Local Anaesthetics

Quick Answer

Local anaesthetics (LAs) are drugs that reversibly block nerve conduction by inhibiting voltage-gated sodium channels (Nav), preventing action potential propagation. They produce regional anaesthesia without loss of consciousness.

Key Concepts:

• Mechanism: Block voltage-gated Na+ channels from the intracellular side; preferential binding to inactivated state (use-dependent block)
• Classification: Esters (metabolized by plasma cholinesterases) vs Amides (hepatic metabolism) - remember: amides have two 'i's in the name (lidocaine, bupivacaine)
• pKa significance: Determines proportion of un-ionized (lipophilic) drug available for membrane penetration; lower pKa = faster onset
• Differential block: Small myelinated fibres (Aδ, C) blocked before large myelinated fibres (Aα, Aβ)

ICU Relevance:

• Procedural analgesia (central lines, chest drains, lumbar puncture)
• Regional anaesthesia techniques (epidural analgesia, nerve blocks)
• Lidocaine as antiarrhythmic (Class Ib)
• Management and prevention of LAST [1,2]

Exam Focus:

• Voltage-gated sodium channel structure and LA binding site
• Use-dependent (frequency-dependent) block mechanism
• Structure-activity relationships (pKa, lipid solubility, protein binding)
• Comparative pharmacology of individual agents
• Maximum doses with and without adrenaline
• LAST presentation and lipid rescue protocol

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CICM First Part Exam Focus

What Examiners Expect

Written SAQ:

Common question stems:

• "Describe the mechanism of action of local anaesthetics" (10 marks)
• "Compare and contrast lidocaine and bupivacaine" (10 marks)
• "Outline the structure-activity relationships of local anaesthetics" (10 marks)
• "Describe the clinical features and management of local anaesthetic systemic toxicity" (10 marks)
• "Explain the concept of differential nerve block" (10 marks)
• "Describe the pharmacology of ropivacaine" (10 marks)

Expected depth:

• Molecular mechanism at ion channel level (sodium channel subunits, LA binding site, gating states)
• Quantitative parameters (pKa values, protein binding percentages, partition coefficients)
• Chemical structure diagrams showing ester vs amide linkages
• Comparative tables for different LA agents
• Clinical application including maximum safe doses
• LAST management algorithm with lipid emulsion dosing

Written MCQ:

Common topics tested:

• pKa values and clinical implications
• Onset and duration of various agents
• Maximum doses (mg/kg with and without adrenaline)
• Ester vs amide metabolism pathways
• Cardiotoxicity mechanisms
• Additive effects (adrenaline, bicarbonate)

Oral Viva:

Expected discussion flow:

1. Define - What are local anaesthetics, classification
2. Mechanism - Sodium channel pharmacology, use-dependent block
3. Structure-activity - Chemical structure, pKa, lipophilicity, protein binding
4. Individual agents - PK/PD of major drugs (lidocaine, bupivacaine, ropivacaine)
5. Maximum doses - With and without adrenaline
6. Toxicity - LAST presentation, mechanism, lipid rescue
7. Clinical applications - Infiltration, nerve blocks, neuraxial

Common viva scenarios:

• "Tell me about the pharmacology of local anaesthetics"
• "A patient develops seizures during a femoral nerve block. What is happening and how would you manage it?"
• "Explain why bupivacaine is more cardiotoxic than lidocaine"
• "What is the mechanism of differential nerve block?"

Pass vs Fail Performance

Pass Standard:

• Accurate description of sodium channel blockade mechanism
• Knowledge of pKa and its clinical significance
• Correct classification (esters vs amides)
• Key pharmacokinetic parameters for major agents
• Recognition and management of LAST
• Appropriate maximum dose calculations

Common Reasons for Failure:

• Confusion about mechanism (blocking from inside vs outside of membrane)
• Unable to explain use-dependent block
• Not knowing pKa values for common agents
• Incorrect maximum doses
• Poor understanding of LAST management
• Confusion between ester and amide metabolism

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Key Points

10 Must-Know Facts

1. Voltage-gated sodium channel (Nav) structure: The alpha subunit contains 4 homologous domains (I-IV), each with 6 transmembrane segments (S1-S6). S4 is the voltage sensor; S5-S6 form the pore. Local anaesthetics bind to the S6 segment of domain IV from the intracellular side [3,4]

2. Three-state sodium channel model: Channels exist in resting (closed), open (activated), and inactivated states. LAs have highest affinity for inactivated and open states, lowest for resting state - this is the basis of use-dependent (frequency-dependent) block [5,6]

3. Use-dependent (frequency-dependent) block: Repeated stimulation increases channel block because LAs bind preferentially to open/inactivated states. Rapidly firing neurons (pain fibres, cardiac tissue during arrhythmias) are blocked more effectively - basis of differential block and antiarrhythmic action [7,8]

4. pKa determines onset time: Only the un-ionized (lipophilic) base form crosses the nerve membrane, but the ionized (hydrophilic) cation binds to the channel. Lower pKa = more un-ionized drug at physiological pH = faster onset. Lidocaine (pKa 7.9) has faster onset than bupivacaine (pKa 8.1) [9,10]

5. Ester vs amide classification: Esters (cocaine, procaine, chloroprocaine, tetracaine) have an ester linkage and are hydrolyzed by plasma cholinesterases. Amides (lidocaine, bupivacaine, ropivacaine, levobupivacaine, prilocaine) have an amide linkage and undergo hepatic metabolism [11,12]

6. Differential nerve block: Small diameter and myelinated fibres are blocked before large diameter fibres. Order of block: B fibres (autonomic) > C fibres (pain, temperature) > Aδ fibres (pain, cold) > Aγ (muscle spindles) > Aβ (touch, pressure) > Aα (motor). "Sympathetic before sensory before motor" [13,14]

7. Bupivacaine cardiotoxicity: Bupivacaine binds tightly to cardiac sodium channels with slow dissociation kinetics ("fast-in, slow-out"). This causes prolonged QRS, refractory ventricular arrhythmias, and cardiac arrest that is resistant to standard resuscitation. R-bupivacaine is more cardiotoxic than S-bupivacaine [15,16]

8. Lipid emulsion rescue mechanism: Intralipid 20% creates a "lipid sink" that extracts lipophilic local anaesthetics from tissues (including myocardium). Additional mechanisms include direct cardiotonic effects, enhanced mitochondrial fatty acid metabolism, and reversal of sodium channel block [17,18]

9. Maximum doses (without/with adrenaline): Lidocaine 3-4.5/7 mg/kg, Bupivacaine 2/2.5 mg/kg, Ropivacaine 3/3.5 mg/kg, Levobupivacaine 2/2.5 mg/kg, Prilocaine 6/8 mg/kg. Absolute maximum for bupivacaine is 150 mg regardless of weight [19,20]

10. Prilocaine methaemoglobinaemia: Prilocaine is metabolized to o-toluidine, which oxidizes haemoglobin Fe2+ to Fe3+ (methaemoglobin). Clinically significant (MetHb >20%) occurs with doses >600 mg. Treatment: methylene blue 1-2 mg/kg IV [21,22]

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Mechanism of Action

Voltage-Gated Sodium Channel Structure

The voltage-gated sodium channel (Nav) is the primary molecular target of local anaesthetics. Understanding its structure is essential for explaining LA mechanism [3,4,23].

Alpha (α) Subunit (260 kDa):

• Forms the functional ion-conducting pore
• Contains 4 homologous domains (I, II, III, IV)
• Each domain has 6 transmembrane segments (S1-S6)
• S1-S4: Voltage-sensing domain
• S5-S6: Pore-forming domain
• S4 segment: Contains positively charged residues (arginine/lysine) acting as voltage sensor
• P-loop (between S5-S6): Contains selectivity filter for Na+ ions

Beta (β) Subunits (33-36 kDa):

• Auxiliary subunits (β1-β4)
• Single transmembrane segment
• Modulate channel kinetics, membrane expression, and localization
• Not directly involved in LA binding

Sodium Channel Isoforms:

Local Anaesthetic Binding Site

Local anaesthetics bind to a specific receptor site within the sodium channel pore, located on the intracellular side of the membrane [5,6,24]:

Binding Site Location:

• S6 segment of domain IV (primarily)
• Contributions from S6 of domains I and III
• Key residues: Phenylalanine 1764, Tyrosine 1771 (Nav1.4 numbering)
• Hydrophobic pocket accessible from cytoplasm

Access Pathways:

1. Hydrophilic pathway: Ionized LA enters through open channel pore
2. Hydrophobic pathway: Un-ionized LA crosses membrane and enters lateral fenestrations between S5-S6 segments

Binding Requirements:

• LA molecule must enter cell (un-ionized form crosses membrane)
• Once inside, ionized form binds to receptor (cationic form has higher affinity)
• Both forms can produce block, but ionized form is more potent

Sodium Channel Gating States

The sodium channel cycles through three conformational states during an action potential [6,7,25]:

1. Resting State (Closed):

• Channel closed, activation gate shut
• Membrane at resting potential (-70 to -90 mV)
• Inactivation gate open
• Low affinity for local anaesthetics

2. Open State (Activated):

• Depolarization moves S4 voltage sensors outward
• Activation gate opens
• Na+ influx occurs
• Channel open for ~1 ms
• High affinity for local anaesthetics

3. Inactivated State:

• Inactivation gate (III-IV linker) swings shut
• "Hinged-lid" mechanism blocks pore
• Channel cannot reopen until repolarization
• Highest affinity for local anaesthetics
• Recovery to resting state requires repolarization (several ms)

State-Dependent Binding Affinity:

Inactivated > Open >> Resting

This differential affinity forms the basis of use-dependent block.

