Local Anaesthetic Agents

Local anaesthetics (LAs) are drugs that produce reversible loss of sensation in a circumscribed region of the body by blocking voltage-gated sodium channels, without loss of consciousness. They are a relentlessly tested topic in NEET PG — classification, maximum safe doses, the sequence of fibre blockade, and the management of Local Anaesthetic Systemic Toxicity (LAST) with Intralipid appear almost every year.

Definition & Classification

A local anaesthetic is a chemical that reversibly blocks nerve conduction when applied locally, in a concentration that does not damage the nerve. Structurally every LA has three parts: an aromatic lipophilic group (benzene ring) + an intermediate chain (ester or amide linkage) + a hydrophilic amine group. The nature of the intermediate chain is the basis of classification.

Feature	Esters	Amides
Examples	Procaine, chloroprocaine, tetracaine (amethocaine), cocaine, benzocaine	Lignocaine (lidocaine), bupivacaine, ropivacaine, mepivacaine, prilocaine, dibucaine
Linkage	–COO– (ester)	–NHCO– (amide)
Metabolism	Plasma pseudocholinesterase (rapid)	Liver (CYP450, microsomal; slower)
Metabolite	PABA (para-aminobenzoic acid) → allergy	Not PABA → allergy rare
Allergy	Relatively common	Very rare
Stability	Unstable in solution	Heat stable
"i" rule	One "i" in the name (lidocaine is the exception → it is an amide)	Two "i"s in the name

High-yield: Mnemonic — amides have two "i"s in their name (lignocaine, bupivacaine, ropivacaine); esters have one. True allergy is far more common with esters because of the PABA metabolite. Cross-reactivity does NOT occur between the two groups.

High-yield: Cocaine is the only LA that causes vasoconstriction (blocks reuptake of noradrenaline). All other LAs cause vasodilatation (exception within amides: ropivacaine has intrinsic vasoconstrictor activity, mild).

Physicochemical Properties → Clinical Correlation

Three physicochemical properties map directly onto three clinical actions:

1. pKa → onset (speed). Only the unionised (lipid-soluble) form crosses the nerve membrane. The lower the pKa (closer to physiological pH 7.4), the larger the unionised fraction, the faster the onset. Lignocaine (pKa 7.7–7.9) acts faster than bupivacaine (pKa 8.1). Chloroprocaine has the fastest onset clinically (low pKa + high concentration used).
2. Lipid solubility → potency. More lipid-soluble = more potent. Bupivacaine, etidocaine, tetracaine are highly lipid-soluble and potent.
3. Protein binding → duration. Greater binding to the sodium channel protein = longer duration. Bupivacaine (~95% bound) lasts longer than lignocaine (~65%).

High-yield: Acidotic / infected tissue (abscess) lowers LA efficacy — the low pH keeps the drug ionised, so little crosses the membrane. This is why LA "doesn't work" in an abscess. Adding bicarbonate raises unionised fraction → faster onset.

LA	pKa	Onset	Potency	Duration	Max dose (plain)	Max dose (+ adrenaline)
Lignocaine	7.9	Fast	Intermediate	Intermediate	3 mg/kg	7 mg/kg
Bupivacaine	8.1	Slow	High	Long	2 mg/kg	3 mg/kg
Ropivacaine	8.1	Slow	High	Long	~3 mg/kg	~3.5 mg/kg
Prilocaine	7.9	Fast	Intermediate	Intermediate	6 mg/kg (highest)	8 mg/kg
Procaine	8.9	Slow	Low	Short	7 mg/kg	—
Chloroprocaine	9.0	Fastest	Low	Short	11 mg/kg	14 mg/kg

High-yield: Remember the lignocaine numbers cold — 3 mg/kg plain, 7 mg/kg with adrenaline. For a 50 kg adult that is ~150 mg plain. A 1% solution = 10 mg/mL, so 15 mL of plain 1% lignocaine. (1% = 10 mg/mL; 2% = 20 mg/mL; 0.5% = 5 mg/mL — know these conversions.)

