Local Anaesthetics

Local anaesthetics (LAs) are drugs that reversibly block nerve conduction in a circumscribed region when applied locally, producing loss of sensation without loss of consciousness. They are a perennial favourite in NEET PG because they combine a clean mechanism (voltage-gated Na⁺ channel block), neat structure-based classification (ester vs amide), and high-yield clinical correlations (toxicity, adrenaline, differential blockade).

Definition & Basic Structure

A local anaesthetic is a membrane-stabilising drug that reversibly prevents generation and propagation of the nerve action potential by blocking voltage-gated sodium channels from the inner (cytoplasmic) side of the axonal membrane.

Every LA has three structural components:

1. Aromatic (lipophilic) group – usually a benzene ring; governs lipid solubility and hence potency.
2. Intermediate chain – an ester or amide linkage; this single bond decides classification, metabolism, and allergenic potential.
3. Tertiary amine (hydrophilic) group – a weak base that exists in ionised and unionised forms depending on pH; governs diffusibility and onset.

High-yield: The intermediate linkage (ester vs amide) is the single most-tested structural fact. Mnemonic — amides have two "i"s in the name (lignocaine, bupivacaine, prilocaine), esters have only one.

Classification

Feature	Ester group	Amide group
Examples	Cocaine, Procaine, Chloroprocaine, Benzocaine, Tetracaine (amethocaine)	Lignocaine (lidocaine), Bupivacaine, Levobupivacaine, Ropivacaine, Prilocaine, Mepivacaine, Dibucaine, Articaine
Metabolism	Plasma pseudocholinesterase (rapid)	Hepatic CYP450 (slower)
Metabolite	PABA (para-aminobenzoic acid)	Non-PABA
Allergy	More common (due to PABA)	Rare
Plasma half-life	Short	Longer
Stability	Less stable in solution	Heat stable, long shelf life

High-yield: Allergy and anaphylaxis are far more common with ester LAs because their metabolite PABA is antigenic. True amide allergy is rare and is usually due to the preservative methylparaben (which is metabolised to a PABA-like compound).

High-yield: Articaine is the odd amide — it contains a thiophene ring and also has an ester side-chain, so it is partly metabolised by plasma esterases, giving it a short half-life.

Mechanism of Action

LAs act on the voltage-gated Na⁺ channel (Nav):

Drug enters axon as unionised base → re-ionises inside cytoplasm → cationic form binds the α-subunit (domain IV S6) of the Nav channel from the inner mouth → blocks Na⁺ influx → no depolarisation → no action potential → conduction block.

Key concepts:

• LAs preferentially bind the channel in its open and inactivated states, not the resting state. Hence rapidly firing fibres are blocked preferentially — this is use-dependent (phasic / frequency-dependent) block. Greater the frequency of stimulation, greater the block.
• They raise the threshold for excitation and slow the rate of rise of the action potential without changing the resting membrane potential.
• The unionised (lipid-soluble) form crosses the membrane; the ionised (cationic) form is the active species that binds the receptor.

The pKa–onset relationship

All LAs are weak bases with pKa between 7.6 and 9.0. At physiological pH (7.4), the fraction present as unionised base determines how fast the drug penetrates the nerve.

High-yield: Lower pKa → more unionised drug at pH 7.4 → faster onset. Lignocaine (pKa 7.9) acts faster than bupivacaine/procaine (pKa ~8.1–8.9).

This also explains the classic clinical pearl:

High-yield: LAs fail to work in infected / inflamed (acidic) tissue because the low local pH traps the drug in its ionised form, leaving little unionised base to penetrate the nerve. Solution — give a regional/nerve block proximal to the inflamed area rather than local infiltration.

Determinants of LA properties

Property	Governed by
Potency	Lipid solubility (higher → more potent)
Onset of action	pKa (lower pKa → faster onset)
Duration of action	Protein binding (higher → longer duration) + vasoactivity

Bupivacaine is highly lipid-soluble and highly protein-bound → very potent and long-acting. Procaine is the opposite → weak, short-acting.

Differential Nerve Block (Order of Blockade)

Smaller and myelinated fibres are blocked before larger and unmyelinated ones. The clinically tested order in which function is lost:

Pain (and temperature) → temperature → touch → pressure → proprioception → motor power.

Functional order of blockade:

1. Autonomic (B & C fibres) — first, hence early vasodilation/hypotension in spinal anaesthesia.
2. Pain & temperature (Aδ and C).
3. Touch & pressure (Aβ).
4. Motor & proprioception (Aα) — blocked last, recover first.

High-yield: Order of loss = B > C > A (autonomic first). By fibre size, small myelinated fibres (Aδ, B) are the most susceptible; large myelinated motor fibres (Aα) are the most resistant. Recovery occurs in the reverse order.

