Overview of local anaesthetics

11 min read Last updated April 9, 2026

Definition and classification

  • Local anaesthetics (LAs) reversibly block nerve conduction by inhibiting voltage-gated sodium channels (Nav), producing loss of sensation ± motor block.
  • Chemical classes
    • Amino-amides: lidocaine, bupivacaine, levobupivacaine, ropivacaine, prilocaine, mepivacaine.
    • Amino-esters: chloroprocaine, procaine, tetracaine, benzocaine, cocaine.
  • Key practical differences
    • Metabolism: amides mainly hepatic, esters mainly plasma cholinesterase (pseudocholinesterase).
    • Allergy: true allergy rare, more common with esters (PABA metabolite) and preservatives (e.g. methylparaben).

Structure–activity relationships (SAR) and physicochemistry

  • Basic structure: lipophilic aromatic ring + intermediate chain (amide/ester) + hydrophilic tertiary amine.
  • pKa and onset
    • LAs are weak bases: unionised form (B) crosses lipid membranes, ionised form (BH+) binds channel from intracellular side.
    • Lower pKa (closer to physiological pH 7.4) → higher fraction unionised → faster onset (e.g. lidocaine faster than bupivacaine).
    • Acidosis (infection, poor perfusion) reduces unionised fraction → slower onset and reduced efficacy (infiltration in infected tissue).
  • Lipid solubility and potency
    • Greater lipid solubility generally increases potency and duration but also increases toxicity risk (more tissue uptake, protein binding).
  • Protein binding and duration
    • Higher protein binding correlates with longer duration (e.g. bupivacaine > lidocaine).
  • Stereochemistry
    • Bupivacaine is racemic, levobupivacaine is S(-) enantiomer, ropivacaine is S(-) and less lipophilic → less cardiotoxic than racemic bupivacaine.

Mechanism of action (sodium channel blockade)

  • Bind to voltage-gated Na+ channels, preferentially in open/inactivated states → use-dependent (frequency-dependent) block.
  • Access pathways
    • Hydrophilic pathway: unionised crosses membrane then re-equilibrates, ionised binds intracellular receptor.
    • Hydrophobic pathway: some direct access through membrane to channel site (drug-dependent).
  • Differential block
    • Smaller, myelinated fibres tend to be blocked earlier (pain/temperature) than larger motor fibres, clinical sequence often: sympathetic → pain → temperature → touch → motor.
    • Not absolute: depends on concentration, fibre type, anatomy, and local conditions.

Pharmacokinetics: absorption, distribution, metabolism, excretion

  • Systemic absorption depends on site vascularity, dose, use of vasoconstrictor, and technique (intravascular injection is highest risk).
  • Relative absorption by site (typical teaching order)
    • IV > tracheal > intercostal > caudal/epidural > brachial plexus > sciatic/femoral > subcutaneous.
  • Distribution
    • Highly perfused organs (brain, heart) exposed early, then redistribution to muscle/fat.
    • Protein binding: mainly α1-acid glycoprotein (AAG) and albumin, low AAG (neonates, pregnancy, severe illness) increases free fraction.
  • Metabolism
    • Amides: hepatic (CYP), reduced clearance in liver disease, low hepatic blood flow states, heart failure, consider dose reduction with infusions.
    • Esters: rapid hydrolysis by plasma cholinesterase, prolonged in pseudocholinesterase deficiency, one metabolite is PABA (allergy association).
  • Excretion: renal (metabolites), severe renal failure can accumulate metabolites (usually less clinically significant than hepatic impairment for amides).

Clinical effects and uses

  • Analgesia/anaesthesia: infiltration, peripheral nerve blocks, neuraxial anaesthesia, topical airway anaesthesia.
  • Antiarrhythmic: lidocaine (class Ib) for ventricular arrhythmias (less common in modern ALS but still relevant pharmacology).
  • Obstetrics: epidural (low concentration LA + opioid), spinal for CS (hyperbaric bupivacaine commonly).

