LOCAL

ANAESTHETICS

BY :DR SUHAIMI TAJUDIN

MODERATOR : PROF MADYA DR SHAMSUL

HUSM ANESTESIOLOGI DEPARTMENT

OUTLINE

1. Introduction

2. Ideal properties

3. Comercial preparation

4. Structure activity relationship

5. Mechanism of action

6. Pharmacokinetic

7. Side effects

8. Individual LA

INTRODUCTION

Drugs that produce reversible conduction blockade of

impulses along central & peripheral nerves producing

ANS blockade, sensory blockade and skeletal muscle

paralysis in the area innervated by affected nerve

Without loss of consciousness and reversible

2. IDEAL PROPERTIES

Physicochemical Pharmacokinetic Pharmacodynamic

•Easy to produce &

economical

•Stability during

storage, stable in light,

air or pH changes

•Formulation free of

additives

•Soluble in water

•sterilisable by heat

without decomposition

•Ease of administration

•Rapid onset

•Duration of action

appropriate to use

•Clearance

independent of hepatic/

renal function

•No active or toxic

metabolites

•High therapeutic index

•No hypersensitivity

reaction

•Absence of toxicity on

local tissues, liver brain

& other tissues

•Administration

effective by topical,

injection near nerve

trunk & infiltration

•Specificity – only

nerve tissue affected

3. COMMERCIAL PREPARATIONS

Poorly soluble in water – marketed most often

as water-soluble hydrochloride salt

These HCl salts are acidic(pH 6) –

contributing to the stability of LA

An acidic pH also important if epinephrine is

present in LA solution, becoz this

cathecolamine is unstable at alkaline pH

sodium metabisulphite (strongly acidic), may

be added to LA-ephephrine solutions to

prevent oxidative decomposition of

epinephrine

COMERCIAL PREPARATION

Alkalinization of LA solution

By adding sodium bicarbonate

Will shortens the onset (more nonionized form)

Enhance dept of sensory and motor blockade (increase

potency)

Increase spread of epidural blockade

4.STRUCTURE ACTIVITY RELATIONSHIP

LIPOPHILIC

PORTION

HYDROPHILIC

PORTION

HYDROCARBON

CHAIN

4. CONT… Lipophilic portion

Usually unsaturated aromatic ring e.g para-aminobenzoic acid

lipid soluble

Potency

Hydrophilic portion

Is usually tertiary amine

Water soluble

Connecting hydrocarbon chains

.ester( -CO.O-)

.amide(-NH.CO)

the nature of this bond is the basis of classification of LA, relate to site of metabolism and potential to produce allergic reaction

COMPARISON

Esters ( -CO.O-)

Procaine, tetracaine, amethocaine, cocaine

Relatively unstable in solution

Allergic reactions are common

Rapidly metabolised by plasma and liver cholinesterase

One metabolite, para-aminobenzoic acid, thought to be responsible for allergic rxn

Metabolism may be prolonged when pl cholinesterase is low

E.g liver disease, pregnancy and atypical enzymes

Amides (-NH.CO)

lignocaine, etidocaine, prilocaine, mepivacaine, bupivacaine,ropivacaine, levobupivacaine

Relatively stable in solution

Allergic reaction is rare, may be ass with preservative vehicle

Slowly metabolised by amidases in liver

Dependent on liver blood flow and function

5. Mechanism of action

RMP

Normal Action potential

Sodium channel

Mechanism of action

Frequency dependent blockade

Membrane volume expansion theory

RESTING MEMBRANE POTENTIAL Steady state potential which exists across the cell membrane

About 70mV with the inside membrane being negative compare to outside

The Na-K-ATPase is electrogenic , pumps 3Na out of cell in exchange for 2K pumped intracellularly. This pump sets up concentration different of Na & K across the cell membrane

small net intracellular loss of +ve charge

The membrane is permeable to Na and K, so these ion tend to leak across membrane down their concentration gradient

membrane is 100x more permeable to K, > K lost from cell than Na enters the cell

Net result is larger amt of +ve charge left the cell than has entered it so inside of membrane left with net negative charge result in RMP are being negative compare to outside