Use-Dependent (Frequency-Dependent) Block

Use-dependent block is a fundamental concept explaining why local anaesthetics preferentially block rapidly firing neurons [7,8,26]:

Definition: The degree of sodium channel block increases with increasing frequency of stimulation (action potential firing rate).

Mechanism:

1. At rest, equilibrium favors LA dissociation (low affinity for resting channels)
2. With each action potential, channels open then inactivate
3. LA binds preferentially to open/inactivated states
4. Rapid firing prevents complete recovery to resting state
5. Cumulative block develops with each successive stimulus

Tonic Block vs Phasic Block:

• Tonic block: Block present at resting state (low frequency stimulation)
• Phasic block: Additional block developing with repeated stimulation (use-dependent component)

Clinical Implications:

This explains:

• Why pain fibres are blocked preferentially
• Why lidocaine is an effective antiarrhythmic (blocks rapidly firing ectopic foci)
• Why cardiotoxicity is worse with bupivacaine (slow dissociation, accumulation in cardiac tissue)

Differential Nerve Block

Differential nerve block refers to the observation that different nerve fibre types are blocked at different rates and concentrations of local anaesthetic [13,14,27]:

Nerve Fibre Classification:

Order of Block (Clinically Observed):

B fibres → C fibres → Aδ fibres → Aγ fibres → Aβ fibres → Aα fibres
Autonomic → Pain → Sensory → Motor

Mechanism of Differential Block:

Several factors contribute [28,29]:

1. Fibre diameter: Smaller fibres have shorter internodal distances; fewer nodes need to be blocked for conduction failure (3 consecutive nodes minimum)

2. Myelination pattern: Myelinated fibres blocked at nodes of Ranvier; saltatory conduction requires multiple consecutive nodes to be blocked

3. Ion channel density: Varies between fibre types

4. Firing frequency: Sensory fibres fire more frequently than motor fibres (use-dependent block)

5. Safety factor: Motor fibres have higher safety factor for conduction

Critical Blocking Length:

• Minimum of 3 consecutive nodes of Ranvier must be blocked
• Internodal distance proportional to fibre diameter
• Small fibres: shorter internodal distance = fewer mm of LA exposure needed
• Large fibres: longer internodal distance = more LA exposure needed

Minimum Blocking Concentration (Cm):

• Concentration at which impulse conduction fails
• Lower for small, frequently firing fibres
• Higher for large motor fibres

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Structure-Activity Relationships

Basic Local Anaesthetic Structure

All local anaesthetics share a common structural template with three essential components [11,12,30]:

Aromatic Ring --- Intermediate Chain --- Amine Group
(Lipophilic)     (Ester or Amide)       (Hydrophilic)

1. Aromatic Ring (Lipophilic End):

• Usually benzene ring (some have thiophene - articaine)
• Responsible for lipid solubility
• Substitutions affect potency and duration
• Para-amino group in esters (PABA metabolite - allergenic)
• Xylidine ring in amides (lidocaine, bupivacaine)

2. Intermediate Chain:

• Connects lipophilic and hydrophilic portions
• Contains either ESTER (-COO-) or AMIDE (-NHCO-) linkage
• Determines metabolic pathway
• Length affects potency (longer chain = higher potency)

3. Amine Group (Hydrophilic End):

• Usually tertiary amine (can be secondary)
• Ionizable: accepts H+ to form cation
• pKa determined by this group
• Substitutions affect onset and duration

Ester vs Amide Classification

Ester Local Anaesthetics:

Characteristics of Esters:

• Metabolized by plasma pseudocholinesterase
• Produce PABA (para-aminobenzoic acid) metabolite
• Higher allergic potential (PABA cross-reactivity)
• Generally shorter duration
• Unstable in solution (shorter shelf life)
• Rapid hydrolysis = short systemic half-life

Amide Local Anaesthetics:

Characteristics of Amides:

• Metabolized by hepatic cytochrome P450 enzymes
• Lower allergic potential (no PABA)
• Cross-allergenicity within class is rare
• More stable in solution (longer shelf life)
• Variable duration depending on agent
• Dose adjustment needed in hepatic impairment

Memory Aid - "Amides have 'i' before 'ine':

• Lidicaine, Bupivacaine, Ropivacaine, Prilocaine, Mepivacaine
• Esters: Cocaine (exception), Procaine, Tetracaine, Chloroprocaine

pKa and Ionization

The pKa of a local anaesthetic is a critical determinant of its clinical properties, particularly onset time [9,10,31]:

Henderson-Hasselbalch Equation:

pH = pKa + log([Base]/[Acid])
pH = pKa + log([Un-ionized]/[Ionized])

At Physiological pH (7.4):

• When pH = pKa: 50% ionized, 50% un-ionized
• When pH < pKa: More ionized (cationic) form
• When pH > pKa: More un-ionized (base) form

Clinical Significance of pKa:

Lower pKa = Faster Onset:

1. More un-ionized drug at tissue pH
2. More drug can cross the lipid nerve membrane
3. Once inside the axoplasm, equilibrium shifts to ionized form
4. Ionized form binds to sodium channel

Effect of Tissue pH:

• Infected/inflamed tissue (pH 6.5-7.0): More ionized drug, less membrane penetration, reduced efficacy
• Alkalized LA solution (adding bicarbonate): Increases un-ionized fraction, faster onset

Lipid Solubility and Potency

Lipid solubility (lipophilicity) correlates with local anaesthetic potency [32,33]:

Partition Coefficient: The octanol:buffer partition coefficient measures the ratio of LA dissolved in lipid vs aqueous phases.

Higher Lipid Solubility = Higher Potency:

• Better penetration into nerve membrane
• Higher concentration at binding site
• Lower dose required for equivalent block

Lipid Solubility Also Affects:

• Duration of action (sequestration in fatty tissues)
• Onset (partially - must cross membrane)
• Toxicity potential (accumulation in lipid-rich tissues like CNS, heart)

Protein Binding and Duration

Protein binding correlates with duration of action for local anaesthetics [34,35]:

Plasma Protein Binding:

• Alpha-1 acid glycoprotein (AAG): Primary binding protein
• Albumin: Secondary binding protein (lower affinity, higher capacity)
• Only free (unbound) drug is pharmacologically active

Higher Protein Binding = Longer Duration:

• Slow release from protein-bound reservoir
• More drug retained at injection site
• Prolonged receptor occupancy

Factors Affecting Protein Binding:

• Acidosis: Decreases AAG binding, increases free drug
• Critical illness: Altered AAG levels (acute phase reactant)
• Pregnancy: Decreased AAG, increased free drug fraction
• Neonates: Low AAG levels, increased toxicity risk
• Renal failure: Altered protein binding
• Drug displacement: Competitive binding at AAG

Stereoisomerism

Many local anaesthetics exist as stereoisomers with different pharmacological properties [36,37]:

Chiral Carbon:

• Bupivacaine, ropivacaine, and mepivacaine have a chiral center
• Two enantiomers: R (dextro) and S (levo)
• Commercial bupivacaine: Racemic mixture (50% R, 50% S)
• Ropivacaine: Pure S-enantiomer
• Levobupivacaine: Pure S-enantiomer

Properties of S-enantiomers:

Mechanism of Reduced Cardiotoxicity:

• S-enantiomers have faster dissociation from cardiac sodium channels
• Less accumulation during diastole
• Less negative inotropy
• Less arrhythmogenic potential

Clinical Advantage:

• Ropivacaine and levobupivacaine have improved safety profiles
• Can use slightly higher doses compared to racemic bupivacaine
• Preferred for high-volume blocks and continuous infusions

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Individual Local Anaesthetic Agents

Lidocaine (Lignocaine)

Lidocaine is the prototypical amide local anaesthetic and remains the most widely used agent worldwide [38,39]:

Physicochemical Properties:

