Local anaesthetics

Dr JM Dippenaar2013

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Local anesthetic drugs

Amides Esters

Lignocaine

Bupivacaine

Ropivacaine

Levobupivacaine

mepivacaine

Cocaine

PABA esters

Procaine

Chloroprocaine

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Local anesthetic drugs

Amides Esters

Liver metabolism

Pseudocholine esterase

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Local anesthetic drugs

Lignocaine

Cocaine

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Local anesthetic drugs

Bupivacaine

Ropivacaine

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Chemical & physical characteristics

Lipid solubility = potency ∝ onset of actionpKa ∝ onset of action

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pKa

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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

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Physico-chemical propertiesDrug Lipid

solubilitypKa Protein

bindingPotency

Lignocaine 2.9 7.7 64 4

Bupivacaine Levo-bupiva

27 8.18.1

95.594.3

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Ropivacaine 25 8.1 94. 16

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Mechanism of action

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Mechanism of action

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Mechanism of action

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Mechanism of action

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Mechanism of action

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Mechanism of action

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Cocaine

Ester derivativeIntense vasoconstrictionIndirect sympathomimetic

Release NABlock reuptake of NA and dopamine

S/EEuphoria, paranoia, seizuresHypertension, tachycardia

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Prilocaine

Emla cream:Eutetic Mixture of Local AnaestheticAdded to lignocaine in equal quantitiesChanges the melting point of the drugsSkin analgesia within 60min

S/E: Methaemoglobinaemia

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Lignocaine

Amide, pKa = 7.7Low lipid solubilityMetabolism:

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 potentHighly lipid soluble

Long duration of actionCVS toxicity

Refractory ventricular fibrillation

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Lignocaine vs bupvacaine

Drug Lignocaine Bupivacaine

Potency 4 16

Onset Short Prolonged

Duration Short Prolonged

Protein binding 64% 95%

Toxicity CNS CVS

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Additives to bupivacaine

Glucose80mg (8%) added to 'spinal bupivacaine'

Increase the baricity of bupivacaineHeavier than CSFGravitates to lower spinal regionsSmaller dose for denser block

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Additives to local anaesthetic

Vasoconstrictor = AdrenalineDecreased absorptionIncreased safe doseIncreased duration of action

Opioids = morphine, fentanyl, sufentanilNeuraxial = morphine vs fentanylIncreased duration of action

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Additives to local anaesthetic

Alkalinize = NaHCO3Increased non-ionized fractionFaster onset of actionPrecipitation of adrenaline - no premix!

Anticholinergics = NeostigmineA2-agonist = colonizing, dexmedetomidine

Denser sensory blockProlonged duration of action

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Dosage

Lignocaine = 1% ↓1g in 100ml ↓1000mg in 100ml ↓10 mg/ml

Bupivacaine = 0.5% ↓0.5g in 100ml ↓500mg in 100ml ↓5mg/ml

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Maximum dose for infiltration

Lignocaine3-4mg/kg without adrenaline7mg with adrenaline

Bupivacaine / L-bupivacaine2mg/kg irrespective of adrenalineMaximum of 150mg

Ropivacaine2mg/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/kgTotal dose - 20kg x 2mg/kg = 40mgEach 0,5% vial has 5mg/ml of bupivacaine Therefore - 40mg /5mg/ml = 8ml of 0.5% bupivacaine!

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Toxicity: Classification

Local toxicityNeurotoxicityTransient neurological symptoms

MyotoxicitySystemic toxicityCNSCVS

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Systemic toxicity

Intravascular injection Increased absorption

↑plasma concentration

Distribution Vessel rich organ group

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Toxicity: ↑ absorption

Excessive doseSite of injection Intercostal>caudal>epidural>brachial plexus

Physico-chemical properties↓ Lipid solubility }↓ Protein binding } ↑ absorption↓ Potency }

Vasoconstrictor

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Toxic doses

Lignocaine3-4mg/kg without adrenaline7mg with adrenaline

Bupivacaine / L-bupivacaine2mg/kg irrespective of adrenalineMaximum of 150mg

Ropivacaine 2mg/kg irrespective of adrenaline

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Toxicity

CNS CVS (Lignocaine 7x more) (Bupivacaine 3x more)

Convulsions Refractory ventricular fibrillation

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CNS toxicityInitial phaseCircumoral paresthesia, tinnitus, confusion

Excitatory phaseConvulsions

Depressive phaseLoss of consciousnessComaRespiratory arrest

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CVS toxicity

Initial phaseHypertension, tachycardia

Intermediate phaseMyocardial depression → COHypotension

Terminal phaseVasodilatation, hypotension, bradycardiaConduction defects, dysrhythmias

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Bupivacaine cardiac toxicity

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Toxicity

To ↓ complications due to bupivacaine

RopivacaineLevo-bupivacaine

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Ropivacaine

Amide , pKa = 8.1Lower lipid solubilityMetabolismLiver 99% (1% unchanged via kidneys)CYP 1A2 (fluvoxamine ↓ metabolism 16%)

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Ropivacaine

Biphasic vascular effectLow[ ] = vasoconstrictionHigh [ ] = 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 bolus

Well differentiated blockGood sensory blockadeMuch less motor blockade

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L-bupivacaine

L isomer of bupivacainepKa 8.1As potent as racemic mixture Potentially less CVS toxicityL-isomer less direct cardiotoxic effects

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Rx of toxicity

ConvulsionsBZ ThiopentonePropofol

Ventricular fibrilationBretilium Intralipid®

K+ channel openers

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Rx of toxicity

Ventricular fibrilationBretilium Intralipid®

K+ channel openers

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Bretilium tosylate

Class III anti arrhythmicSlows phase 3 repolarisationProlongs 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

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K+ channel openers: side effects

Shorten action potential =↓ Ca++ influxReduced contractility

Excessive coronary vasodilatationCoronary steal with steal prone anatomy

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K+ channel openers

Improve AV conduction ButMyocardial depression

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Intralipid®

Lipid emulsionSoya oilEgg phospholipidsGlycerol

TPN, Propofol↑ effective antidoteBupivacaine induced CVS collapse

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Intralipid® : proposed actions

Lipid sinkDraws Bupivacaine from plasmaDecreased free fraction

High lipid concentrationForced lipid influx into myocyteOverwhelms L-CAT↑ FFA for energy production↑ susceptibility for resuscitation

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