ACTION POTENTIAL Generated by altered Na

permeability across phospholipid membrane

Last only 1-2ms

Electrical or chemical trigger initially cause slow rise in membrane potential until threshold potential (50mV) is reached

Voltage sensitive Na channels then open, increasing Na pemeability dramatically and membrane potential briefly reaches +30mV, at which Na channels close

The membrane potential return to its resting value with an increased efflux of K

The Na/K ATPase restores the concentration gradients

SODIUM CHANNEL

Voltage gated channel responsible

for upstroke of action potential in

nerve and skeletal muscle

Exist in 3 functional states

Activated, open

Inactivated closed

Resting closed

During RMP Na channel are

distributed in equilibrium between

the rested closed and inactivated

closed state

LA has high affinity for the open and

inactivated closed state and low

affinity for the rested closed state

MECHANISM OF ACTION

LA selectively binds to Na

channel in inactivated-closed

state.

It stabilizes it in this

configuration and prevent their

change to rested-closed and

activated-open states in

response to nerve impulse

Na channel impermeable to Na

Slows the rate of depolarisation,

threshold potential not reached &

action potential not propagated

Frequency- dependent blockade

1. Defines a situation where the more frequent the channel

are activated, the greater the degree of block produced

2. After AP, Na channel develop a low affinity state where

some drugs dissociate/ unbind and Na channel recover

3. If another AP arrived before all LA dissociates it regain

access into the Na channel at open activated state →

additional increment of block

4. ↑ Frequency of AP - ↑ degree of blockade

MEMBRANE VOLUME EXPANSION THEORY

1. Lipophilic LA incorporated into lipid bilayer causing a volume

expansion & distortion to the conformation of axonal

membrane and hence the Na channel resulting in its

inactivation

2. Mode of action of Benzocaine, and other LA when given in

high dosage

6.PHARMACOKINETIC

Physicochemical properties

Absorption

Distribution

Metabolism

Excretion

PHYSICOHEMICAL PROPERTIES

The chemical structure and physicochemical characteristics of

LA affect their clinical properties

Modification of the chemical structure (lengthening of the

hydrocarbon chain within critical length or increasing the

number of carbon atoms in the aromatic ring or tertiary amine )

may alter lipid solubility, potency, rate of metabolism &

duration of action

In particular, these are modified by

a) Lipid solubility

b) Protein binding

c) Dissociation constant (pKa value)

a) Lipid solubility

Lipid solubility of different anaesthetics governs their ability to

penetrate perineuronal tissues and neural membrane, and

reaches their site of action in neuroplasm

More lipid soluble – penetrates membrane more easily, less

molecule requires for nerve conduction blockade i.e. more

potent

E.g. Bupivacaine, levobupivacaine and ropivacaine are app

3-4x as potent as lidocaine or prilocaine, dt differences in

their lipid-solubility

PHYSICOCHEMICAL PROPERTIESAgent Molecula

r Wt

Lipid

solubility

Relative

potency

pKa Onset Plasma

protein

binding,

%

Duration

after

infiltration

(Min)

Toxic

plasma

conc

(g/ml)

Dose

[+Adrenaline]

(mg/kg)

Procaine 236 0.6 1 8.9 Slow 6 45-60

Chloroprocaine 271 4 8.7 Rapid 30-45

Tetracaine 264 80 16 8.5 Slow 76 60-180

Lidocaine 234 2.9 1 7.9 Rapid 70 60-120 >5 4[7]

Etidocaine 276 141 4 7.7 Slow 94 240-480 ~2

Prilocaine 220 0.9 1 7.9 Slow 55 60-120 >5 6[8]

Mepivacaine 246 1 1 7.6 Slow 77 90-180 >5

Bupivacaine 288 28 4 8.1 Slow 95 240-480 >1.5 2[3]