• Molecular weight: 234 Da
• pKa: 7.9
• % un-ionized at pH 7.4: 24%
• Partition coefficient: 2.9
• Protein binding: 64%

Pharmacokinetics:

Metabolism:

• Hepatic N-dealkylation by CYP1A2 and CYP3A4
• Monoethylglycinexylidide (MEGX): 80% activity of lidocaine
• Glycinexylidide (GX): 10% activity
• Metabolites accumulate in renal failure

Onset and Duration:

• Onset: Rapid (2-5 minutes for infiltration)
• Duration: 60-120 minutes (infiltration without adrenaline)
• Duration: 120-240 minutes (with adrenaline)

Maximum Doses:

Clinical Uses:

• Infiltration anaesthesia
• Peripheral nerve blocks
• Intravenous regional anaesthesia (Bier's block)
• Epidural anaesthesia
• Topical anaesthesia (4% spray, EMLA cream)
• Antiarrhythmic therapy (Class Ib)

Special Considerations:

• IV lidocaine for analgesic adjunct: Loading 1-1.5 mg/kg, infusion 1-2 mg/min
• Therapeutic window for antiarrhythmic: 1.5-5 μg/mL
• Toxic at >6-8 μg/mL
• Reduce dose in hepatic impairment, heart failure (reduced clearance)

Bupivacaine

Bupivacaine is a long-acting amide LA with potent sensory and motor block, but significant cardiotoxicity risk [15,16,40]:

Physicochemical Properties:

• Molecular weight: 288 Da
• pKa: 8.1
• % un-ionized at pH 7.4: 17%
• Partition coefficient: 27.5
• Protein binding: 95%
• Available as: Racemic mixture (R/S-bupivacaine)

Pharmacokinetics:

Onset and Duration:

• Onset: Moderate (5-15 minutes)
• Duration: 180-480 minutes (longest among common LAs)
• More pronounced motor block than ropivacaine at equivalent concentrations

Maximum Doses:

Cardiotoxicity Mechanism:

The enhanced cardiotoxicity of bupivacaine compared to lidocaine is due to several factors [15,41]:

1. "Fast-in, slow-out" kinetics: Bupivacaine binds rapidly to cardiac sodium channels but dissociates slowly
2. Accumulation during diastole: Slow unbinding means channel block accumulates with each cardiac cycle
3. Sodium channel block: Prolonged QRS, slowed conduction
4. Potassium channel block: Prolonged QT, delayed repolarization
5. Calcium channel block: Negative inotropy
6. Mitochondrial toxicity: Impaired cardiac energy metabolism
7. Lipid interference: Disruption of membrane lipid organization

Bupivacaine:Lidocaine Cardiotoxicity Ratio:

• Ratio of CC/CNS toxic doses: Bupivacaine 4:1, Lidocaine 7:1
• This means CNS toxicity provides less warning before cardiovascular collapse with bupivacaine

Clinical Uses:

• Epidural analgesia (0.0625-0.25%)
• Spinal anaesthesia (0.5% hyperbaric)
• Peripheral nerve blocks (0.25-0.5%)
• Infiltration (0.25-0.5%)
• Avoid for Bier's block (risk of tourniquet release)

Ropivacaine

Ropivacaine is a pure S-enantiomer amide LA with reduced cardiotoxicity compared to bupivacaine [42,43]:

Physicochemical Properties:

• Molecular weight: 274 Da
• pKa: 8.1
• % un-ionized at pH 7.4: 17%
• Partition coefficient: 6.1
• Protein binding: 94%
• Configuration: Pure S-enantiomer

Pharmacokinetics:

Advantages Over Bupivacaine:

• Reduced cardiotoxicity (faster dissociation from cardiac channels)
• Reduced CNS toxicity
• Intrinsic vasoconstrictive properties (unlike bupivacaine which is vasodilatory)
• More pronounced differential block (sensory > motor)
• Preferred for continuous infusions

Potency Comparison:

• Approximately 0.6-0.75× potency of bupivacaine
• Need higher concentration for equivalent motor block
• Motor-sparing at lower concentrations (useful for ambulatory surgery)

Maximum Doses:

Clinical Uses:

• Epidural analgesia (0.1-0.2% for labour, 0.5-1% for surgery)
• Peripheral nerve blocks (0.5-0.75%)
• Continuous regional anaesthesia (0.2%)
• Preferred over bupivacaine for:
  • High-volume blocks
  • Continuous infusions
  • Ambulatory surgery (motor-sparing)

Levobupivacaine

Levobupivacaine is the pure S-enantiomer of bupivacaine, offering similar efficacy with improved safety profile [36,44]:

Physicochemical Properties:

• Molecular weight: 288 Da
• pKa: 8.1
• % un-ionized at pH 7.4: 17%
• Partition coefficient: 27.5
• Protein binding: 97%
• Configuration: Pure S-enantiomer

Comparison with Racemic Bupivacaine:

Maximum Doses:

• Same as racemic bupivacaine: 2 mg/kg without adrenaline, 2.5 mg/kg with adrenaline
• Maximum single dose: 150 mg

Clinical Uses:

• Same indications as bupivacaine
• May be preferred in high-risk patients
• Some centres use as standard alternative to bupivacaine
• Limited availability in some regions

Prilocaine

Prilocaine is an amide LA with intermediate potency and duration, notable for causing methaemoglobinaemia [21,22,45]:

Physicochemical Properties:

• Molecular weight: 220 Da
• pKa: 7.9
• % un-ionized at pH 7.4: 24%
• Partition coefficient: 0.9
• Protein binding: 55%

Pharmacokinetics:

Unique Features:

• Highest volume of distribution among amides
• Fastest clearance (hepatic + pulmonary amidases)
• Least toxic amide LA
• Causes methaemoglobinaemia (unique side effect)

Methaemoglobinaemia:

• Metabolite: o-toluidine (ortho-toluidine)
• O-toluidine oxidizes Fe2+ to Fe3+ in haemoglobin
• Methaemoglobin cannot carry oxygen
• Symptoms at MetHb >15-20%: Cyanosis, dyspnea
• Symptoms at MetHb >40%: Confusion, cardiac dysfunction
• Clinically significant with doses >600 mg
• Treatment: Methylene blue 1-2 mg/kg IV

Maximum Doses:

Clinical Uses:

• EMLA cream (lidocaine 2.5% + prilocaine 2.5%)
• Intravenous regional anaesthesia (lower toxicity than lidocaine)
• Dental anaesthesia
• Infiltration

Contraindications:

• Methaemoglobin reductase deficiency
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Use of other methaemoglobin-inducing drugs
• Large doses in pregnancy (fetal methaemoglobinaemia)
• Infants less than 6 months (EMLA cream)

Cocaine

Cocaine is the original local anaesthetic, an ester with unique sympathomimetic properties [46,47]:

Physicochemical Properties:

• Molecular weight: 303 Da
• pKa: 8.6
• Protein binding: 91%
• Origin: Natural alkaloid from Erythroxylum coca leaves

Unique Pharmacology:

• Only LA that inhibits noradrenaline and dopamine reuptake
• Produces vasoconstriction (unique among LAs)
• CNS stimulant effects
• Abuse potential

Mechanism of Vasoconstriction:

• Blocks presynaptic noradrenaline reuptake
• Increases local noradrenaline concentration
• Alpha-adrenergic stimulation causes vasoconstriction
• Useful for reducing bleeding (ENT surgery)

Clinical Uses:

• Topical anaesthesia of mucous membranes only
• ENT surgery (4-10% solution)
• Provides anaesthesia + haemostasis
• No other LA provides both properties simultaneously

Maximum Dose:

• 1.5 mg/kg (topical only)
• Maximum 200 mg absolute

Adverse Effects:

• Cardiovascular: Tachycardia, hypertension, coronary vasospasm, arrhythmias
• CNS: Euphoria, agitation, seizures
• Addiction potential
• Nasal septum necrosis (chronic intranasal use)

Legal Status:

• Schedule 8 (S8) in Australia
• Controlled substance in most jurisdictions
• Limited to hospital use

Other Local Anaesthetics

Articaine:

• Unique thiophene ring structure
• pKa 7.8, 95% protein binding
• Metabolized by plasma esterases (amide with ester hydrolysis)
• Very rapid onset, intermediate duration
• Popular in dental anaesthesia
• May cause paresthesia with inferior alveolar nerve blocks

Mepivacaine:

• pKa 7.6 (lowest, fastest onset)
• 78% protein binding
• Intermediate duration
• Less vasodilatory than lidocaine
• Useful without adrenaline

Chloroprocaine:

• Ester LA with fastest metabolism (plasma cholinesterase)
• Short duration (30-45 minutes)
• Low systemic toxicity (rapid breakdown)
• Useful for short procedures
• Historical concerns with epidural neurotoxicity (preservatives)
• Modern preservative-free formulations available

