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Local Anaesthetics: Complete Reference

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1. CHEMICAL STRUCTURE

Classification by intermediate linkage

• Cocaine, Procaine, Chloroprocaine, Tetracaine, Benzocaine

• Lidocaine, Bupivacaine, Ropivacaine, Levobupivacaine, Mepivacaine, Prilocaine, Articaine

Memory trick: Amides have two "i"s in their names (lIdocaIne, bupIvacaIne, ropIvacaIne, etc.)

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2. PHYSIOLOGY OF NERVE CONDUCTION

Voltage-Gated Sodium Channel Structure

• S4 segments - voltage sensors (positively charged amino acids every third position); move outward on depolarisation to open the channel
• S5-S6 loop (P region) - forms the ion selectivity filter and narrow pore
• D-III to D-IV intracellular loop - the fast inactivation gate (contains the IFM triplet: isoleucine-phenylalanine-methionine)

Channel States

1. Resting (closed) - at negative resting membrane potential
2. Open (activated) - on depolarisation; Na+ floods in
3. Inactivated (fast-inactivated) - a few milliseconds after opening; gate closes; cannot reopen until membrane repolarises

Nerve Fibre Classification (relevant to differential blockade)

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3. MECHANISM OF ACTION

Two Pathways of Access

1. Hydrophilic pathway - the charged (protonated, BH+) form enters the channel through the open intracellular gate
2. Hydrophobic pathway - the uncharged (free base, B) form partitions into and through the lipid membrane to access the receptor from within

pH and the Importance of pKa

• uncharged form (B) - crosses the nerve membrane (lipid-soluble), gets access to the channel interior
• charged form (BH+) - is the active form that binds the Na+ channel receptor

Use-Dependent (Phasic) Block

Differential Blockade

1. Autonomic (B fibres) - first
2. Cold/temperature (Aδ and C)
3. Warmth
4. Sharp pain (Aδ)
5. Touch/pressure (Aβ)
6. Deep pressure
7. Motor function (Aα) - last

Critical Length Concept

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4. PHYSICOCHEMICAL PROPERTIES & THEIR CLINICAL RELEVANCE

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5. INDIVIDUAL DRUG PROFILES

AMINOAMIDES

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Lidocaine (Lignocaine)

• Class: Aminoamide (aminoethylamide)
• pKa: 7.9 | Protein binding: 65% | Lipid solubility: Intermediate
• Onset: Fast | Duration: Intermediate (1-2 hours; up to 3-4 hrs with epinephrine)
• Max dose: 3 mg/kg plain; 7 mg/kg with epinephrine
• Metabolism: Hepatic CYP enzymes → monoethylglycine xylidide (MEGX) and glycine xylidide - both retain some LA activity; ~75% eventually excreted as 4-hydroxy-2,6-dimethylaniline

• Prototypical amide local anaesthetic
• Produces faster, more intense, longer-lasting anaesthesia than equal concentrations of procaine
• Also used as Class Ib antiarrhythmic (IV for ventricular arrhythmias)
• Available as patch (postherpetic neuralgia), EMLA (50:50 with prilocaine for topical use), gel, spray, solution
• Epidural: should be used with epinephrine as plain lidocaine does not consistently provide surgical anaesthesia
• Spinal: used for short procedures (T4 block with ~100 mg)
• Toxicity progression with increasing dose: drowsiness → tinnitus → dysgeusia → dizziness → twitching → seizures → coma → respiratory arrest → cardiovascular depression

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Bupivacaine

• Class: Aminoamide (butyl piperidine group)
• pKa: 8.1 | Protein binding: 95% | Lipid solubility: High
• Onset: Slow | Duration: Long (3-10 hours)
• Max dose: 2 mg/kg plain; 3 mg/kg with epinephrine (NEVER 0.75% in obstetrics)
• Metabolism: Hepatic CYP3A4 → pipecolylxylidine → glucuronidated and excreted

• Long-acting workhorse for regional anaesthesia and epidural analgesia in labour
• Tends to produce more sensory than motor block at lower concentrations - ideal for labour epidurals (0.0625-0.1%)
• Absorbed more slowly than lidocaine but plasma levels fall more slowly after stopping an infusion
• Cardiotoxicity - the major concern: causes severe ventricular arrhythmias and myocardial depression after intravascular injection. Mechanism: bupivacaine blocks cardiac Na+ channels rapidly during systole but dissociates very slowly during diastole (unlike lidocaine which dissociates quickly). Block is therefore cumulative at physiological heart rates. Some cardiac toxicity may be centrally mediated (injection into medulla produces arrhythmias)
• Cardiotoxicity worsened by acidosis, hypercapnia, and hypoxaemia
• 0.75% concentration contraindicated in obstetrics (FDA warning) due to cardiac arrest risk
• Liposomal bupivacaine (Exparel) - FDA-approved; provides extended release, but clinical superiority over standard bupivacaine not yet conclusively established
• Spinal: used for intermediate-to-long procedures (T4 block with ~20 mg)