Mechanism of Action — Sodium Channel Blockade

LAs bind to the voltage-gated sodium channel from the intracellular (cytoplasmic) side, at the inner vestibule/H-gate of the channel. Steps:

Unionised LA crosses the lipid membrane → re-ionises inside the axoplasm → the charged cation binds the inner pore of the Na⁺ channel → blocks Na⁺ influx → no depolarisation → conduction block.

Key mechanistic facts:

• LAs bind preferentially to channels in the open and inactivated states — hence use-dependent (phasic, frequency-dependent) block. Rapidly firing pain fibres are blocked more readily.
• The cation (ionised) form is the active blocking species at the receptor, but the unionised form is needed for membrane penetration — both forms matter.
• LAs raise the threshold for excitation, slow impulse conduction, reduce the rate of rise of the action potential, and ultimately abolish it — without changing the resting membrane potential.
• Benzocaine is an exception: being almost entirely unionised, it acts within the membrane.

Order (Sequence) of Nerve Fibre Blockade

Smaller and myelinated fibres are blocked before larger unmyelinated ones; clinically the modalities are lost in a characteristic order:

Autonomic (B fibres) → Pain & Temperature (Aδ, C) → Touch & Pressure → Proprioception → Motor (Aα) (last to be blocked, first to recover).

Fibre	Function	Susceptibility to block
B (preganglionic autonomic)	Sympathetic	Blocked first (most sensitive)
C (unmyelinated)	Pain (slow), temperature	Early
Aδ	Pain (fast), temperature	Early
Aγ	Muscle tone	Intermediate
Aβ	Touch, pressure	Later
Aα	Motor, proprioception	Blocked last

High-yield: Order of loss of sensation clinically: Pain → Temperature → Touch → Pressure → Motor. Autonomic (vasomotor) fibres are blocked first overall, explaining hypotension in spinal/epidural anaesthesia. Recovery is in reverse order.

Adjuvants and Their Logic

• Adrenaline (1:200,000 = 5 µg/mL): vasoconstriction → slows absorption → prolongs duration, reduces systemic toxicity, allows a higher maximum dose, provides a bloodless field, and acts as a marker of intravascular injection (tachycardia). Contraindicated in end-artery regions — fingers, toes, penis, nose, ear (pinna) — risk of ischaemic necrosis. (Modern evidence questions the absolute fingertip rule, but for exams: avoid in end-arteries.)
• Sodium bicarbonate: raises pH → more unionised drug → faster onset, less injection pain.
• Clonidine / dexmedetomidine, opioids, dexamethasone: prolong block in regional anaesthesia.

Specific Agents — Clinical Pearls

• Lignocaine: the prototype; also a Class Ib antiarrhythmic (ventricular arrhythmias). Available as jelly, spray, patch, IV. EMLA (Eutectic Mixture of Local Anaesthetics) = lignocaine 2.5% + prilocaine 2.5% — used for surface analgesia before venepuncture; applied ~60 min before.
• Bupivacaine: long-acting, most cardiotoxic LA. Avoid 0.75% bupivacaine in obstetrics (cardiac arrest reports). Highly protein-bound, so resistant to resuscitation once toxic.
• Levobupivacaine (S-enantiomer) and Ropivacaine: less cardiotoxic than racemic bupivacaine; ropivacaine produces relatively more sensory than motor block (good for labour epidural).
• Prilocaine: highest max dose; metabolite o-toluidine causes methaemoglobinaemia (dose >600 mg). Treat with methylene blue.
• Benzocaine: surface use; also causes methaemoglobinaemia.
• Cocaine: vasoconstrictor, used in ENT (nasal) surgery; causes sympathetic stimulation, hypertension, arrhythmias.
• Chloroprocaine: ester, rapid onset/short duration, very low systemic toxicity (fast plasma hydrolysis) — favoured in obstetrics and day-care.
• Tetracaine/amethocaine: potent ester for spinal/topical (ophthalmic).

