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Local Anaesthetic Agents - Complete Study Guide

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Overview

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1. Chemistry and Classification

The LA Molecule

• Aromatic ring (lipophilic end, gives membrane affinity)
• Intermediate chain - either an ester (-COO-) or amide (-NHCO-) linkage
• Tertiary amine (hydrophilic end, partly protonated at physiologic pH)

Two Major Classes

Physicochemical Properties to Know

• pKa: Determines onset speed. Lower pKa = more unionised drug at pH 7.4 = faster onset (e.g. lidocaine pKa 7.7, chloroprocaine pKa 8.7)
• Lipid solubility: Determines potency. More lipophilic = more potent (bupivacaine > lidocaine > procaine)
• Protein binding: Determines duration. Higher protein binding = longer duration (bupivacaine ~95% protein bound)
• pKa, lipid solubility, and protein binding are the three pillars of structure-activity relationships

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2. Mechanism of Action

Physiology of Nerve Conduction (prerequisite)

• Resting membrane potential: -60 to -90 mV
• Na+/K+ ATPase maintains the gradient
• Action potential is driven by rapid Na+ influx through voltage-gated Na+ channels (VGNCs)

How LAs Work (step by step)

1. LA deposited near the nerve diffuses through the nerve sheath
2. Unionised (base) form crosses the axonal membrane
3. Inside the axoplasm, at lower pH, the drug re-ionises to the cationic (charged) form
4. The cationic form binds to the intracellular face of voltage-gated Na+ channels
5. This blocks channel opening (prevents activation/depolarisation)
6. No action potential = no nerve conduction = anaesthesia

Key Concepts

• Tonic (resting) block: Drug binds when channel is in resting state
• Phasic (use-dependent) block: Repeated stimulation allows more drug to enter open channels; block deepens with activity
• Ion trapping: In infected/inflamed tissue (acidic pH), more drug stays ionised outside the cell and cannot cross the membrane - this is why LAs work poorly in infected tissue

Na+ Channel Isoforms

• Nav1.7, Nav1.8, Nav1.9 are key neuronal isoforms - mutations lead to congenital pain insensitivity or erythromelalgia (clinically relevant)

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3. Differential Nerve Block (Order of Block)

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4. Clinical Pharmacology

Factors Affecting LA Activity in Practice

Vasoconstrictors as Additives

• Epinephrine (most common): 1:200,000 concentration; prolongs block, reduces peak plasma concentration
• Clonidine/Dexmedetomidine: Alpha-2 agonists, prolong block
• Dexamethasone: Prolongs duration (mechanism: anti-inflammatory + direct neuronal effect)
• Buprenorphine: Opioid additive, prolongs analgesia

Specific Drugs to Know

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5. Routes and Types of Regional Anaesthesia

• Infiltration anaesthesia: Subcutaneous injection at the surgical site
• Topical/surface anaesthesia: EMLA cream (lidocaine + prilocaine), throat spray
• Nerve block: Single nerve (ulnar, radial) or major plexus (brachial plexus)
• IV Regional Anaesthesia (Bier's block): IV LA into exsanguinated, tourniquet-isolated limb; lidocaine used
• Spinal (intrathecal) anaesthesia: Injected into CSF (subarachnoid space); bupivacaine/tetracaine
• Epidural anaesthesia: Injected into epidural space; bupivacaine/ropivacaine
• Tumescent anaesthesia: Large volumes of dilute LA + epinephrine + NaHCO3 (used in liposuction)

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6. Pharmacokinetics

• Absorption: Depends on site, vascularity, drug properties, and use of vasoconstrictors. Order: IV > tracheal > intercostal > caudal > epidural > brachial plexus > subcutaneous
• Distribution: Highly bound to alpha-1-acid glycoprotein (AAG) and albumin in plasma
• Metabolism:
  • Esters: Rapid hydrolysis by plasma pseudocholinesterase (to PABA in some)
  • Amides: Hepatic cytochrome P450 (slower; accumulate in liver disease)
• Excretion: Renal (metabolites)

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7. Toxicity (High-Yield!)

Systemic Toxicity (LAST - Local Anaesthetic Systemic Toxicity)

• Early: perioral tingling, metallic taste, tinnitus, lightheadedness, visual/auditory disturbance
• Progressive: disorientation, drowsiness, muscular twitching
• Severe: tonic-clonic seizures
• Very severe: CNS depression, respiratory arrest

• Myocardial depression, bradycardia, conduction block
• Hypotension, ventricular arrhythmias, cardiac arrest
• Bupivacaine is the most cardiotoxic - causes "3 Cs": reentrant arrhythmias, cardiac depression, cardiovascular collapse
• Bupivacaine cardiotoxicity difficult to treat; may require Intralipid (lipid emulsion rescue)

• Stop injection, call for help
• Airway/O2/ventilation (prevent acidosis - worsens toxicity)
• Benzodiazepine or propofol for seizures
• 20% Intralipid emulsion IV (lipid sink - sequesters LA from cardiac tissue)
• CPR if needed; avoid vasopressin and Ca2+ channel blockers

Specific Adverse Effects

Local Tissue Toxicity

• All LAs are neurotoxic at high concentrations in direct contact with nerve (transient neurological symptoms with spinal lidocaine)
• Myotoxicity possible with direct muscle injection

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8. Special Topics

Chiral LAs

• Bupivacaine is a racemic mixture (R+S enantiomers)
• Ropivacaine and levobupivacaine are pure S(-) enantiomers
• S-enantiomers have lower cardiac toxicity than the R(+) form
• This is the basis for preferring ropivacaine/levobupivacaine over bupivacaine when prolonged block is needed

Why LAs Fail in Infection

• Infected tissue is acidic (low pH)
• At low pH, more drug remains in ionised (cationic) form
• Ionised form cannot cross the lipid membrane to reach the binding site
• Result: poor block

Cocaine - Unique Properties

• The only LA that causes vasoconstriction (blocks norepinephrine reuptake)
• Used in ENT (nasal surgeries) as both LA + vasoconstrictor
• Has abuse potential; not used for injection anaesthesia

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9. Key High-Yield One-Liners to Memorise

1. LAs block Na+ channels from the inside (intracellular face) in the ionised form
2. They cross membranes in the unionised (base) form
3. Lower pKa = faster onset
4. Higher lipid solubility = greater potency
5. Higher protein binding = longer duration
6. Esters metabolised by plasma cholinesterase; amides by liver
7. Prilocaine causes methemoglobinemia
8. Bupivacaine has the highest cardiotoxicity
9. Treat LAST with 20% intralipid
10. Epinephrine prolongs block by local vasoconstriction (reduces vascular absorption)
11. LAs fail in infection because of ion trapping
12. Differential block order: pain first, motor last

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10. Likely Exam Questions (Semester 4 Level)

• Classify local anaesthetics with examples
• Mechanism of action of local anaesthetics
• Differences between ester and amide local anaesthetics
• Factors determining onset, potency, and duration
• Why does adrenaline prolong local anaesthesia?
• Why do LAs fail in infected tissue?
• Systemic toxicity of local anaesthetics - signs and management
• Methemoglobinemia - which drugs cause it and how is it treated?
• Bupivacaine vs. lidocaine - comparison
• Cocaine - unique pharmacological properties
• Order of nerve fibre susceptibility to LAs

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