Dr JM Dippenaar 2013 1 Local anesthetic drugs Amides Esters Lignocaine Bupivacaine Ropivacaine Levobupivacaine mepivacaine Cocaine PABA esters Procaine Chloroprocaine 2 Local anesthetic drugs ID: 208611
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Local anaesthetics
Dr JM Dippenaar2013
1Slide2
Local anesthetic drugs
Amides
Esters
Lignocaine
Bupivacaine
Ropivacaine
Levobupivacaine
mepivacaine
Cocaine
PABA estersProcaineChloroprocaine
2Slide3
Local anesthetic drugs
Amides
Esters
Liver metabolism
Pseudocholine esterase
3Slide4
Local anesthetic drugs
Lignocaine
Cocaine
4Slide5
Local anesthetic drugs
Bupivacaine
Ropivacaine
5Slide6
Chemical & physical characteristics
Lipid solubility = potency
∝
onset of actionpKa ∝ onset of action
6Slide7
pKa
7Slide8
Chemical & physical characteristics
Lipid solubility = potency,
∝
onset of actionpKa ∝ onset of actionProtein binding = duration of actionIsomerism – Left turning=↑ duration, potency,↓ toxicityLocal factors (inject)– spinal, subcostal (faster) vs. peripheral, epidural (longer) etcNerve anatomy Diameter, myelinated or not, activity
8Slide9
Physico-chemical properties
Drug
Lipid solubility
pKa
Protein binding
Potency
Lignocaine
2.9
7.7
64
4
Bupivacaine Levo-bupiva
27
8.1
8.1
95.5
94.3
16
Ropivacaine
25
8.1
94.
16
9Slide10
Mechanism of action
10Slide11
Mechanism of action
11Slide12
Mechanism of action
12Slide13
Mechanism of action
13Slide14
Mechanism of action
14Slide15
Mechanism of action
15Slide16
Cocaine
Ester derivativeIntense vasoconstriction
Indirect sympathomimetic
Release NA
Block reuptake of NA and dopamineS/EEuphoria, paranoia, seizuresHypertension, tachycardia
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Prilocaine
Emla cream:Eutetic Mixture of Local Anaesthetic
Added to lignocaine in equal quantities
Changes the melting point of the drugs
Skin analgesia within 60minS/E: Methaemoglobinaemia
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Lignocaine
Amide, pKa = 7.7Low lipid solubility
Metabolism:
Liver
99% (1% unchanged via kidneys)CYP 2D6 and 3A4Monoethylglycinexilidide (MEGX)Active metaboliteAdditive to CNS side effects
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Bupivacaine
pKa 8.1Slow onset of action
Very potent
Highly lipid soluble
Long duration of actionCVS toxicityRefractory ventricular fibrillation
19Slide20
Lignocaine vs bupvacaine
Drug
Lignocaine
Bupivacaine
Potency
4
16
Onset
Short
Prolonged
Duration
Short
Prolonged
Protein binding
64%
95%
Toxicity
CNS
CVS
20Slide21
Additives to bupivacaine
Glucose80mg (8%) added to 'spinal bupivacaine'
Increase the baricity of bupivacaine
Heavier than CSF
Gravitates to lower spinal regionsSmaller dose for denser block
21Slide22
Additives to local anaesthetic
Vasoconstrictor = AdrenalineDecreased absorption
Increased safe dose
Increased duration of action
Opioids = morphine, fentanyl, sufentanilNeuraxial = morphine vs fentanylIncreased duration of action
22Slide23
Additives to local anaesthetic
Alkalinize = NaHCO3Increased non-ionized fraction
Faster onset of action
Precipitation of adrenaline - no premix!
Anticholinergics = NeostigmineA2-agonist = colonizing, dexmedetomidineDenser sensory blockProlonged duration of action
23Slide24
Dosage
Lignocaine
= 1%
↓
1g in 100ml ↓1000mg in 100ml ↓10 mg/ml
Bupivacaine = 0.5% ↓0.5g in 100ml ↓500mg in 100ml
↓
5mg/ml
24Slide25
Maximum dose for infiltration
Lignocaine3-4mg/kg without adrenaline
7mg with adrenaline
Bupivacaine / L-bupivacaine
2mg/kg irrespective of adrenalineMaximum of 150mgRopivacaine2mg/kg irrespective of adrenaline
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Dosage calculation
Child of 20kg for suture laceration. How many mls of 0.5% bupivacaine with adrenaline may he receive?