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Pharmacokinetics

Absorption

Local anaesthetic absorption depends on the site of injection and tissue characteristics [48,49]:

Factors Affecting Absorption:

1. Site of injection (highest to lowest absorption):

   • Intercostal > Caudal > Epidural > Brachial plexus > Sciatic/femoral > Subcutaneous

2. Vascularity: More vascular sites → faster absorption → higher peak levels

3. Dose/Concentration: Higher doses → higher peak plasma levels

4. Addition of vasoconstrictors: Adrenaline reduces absorption, lowers peak levels

5. Drug properties: Vasoactive effects (cocaine constricts, most others dilate)

6. Tissue binding: Local protein and lipid binding creates depot

Peak Plasma Concentrations by Site:

Distribution

Volume of Distribution:

Distribution Phases:

1. Alpha phase: Rapid distribution to highly perfused organs (heart, brain, lungs, kidneys)
2. Beta phase: Redistribution to less perfused tissues (muscle, fat)
3. Terminal phase: Elimination

Tissue Distribution:

• High concentrations initially in well-perfused organs (explains CNS/cardiac toxicity)
• Eventual equilibration with muscle and fat
• Plasma levels depend on balance of absorption, distribution, elimination

Protein Binding:

• Alpha-1 acid glycoprotein (AAG): High affinity, low capacity
• Albumin: Low affinity, high capacity
• Only free drug crosses into tissues and is pharmacologically active
• Acidosis reduces protein binding → increased free drug → increased toxicity

Metabolism

Ester Metabolism:

• Plasma pseudocholinesterase (butyrylcholinesterase)
• Very rapid hydrolysis
• Produces PABA (allergenic metabolite)
• Prolonged in cholinesterase deficiency

Amide Metabolism:

• Phase I: Hepatic microsomal enzymes (CYP450)
• Phase II: Conjugation (glucuronidation, amide hydrolysis)
• Slower than ester hydrolysis
• Affected by hepatic blood flow and enzyme activity

Cytochrome P450 Involvement:

Hepatic Extraction Ratio:

• Low extraction (capacity-limited): Bupivacaine, ropivacaine
  • Clearance depends on enzyme activity
  • Less affected by hepatic blood flow
• Intermediate extraction: Lidocaine
  • Clearance depends on both flow and enzymes
• High extraction (flow-limited): None in common use
  • Clearance would depend mainly on hepatic blood flow

Elimination

Elimination Half-lives:

Renal Excretion:

• Less than 5% of unchanged drug excreted in urine
• Metabolites excreted renally
• Renal impairment: Metabolite accumulation (minor clinical significance)

Special Populations:

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Maximum Doses

Standard Maximum Doses

Maximum doses are guidelines to reduce LAST risk but do not guarantee safety [19,20,50]:

Without Adrenaline:

With Adrenaline (1:200,000):

Factors Requiring Dose Reduction

Several patient factors necessitate dose reduction below standard maximums [51,52]:

Patient Factors:

Site of Injection:

• High-absorption sites (intercostal, epidural): More conservative dosing
• Low-absorption sites (subcutaneous): Standard dosing appropriate

Limitations of Maximum Dose Concept:

• Doses are not based on rigorous pharmacokinetic studies
• Individual variation in metabolism and sensitivity
• Site of injection critically affects plasma levels
• Maximum dose does not equal safe dose
• LAST can occur below "maximum" doses

Dose Calculation Examples

Example 1: Lidocaine for Infiltration

• Patient: 70 kg adult
• Without adrenaline: 3 mg/kg × 70 = 210 mg (use 200 mg absolute max)
• With adrenaline: 7 mg/kg × 70 = 490 mg (within 500 mg max)
• 1% lidocaine = 10 mg/mL
• Maximum volume without adrenaline: 200 mg ÷ 10 mg/mL = 20 mL
• Maximum volume with adrenaline: 490 mg ÷ 10 mg/mL = 49 mL

Example 2: Bupivacaine for Nerve Block

• Patient: 60 kg adult
• Without adrenaline: 2 mg/kg × 60 = 120 mg
• With adrenaline: 2.5 mg/kg × 60 = 150 mg (equals absolute max)
• 0.5% bupivacaine = 5 mg/mL
• Maximum volume without adrenaline: 120 mg ÷ 5 mg/mL = 24 mL
• Maximum volume with adrenaline: 150 mg ÷ 5 mg/mL = 30 mL

Example 3: Elderly Patient

• Patient: 80 years, 65 kg, for epidural
• Use ideal body weight if obese
• Reduce dose by 25%: 2 mg/kg × 0.75 × 65 = 97.5 mg bupivacaine
• Maximum volume 0.25% bupivacaine: 97.5 ÷ 2.5 = 39 mL

---

Additives

Adrenaline (Epinephrine)

Adrenaline is the most commonly added adjunct to local anaesthetics [53,54]:

Mechanism:

• Alpha-1 adrenergic receptor activation
• Local vasoconstriction
• Reduces LA absorption into bloodstream
• Maintains higher local tissue concentration

Effects:

• Prolongs duration of block (30-50%)
• Reduces peak plasma concentration
• Allows higher maximum doses
• Improves quality of block
• Reduces surgical bleeding (infiltration)
• Provides marker of intravascular injection (tachycardia, hypertension)

Standard Concentrations:

• 1:200,000 (5 μg/mL) - most common
• 1:400,000 (2.5 μg/mL) - used in some nerve blocks
• 1:80,000 (12.5 μg/mL) - dental use

Maximum Adrenaline Doses:

• Adults: 200-250 μg total
• Children: 10 μg/kg
• Cardiac patients: 50-100 μg total

Contraindications:

• Ring blocks (fingers, toes, penis, nose, ears) - controversial, recent evidence suggests safety
• End-artery territories - risk of ischemia
• Intravenous regional anaesthesia
• Patients on MAOIs, TCAs (relative)
• Severe hypertension, arrhythmias
• Thyrotoxicosis

Adrenaline and Cocaine:

• Never combine (additive sympathomimetic effects)
• Risk of severe hypertension, arrhythmias, myocardial ischemia

Sodium Bicarbonate

Bicarbonate alkalinizes the LA solution to speed onset [55,56]:

Mechanism:

• Raises pH of LA solution
• Increases proportion of un-ionized (lipophilic) drug
• Faster penetration across nerve membrane
• Reduces injection pain (commercial solutions are acidic)

Dosing:

• 1 mL 8.4% sodium bicarbonate per 10 mL lidocaine
• 0.1 mL 8.4% sodium bicarbonate per 10 mL bupivacaine (higher risk of precipitation)

Effects:

• Reduces onset time by 30-50%
• Reduces injection discomfort
• May slightly reduce duration

Precautions:

• Excess bicarbonate can precipitate LA (especially bupivacaine)
• Must be freshly mixed
• Some advocate adding just before injection

Hyaluronidase

Hyaluronidase is an enzyme that enhances LA spread [57,58]:

Mechanism:

• Hydrolyzes hyaluronic acid in tissue
• Breaks down intercellular barriers
• Facilitates diffusion of LA through tissues

Uses:

• Ophthalmic blocks (retrobulbar, peribulbar)
• Subcutaneous infiltration for wide field
• Improve spread in tissue planes

Dosing:

• 15-150 units mixed with LA

Effects:

• Faster onset
• Wider spread of block
• Reduced tissue distension
• May slightly shorten duration (faster absorption)

Precautions:

• Allergic reactions possible
• Accelerates systemic absorption
• Should not exceed maximum LA doses

Opioids (Neuraxial)

Opioids are added to neuraxial LAs to enhance analgesia [59,60]:

Agents:

• Fentanyl 10-25 μg (epidural), 10-25 μg (spinal)
• Morphine 2-4 mg (epidural), 0.1-0.3 mg (spinal)
• Diamorphine (UK/Europe)

Mechanism:

• Opioid receptors in spinal cord dorsal horn
• Synergistic with LA sodium channel block
• Allows reduced LA concentration (motor-sparing)

Effects:

• Enhanced analgesia
• Prolonged duration
• Reduced LA requirements
• Dose-sparing

Adverse Effects:

• Pruritus (most common)
• Nausea and vomiting
• Urinary retention
• Delayed respiratory depression (morphine)
• Sedation

Other Additives

Clonidine:

• Alpha-2 agonist
• 50-150 μg added to LA
• Prolongs block duration
• May cause hypotension, sedation

Dexmedetomidine:

• Alpha-2 agonist (more selective than clonidine)
• 50-100 μg perineural
• Prolongs sensory and motor block
• May cause bradycardia

Dexamethasone:

• 4-8 mg added to LA or IV
• Prolongs duration of peripheral nerve blocks
• Mechanism: Anti-inflammatory, vasoconstriction
• Perineural vs IV debated (similar effect)

Magnesium:

• NMDA receptor antagonist
• May prolong neuraxial block
• Evidence limited

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Local Anaesthetic Systemic Toxicity (LAST)

Definition and Epidemiology

Local anaesthetic systemic toxicity (LAST) is a potentially life-threatening complication resulting from elevated plasma concentrations of local anaesthetics [1,2,61]:

Definition: Systemic toxicity manifesting as CNS and/or cardiovascular dysfunction following local anaesthetic administration.