Adjuvants and formulation issues

  • Adrenaline (epinephrine)
    • Reduces systemic absorption (vasoconstriction) → prolongs duration and reduces peak plasma level, provides marker for intravascular injection (tachycardia).
    • Caution: end-artery areas (traditional teaching: fingers, toes, penis, pinna, nose) and in severe peripheral vascular disease, also caution with arrhythmias and some volatile/TCAs/cocaine use.
  • Sodium bicarbonate (buffering)
    • Raises pH → increases unionised fraction → faster onset and less injection pain (notably lidocaine infiltration).
    • Risk of precipitation, especially with bupivacaine/ropivacaine, use appropriate dilution and mix immediately before use.
  • Opioids (neuraxial)
    • Synergistic analgesia, reduce LA dose, side effects include pruritus, nausea, urinary retention, respiratory depression (esp. intrathecal morphine).
  • Alpha-2 agonists (clonidine/dexmedetomidine)
    • May prolong block and improve analgesia, side effects: hypotension, bradycardia, sedation.
  • Dexamethasone (perineural vs IV)
    • Often prolongs analgesia duration, IV effect may account for much benefit, perineural use is off-label in many settings—follow local governance.
  • Hyaluronidase (ophthalmic blocks)
    • Facilitates spread through connective tissue, may improve akinesia, allergy possible.

Toxicity overview (systemic and local)

  • Local Anaesthetic Systemic Toxicity (LAST): CNS and cardiovascular toxicity due to high plasma levels (usually from intravascular injection or excessive dose).
  • CNS toxicity (often earlier than CVS, but may be masked under GA/sedation)
    • Early: circumoral numbness, metallic taste, tinnitus, dizziness, agitation, slurred speech.
    • Progression: seizures → CNS depression → coma/respiratory arrest.
  • Cardiovascular toxicity
    • Conduction block, arrhythmias, myocardial depression, hypotension, cardiac arrest, bupivacaine is particularly cardiotoxic (strong Na+ channel binding, slow dissociation).
  • Risk factors for LAST
    • Extremes of age, pregnancy, low muscle mass, hepatic dysfunction, cardiac failure/low flow, low plasma proteins, high vascular injection sites, large volumes, catheter top-ups, concomitant QT/pro-arrhythmic drugs.
  • Local/regional toxicity
    • Neurotoxicity: intraneural injection, high concentration exposure, transient neurological symptoms (TNS) classically with intrathecal lidocaine.
    • Myotoxicity: LA-induced muscle injury (usually reversible) with high concentrations/continuous infusions.
    • Chondrotoxicity: intra-articular LA infusions associated with chondrolysis (avoid continuous intra-articular infusions).
    • Methaemoglobinaemia: prilocaine (and benzocaine topical) → cyanosis with normal PaO2, treat with oxygen ± methylene blue if significant.

Prevention and management of LAST (exam framework)

  • Prevention
    • Use lowest effective dose, calculate mg/kg, consider lean body weight for very obese, reduce dose in frail/elderly/pregnancy/hepatic impairment.
    • Incremental injection with frequent aspiration, use ultrasound guidance, consider adrenaline test dose, avoid high-pressure injection, communicate symptoms in awake patient.
    • Monitoring: ECG, NIBP, SpO2 during and after large-volume blocks, observe for delayed toxicity (especially with long-acting agents).
  • Immediate management (structured)
    • Stop LA injection, call for help, maintain airway/oxygenation/ventilation (avoid hypoxia, hypercapnia, acidosis).
    • Treat seizures: benzodiazepine first-line, consider small-dose propofol if haemodynamically stable, avoid large propofol doses in cardiovascular compromise.
    • Start lipid emulsion therapy early when significant LAST suspected (seizures, arrhythmias, cardiovascular instability).
    • Cardiac arrest: follow modified ALS for LAST (high-quality CPR, avoid vasopressin, use lower-dose adrenaline, avoid lidocaine, amiodarone acceptable, consider early cardiopulmonary bypass/ECMO if refractory).
  • Principles
    • Dose limits vary by reference and clinical context, use conservative dosing, especially with large-volume blocks and catheters.
    • Adrenaline increases maximum recommended dose for some LAs by reducing systemic absorption (not a guarantee of safety).
  • Commonly quoted maxima (single-shot, healthy adult)
    • Lidocaine: 3 mg/kg (plain), 7 mg/kg with adrenaline.
    • Bupivacaine: 2 mg/kg (plain), ~3 mg/kg with adrenaline (varies).
    • Levobupivacaine: similar to bupivacaine (often quoted 2 mg/kg, check local).
    • Ropivacaine: often quoted 3 mg/kg (check local).
    • Prilocaine: 6 mg/kg (plain), 8 mg/kg with adrenaline, higher risk of methaemoglobinaemia at large doses.