Ropivacaine 274 4 8.1 Slow 94 240-480 >4

b) Protein binding

Tissue protein binding primarily affect the duration of axn

of LA

plasma protein binding, >longer duration of action

Plasma protein binding acts as depot

E.g

Procaine is not extensively bound to tissue protein, has short

duration of action

Bupivacaine, levobupivacaine & ropivacaine are extensively

bound to plasma and tissue protein --- prolonged effect

PHYSICOCHEMICAL PROPERTIESAgent Molecul

ar Wt

Lipid

solubility

Relative

potency

pKa Onset Plasma

protein

binding,

%

Duration

after

infiltration

(Min)

Toxic

plasma

conc

(g/ml)

Dose

[+Adrenaline]

(mg/kg)

Procaine 236 0.6 1 8.9 Slow 6 45-60

Chloroprocaine 271 4 8.7 Rapid 30-45

Tetracaine 264 80 16 8.5 Slow 76 60-180

Lidocaine 234 2.9 1 7.9 Rapid 70 60-120 >5 4[7]

Etidocaine 276 141 4 7.7 Slow 94 240-480 ~2

Prilocaine 220 0.9 1 7.9 Slow 55 60-120 >5 6[8]

Mepivacaine 246 1 1 7.6 Slow 77 90-180 >5

Bupivacaine 288 28 4 8.1 Slow 95 240-480 >1.5 2[3]

Ropivacaine 274 4 8.1 Slow 94 240-480 >4

c) Dissociation constant (pKa value)

pKa is equal to pH at which the concentration of

ionized base and non-ionized base are equal

Is the most important factor affecting rapidity of

onset of axn

pKa value governs the proportions of LA that is

present in non-ionized form at physiological pH

values and therefore available to diffuse across

tissue barrier to its site of axn

LA with a pKa near physiological pH will have a

greater degree of unionized molecules → More LA

diffused across membrane → rapid onset of action

PHYSICOCHEMICAL PROPERTIESAgent Molecula

r Wt

Lipid

solubility

Relative

potency

pKa Onse

t

Plasma

protein

binding,

%

Duration

after

infiltration

(Min)

Toxic

plasma

conc

(g/ml)

Dose

[+Adrenaline]

(mg/kg)

Procaine 236 0.6 1 8.9 Slow 6 45-60

Chloroprocaine 271 4 8.7 Rapid 30-45

Tetracaine 264 80 16 8.5 Slow 76 60-180

Lidocaine 234 2.9 1 7.9 Rapid 70 60-120 >5 4[7]

Etidocaine 276 141 4 7.7 Slow 94 240-480 ~2

Prilocaine 220 0.9 1 7.9 Slow 55 60-120 >5 6[8]

Mepivacaine 246 1 1 7.6 Slow 77 90-180 >5

Bupivacaine 288 28 4 8.1 Slow 95 240-480 >1.5 2[3]

Ropivacaine 274 4 8.1 Slow 94 240-480 >4

ABSORPTION

Absorption of LA from its site of injection into

systemic circulation is influenced by;a. Site of injection

b. Dosage

c. Addition of vasoconstrictor

d. Physicochemical properties of LA

e. Vasoactive properties of the LA

f. Pathophysiological process – acidity of tissue reduces

absorption ( e.g. abscess, metabolic acidosis)

a. Site of injection

• Relates to the blood flow and presence of tissue capable of

binding LA at site of administration

• Blood concentration in decreasing order

• Intercostal > caudal > epidural > brachial plexus > sciatic-

femoral > subcutaneous infiltration

b. Dosage

• Blood level of LA is related to total dose of drug rather than

specific volume or conc of solution

• Linear relationship between total dose & peak blood conc

achieved

c. Addition of vasoconstrictor

By addition of adrenaline 5g/ml (1:200000)

Higher Dosage offers no additional benefits but increases symphatomimetic activites

limit systemic absorption and maintain the drug concentration in nerve fibre and prolong the time the drug in contact with nerve fibre

