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TRANSCRIPT
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. 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
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
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
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