Special situations

  • Pregnancy
    • Increased sensitivity to neuraxial LAs, reduced epidural space volume (engorged veins) → higher spread, reduced AAG → higher free fraction, consider dose reduction.
  • Paediatrics
    • Higher risk of toxicity due to dosing errors and lower protein binding in neonates/infants, calculate carefully, consider ultrasound and dilute solutions.
  • Hepatic/cardiac disease
    • Amide clearance reduced (liver disease, low hepatic blood flow), increased risk with infusions and repeated boluses.
  • Infection/inflamed tissue
    • Low pH reduces efficacy of infiltration, consider regional block proximal to infection or alternative analgesia/GA.

Test yourself…

Classify local anaesthetics and describe key differences between amides and esters.

Aim: show clear classification + metabolism + allergy implications.

  • Classes: amino-amides (lidocaine, bupivacaine, levobupivacaine, ropivacaine, prilocaine) vs amino-esters (chloroprocaine, procaine, tetracaine, benzocaine, cocaine).
  • Metabolism: amides mainly hepatic, esters mainly plasma cholinesterase → faster breakdown.
  • Allergy: true LA allergy rare, more associated with esters (PABA) and preservatives, consider preservative-free preparations if concern.
  • Clinical relevance: hepatic impairment/low cardiac output increases amide toxicity risk, pseudocholinesterase deficiency may prolong ester action.
Explain how pKa affects onset of action of local anaesthetics and what happens in infected tissue.

This is a common FRCA viva theme: Henderson–Hasselbalch applied clinically.

  • LAs are weak bases: unionised (B) crosses membranes, ionised (BH+) is the active channel-binding form intracellularly.
  • Lower pKa (closer to 7.4) → more unionised at physiological pH → faster onset (e.g. lidocaine faster than bupivacaine).
  • Infection/inflammation lowers tissue pH → shifts equilibrium to ionised form outside the nerve → reduced membrane penetration → slower onset and poorer block with infiltration.
  • Practical responses: block proximal to infection, consider buffering (where appropriate), or alternative anaesthesia/analgesia.
Describe the mechanism of action of local anaesthetics at the sodium channel, including use-dependence.

Examiners want the state-dependent binding concept and clinical implications.

  • Block voltage-gated Na+ channels from the intracellular side, reducing rate of depolarisation and preventing action potential propagation.
  • Preferential binding to open/inactivated channel states → use-/frequency-dependent block (more effective in rapidly firing nerves).
  • Unionised drug crosses membrane, ionised form binds receptor, both forms exist in equilibrium depending on pH and pKa.
What is differential blockade? Give the typical order of block and explain why it occurs.

Be cautious: the ‘order’ is a useful clinical rule but not absolute.

  • Differential block = different nerve fibre types/functions blocked at different times and concentrations.
  • Typical clinical sequence: sympathetic (vasodilation, warmth) → pain → temperature → touch → motor.
  • Reasons: fibre diameter, myelination, firing frequency, and anatomical arrangement, concentration and distance from injection site are key determinants.
List factors that influence systemic absorption and toxicity risk after a peripheral nerve block.

This is frequently examined in the context of LAST prevention.

  • Dose and concentration: total mg administered is critical.
  • Site vascularity: intercostal and paravertebral blocks have higher absorption than more distal limb blocks, subcutaneous is lowest.
  • Technique: inadvertent intravascular injection, lack of incremental dosing, high-pressure injection, catheter boluses.
  • Adjuncts: adrenaline reduces absorption and peak levels, not fully protective.
  • Patient factors: extremes of age, pregnancy, low AAG/albumin, hepatic/cardiac dysfunction, low muscle mass.
Outline the clinical features of LAST and how they may differ under GA or heavy sedation.