Ropivacaine & Cocaine has intrinsic vasoconstrictor activities

Lignocaine, mepivacaine, bupivacaine, etidocaine exhibit vasodilator effects

d. Vasoactive properties of LA

Influence potency and duration of action

All LA has vasodilator effect except ropivacaine and

coccaine

More vasoactive like lidocaine more greater systemic

absorption result in shorter duration of action

e. Pathophysiological process

Acidosis environment

Will increase ionized fraction of the drug

Result in poor quality of LA

f. Physiocochemical properties

Lipid solubility

Protein binding

Dissociation constant

DISTRIBUTION

Depends on organ uptake, which determined by;

a)Tissue perfusion

Highly diffuse organ (brain, lung ,liver,kidney&heart) responsible for initial rapid uptake

Followed by slower redistribution to moderately profused tissue (muscle&gut)

b) Protein binding strong plasma protein binding eg Bupi., tends to retain LA in the blood Influence by changes in conc. of alpha1 acid glycoprotein (eg; pregnancy,old

age, concurrent Liver Disease)

c) high lipid solubility; facilitates tissue uptake

d) Tissue mass muscle provides greatest reservoir for LA agents dt its large mass

overall amide are more widely distributed in tissue than ester group

Lung extraction

The lung capable of extracting local anesthetic such as lidocaine and bupivacaine from circulation

Limit the concentration of drug that reaches systemic circulation to be distributed to coronary & cerebral circulation

Placental transfer

Highly plasma protein binding LA limits diffusion across placenta

Esters undergo rapid hydrolysis hence not available for transfer across placenta

Acidosis in fetus, which may occur during prolonged labour, can result in accumulation of LA molecules in the fetus (ion trapping)

METABOLISM

a) ESTER group

Undergo hydrolysis by cholinesterase enzyme, in the plasma and liver

Rate of hydrolysis varies, and resulting metabolites are pharmacologically inactive

Paraaminobenzoic acid metabolite may be responsible for allergic reaction

CSF – lacks estrase enzyme; so the termination of action of intrathecal injection of LA depends on absorption into bld. Stream

o Prolonged in neonates, liver ds, ↑BUN, parturient and atypical plasma cholinesterase homozygotes

b)Amides group

Metabolized by microsomal enzymes in the liver

Initial step corversion of amide base →

aminocarboxilic acid + cyclic aniline derivative

↓ ↓

N-dealkylation hydroxylation

Compare with ester, amide metabolism is more complex and

slower , predispose to systemic toxicity

impaired hepatic function, will reduce metabolic rate

Prilocaine Deakylation Orthotoluidine → 4OH toluidine + 6OH toluidine

- excessive plasma concentration of o-toluidin lead to

methaemoglobinaemia

Lignocaine

(High extraction

drug)

N-deakylation

Hydrolysis

Monoethylglycinexylidide (MEGX) – 80% cardiac protective effect

→Glycinexylidide(GX)

→2,6-xylidine ( 10% cardiac protective effect)

→4OH-2,6-xylidine (appears in urine)

Mepivacaine N-demethylation 2,6 pipecoloxylidine (PPX)

Bupivacaine Deakylation PPX

N-desbutyl bupivacaine & 4OH bupivacaine

Ropivacaine Deakylation PPX

3 & 4OH ropivacaine

Etidocaine Deakylation 2,6 xylide

EXCRETION

Poor water solubility of LA limit renal excretion of

unchanged drugs to < 5% of injected dose (except cocaine

10-12%)

Water soluble para-aminobenzoic acid readily excreted

7. SIDE EFFECTS

A. Local Allergic reaction

B. Systemic

Central Nervous system Central

Peripheral neurotoxicity

TNS

Cauda equina syndrome

Anterior spinal artery syndrome

Cardiovascular system

Blood methemoglobinemia

Respiratory Ventilatory response to hypoxia

Git Hepatotoxicity

Local Allergic rxn

Rare estimated < 1% of all adverse reaction

to LA

Ester LA that produce metabolites related

PABA are more likely to evoke allergic rxn

Amides – cross sensitivity occurs with the

preservatives (methylparaben acid –

structurally similar to PABA) but rare on LA

itself

CNS - SYSTEMIC

Low plasma concentration of LA are likely to produce numbness of tongue and circumoral tissue ( reflecting delivery of drug to these highly vascular tissue)

