation Midazolam 0.05mg/kg i.v. Thiopentone 50-100 mg i.v.

 CARDIAC

TOXICITY:-

Bupivacaine>Ropivacaine>Lignocaine Factors enhancing toxicity of bupivacaine: Pregnancy B-blocker, CCB, digoxin Addition of epinephrine Hypoxia/hypercarbia/acidosis

Effects of Bupivacaine Isomers on Cardiac Sodium Channels

Dextrobupivacaine

Has faster onset of action than

levobupivacaine Has greater affinity for cardiac sodium channels Has a slower offset time

Clinical features Hypotension, chest pain, palpitations, dyspnea, diaphoresis, lightheadedness Wide QRS PR interval VPC Ventricular tachycardia Supraventricular tachycardia AV heart block

Treatment supportive and CPR as under standard protocols Bretylium 20mg/kg

LIPID RESCUE: Use of i.v. lipid emulsion to treat severe LA toxicity Pioneered by DR. Guy Weinberg in 1998

Mechanism of action: lipid sink theory

Exogenous lipid provides an alternate source for binding of lipid soluble LA

1. Bupivacaine molecules preferentially segregate from plasma to lipid in a 1:12 ratio.

2. It also reacts significantly with tissue bupivacaine 3. Lipid acts as a substrate for cellular energy production 4. May act on NO pathways

 DOSAGE:-

It is advisable to initiate the lipid infusion once the conventional treatment modalities have begun.
i.v. bolus intralipid 20% 1.5 ml/kg over 1 min. i.v. infusion @ 0.25 ml/kg/min Bolus injection at 5 min interval if circulation not restored Increase infusion to 0.5 ml/kg/min after 5 min if circulation not restored

SIDE

EFFECTS:pulmonary hypertension warfarin resistance ICP after head injury seizures in children

Thrombophlebitis Infection Allergic reactions Fat emboli

 METHEMOGLOBINEMIA:-

m/c with prilocaine, benzocaine & lignocaine are also responsible Prilocaine Orthotoluidine

Hb Oxy Hb Methemoglobinemia
Risk

factors: neonates, patients on oxidising drugs Central cyanosis @ methemoglobin> 15%

Methemoglobinemia
10%:

clinical anoxia 60%: stupor, coma, and death.

Documented with benzocaine, prilocaine
Associated

with benzocaine and prilocaine Treat with methylene blue, 1-2 mg/kg given over 5 minutes
Faster

administration may exacerbate methemoglobinemia

Drug Interactions
Esters

are metabolized by pseudocholinesterase

Compete

with succinylcholine for metabolism, so when given together each lasts longer Metabolism slowed by administration of anticholinesterase (e.g., neostigmine)

Drug Interactions
Local

anesthetic toxicities are ADDITIVE

Divide

lidocaine dose / 4 to convert to bupivacaine equivalents Keep lidocaine / 4 + bupivacaine less than 3 mg/kg

ANALGESIA WITH LOCAL ANAESTHETICS

Regional anesthesia - Uses

Provide

anesthesia for a surgical procedure Provide analgesia post-operatively or during labor and delivery Diagnosis or therapy for patients with chronic pain syndromes

Regional anesthesia - types

Topical Local/Field Intravenous

block (Bier block) Peripheral (named) nerve, e.g. radial n. Plexus - brachial, lumbar Central neuraxial - epidural, spinal

ADJUNCTS TO IMPROVE ANALGESIA WITH LA

-Opiods -Alpha 2 adrenergic receptor agonists -Anticholinesteres -Steroids

OPIODS
Analgesic

properties are due to spinal and supraspinal effect . No motor block . Synergy with LA . Decrease LA consumption . Improve analgesia . Decrease shievering . S/E are nausea , vomitting, respiratory depression.

ADRENERGIC AGONISTS
Epinephrine

,clonidine ,dexmedetomidine Lipophillic compounds . Analgesic effect is due to alpha 2 receptor binding . Decrease venous uptake of LA and increase analgesic and motor block .

CLONIDINE
Show

synergy with LA and opiods . No respiratory depression and no motor block . It improve analgesia in both spinal and epidural but hypotension limits its use . Analgesic effect IT > epidural > systemic 0.2-0.3g/kg prolongs the duraion of sensory block by 30% Optimal dose for ambulatory surgery is 30-45g

ANTICHOLINESTERES
Neostigmine Ach itself has

analgesic effect so analgesia is due to increased Ach conc. as neostigmine inhibites cholinesterases No intrathecal use It has modest analgesic action Decrease postop. Analgesic needs particularly effective to spare opiod use Bolus dose 4-7g/kg and infusion 7g/ml solution It increase postop. Analgesia upto 8 hrs with lignocaine.

STEROIDS
Steroids

have nerve block prolonging action. They block the nociceptive impulse transmission along unmyelinated c fibres Steroid prolongs analgesia significantly when used in nerve blocks They have nerve block prolonging effect accoding to their anti inflammatory potency.