Overview of local anaesthetics

11 min read Last updated April 10, 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).

Maximum recommended doses (typical adult teaching values; always check local policy)

  • 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.
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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