As the plasma concentration increased, LA readily cross the BBB and produce cns changes

Restlessness, vertigo, tinnitus and difficulty in focusing

Slurred speech and skeletal muscle twiching- face and extremities

Seizures and CNS depression

Plasma concentration of LA depend on specific drug involve

Lidocaine, mepivacaine, prilocaine (5-10ug/ml)

Bupivacaine (4.5-5.5ug/ml)

The threshold for convulsions is also influenced by presence of other drugs that affect CNS like hypoxia and acidosis

The excitatory efffect of LA are probably due to selective depression of inhibitory cortical pathway, and may be followed signs of cortical and medulary depression (coma, apnoea)

Convulsions should be treated by maintaning adequate ventilation and oxygenation, and controlled by anticonvulsant drugs

Diazepam 10-20mg iv

Thiopental 150-250mg iv

Accidental injection of large vol of LA into CSF during epidural or paravertebral block can produce total SA

Treatment include mechanical ventilation and circulatory support, use of vasopressor may be indicated

CNS - PERIPHERAL

Neurotoxicity from placement of LA solution into epidural and

subarachnoid space

a. Transient neurologic symptoms

Manifest as moderate to severe pain in lower back, buttocks

and post thigh that appear within 6- 36H after complete

recovery from spinal anesthesia

Resolving within 1 week

Ass with use of vasoconstrictor

The incidence of TNS is greatest following itrathecal

injection of lignocaine ( as high as 30%)

b. Cauda equina syndrome

Occur when diffuse injury across lumbosacral plexus produce varying degree of;

Sensory anaesthesia

Bowel and bladder sphincter dysfunction

paraplegia

Following repeated doses of 5% lidocaine & 0.5% tetracaine used in continuous spinal anesthesia

Pooling of drugs around the cauda equina, result in permanent neuronal damage.

c. Anterior spinal artery syndrome

Lower extremity paresis with variable sensory deficit that is ususally diagnosed as neural blokade resolves

Aetiology?

Uncertain

Thrombosis or spasm of ant spinal artery due to effects of hypotension, vasoconstrictor drugs

Risk factor

Old age

peripheral vascular ds

CVS

Overdose of LA may cause profound hypotension, bradycardia,

bradyarhythmias and even cardiac arrest, and usually follows

sign of CNS toxicity

E.g. – high systemic conc of bupivacaine are particularly ass

with significant toxicity

Produce prolonged blockade of Na channel

also affects myocardial Ca and K channels, and is

preferentially bound by cardiac muscle

Myocardial contractility and conduction in junctional tissue

is depressed, with widening of QRS complex and distortion

of St segment

Predispose to re-entrant phenomena and ventricular

arrthyhmias, which are potentiated by hypoxia, acidosis and

hyperK

Arrthyhmias and bradycardia may respond to iv atropine (1.2-

1.8mg) and colloid/crystalloid infusions may be required to

expand pl vol

Current evidence suggest that use of LA enantiomers with (S)-

configuration reduce risk of cardiac depression and

cardiotoxicity, and ropivacaine (an S-isomer) and

levoupivacaine (S-bupivacaine) may have significant

advantages compare to racemic bupivacaine

Hematology --Methemoglobinemia

Rare but potentially life treatening complication (decreased O2-carrying capacity)

Cause by oxidation of Hb to methemoglobin more rapidly than methemoglobin is reduced by Hb

Prilocaine ( > 600mg @ >10mg/kg)

Amide LA that is metabolized to othotoluidine

Othotoluidine is oxidizing compound, capable of converting Hb to methemoglobin ----methemoglobinaemia

Cause pt to appear cyanotic

Also caused by Benzocaine ( topical application > 200-300mg)

Is readily reversed by administration of iv methylene blue, 1-2mg/kg over 5 min (total dose 7-8mg/kg)