Incidence:

• All regional anaesthesia: 1-2 per 1,000 nerve blocks
• Peripheral nerve blocks: 0.4-1.8 per 1,000
• Epidural: 1-4 per 10,000
• Serious complications (cardiac arrest): 1-2 per 10,000

Causes:

1. Intravascular injection (most common)
   • Arterial or venous
   • Direct injection or catheter migration
2. Excessive dose (exceeding maximum)
3. Rapid absorption from highly vascular site
4. Decreased clearance (hepatic impairment, heart failure)
5. Increased sensitivity (acidosis, hypoxia, pregnancy)

Risk Factors:

Pathophysiology

LAST involves both CNS and cardiovascular toxicity with distinct mechanisms [62,63]:

CNS Toxicity:

1. Initial cortical inhibition blockade:

   • LAs preferentially block inhibitory cortical neurons first
   • Results in disinhibition → excitatory symptoms

2. Progressive CNS depression:

   • Higher concentrations block all neurons
   • Leads to seizures, then CNS depression

3. Brainstem effects:

   • Respiratory depression
   • Loss of consciousness

Cardiovascular Toxicity:

1. Sodium channel block:

   • Slows conduction (prolonged QRS)
   • Re-entrant arrhythmias

2. Potassium channel block:

   • Delayed repolarization (prolonged QT)
   • Torsades de pointes risk

3. Calcium channel block:

   • Negative inotropy
   • Vasodilation

4. Mitochondrial dysfunction:

   • Impaired cardiac energy metabolism
   • Especially with bupivacaine

5. Autonomic effects:

   • Initial sympathetic stimulation (tachycardia, hypertension)
   • Later vagotonic effects (bradycardia)

CNS vs Cardiovascular Toxic Ratio:

This ratio explains why bupivacaine LAST can present with cardiovascular collapse without preceding CNS symptoms.

Clinical Presentation

LAST typically follows a biphasic pattern, but presentation is highly variable [64,65]:

Classic Biphasic Presentation:

Phase 1 - CNS Excitation:

• Prodromal symptoms:
  • Perioral numbness/tingling
  • Metallic taste
  • Tinnitus
  • Visual disturbances
  • Lightheadedness
  • Dizziness
• Excitation:
  • Agitation
  • Confusion
  • Tremor
  • Muscle twitching
  • Seizures (generalized tonic-clonic)

Phase 2 - CNS Depression:

• Drowsiness
• Loss of consciousness
• Respiratory depression
• Respiratory arrest

Phase 3 - Cardiovascular Toxicity:

• Initial: Hypertension, tachycardia
• Progressive:
  • Hypotension
  • Bradycardia
  • Conduction abnormalities (prolonged PR, QRS, QT)
  • Ventricular arrhythmias (VT, VF)
  • Asystole
  • Refractory cardiac arrest

Atypical Presentations:

• Cardiovascular collapse without CNS symptoms (bupivacaine)
• Delayed onset (20-60 minutes post-injection)
• Gradual onset (continuous infusions)
• Isolated CNS symptoms only
• Isolated cardiovascular symptoms only

Signs of Intravascular Injection:

• Sudden onset during injection
• Tachycardia (if adrenaline-containing solution)
• Immediate CNS symptoms
• Metallic taste

LAST Management Protocol

Management follows the AAGBI/ASRA consensus guidelines [66,67]:

Immediate Actions:

1. Stop LA injection immediately
2. Call for help - "LAST emergency"
3. Get lipid emulsion and LAST checklist
4. Maintain airway - 100% oxygen, consider intubation
5. IV access if not already present

Seizure Management:

• Benzodiazepines first-line:
  • Midazolam 2-4 mg IV
  • Diazepam 5-10 mg IV
• Avoid propofol if cardiovascular instability (cardiac depression)
• Small doses of propofol acceptable if stable
• Secure airway - may need intubation

Cardiovascular Support:

• Standard ACLS with modifications:
  • "Reduce adrenaline dose: 10-100 μg boluses (NOT 1 mg)"
  • Avoid vasopressin, calcium channel blockers, beta-blockers, lidocaine
  • Amiodarone preferred for arrhythmias

Lipid Emulsion Rescue

Lipid emulsion therapy is the cornerstone of LAST treatment [17,18,68]:

Indications:

• Any signs of LAST beyond mild CNS symptoms
• Should be given early, not as last resort
• Do not wait for cardiac arrest

Protocol (AAGBI/ASRA 2020):

Initial Bolus:

• Intralipid 20% 1.5 mL/kg over 1 minute
• (Approximately 100 mL for 70 kg adult)

Infusion:

• 0.25 mL/kg/min continuous infusion
• Continue for at least 10 minutes after cardiovascular stability

Repeat Bolus:

• If cardiovascular instability persists at 5 minutes
• Repeat 1.5 mL/kg bolus (max 2 additional boluses)

Maximum Dose:

• 12 mL/kg total over first 30 minutes
• (Approximately 840 mL for 70 kg adult)

Mechanism of Lipid Emulsion:

1. Lipid sink theory: Lipid droplets extract lipophilic LA from tissues (especially myocardium)
2. Direct cardiotonic effect: Increased intracellular calcium
3. Metabolic rescue: Enhanced fatty acid metabolism in myocardium
4. Sodium channel effect: May facilitate LA dissociation

Key Points:

• Intralipid 20% preferred (most evidence)
• Other lipid emulsions (Clinoleic, SMOFlipid) may be used if Intralipid unavailable
• Propofol is NOT a substitute (insufficient lipid, cardiac depression)

Post-LAST Care

After Initial Resuscitation:

1. Continue monitoring - ECG, BP for at least 2 hours (6-12 hours for bupivacaine)
2. ICU admission - for cardiac arrest, seizures, or significant CVS instability
3. Serial ECGs - QRS and QT monitoring
4. Lipid effects - monitor for pancreatitis (rare), interference with lab tests
5. Document and report - complete adverse event reporting

Potential Late Complications:

• Recurrence of toxicity (redistribution, reabsorption)
• Pancreatitis (from lipid)
• ARDS (massive lipid)
• Fat embolism syndrome (rare)

LAST Prevention

Strategies to Prevent LAST [69,70]:

1. Aspiration before injection:

   • May not detect intravascular placement (30-50% sensitivity)
   • Negative aspiration does not guarantee safety

2. Incremental injection:

   • Inject in 3-5 mL aliquots
   • Wait 30-45 seconds between injections
   • Observe for signs of intravascular injection

3. Test dose:

   • Adrenaline-containing solution (10-15 μg = 2-3 mL of 1:200,000)
   • Tachycardia (>20 bpm) suggests intravascular injection
   • Less reliable in beta-blocked, laboring, or anesthetized patients

4. Ultrasound guidance:

   • Visualize needle position
   • Observe LA spread
   • Reduces LA volume requirements
   • Does not eliminate LAST risk

5. Appropriate dosing:

   • Use lowest effective dose
   • Consider site-specific maximum doses
   • Account for patient factors

6. Equipment availability:

   • Lipid emulsion immediately accessible
   • LAST checklist posted
   • Resuscitation equipment ready

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Clinical Applications

Infiltration Anaesthesia

Local infiltration is the simplest form of regional anaesthesia [71,72]:

Technique:

• Direct injection into tissue around surgical site
• Subcutaneous, submucosal, or intradermal
• No specific nerve targeted

Common Agents:

• Lidocaine 0.5-1% (with or without adrenaline)
• Bupivacaine 0.25-0.5%
• Ropivacaine 0.5%

Applications:

• Wound suturing
• Skin lesion excision
• Central line insertion
• Chest drain insertion
• Minor surgical procedures

Tumescent Anaesthesia:

• Very dilute LA (0.05-0.1%) in large volumes
• Klein's solution: Lidocaine + adrenaline + bicarbonate in saline
• Used for liposuction
• Allows doses up to 35-55 mg/kg lidocaine (slow absorption)

Peripheral Nerve Blocks

Nerve blocks provide targeted anaesthesia/analgesia for specific regions [73,74]:

Upper Extremity:

Lower Extremity:

Common LA Choices:

• Lidocaine 1-2% (short duration)
• Bupivacaine/ropivacaine 0.25-0.5% (long duration)
• Volumes: 15-40 mL depending on block