Fibre	Function	Myelin	Susceptibility to block
B	Preganglionic autonomic	Yes (thin)	Most sensitive
C	Pain, temperature, postganglionic autonomic	No	Very sensitive
Aδ	Pain, temperature	Yes	Sensitive
Aβ	Touch, pressure	Yes	Intermediate
Aγ	Muscle spindle	Yes	Intermediate
Aα	Motor, proprioception	Yes (thick)	Most resistant

Role of Adrenaline (Vasoconstrictor)

Adding adrenaline (1:200,000, i.e. 5 µg/mL) to LA solutions is standard exam content.

Rationale:

• Local vasoconstriction → slows systemic absorption → prolongs duration of action.
• Reduces systemic toxicity by keeping the drug local.
• Reduces local bleeding (useful surgically) and provides a bloodless field.
• Allows a higher maximum safe dose.

High-yield: Adrenaline is contraindicated in LA used for end-arteries / acral parts — fingers, toes, penis, pinna of ear, tip of nose ("digits, ears, nose, penis" → rule of "extremities"), because vasoconstriction can cause ischaemic gangrene. Classic exam mnemonic: "Fingers, toes, ears, nose, penis (hose)."

High-yield: Adrenaline least prolongs the action of cocaine (already a vasoconstrictor) and bupivacaine (already very long-acting, highly protein-bound). It most usefully prolongs lignocaine and procaine.

Maximum Safe Doses (must memorise)

Drug	Without adrenaline	With adrenaline
Lignocaine	3 mg/kg (≈ 200–300 mg)	7 mg/kg (≈ 500 mg)
Bupivacaine	2 mg/kg	2–3 mg/kg
Procaine	~7–10 mg/kg	higher
Prilocaine	~6 mg/kg	~8 mg/kg

(1% solution = 10 mg/mL.)

Individual Agents — Key Points

• Cocaine — the only LA that is a vasoconstrictor (blocks reuptake of noradrenaline → sympathomimetic). Only LA causing mydriasis. Used historically for ENT/ophthalmic topical anaesthesia. Drug of abuse; causes euphoria, hypertension, arrhythmia, MI. Ester; the only naturally occurring LA.
• Lignocaine (lidocaine) — prototype amide; most versatile (topical, infiltration, nerve block, spinal, epidural, IV regional). Also a Class Ib antiarrhythmic for ventricular arrhythmias.
• Bupivacaine — long-acting; preferred for epidural/spinal in labour (sensory > motor block at low concentration). Most cardiotoxic LA — avid Na⁺ channel binding in cardiac tissue → refractory ventricular arrhythmias. Avoid IV regional (Bier's) block. Levobupivacaine/ropivacaine are less cardiotoxic (S-enantiomers).
• Procaine — first synthetic LA; short, weak, poor topical activity.
• Benzocaine — very low pKa, exists mostly as unionised base; used only topically (lozenges, ulcers). Classic cause of methaemoglobinaemia.
• Prilocaine — least toxic amide; metabolite o-toluidine causes methaemoglobinaemia. Component of EMLA.
• Tetracaine (amethocaine) — potent, long-acting ester for spinal/topical (eye).
• Dibucaine (cinchocaine) — most potent and most toxic; used in the dibucaine number test for atypical pseudocholinesterase.

High-yield: EMLA = Eutectic Mixture of Local Anaesthetics = lignocaine 2.5% + prilocaine 2.5%, applied to intact skin under occlusion for painless venepuncture. Risk → methaemoglobinaemia in infants.

Systemic Toxicity (LAST – Local Anaesthetic Systemic Toxicity)

Toxicity results from inadvertent intravascular injection or excess dose. Two systems dominate: CNS first, then cardiovascular.

CNS: circumoral numbness/tongue paraesthesia → metallic taste → tinnitus → light-headedness → visual disturbance → muscle twitching → convulsions → CNS depression, coma, respiratory arrest.

CVS (occurs at higher levels): the CNS is more sensitive than the heart, so cardiac toxicity is a late, ominous sign → hypotension, bradycardia, conduction block, ventricular arrhythmias, cardiac arrest.

High-yield: CNS toxicity precedes CVS toxicity (CNS is more sensitive). Earliest CNS symptom = circumoral/tongue numbness and tinnitus. Bupivacaine is the exception with cardiac collapse occurring close to seizures → the "CC/CNS ratio" is lowest for bupivacaine (cardiotoxic without much warning).

Management of LAST

Stop injection → ABC, 100% oxygen, secure airway → control seizures with benzodiazepines (midazolam/diazepam) → 20% lipid emulsion ("lipid rescue") bolus + infusion → manage arrhythmias (avoid lignocaine and vasopressin; use small adrenaline doses) → prolonged CPR / cardiopulmonary bypass if needed.