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Ropivacaine

• Class: Aminoamide (S-enantiomer, propyl group)
• pKa: 8.1 | Protein binding: 94% | Lipid solubility: Intermediate (less than bupivacaine)
• Onset: Similar to bupivacaine | Duration: Long
• Max dose: 3 mg/kg

• Pure S-enantiomer - the S-form is less cardiotoxic than the racemate
• Intrinsically less lipid-soluble than bupivacaine → less potent but with a better safety profile
• Produces profound sensory block with less motor blockade than bupivacaine at equivalent concentrations - preferred for labour epidurals and postoperative infusions when motor sparing is desired
• Less cardiotoxic and CNS-toxic than bupivacaine
• Causes vasoconstriction (unlike most other LAs) → may reduce the need for epinephrine

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Levobupivacaine

• Class: Aminoamide (S-enantiomer of bupivacaine)
• Essentially bupivacaine but as pure S-(-) enantiomer
• Less cardiotoxic and less CNS-toxic than racemic bupivacaine
• Similar clinical profile to ropivacaine - considered safer alternative to bupivacaine
• Available in UK and Europe; not separately approved in the US

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Mepivacaine

• Class: Aminoamide
• pKa: 7.6 | Protein binding: 75% | Duration: Intermediate
• Max dose: 5 mg/kg plain; 7 mg/kg with epinephrine

• Intermediate duration; slightly faster onset than lidocaine
• Does NOT cause vasodilation (unlike lidocaine) → can be used without epinephrine for dental anaesthesia
• Epinephrine prolongs its block minimally compared to lidocaine
• Not suitable for epidural or spinal in obstetrics - neonates poorly metabolise it (long half-life in neonates)
• Used frequently in dental practice

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Prilocaine

• Class: Aminoamide
• pKa: 7.9 | Protein binding: 55% | Duration: Intermediate
• Max dose: 6 mg/kg plain; 8.5 mg/kg with epinephrine (HIGHEST safe dose among amides)

• Lowest systemic toxicity among the amide LAs (high Vd, rapid tissue metabolism)
• Component of EMLA cream (2.5% lidocaine + 2.5% prilocaine) for topical anaesthesia prior to venipuncture, skin grafts, genital procedures
• Unique toxicity: Methaemoglobinaemia - prilocaine is metabolised to orthotoluidine, which oxidises haemoglobin to methaemoglobin (Fe3+). This becomes clinically significant at doses >600 mg. Treat with IV methylene blue 1-2 mg/kg
• Contraindicated in conditions with pre-existing methaemoglobinaemia, G6PD deficiency
• Not used for spinal anaesthesia (associated with transient neurological symptoms)

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Articaine (Carticaine)

• Class: Aminoamide with a thiophene ring (instead of benzene) - structurally unique; also contains an ester group metabolised by plasma esterases
• Duration: Intermediate
• Max dose: 7 mg/kg

• The only amide that is also partially hydrolysed by plasma esterases (through its ester side chain) → shorter half-life
• Extremely popular in dentistry - penetrates bone better than lidocaine
• Available as 4% solution with 1:100,000 or 1:200,000 epinephrine
• Highest concentration of any dental LA (4%)
• May have a slightly higher risk of paraesthesia/nerve injury when used for inferior alveolar nerve blocks

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AMINOESTERS

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Procaine (Novocaine)

• Class: Aminoester (the original LA)
• pKa: 9.1 | Protein binding: Low | Duration: Short
• Metabolism: Plasma pseudocholinesterase → PABA (para-aminobenzoic acid)
• Max dose: 14 mg/kg plain; 14 mg/kg with epinephrine

• Historical significance - first synthetic LA (1905)
• Short acting, slow onset, low potency - largely replaced by lidocaine
• PABA metabolite is responsible for allergic reactions to ester LAs
• Still used for spinal anaesthesia in some countries
• Vasodilatory; patients sensitive to ester LAs (PABA allergy) should receive amide LAs instead
• Patients with pseudocholinesterase deficiency cannot metabolise esters efficiently → prolonged action and toxicity

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Chloroprocaine

• Class: Aminoester
• pKa: 9.1 | Duration: Very short (30-60 min)
• Fastest onset of all LAs due to very rapid hydrolysis generating large concentration gradient
• Used primarily for epidural anaesthesia when short duration is desired (e.g., outpatient procedures)
• Historically: associated with neurotoxicity in spinal use (contained sodium bisulphite preservative) - newer preservative-free formulations are safe for intrathecal use
• Can inhibit subsequent epidural opiate analgesia (antagonises opioid binding)

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Tetracaine (Amethocaine)

• Class: Aminoester
• pKa: 8.5 | Protein binding: High | Duration: Long (2-5 hours)
• Significantly more potent and toxic than procaine

• Used for spinal anaesthesia for long procedures (T4 block with ~12 mg); epinephrine greatly prolongs its effect
• Topical anaesthesia - eye drops (ophthalmic), throat/airway
• AMETOP gel (4% tetracaine) - topical skin anaesthetic for venipuncture in children (UK); faster onset than EMLA but cannot be used near eyes
• Highly cardiotoxic systemically - not suitable for nerve blocks