Neuraxial Anaesthesia

Spinal Anaesthesia [75,76]:

Injection of LA into subarachnoid space (CSF):

Complications:

• Hypotension (sympathetic block)
• Bradycardia (block of cardiac accelerator fibres T1-T4)
• Post-dural puncture headache
• High spinal (respiratory compromise)
• Transient neurologic symptoms (TNS)
• Cauda equina syndrome (rare)

Epidural Anaesthesia [77,78]:

Injection of LA into epidural space:

Applications:

• Labour analgesia
• Postoperative analgesia (thoracic, abdominal surgery)
• Surgical anaesthesia
• Chronic pain management

ICU Applications

Local anaesthetics have specific applications in the ICU setting [79,80]:

Procedural Analgesia:

• Central venous catheter insertion
• Arterial line placement
• Chest drain insertion
• Lumbar puncture
• Percutaneous tracheostomy
• Wound care

IV Lidocaine:

• Antiarrhythmic: Ventricular tachycardia (loading 1-1.5 mg/kg, infusion 1-4 mg/min)
• Analgesic adjunct: Loading 1-2 mg/kg, infusion 1-2 mg/kg/hr
• May reduce opioid requirements
• Therapeutic level: 1.5-5 μg/mL, toxic >6 μg/mL

Epidural Analgesia in ICU:

• Post-surgical pain (thoracic, abdominal)
• Rib fractures (thoracic epidural)
• May improve respiratory function
• Requires close monitoring for complications

Regional Techniques:

• Continuous peripheral nerve blocks
• Paravertebral blocks for rib fractures
• Fascia iliaca block for hip fractures
• Reduce systemic analgesic requirements

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Australian/NZ Context

ANZCA Guidelines

The Australian and New Zealand College of Anaesthetists (ANZCA) provides guidance on local anaesthetic use [81,82]:

ANZCA Professional Standards:

• PS03: Guidelines for Management of Major Regional Analgesia
• PS28: Guidelines on Infection Control in Anaesthesia
• PG02: Position Statement on the Early Management of LA Toxicity

Key ANZCA Recommendations:

1. Lipid emulsion must be immediately available wherever regional anaesthesia is performed
2. LAST protocols should be displayed in all regional anaesthesia locations
3. Regular equipment checks including lipid emulsion expiry dates
4. Training in LAST recognition and management for all practitioners

TGA Approvals

All local anaesthetics used in Australia require Therapeutic Goods Administration (TGA) registration [83]:

Currently Registered:

• Lidocaine (various formulations)
• Bupivacaine (Marcain)
• Levobupivacaine (Chirocaine)
• Ropivacaine (Naropin)
• Prilocaine (Citanest)
• Articaine (Septanest)
• Cocaine (restricted - Schedule 8)

Lipid Emulsion Products:

• Intralipid 20% (Fresenius Kabi) - preferred
• Clinoleic 20% (Baxter)
• SMOFlipid 20% (Fresenius Kabi)

Indigenous Health Considerations

When providing regional anaesthesia to Aboriginal and Torres Strait Islander or Māori patients [84,85]:

Cultural Considerations:

• Family involvement in consent discussions
• Respect for cultural beliefs about body and spirit
• Awareness that procedures may have cultural significance
• Use of Aboriginal Health Workers/Liaison Officers
• Interpreter services for language barriers

Health Disparities:

• Higher rates of diabetes, renal disease, cardiac disease
• May affect LA dosing and risk assessment
• Limited access to specialist services in remote areas
• Telehealth consultation for complex cases

Communication:

• Use simple, clear language
• Avoid medical jargon
• Confirm understanding (not just ask "do you understand?")
• Written materials in appropriate languages if available

Remote and Rural Considerations

Regional anaesthesia in remote/rural settings requires special planning [86,87]:

Equipment Requirements:

• Lipid emulsion (Intralipid 20%) must be available
• Shelf life and storage considerations
• Emergency airway equipment
• Resuscitation drugs

Retrieval Planning:

• Know local retrieval services (RFDS, state services)
• Have contingency for LAST requiring prolonged resuscitation
• Consider proximity to definitive care

RFDS Considerations:

• Fixed-wing aircraft limitations
• Flight physiology effects on drug distribution
• Communication with retrieval team early if concerns

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SAQ Practice

SAQ 1: Local Anaesthetic Mechanism and Toxicity (15 marks)

Question:

A 35-year-old woman is scheduled for a right femoral nerve block for knee arthroscopy. During injection of 30 mL of 0.5% bupivacaine, she develops perioral numbness, tinnitus, and then a generalized tonic-clonic seizure.

(a) Describe the mechanism by which local anaesthetics block nerve conduction. (5 marks)

(b) Explain the concept of use-dependent (frequency-dependent) block and its clinical significance. (4 marks)

(c) Outline your immediate management of this patient. (6 marks)

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Model Answer:

(a) Mechanism of Local Anaesthetic Action (5 marks)

Local anaesthetics reversibly block voltage-gated sodium channels (Nav) to prevent action potential generation and propagation:

Sodium Channel Structure (1 mark):

• Alpha subunit contains 4 domains (I-IV) with 6 transmembrane segments each
• LA binding site on S6 segment of domain IV (intracellular side)
• S4 segment acts as voltage sensor

Access and Binding (2 marks):

• Un-ionized (base) form crosses lipid membrane (lipophilic)
• Once inside axoplasm, ionized (cationic) form binds to receptor
• Henderson-Hasselbalch equation determines ionized/un-ionized ratio based on pKa
• LAs bind preferentially to inactivated and open channel states (higher affinity)

Effect on Action Potential (2 marks):

• Blockade prevents Na+ influx during depolarization
• Threshold for action potential not reached
• Conduction failure occurs when 3+ consecutive nodes of Ranvier are blocked
• Reversible when LA dissociates and diffuses away

---

(b) Use-Dependent (Frequency-Dependent) Block (4 marks)

Definition (1 mark): The degree of sodium channel block increases with increasing frequency of nerve stimulation.

Mechanism (2 marks):

• Sodium channels exist in resting (closed), open, and inactivated states
• LAs have highest affinity for open and inactivated states, lowest for resting
• With each action potential, channels transition through open → inactivated states
• Rapid firing prevents complete recovery to resting state
• Block accumulates with each successive stimulus (phasic block)

Clinical Significance (1 mark):

• Differential nerve block: Rapidly firing sensory C-fibres blocked before slowly firing motor neurons
• Antiarrhythmic action: Lidocaine preferentially blocks rapidly firing ectopic cardiac foci
• Cardiotoxicity mechanism: Bupivacaine accumulates in cardiac tissue during arrhythmias (slow dissociation kinetics)

---

(c) Immediate Management of LAST (6 marks)

Recognition and Initial Steps (1 mark):

• Recognize LAST: Perioral numbness, tinnitus, seizure are classic prodrome/presentation
• Stop injection immediately
• Call for help - declare "LAST emergency"
• Note time and amount of LA injected (150 mg bupivacaine = at maximum dose for 60 kg patient)

Airway and Breathing (1 mark):

• 100% oxygen via face mask
• Support ventilation (bag-valve-mask if respiratory depression)
• Prepare for intubation if seizures continue or airway compromised
• Left lateral position if vomiting risk

Seizure Control (1 mark):

• Benzodiazepine first-line: Midazolam 2-4 mg IV or Diazepam 5-10 mg IV
• Small dose propofol if cardiovascular stable
• Avoid propofol if hypotension (cardiac depression)
• Prepare for intubation if prolonged seizure

Lipid Emulsion Therapy (2 marks):

• Intralipid 20% 1.5 mL/kg bolus over 1 minute (≈100 mL for 70 kg)
• Start infusion 0.25 mL/kg/min after bolus
• Repeat bolus at 5 minutes if cardiovascular instability persists (max 2 additional boluses)
• Maximum total dose: 12 mL/kg in first 30 minutes

Cardiovascular Support (1 mark):

• Standard resuscitation with modifications if cardiac arrest:
  • "Reduce adrenaline dose: 10-100 μg boluses (NOT 1 mg standard dose)"
  • Avoid vasopressin, calcium channel blockers, beta-blockers, lidocaine
  • Amiodarone for arrhythmias
• Consider ECMO/cardiopulmonary bypass for refractory arrest
• Continue CPR for at least 60 minutes (LA will eventually be metabolized)
• Post-event: Monitor minimum 2-6 hours, ICU admission if cardiac arrest

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SAQ 2: Structure-Activity Relationships (15 marks)

Question:

Compare and contrast lidocaine and bupivacaine as local anaesthetic agents.