High-yield: 20% Intralipid (lipid emulsion) is the specific antidote for bupivacaine-induced cardiotoxicity ("lipid sink"). Bolus 1.5 mL/kg over 1 min, then infusion 0.25 mL/kg/min.

Other Important Adverse Effects

• Methaemoglobinaemia — benzocaine and prilocaine (and EMLA). Treat with IV methylene blue 1–2 mg/kg.
• Allergy / anaphylaxis — esters (PABA) >> amides.
• Transient neurological symptoms (TNS) and rarely cauda equina syndrome — classically with spinal lignocaine 5% (microcatheter pooling).
• Cardiovascular collapse — bupivacaine.
• Cocaine — sympathomimetic toxicity, arrhythmia, MI, perforated nasal septum.

Routes / Techniques of Regional Anaesthesia

Technique	Description / use
Surface (topical)	Mucous membranes, skin (EMLA, benzocaine, tetracaine)
Infiltration	Drug injected into tissue (suturing, minor surgery)
Field block	Subcutaneous injection encircling operative field
Nerve block	Around a nerve/plexus (e.g. brachial plexus, dental)
IV regional (Bier's block)	Limb exsanguinated, tourniquet, IV LA — lignocaine/prilocaine; never bupivacaine
Spinal (subarachnoid)	Into CSF; rapid dense block below umbilicus; hyperbaric bupivacaine/ lignocaine
Epidural	Into epidural space; labour analgesia, surgery

High-yield: Bier's block must use a short-acting amide (lignocaine/prilocaine) and never bupivacaine, because accidental tourniquet release → systemic bolus → fatal cardiac arrest.

High-yield: Spinal anaesthesia blocks autonomic (sympathetic) fibres first and highest — sympathetic level is ~2 segments above sensory, which is ~2 above motor — explaining hypotension and bradycardia (high block reaching cardiac accelerator fibres T1–T4).

Key Differentials / Compare-Contrast

• Ester vs amide — allergy, metabolism, the "two-i" rule (see table above).
• Lignocaine vs bupivacaine — onset (lignocaine faster, lower pKa), duration (bupivacaine longer), cardiotoxicity (bupivacaine worst), antiarrhythmic use (lignocaine).
• Methaemoglobinaemia culprits — prilocaine & benzocaine vs others.
• Cocaine — the only vasoconstrictor and only mydriatic LA, distinguishing it from all others.

Recently asked / exam angle

• Mechanism & site: LAs block Na⁺ channels from the intracellular side; the ionised cationic form is active but the unionised form penetrates the membrane. Frequently framed as "active form vs penetrating form."
• Order of nerve block: Repeatedly asked — autonomic/pain lost first, motor last. "Which sensation is lost first?" → pain & temperature.
• pKa & inflamed tissue: "Why do LAs fail in an abscess?" → acidic pH ionises the drug.
• Adrenaline contraindication: end-arteries (fingers, penis, etc.) — image/clinical vignettes.
• Maximum safe dose of lignocaine: 3 mg/kg plain, 7 mg/kg with adrenaline — a recurrent numerical.
• Bupivacaine cardiotoxicity + Intralipid antidote — modern favourite.
• Methaemoglobinaemia — prilocaine/benzocaine/EMLA; antidote methylene blue.
• Cocaine as the only vasoconstrictor LA and only LA causing mydriasis.
• EMLA composition (lignocaine + prilocaine).
• Articaine thiophene ring / dual metabolism — newer pattern question.

Rapid revision

1. Amides = two "i"s (lignocaine, bupivacaine, prilocaine); esters metabolised by plasma cholinesterase → PABA → allergy.
2. LAs block voltage-gated Na⁺ channels from inside; use-dependent block of rapidly firing fibres.
3. Unionised base penetrates; ionised cation binds the channel.
4. Potency ∝ lipid solubility; onset ∝ low pKa; duration ∝ protein binding.
5. LAs fail in infected/acidic tissue (drug trapped ionised).
6. Order of block: autonomic (B) → pain/temp (C, Aδ) → touch/pressure → motor last; recovery reverse.
7. Adrenaline prolongs action, reduces toxicity; never in fingers, toes, ears, nose, penis.
8. Lignocaine max dose: 3 mg/kg plain, 7 mg/kg with adrenaline.
9. Bupivacaine = most cardiotoxic; antidote 20% Intralipid; never use in Bier's block.
10. Prilocaine & benzocaine (EMLA) → methaemoglobinaemia; treat with methylene blue.
11. Cocaine = only vasoconstrictor & only mydriatic LA; sympathomimetic; ester.
12. CNS toxicity precedes CVS — earliest sign circumoral numbness + tinnitus; bupivacaine is the dangerous exception.