Toxic dose with adrenaline = 2mg/kg
Total dose - 20kg x 2mg/kg = 40mg
Each 0,5% vial has 5mg/ml of bupivacaine Therefore - 40mg /5mg/ml = 8ml of 0.5% bupivacaine!
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Toxicity: Classification
Local toxicity
Neurotoxicity
Transient neurological symptoms
MyotoxicitySystemic toxicityCNSCVS
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Systemic toxicity
Intravascular injection Increased absorption
↑
plasma concentration Distribution Vessel rich organ group
28Slide29
Toxicity:
↑
absorption
Excessive doseSite of injectionIntercostal>caudal>epidural>brachial plexusPhysico-chemical properties↓ Lipid solubility }↓ Protein binding } ↑ absorption↓ Potency } Vasoconstrictor
29Slide30
Toxic doses
Lignocaine
3-4mg/kg without adrenaline
7mg with adrenaline
Bupivacaine / L-bupivacaine2mg/kg irrespective of adrenalineMaximum of 150mgRopivacaine 2mg/kg irrespective of adrenaline
30Slide31
Toxicity
CNS
CVS (Lignocaine 7x more) (Bupivacaine 3x more) Convulsions Refractory ventricular fibrillation
31Slide32
CNS toxicity
Initial phase
Circumoral paresthesia, tinnitus, confusion
Excitatory phase
ConvulsionsDepressive phaseLoss of consciousnessComaRespiratory arrest
32Slide33
CVS toxicity
Initial phase
Hypertension, tachycardia
Intermediate phase
Myocardial depression → COHypotensionTerminal phaseVasodilatation, hypotension, bradycardiaConduction defects, dysrhythmias
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Bupivacaine cardiac toxicity
34Slide35
Toxicity
To
↓
complications due to bupivacaineRopivacaineLevo-bupivacaine
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Ropivacaine
Amide ,
pKa
= 8.1
Lower lipid solubilityMetabolismLiver 99% (1% unchanged via kidneys)CYP 1A2 (fluvoxamine ↓ metabolism 16%)
36Slide37
Ropivacaine
Biphasic vascular effect
Low[ ] = vasoconstriction
High [ ] = vasodilatation
Faster dissociation from cardiac Na+ channels than bupivacaineHigher threshold for CNS symptoms
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Ropivacaine: clinical uses
Pain relief:
Epidural for labour, post op:
0.2%
@6-15ml/hSurgery: 0.75%-1% up to 12ml bolusWell differentiated blockGood sensory blockadeMuch less motor blockade
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L-bupivacaine
L isomer of bupivacaine
pKa 8.1
As potent as racemic mixture
Potentially less CVS toxicityL-isomer less direct cardiotoxic effects
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Rx of toxicity
Convulsions
BZ
Thiopentone
PropofolVentricular fibrilationBretiliumIntralipid®K+ channel openers
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Rx of toxicity
Ventricular fibrilation
Bretilium
Intralipid
®K+ channel openers
41Slide42
Bretilium tosylate
Class III anti arrhythmic
Slows phase 3
repolarisation
Prolongs refractory period↓ release of NANot manufactured currently
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K
+
channel openers
Pinacidil
, bimakalimOpens K+ATP channelsShorten action potential in Purkinje fibersProlongs plateau phaseHyperpolarise resting membrane potential
43Slide44
K
+
channel openers: side effects
Shorten action potential =
↓ Ca++ influxReduced contractilityExcessive coronary vasodilatationCoronary steal with steal prone anatomy
44Slide45
K
+
channel openers
Improve AV conduction
ButMyocardial depression
45Slide46
Intralipid
®
Lipid emulsion
Soya oil
Egg phospholipidsGlycerolTPN, Propofol↑ effective antidoteBupivacaine induced CVS collapse
46Slide47
Intralipid
®
: proposed actions
Lipid sink
Draws Bupivacaine from plasmaDecreased free fractionHigh lipid concentrationForced lipid influx into myocyteOverwhelms L-CAT↑ FFA for energy production↑ susceptibility for resuscitation
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