(a) Describe the chemical structure of local anaesthetics and explain how structural differences between lidocaine and bupivacaine affect their clinical properties. (6 marks)

(b) Explain why bupivacaine is more cardiotoxic than lidocaine. (4 marks)

(c) Outline how stereoisomerism has been used to develop safer long-acting local anaesthetics. (5 marks)

---

Model Answer:

(a) Chemical Structure and Clinical Properties (6 marks)

Basic LA Structure (2 marks): All local anaesthetics have three components:

1. Aromatic ring (lipophilic end) - determines lipid solubility
2. Intermediate chain (ester or amide linkage) - determines metabolism
3. Amine group (hydrophilic end) - determines pKa and ionization

Both lidocaine and bupivacaine are amides (metabolized by hepatic CYP450).

Structural Comparison and Properties (4 marks):

Onset: Lidocaine faster (lower pKa → more un-ionized at pH 7.4 → faster membrane penetration)

Potency: Bupivacaine 4× more potent (higher lipid solubility → better penetration, higher receptor affinity)

Duration: Bupivacaine longer (higher protein binding → slow release from tissue proteins)

---

(b) Bupivacaine Cardiotoxicity (4 marks)

"Fast-in, Slow-out" Kinetics (2 marks):

• Bupivacaine binds rapidly to cardiac sodium channels
• Dissociation is very slow during diastole
• Channels remain blocked even between beats
• Block accumulates with each cardiac cycle
• Lidocaine dissociates rapidly (fast-on, fast-off) allowing recovery between beats

Cardiac Ion Channel Effects (1 mark):

• Sodium channels: Prolonged block → slowed conduction → widened QRS
• Potassium channels (hERG): Also blocked → delayed repolarization → prolonged QT
• Calcium channels: Blocked → negative inotropy
• Combined effects create substrate for re-entrant arrhythmias

Additional Factors (1 mark):

• CC/CNS ratio: Bupivacaine 3-4:1 (poor warning) vs Lidocaine 7:1 (good warning)
• CNS symptoms provide less warning before cardiovascular collapse
• Mitochondrial toxicity impairs cardiac energy metabolism
• High lipophilicity leads to tissue accumulation
• Resuscitation from bupivacaine arrest is difficult (prolonged CPR often required)

---

(c) Stereoisomerism and Safer Agents (5 marks)

Stereochemistry of Bupivacaine (1 mark):

• Bupivacaine has a chiral center → exists as R (dextro) and S (levo) enantiomers
• Commercial bupivacaine is racemic (50% R-bupivacaine + 50% S-bupivacaine)
• Enantiomers have identical physical properties but different biological activities

Single Enantiomer Agents (2 marks):

Ropivacaine (pure S-enantiomer):

• Developed as S-enantiomer only
• Similar clinical efficacy to bupivacaine (0.6-0.75× potency)
• Significantly reduced cardiotoxicity
• Intrinsic vasoconstriction (reduces absorption)
• Allows higher maximum doses

Levobupivacaine (pure S-bupivacaine):

• S-enantiomer of bupivacaine isolated
• Equipotent to racemic bupivacaine
• Reduced cardiac and CNS toxicity
• Same duration of action

Mechanism of Reduced Toxicity (1 mark):

• S-enantiomers have faster dissociation from cardiac sodium channels
• Less accumulation during diastole
• Less negative inotropy
• Less arrhythmogenic potential
• R-enantiomer is preferentially more cardiotoxic

Clinical Implications (1 mark):

• Ropivacaine and levobupivacaine preferred for:
  • High-volume blocks (fascia iliaca, TAP)
  • Continuous epidural infusions
  • Labour analgesia
  • Patients with cardiac disease
• Trade-off: Ropivacaine slightly less potent, more expensive

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Viva Scenarios

Viva 1: Local Anaesthetic Pharmacology

Stem: "A 45-year-old man is scheduled for surgical repair of a ruptured Achilles tendon. The anaesthetist plans to perform an ultrasound-guided popliteal sciatic nerve block with ropivacaine."

---

Examiner: Tell me about the mechanism of action of local anaesthetics.

Candidate: Local anaesthetics work by blocking voltage-gated sodium channels in neuronal membranes, preventing action potential generation and propagation.

The sodium channel has an alpha subunit containing four domains, each with six transmembrane segments. The LA binding site is located on the S6 segment of domain IV, on the intracellular side of the membrane.

For an LA to work, the un-ionized form crosses the lipid membrane, then inside the axoplasm the ionized cation binds to the receptor. The ratio of ionized to un-ionized drug depends on the pKa of the agent and tissue pH, according to the Henderson-Hasselbalch equation.

Examiner: What is use-dependent block?

Candidate: Use-dependent or frequency-dependent block refers to the increased channel blockade that occurs with repeated nerve stimulation.

Sodium channels cycle through resting, open, and inactivated states. LAs have highest affinity for the open and inactivated states, and lowest for the resting state.

During rapid nerve firing, channels spend more time in open and inactivated states, allowing more LA binding. The block accumulates with each successive action potential because there isn't enough time between stimuli for complete LA dissociation.

This has clinical significance in three ways:

1. Differential nerve block - pain fibres firing rapidly are blocked before motor neurons
2. Antiarrhythmic action of lidocaine - preferentially blocks rapidly firing ectopic foci
3. Cardiotoxicity with bupivacaine - slow dissociation causes accumulation in cardiac tissue

Examiner: Why was ropivacaine chosen for this block?

Candidate: Ropivacaine offers several advantages for peripheral nerve blocks:

First, it's a pure S-enantiomer with reduced cardiotoxicity compared to bupivacaine. It has faster dissociation from cardiac sodium channels.

Second, it has differential motor-sparing properties at lower concentrations, which may be useful for postoperative mobilization.

Third, it has intrinsic vasoconstrictive properties, which reduces systemic absorption and may prolong block duration without added adrenaline.

Fourth, it has a better safety profile for high-volume blocks like the popliteal approach, where 20-30 mL is typically used.

The pharmacokinetic parameters are: pKa 8.1, protein binding 94%, and an intermediate duration of 3-6 hours for nerve blocks.

Examiner: What is the maximum dose of ropivacaine for this block?

Candidate: The maximum dose of ropivacaine is 3 mg/kg for a single injection, with an absolute maximum of around 225 mg.

For a 70 kg man, that would be 210 mg maximum.

Using 0.5% ropivacaine (5 mg/mL), the maximum volume would be 42 mL.

For a popliteal block, we typically use 20-30 mL, so this is within the safe range.

For continuous infusions, the maximum is 0.5 mg/kg/hour, and the 24-hour maximum is 770 mg.

Examiner: During the block, after injecting 25 mL, the patient complains of a metallic taste and becomes confused. What is happening and what do you do?

Candidate: This presentation is highly suspicious for local anaesthetic systemic toxicity (LAST). The metallic taste and confusion are classic early CNS symptoms.

My immediate actions:

1. Stop the injection immediately
2. Call for help and announce "LAST emergency"
3. Request the lipid emulsion kit and LAST checklist
4. Provide 100% oxygen and assess airway

At this stage, the patient has early CNS symptoms. I would:

• Ensure IV access is secure
• Monitor closely for progression to seizures or cardiovascular instability
• Prepare benzodiazepines (midazolam 2-4 mg IV) in case of seizure

Given the progression of symptoms, I would start lipid emulsion therapy early:

• Intralipid 20% 1.5 mL/kg bolus (about 100 mL) over 1 minute
• Follow with 0.25 mL/kg/min infusion
• Repeat bolus at 5 minutes if symptoms persist or worsen

If cardiovascular instability develops, I would modify resuscitation by using reduced doses of adrenaline (10-100 μg rather than 1 mg), avoiding vasopressin and beta-blockers, and be prepared for prolonged resuscitation.

Examiner: How does lipid emulsion work to treat LAST?

Candidate: There are several proposed mechanisms:

The primary theory is the "lipid sink" hypothesis - the lipid droplets extract lipophilic local anaesthetics from tissues, including the myocardium, reducing the drug concentration at toxic sites.

Additional mechanisms include:

• Direct cardiotonic effect - fatty acids may increase intracellular calcium
• Metabolic rescue - provides substrate for myocardial fatty acid oxidation
• May facilitate dissociation of LA from sodium channels
• Possible reversal of LA-induced mitochondrial dysfunction

The lipid sink effect correlates with drug lipophilicity, which explains why it works well for bupivacaine and ropivacaine, which are highly lipophilic.

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Viva 2: Structure-Activity Relationships and Clinical Applications

Stem: "You are reviewing local anaesthetics with a trainee before a teaching session on regional anaesthesia."

---

Examiner: Describe the chemical structure common to all local anaesthetics.

Candidate: All local anaesthetics share a common structural template with three components:

1. An aromatic ring at the lipophilic end - usually a benzene ring, though articaine has a thiophene ring. This determines lipid solubility.

