What is the fundamental mechanism of local anaesthetic action and how does structure affect function?

Local anaesthetics are amphipathic molecules with a lipophilic aromatic ring and hydrophilic amine group. They must cross the nerve membrane as unionised molecules, then re-equilibrate to ionised form inside the neuron to block voltage-gated sodium channels from the internal aspect. The linkage (amide vs ester) determines metabolism: amides require hepatic metabolism while esters are rapidly cleared by plasma esterases.

How do pKa and protein binding affect local anaesthetic onset and duration?

Lower pKa means more unionised molecules at physiological pH, enabling faster membrane penetration and onset (lidocaine pKa 7.7 = 25% unionised, prilocaine 33% vs bupivacaine pKa 8.1 = 15% unionised). Higher protein binding creates a drug reservoir prolonging duration (bupivacaine 95% bound = 5-16 hours vs lidocaine 64-70% bound = 90min-3 hours).

Why is bupivacaine more cardiotoxic than other local anaesthetics and how does levobupivacaine improve safety?

Bupivacaine is a racemic mixture with high cardiotoxicity due to prolonged sodium channel binding and effects on cardiac conduction (prolongs PR, QRS, QT intervals). Levobupivacaine, the pure S-enantiomer, has reduced cardiotoxicity as its major selling point - CNS toxicity occurs before cardiovascular collapse, providing warning signs. Both have the same 2mg/kg maximum dose.

What makes ropivacaine unique and when should it be selected over other agents?

Ropivacaine is a pure S-enantiomer with differential blockade properties - sensory block onset similar to bupivacaine but motor blockade takes longer to develop and recovers faster. Patients may have numb but mobile limbs initially. It has a higher safety margin (3mg/kg vs 2mg/kg for bupivacaine) and is ideal when motor-sparing block is desired.

Why should lidocaine never be used for spinal anaesthesia and what are the alternatives?

Lidocaine causes Transient Neurological Symptoms (TNS) with up to 33% incidence - back and buttock pain radiating to lower extremities. Using any other local anaesthetic reduces TNS risk by 82-90%. Alternatives include: bupivacaine/levobupivacaine for duration, prilocaine for day surgery rapid recovery, or 2-chloroprocaine for ultra-rapid procedures like varicose vein surgery.

What is the emergency management protocol for Local Anaesthetic Systemic Toxicity (LAST)?

Recognition: Only 60% follow textbook biphasic pattern - any weird behaviour after local anaesthetic injection should raise suspicion. Management: Stop injection, 100% oxygen, call for help, obtain QRH handbook. Intralipid 20%: 1.5ml/kg bolus (~100ml for 75kg patient) over 1 minute, then 15ml/kg/hour infusion, additional boluses at 5 and 10 minutes. Prevention: ultrasound guidance reduces risk 4-fold.

Local Anaesthetics for the FRCA Primary: Complete Series Guide

Contents

What You’ll Learn
Episode Guide – Local Anaesthetics For The FRCA Primary
Key Pharmacological Concepts Covered
References

Welcome to the comprehensive GasGasGas collection of knowledge regarding local anaesthetics for the FRCA Primary Exam.

This full series covers every major local anaesthetic you’ll encounter in uk anaesthetic practice, handles the fundamentals of sodium channel pharmacology and onset pharmacokinetics to advanced clinical decision-making and emergency management.

What You’ll Learn

This series covers the full local anaesthetics curriculum required for FRCA Primary: mechanism of action, individual drug pharmacokinetics, LAST recognition and treatment, and comparative pharmacology.

Core Pharmacology: Understand how all local anaesthetics work through voltage-gated sodium channel blockade, their classification into amides and esters, and why these differences matter clinically.

Individual Drug Profiles: Complete pharmacokinetic and pharmacodynamic data for lidocaine, bupivacaine, levobupivacaine, ropivacaine, prilocaine, and cocaine.

Clinical Decision Making: Learn when to choose each local anaesthetic based on onset time, duration, toxicity profile, and patient factors.

Emergency Management: Recognise and treat local anaesthetic systemic toxicity (LAST) with intralipid rescue protocols.

Advanced Concepts: Perineural adjuncts, IV lidocaine infusions, and comparative pharmacology for exam-style viva scenarios.

Episode Guide – Local Anaesthetics For The FRCA Primary

Eight episodes cover the complete local anaesthetics curriculum: mechanism of action, individual drug profiles for lidocaine, bupivacaine, levobupivacaine, ropivacaine, prilocaine, and cocaine, plus LAST management and comparative pharmacology.