Examiners want recognition + the concept that CNS signs can be absent.

  • CNS: circumoral numbness, metallic taste, tinnitus, agitation → seizures → coma/respiratory arrest.
  • CVS: hypotension, conduction block, ventricular arrhythmias, myocardial depression, cardiac arrest (bupivacaine higher risk).
  • Under GA/sedation: early CNS symptoms may be masked, first sign may be sudden cardiovascular collapse or arrhythmia.
Describe a stepwise management plan for suspected LAST, including lipid emulsion therapy principles.

Give a structured answer: stop, oxygenate, treat seizures, lipid, modified ALS, escalate.

  • Stop LA injection, call for help, ABC approach with 100% oxygen, ventilate to avoid hypoxia/hypercapnia/acidosis.
  • Seizure control: benzodiazepine first-line, consider small-dose propofol only if stable, avoid large propofol doses in cardiovascular compromise.
  • Lipid emulsion: start early in significant toxicity (seizures, arrhythmias, hypotension). Follow local/national guideline dosing and continue with cardiovascular instability.
  • Cardiac arrest: high-quality CPR, modified ALS (lower-dose adrenaline, avoid vasopressin, avoid lidocaine, amiodarone acceptable), consider ECMO/CPB early if refractory.
  • Post-event: ICU monitoring, report/incident review, document total LA dose and timing, counsel patient.
Compare bupivacaine, levobupivacaine and ropivacaine in terms of potency, sensory vs motor block, and cardiotoxicity.

A classic pharmacology viva: stereochemistry and lipophilicity matter.

  • Bupivacaine: racemic, potent, long-acting, more cardiotoxic (strong Na+ channel binding, slow dissociation).
  • Levobupivacaine: S(-) enantiomer of bupivacaine, similar clinical duration/potency with reduced cardiotoxicity vs racemic bupivacaine.
  • Ropivacaine: S(-), less lipophilic than bupivacaine, tends to produce relatively less motor block at equipotent analgesic doses and has a better cardiotoxicity profile.
A patient becomes cyanosed after a large dose of prilocaine for a Bier’s block. SpO2 is ~85% and does not improve much with oxygen, PaO2 is normal. What is happening and how do you treat it?

This is a recurrent exam scenario: methaemoglobinaemia recognition and management.

  • Diagnosis: methaemoglobinaemia (oxidation of Hb iron to Fe3+), classically after prilocaine or benzocaine, causes saturation gap (low SpO2 with normal PaO2).
  • Clinical features: cyanosis, headache, dyspnoea, fatigue, severe levels can cause arrhythmias, seizures, coma.
  • Management: high-flow oxygen, confirm with co-oximetry (MetHb level), treat significant symptoms/high level with methylene blue (if not contraindicated, e.g. G6PD deficiency).
  • Stop causative agent and avoid re-exposure, consider alternative LAs for future (e.g. lidocaine).
What is the rationale for adding adrenaline to a local anaesthetic solution, and when might it be undesirable?

Examiners want benefits + limitations + cautions.

  • Benefits: vasoconstriction → reduced systemic absorption and peak plasma level, prolongs duration, may improve block density, intravascular marker (tachycardia).
  • Undesirable/caution: severe peripheral vascular disease, theoretical end-artery compromise, arrhythmias/ischaemic heart disease, interactions (e.g. cocaine, some antidepressants), poorly controlled hyperthyroidism.
  • Not a substitute for safe technique: incremental injection, aspiration, ultrasound guidance, dose calculation.
Why might a local anaesthetic block fail? Give a structured approach to troubleshooting.

Common OSCE/viva topic: show systematic thinking and patient safety.

  • Wrong target/anatomy variation: needle placement not near nerve/plane, inadequate spread, septae/fascial barriers.
  • Inadequate dose/volume/concentration, insufficient time for onset, drug error (wrong LA, wrong concentration, expired).
  • Physiology: acidosis/infection, poor tissue perfusion, high sympathetic tone/anxiety affecting assessment.
  • Troubleshoot: reassess dermatomes/nerve territories, confirm technique (US images, injection pressure), consider top-up/reblock, add systemic analgesia, have clear conversion-to-GA plan.

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