2. An intermediate chain containing either an ester or amide linkage. This bond determines the metabolic pathway - esters are hydrolyzed by plasma cholinesterases, while amides undergo hepatic metabolism.

3. An amine group at the hydrophilic end - usually a tertiary amine that can accept a proton to become ionized. The pKa is determined by this group.

A simple way to remember which drugs are amides is that they contain the letter 'i' before '-caine' - lidocaine, bupivacaine, ropivacaine, prilocaine. Most esters don't follow this pattern - procaine, cocaine, tetracaine.

Examiner: How does pKa affect onset time?

Candidate: pKa is the pH at which 50% of the drug is ionized and 50% un-ionized.

According to the Henderson-Hasselbalch equation, when the tissue pH equals the pKa, the drug is 50% ionized.

At physiological pH (7.4), which is lower than most LA pKa values, the drug is predominantly in the ionized form.

The lower the pKa (closer to physiological pH), the greater the proportion of un-ionized drug. The un-ionized form is lipophilic and can cross the nerve membrane.

For example:

• Lidocaine (pKa 7.9): 24% un-ionized at pH 7.4 → faster onset
• Bupivacaine (pKa 8.1): 17% un-ionized → slower onset

Once inside the axoplasm, the drug re-equilibrates and the ionized form binds to the sodium channel.

This also explains why LA efficacy is reduced in infected tissue - the acidic pH increases ionization, reducing membrane penetration.

Examiner: What determines the duration of action?

Candidate: Duration of action correlates primarily with protein binding.

Highly protein-bound drugs dissociate slowly from tissue proteins, creating a local reservoir that prolongs the effect.

For example:

• Lidocaine: 64% protein bound → intermediate duration (1-2 hours)
• Bupivacaine: 95% protein bound → long duration (3-8 hours)

Other factors affecting duration include:

• Lipid solubility - sequestration in fatty tissues
• Local vasoactivity - bupivacaine is vasodilatory, ropivacaine is vasoconstrictive
• Addition of adrenaline - reduces absorption by vasoconstriction
• Dose - higher doses generally produce longer blocks
• Site of injection - affects absorption rate

The main plasma protein involved is alpha-1 acid glycoprotein (AAG), which is an acute phase reactant. In critical illness, AAG levels may be altered, affecting free drug fraction.

Examiner: Explain why prilocaine causes methaemoglobinaemia.

Candidate: Prilocaine is unique among local anaesthetics in causing methaemoglobinaemia through its metabolite.

Prilocaine is metabolized to ortho-toluidine (o-toluidine) in the liver.

O-toluidine oxidizes the iron in haemoglobin from the ferrous (Fe2+) state to the ferric (Fe3+) state. Haemoglobin with ferric iron is called methaemoglobin.

Methaemoglobin cannot bind and release oxygen normally, shifting the oxygen-haemoglobin dissociation curve to the left and reducing oxygen delivery to tissues.

This is a dose-dependent phenomenon. Clinically significant methaemoglobinaemia (MetHb >20%) typically occurs with doses exceeding 600 mg.

Clinical features include:

• Cyanosis that doesn't respond to oxygen
• Chocolate-brown appearance of blood
• SpO2 reads around 85% regardless of actual oxygenation
• Symptoms at >20%: dyspnea, headache
• Symptoms at >40%: confusion, tachycardia, acidosis

Treatment is methylene blue 1-2 mg/kg IV over 5 minutes, which acts as an electron donor to reduce methaemoglobin back to haemoglobin.

Contraindications include G6PD deficiency, methaemoglobin reductase deficiency, and large doses in pregnancy due to risk of fetal methaemoglobinaemia.

Examiner: What are the maximum doses for the common local anaesthetics?

Candidate: Maximum doses are guidelines, not guarantees of safety. They vary with and without adrenaline:

These doses should be reduced in elderly patients by 20-30%, in hepatic impairment for amides, and in cardiac failure due to reduced clearance.

The site of injection also matters - intercostal blocks have highest absorption, so more conservative dosing is needed despite the same maximum dose.

Examiner: When should adrenaline NOT be added to local anaesthetics?

Candidate: Adrenaline should be avoided or used with caution in several situations:

Traditional contraindications include ring blocks of digits, penis, ears, and nose - the "end-artery" territories - due to risk of ischemia. However, recent evidence challenges this for digital blocks.

It should not be used with cocaine - additive sympathomimetic effects can cause severe hypertension, arrhythmias, and myocardial ischemia.

It's contraindicated in intravenous regional anaesthesia (Bier's block) - risk of systemic release if tourniquet fails.

Relative contraindications include:

• Patients on MAOIs or TCAs - potentiation of catecholamine effects
• Severe hypertension or unstable cardiac disease
• Arrhythmias
• Thyrotoxicosis
• Phaeochromocytoma

The test dose to detect intravascular injection may not be reliable in beta-blocked patients, those in labour, or under general anaesthesia - the tachycardia response is blunted.

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MCQ Practice

Question 1

A 28-year-old woman undergoes epidural placement for labour analgesia. Which local anaesthetic property most directly determines the onset time of the block?

A. Molecular weight B. Lipid solubility C. Protein binding D. pKa E. Volume of distribution

Answer: D

Explanation: pKa determines the proportion of un-ionized (lipophilic) drug at tissue pH. Only the un-ionized form can cross the lipid nerve membrane. Agents with lower pKa (closer to physiological pH 7.4) have more un-ionized drug and faster onset. Lipid solubility affects potency, protein binding affects duration, and molecular weight/Vd have minimal direct effect on onset.

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Question 2

Which of the following mechanisms best explains why bupivacaine is more cardiotoxic than lidocaine?

A. Higher lipid solubility of bupivacaine B. Faster association with cardiac sodium channels C. Slower dissociation from cardiac sodium channels during diastole D. Greater blockade of cardiac potassium channels E. Lower plasma protein binding

Answer: C

Explanation: The key mechanism is the "fast-in, slow-out" kinetics of bupivacaine. While bupivacaine associates rapidly with cardiac sodium channels, it dissociates very slowly during diastole. This allows block to accumulate with each cardiac cycle, leading to progressive conduction slowing and eventual cardiovascular collapse. While bupivacaine does block potassium channels and is more lipophilic, the slow dissociation kinetics is the primary factor distinguishing its cardiotoxicity from lidocaine.

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Question 3

A 65-year-old man with end-stage renal disease requires a femoral nerve block. Which local anaesthetic would be LEAST affected by his renal impairment?

A. Lidocaine B. Bupivacaine C. Ropivacaine D. Chloroprocaine E. Mepivacaine

Answer: D

Explanation: Chloroprocaine is an ester local anaesthetic metabolized by plasma cholinesterases (pseudocholinesterase), not by hepatic or renal mechanisms. It has the shortest half-life (≈1 minute) and is minimally affected by organ dysfunction. Amide local anaesthetics (lidocaine, bupivacaine, ropivacaine, mepivacaine) are hepatically metabolized, but their metabolites are renally excreted and may accumulate. While the parent drugs are not significantly affected, chloroprocaine offers the most organ-independent elimination.

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Question 4

During lipid emulsion rescue for local anaesthetic systemic toxicity, what is the recommended initial bolus dose of Intralipid 20%?

A. 0.5 mL/kg B. 1.0 mL/kg C. 1.5 mL/kg D. 2.0 mL/kg E. 3.0 mL/kg

Answer: C

Explanation: Per AAGBI/ASRA guidelines, the initial bolus of Intralipid 20% is 1.5 mL/kg over 1 minute (approximately 100 mL for a 70 kg adult). This is followed by an infusion of 0.25 mL/kg/min. The bolus may be repeated twice at 5-minute intervals if cardiovascular instability persists. The maximum total dose is 12 mL/kg in the first 30 minutes.

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Question 5

Which nerve fibre type is blocked FIRST during differential nerve block with local anaesthetics?

A. Aα fibres (motor) B. Aβ fibres (touch, pressure) C. Aδ fibres (pain, temperature) D. B fibres (preganglionic autonomic) E. C fibres (pain, postganglionic autonomic)

Answer: D

Explanation: The order of block from first to last is: B (autonomic) → C (pain) → Aδ (pain, cold) → Aγ (muscle spindles) → Aβ (touch) → Aα (motor). B fibres are small, myelinated preganglionic autonomic fibres that are blocked earliest. This explains why sympathetic blockade (hypotension) often precedes sensory and motor block, particularly with neuraxial anaesthesia.

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Summary Tables

Pharmacokinetic Comparison

Maximum Dose Reference

LAST Management Summary

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Last updated: January 2026

This topic covers the CICM First Part syllabus requirements for local anaesthetic pharmacology and should be studied in conjunction with clinical regional anaesthesia topics.