Listen to the Fundamentals episode here

The essential foundation
Sodium channel blockade mechanism – must cross membrane as unionised, work as ionised
Classification: Amides (2 i’s) vs Esters (1 i) – determines metabolism
Nerve fibre selectivity: C fibres most sensitive → A-alpha least sensitive
pKa determines onset speed, protein binding affects duration
LAST recognition and intro emergency management protocols

Listen to the Lidocaine episode here

The ubiquitous LA
Rapid onset (20-30 seconds skin, 3-5 min nerve block)
pKa 7.7 – “L looks like 7 backwards” – 25% unionised
Also Class 1b antiarrhythmic agent
Multiple formulations: sprays, gels, infiltration, IV infusions
Never use for spinal anaesthesia – TNS risk up to 33%
IV infusions: 120mg/hour maximum, monitored bed space and institutional awareness required

Listen to the Bupivacaine episode here

Long-acting amide agent
Slow onset (10-20 min) but long duration (5-16 hours)
Racemic mixture – R and S enantiomers
95% protein bound creating long-lasting reservoir
Highly cardiotoxic – respect 2mg/kg dosing limit
Don’t mix with lidocaine – pH incompatibility impairs function

+ Levobupivacaine

The ‘safer’ S-enantiomer (anything is a poison in a high enough dose!)
Pure S-enantiomer of bupivacaine
Reduced cardiotoxicity – the major selling point
Less motor block relative to sensory at low concentrations
Same maximum dose: 2mg/kg (but some sources suggest 2.5mg/kg)
CNS toxicity occurs before cardiovascular – gives warning

Listen to the Ropivacaine episode here

The somewhat differential blocker..
Pure S-enantiomer with differential blockade properties
Sensory block similar to bupivacaine, motor slower onset/faster recovery
Higher safety margin: 3mg/kg toxic dose
Patients may have numb but mobile limbs initially
Gained prominence during levobupivacaine shortages courtesy of…????

Listen to the Prilocaine episode here

Fast onset (33% unionised at physiological pH)
Faster recovery than bupivacaine – motor block 158min vs 220min
EMLA component (with lidocaine)
Methaemoglobinaemia risk >600mg – treat with methylene blue
Fixes quickly – position patient immediately ‘no time for conversations about trains from 1970‘

Listen to the Cocaine episode here

The pioneer! with testicular traction and hammers vs shins
Launched spinal anaesthesia (August Bier, 1898)
Dual mechanism: sodium channel blockade + monoamine reuptake inhibition
Still used in ENT for excellent vasoconstriction
Only 6% unionised at physiological pH
Contraindicated in IHD, uncontrolled hypertension, porphyria
Emergency management: benzodiazepines first-line for most complications

Listen to the Local Anaesthetic Systemic Toxicity (LAST) episode here

Recognition: Only 60% follow textbook biphasic pattern
Any weird behaviour after LA injection should raise suspicion
Emergency management: Stop injection, 100% O₂, call for help, QRH
Intralipid 20%: 1.5ml/kg bolus (~100ml for 75kg), then 15ml/kg/hour (AAGBI LAST guidelines)
Mechanism: Na / K / Ca Channel Blockade + Mitochondrial impairment
Prevention: Ultrasound reduces risk 4-fold, but many ways to reduce this issue!

Listen to the Local Anaesthetics Comparison episode here

Absorption hierarchy: Intercostal > Caudal > Epidural > Brachial > Subcutaneous
Day surgery: Prilocaine for faster recovery
Safety: Levobupivacaine over bupivacaine when possible
Emergency procedures: Consider onset vs duration needs
Special populations: Dosing adjustments for age, hepatic function etc

Listen to the Perineural Adjuncts episode here

Off-license enhancement strategies
All perineural adjuncts are off-license – this is a medico-legal consideration.
Dexamethasone: IV as effective as perineural (4-8h prolongation)
Dexmedetomidine: 4h sensory, 3h motor prolongation
Buprenorphine: 8.5h sensory prolongation via sodium channel blockade action :O
Drug interactions: Dexamethasone + Ropivacaine = crystallization

Key Pharmacological Concepts Covered

All local anaesthetics produce reversible conduction block by entering voltage-gated sodium channels from the intracellular side, with onset and duration determined by pKa, lipophilicity, and plasma protein binding.

Receptor Pharmacology: All local anaesthetics work through voltage-gated sodium channels causing blockade from the internal aspect of the channel within the neuronal membrane.

Structure-Activity Relationships: Amphipathic molecules with lipophilic aromatic ring and hydrophilic amine group, linked by either ester or amide bond.

Pharmacokinetic Principles:

pKa determines onset speed (lower pKa = faster onset)
Protein binding affects duration (higher binding = longer duration)
Lipophilicity affects potency and redistribution
Metabolism: Amides hepatic, esters plasma esterases

Start with any episode, but the logical progression builds understanding. Whether you’re cramming for exams or building a robust pharmacological foundation, this series delivers the local anaesthetic knowledge essential for modern anaesthetic practice.

References

AAGBI/ACSA Local Anaesthetic Toxicity guidelines — Management of severe local anaesthetic toxicity (Association of Anaesthetists) — source for Intralipid 20% dosing: 1.5 ml/kg bolus, 15 ml/kg/hour infusion.
Transient neurological symptoms (TNS) incidence with lidocaine spinal up to 33%: see Ep.34 – Lidocaine For The FRCA Primary and the Local Anaesthetic Systemic Toxicity episode for further clinical context.

Local Anaesthetics for the FRCA Primary — Complete Series Guide