Respiratory

Lidocaine at high plasma concentration depress

ventilatory response to arterial hypoxaemia

So patient with CO2 retention which resting

ventilation depend on hypoxic drive may be at risk

of ventilatory failure when lidocaine is administered

for treatment of cardiac dysrythmia

Hepatotoxicity

Continous or intermittent epidural administration of bupivacaine

to treat postherpetic nuralgia has been associated with increase

plasma concentration of liver transaminase enzyme that

normalized when bupivacaine infusion was discontinued

It could be due to a direct toxic injury or an allergic reaction

Dysphoria

Vivid fear of imminent death and a delusional belief of having

died

TOXICITY

26

24

22

20

18

16

14

12

10

8

6

4

2

0

Death

Ventricular Arrest

Cardiac ArrhythmiaRespiratory arrest

Myocardial depression

Plasma lidocaine concentration µg/ml

Coma

Loss of conciousness

Convulsion

Muscle twitching

Visual disturbances

Lightheadness, tinnitus,

circumoral & tongue numbness

Positive inotropy,

anticonvulsant, antiarrythmic

CNS

excitation

8. INDIVIDUAL LA

Bupivacaine

Ropivacaine

Lignocaine

Cocaine

Prilocaine

BUPIVACAINE

Structure – amide LA, pipecoloxylidide group, racemic

Presentation – clear colourless, aques solution (bupivacaine hydrochloride ) Plain (0.25%, 0.5%, 0.75%)

With 1:200 000 (5µg/ml ) adrenaline

Heavy 0.5% with 80mg/ml dextrose ( SG 1.026) used for SA

Recommended max dose 2mg/kg, 0.75% produces more prolonged motor block

Clinical- acts within 10-20min and almost immediate with intrathecal administration,

Duration of action 4-8hrs.

4X as potent as lidocaine, propensity for cardiotoxicity

Pharmacokinetics

MW pKa Part coef

288 8.1 27.5

Absorption – addition of adrenaline does not influence rate of systemic absorption

Distribution

prot.bind Vd

95% 1L/kg(41-103L)

Metabolism – liver microsomal enzymes P450 to 2,6-Pipecoloxylidine (N-deakylation), N-desbutyl bupivacaine & 4OH bupivacaine also formed

Excretion – 5% excreted as PPX, 16% excreted unchanged in urine,

Cl 0.47L/m t½ 0.31-0.61Hr (after IV admin)

ROPIVACAINE

Structure – Amide LA, pipecoloxylidide group, pure S-enantiomer

Presentation – Clear colourless solution containing 0.2/ 0.75/ 1.0% ropivacaine hydrochloride

Recommended dose –3.5mg/kg, 250mg (150mg for C-section under epidural), not currently intended for intrathecal admin and in children < 12 years

Clinical – sensory blockade similar in time course to that produced by bupivacaine; motor blockade is slower in onset & shorter in duration than after an equivalent dose of bupivacaine; less cardiotoxic than bupivacaine; Intrinsic vasoconstrictor, mild CNS Sx

Pharmacokinetics

MW pKa Part coef

274 8.1 6.1

Absorption

Distribution

prot.bind Vd

94% 0.8L/kg (52-66L)

Metabolism – occurs in liver to 2,6 pipecoloxylidine (N-deakylation), Aromatic hydroxylation to 3 & 4OH ropivacaine

Excretion – 86% (mostly conjugated) excreted in the urine, 1% unchanged

Cl – 0.82L/m t½ - 59-172min

LEVOBUPIVACAINE

Structure – amide LA, Pure S-enantiomer of Bupivacaine Presentation – clear colourless, aq solution (pH 4.0-6.5)

Plain (0.25%, 0.5%, 0.75%) Recommended max dose 2mg/kg (150mg plus up to 50mg 2 hourly

subsequently), 0.75% CI in Obstetric use Clinical- both the CNS and the cardiac toxicity of levobupivacaine were less than

that of bupivacaine.- less prolonged motor blockade but longer sensory blockade after epidural

administration

Pharmacokinetics

MW pKa Part coef

324 8.1 27.5

Absorption – depend on dose and route

Distribution

Prot.bind Vd

97% 67 liters

Metabolism – Levobupivacaine is extensively metabolized, to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, 3-hydroxy levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates

Excretion – mostly conjugated 71% urine 24% faeces ,no unchanged levobupivacaine detected in urine,

Cl 39 liters/hour t½ 1.3 hours(after IV admin)

LIDOCAINE(1947)

Structure – Amide LA; derivative of diethylaminoacetic acid

Presentation – Clear aq solution lidocaine hydrochloride Plain 0.5%( local infiltration, IVRA ), 1%, 2%(nerve blocks, extradural anaesthesia) with adrenaline 1:200 000 Gel 2% with or without chlorhexidine 4% aq solution for topical application to pharynx, larynx, trachea 10% spray for oral cavity & upper resp tract

Recommended max dose 3mg/kg (7mg/kg with adrenaline), toxic plasma level >10ug/ml Acute ventricular dysrhythmia ( class 1)– 1mg/kg over 2 min followed by infusion 4mg/kg/min

(30min), 2mg/kg/min ( 2 hr) & subsequently 1mg/kg/min. Reduce stress response – 1-2mg/kg IV 5min before intubation

Clinical – acts in 2-20min; duration 60-120min depending on conc, vasoconst

Thought to be more toxic to nerve tissue when directly applied than other LA, hence increased incidence of transient radicular irritation following its use for SA

Pharmacokinetic

MW pKa Part coef

234 7.9 2.9

Absorption – bioavailability by oral route is 24-46% due to high extraction & 1st pass hepatic metabolism

Distribution

prot.bind Vd64% 0.75-1.5L/kg

Metabolism – 70% metabolised in liver by N-deakylation to MEGX, GX with further hydrolysis prior to renal excretion

Excretion - <10% excreted unchangedCl – 6.8-11.6ml/kg/min t½ - 90-110min

PRILOCAINE

Structure –Amide LA; secondary amine derived from toluidine

Presentation – clear colourless aq prilocaine hydrochloride Plain 1%, 4%

Solution with 0.03 u/ml felypressin(3%) for dental infiltration

EMLA

Recommended max dose – 5mg/kg; with felypressin 8mg/kg

Clinical – rapid onset, intermediate duration between lidocaine & bupivacaine; potency similar to lidocaine;

less toxic

may be used for IVRA(0.5%); 1-2% for nerve block

problem with metHb (>600mg IV)

Pharmacokinetic

MW pKa Part coef

220 7.9 0.9

Absorption

Distribution

prot.bind Vd

55% 3.7L/kg

Metabolism – metabolised in the liver to O-toluidine then 4 & 6OH-toluidine. Some metabolism occurs in the lungs & kidney

Excretion – inactive metabolites, <1% unchanged

COCAINE Structure – Ester of benzoic acid, an alkaloid derived naturally from leaves of

Erythroxylon coca

Restricted use to surface analgesia because of its toxicity

Commonly used as 10% spray or paste to reduce bleeding caused by nasal intubation

Causes vasoconstriction by preventing uptake of noradrenaline by presynaptic nerve endings, also inhibit monoamine oxidase

Recommended dose – admin topically 3mg/kg

Clinical – inhibit uptake of adrenaline and noradr by central and peripheral symphatetic nerve endings, and enhances effect of sympt nerve stimulation

CNS – increased neuronal activity in symphatetic pathways in hypothalamus and medulla

It may produce mental stimulation, euphoria, hallucinations, vasoC, pupillary dilatation, hypertension, tachycardia and arrhythmias

Pharmacokinetic

Absorption – well absorb from mucosa; bioavailability-intranasal 0.5%

Distribution – 98% protein bound, Vd 0.9-3.3L/kg

Metabolism – degraded by plasma esterase predominantly to benzoylecgonine, ecgonine

Excretion – metabolites excreted in urine , 10-12% unchanged

Cl 26-44ml/kg/min t½ 25-60min

Toxicity: (fatal dose > 1gm)