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Cocaine

• Class: Aminoester (naturally occurring - unique)
• Unique properties: The ONLY local anaesthetic that is also a vasoconstrictor (blocks norepinephrine reuptake transporter, NET)
• The ONLY LA that causes mydriasis and sensitises tissues to catecholamines
• Used as 4-10% topical solution for ENT procedures (nose and throat) - combines anaesthesia + vasoconstriction + shrinking of mucosa
• Schedule II controlled substance
• Euphoria due to inhibition of dopamine reuptake in CNS
• Systemic toxicity: HTN, tachycardia, coronary vasospasm, ventricular arrhythmias, stroke
• NOT suitable for injection (only topical use in current medicine)

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Benzocaine

• Class: Aminoester
• Very low water solubility - does not form a salt at physiological pH → exists mainly as uncharged base
• Used exclusively for topical anaesthesia (gels, sprays, lozenges, otic drops)
• Can cause methaemoglobinaemia with excessive use of sprays (particularly 20% benzocaine spray) - especially in patients with G6PD deficiency

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6. ADDITIVES TO LOCAL ANAESTHETICS

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7. PHARMACOKINETICS

Systemic Absorption (rate from highest to lowest)

Distribution

• LAs bind extensively to plasma proteins (particularly alpha-1-acid glycoprotein, AGP)
• AGP is an acute-phase reactant - elevated in post-surgical, post-MI, and inflammatory states → more protein-bound drug → less free drug available for toxicity (protective)
• Crosses blood-brain barrier and placenta

Metabolism

• Esters: Rapid hydrolysis by plasma pseudocholinesterase (and liver esterases) → PABA (allergenic metabolite)
• Amides: Hepatic CYP metabolism (lidocaine: CYP1A2, CYP3A4; bupivacaine: CYP3A4)
• Patients with severe hepatic disease or reduced hepatic blood flow (heart failure, beta-blockers): reduced clearance of amides → risk of accumulation

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8. LOCAL ANAESTHETIC SYSTEMIC TOXICITY (LAST)

Causes

• Inadvertent intravascular injection (most common)
• Excessive total dose absorbed from injection site
• Impaired clearance

Clinical Presentation (dose-dependent, CNS before CVS usually)

• Circumoral/tongue numbness
• Tinnitus, dysgeusia (metallic taste)
• Dizziness, visual disturbances
• Agitation, confusion
• Twitching, tremors → Tonic-clonic seizures
• CNS depression, respiratory arrest

• Hypertension and tachycardia (early, due to sympathomimetic effect)
• PR prolongation, QRS widening
• Severe bradycardia, heart block
• Ventricular fibrillation / pulseless VT
• Cardiovascular collapse

Key point: Bupivacaine can cause CV collapse with minimal CNS warning. Ropivacaine/levobupivacaine are safer in this regard.

Treatment of LAST (ASRA Guidelines)

1. Stop injecting LA immediately
2. Call for help; get lipid emulsion
3. Airway management - 100% O2; intubation if needed; avoid hypercapnia/acidosis (worsens toxicity by increasing free drug fraction and decreasing protein binding)
4. Seizures: Benzodiazepines preferred; propofol and thiopental acceptable but use with caution (may worsen cardiovascular depression); avoid succinylcholine (masks seizures without treating them)
5. Cardiac arrest: ACLS; adrenaline in small doses (1 mcg/kg); avoid vasopressin; avoid calcium channel blockers, beta-blockers
6. Intravenous Lipid Emulsion (20% Intralipid):
   • Bolus: 1.5 mL/kg over 1 minute
   • Infusion: 0.25 mL/kg/min; continue for at least 10 minutes after cardiovascular stability achieved
   • Max: ~10 mL/kg
   • Mechanism: "lipid sink" - creates a separate lipid phase in blood that sequesters lipid-soluble LA molecules away from tissues
7. Cardiopulmonary bypass if refractory (centre should be notified early)

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9. OTHER TOXICITIES

Neural Toxicity

• Transient Neurological Symptoms (TNS): Backache + pain radiating to buttocks/legs within 24 hours of spinal anaesthesia, resolving within days. Most common with intrathecal lidocaine (5-30% incidence), especially in the lithotomy position. Also seen with chloroprocaine, mepivacaine. Rare with bupivacaine, ropivacaine, levobupivacaine, prilocaine.
• Cauda Equina Syndrome: Permanent neurological deficit after continuous spinal with hyperbaric 5% lidocaine in microcatheters (now withdrawn). Due to pooling of hyperbaric LA around sacral roots.

Allergic Reactions

• True allergy is rare and almost exclusively caused by ester LAs (due to PABA metabolite)
• Amide LA allergy is extremely rare - reactions more often due to preservatives (methylparaben, a PABA derivative)
• Cross-reactivity between esters and amides does NOT occur clinically
• Patients allergic to esters can safely receive amides

Specific Drug Toxicities

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10. QUICK COMPARISON TABLE

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