CNS stimulation: convulsions at high doses, followed by central

depression and apnoea

Symphatetic stimulation: arrhythmias, tachycardia and hypertension

may occur

Addiction may occur with chronic use

Cardiomyopathy and sudden death have been associated with

chronic abuse

Use with caution in pts with HPT, CAD or on drugs that

potentiate the effects of cathecholamine eg MAOI

EMLA Eutectic Mixture of local anaesthetic

Mixture of 2.5% lidocaine + 2.5% prilocaine as oil- water emulsion

Melting point of each LA is lowered by presence of the other

May produce blanching (addition of nitroglycerine ointment may promote venodilation) and increase in metHb (esp < 3mths-immature reductase pathway)

Useful for children

Effective analgesia 60-90 min after topical application and covering with occlusive dressing

Uses described include analgesia for venopuncture, venous and arterial cannulation, lumbar puncture, epidural injection, superficial skin surgery and relief of tourniquet pain during IVRA

Factors affecting onset, efficacy, duration – skin blood flow, epidermal & dermal thickness, duration of application, skin pathology

MCQ

MCQ

1. Lidocaine can cause:

a) sedation

b) convulsions

c) slowed A-V conduction

d) prolongation of the cardiac action potential

e) shortening of the refractory phase

f) Is more potent than ropivacaine

MCQ

1. Lidocaine can cause:

a) sedation T

b) convulsions T

c) slowed A-V conduction T

d) prolongation of the cardiac action potential F

e) shortening of the refractory phase T

f) Is more potent than ropivacaine F

2. Regarding local anaesthetic agents (LA):

a) the potency of LAs is proportional to their lipid

solubility

b) the duration of action is dependent on protein

binding

c) agents with low pKa have a faster onset of action

d) all local anaesthetics are vasodilators

e) the depth of local anaesthetic block is increased

by increasing the dose

2. Regarding local anaesthetic agents (LA):

a) the potency of LAs is proportional to their lipid

solubility T

b) the duration of action is dependent on protein

binding T

c) agents with low pKa have a faster onset of action

T

d) all local anaesthetics are vasodilators F

e) the depth of local anaesthetic block is increased

by increasing the dose T

3. Concerning local anaesthetics:

a) they are absorbed more rapidly after intercostal

block than after caudal administration

b) in the foetus they are able to cross the placenta

as readily as from the mother

c) they are weak acids

d) those which are esters are rapidly metabolised

by liver enzymes

e) pKa is the pH at which more than half of a local

anaesthetic exists in non-ionised form

3. Concerning local anaesthetics:

a) they are absorbed more rapidly after intercostal block

than after caudal administration T

b) in the foetus they are able to cross the placenta as

readily as from the mother F

c) they are weak acids F

d) those which are esters are rapidly metabolised by liver

enzymes F

e) pKa is the pH at which more than half of a local

anaesthetic exists in non-ionised form F

4.Cocaine:

A. Blocks reuptake of dopamine and noradrenaline

B. Central effects are due to noradrenaline

C. Crosses lipid soluble membranes because its

pKa is 2.8

D. Is not metabolised by plasma

pseudocholinesterase

E. Rapidly absorbed by nasal mucosa

Cocaine:

A. Blocks reuptake of dopamine and noradrenaline

T

B. Central effects are due to noradrenaline F

C. Crosses lipid soluble membranes because its

pKa is 2.8 F

D. Is not metabolised by plasma

pseudocholinesterase F

E. Rapidly absorbed by nasal mucosa ?

5.Ropivacaine

A. Is a pure R isomer

B. Is an isomer of bupivacaine

C. Provides more motor block than bupivacaine D.

Has more toxicity than bupivacaine

E. Has similar physico-chemical properties to

bupivacaine

5.Ropivacaine

A. Is a pure R isomer F

B. Is an isomer of bupivacaine F

C. Provides more motor block than bupivacaine F

D. Has more toxicity than bupivacaine F

E. Has similar physico-chemical properties to

bupivacaine T

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