Local Anaesthetic Systemic Toxicity (LAST)

Toxicity results from excessive plasma concentration — either accidental intravascular injection or absorption of an excess dose. Vascularity governs absorption rate:

Intercostal > Caudal > Epidural > Brachial plexus > Femoral/Sciatic > Subcutaneous (mnemonic "I Can't Even Be Funny — Subcutaneous" for descending absorption/peak plasma level).

CNS toxicity sequence (occurs before cardiac)

The CNS is more sensitive than the heart. Early excitation (block of inhibitory neurons) precedes later depression:

Circumoral/tongue numbness → lightheadedness, tinnitus → visual disturbance → muscle twitching → convulsions (tonic-clonic) → unconsciousness → coma → respiratory arrest.

Cardiac toxicity sequence

Hypertension & tachycardia (early) → myocardial depression, hypotension → conduction block, bradycardia, widened QRS → ventricular arrhythmias (VT/VF) → cardiovascular collapse / asystole.

High-yield: CNS toxicity appears before cardiovascular toxicity for most LAs — circumoral numbness and tinnitus are the earliest warning signs. The CC/CNS ratio (dose causing cardiovascular collapse vs convulsions) is low for bupivacaine (cardiac and CNS toxicity occur at nearly the same dose), making it the most dangerous; the ratio is high (safer) for lignocaine.

High-yield: Bupivacaine cardiotoxicity is hard to resuscitate because it binds Na⁺ channels avidly ("fast in, slow out") and is highly protein bound.

Management of LAST

1. Stop injection; call for help.
2. Airway — 100% oxygen, secure airway, prevent hypoxia/acidosis (which worsen toxicity).
3. Suppress seizures — benzodiazepines (midazolam) are first line; small-dose propofol if no lipid available (avoid large-dose propofol if cardiovascularly unstable).
4. Cardiopulmonary resuscitation if arrest — modified ACLS: avoid/reduce vasopressin, avoid calcium channel blockers, beta-blockers and further local anaesthetic; use small adrenaline boluses (≤1 µg/kg); amiodarone for ventricular arrhythmias (NOT lignocaine/procainamide).
5. Intralipid (lipid emulsion) rescue therapy — the definitive treatment.

High-yield (Intralipid / "Lipid Sink"): 20% lipid emulsion, bolus 1.5 mL/kg over ~1 min, then infusion 0.25 mL/kg/min. Repeat bolus 1–2 times and/or double the infusion rate if circulation not restored. Maximum ~10–12 mL/kg over the first 30 min. Mechanism — creates a lipid compartment that draws lipophilic LA away from the heart and brain ("lipid sink"), plus a cardiotonic/metabolic effect.

Methaemoglobinaemia

A specific complication of prilocaine (metabolite o-toluidine) and benzocaine. Presents with cyanosis unresponsive to oxygen, "chocolate-brown" blood, and a saturation gap (pulse oximeter often reads ~85%). Treatment: IV methylene blue 1–2 mg/kg.

Other Adverse Effects & Complications

• Allergy — esters (PABA) >> amides. May rarely be due to the preservative methylparaben.
• Transient Neurologic Symptoms (TNS) — back/leg pain after spinal, classically with lignocaine spinal anaesthesia.
• Cauda equina syndrome — high-dose/concentrated intrathecal lignocaine (microcatheters).
• Tissue/cardiac toxicity as above.

Key Differentials / Comparisons

Question stem clue	Answer
Fastest onset LA	Chloroprocaine
Most cardiotoxic LA	Bupivacaine
LA causing vasoconstriction	Cocaine
LA causing methaemoglobinaemia	Prilocaine, benzocaine
Most potent	Bupivacaine/tetracaine
Highest max safe dose	Prilocaine (6 mg/kg)
LA that is also antiarrhythmic	Lignocaine (Class Ib)
Earliest sign of toxicity	Circumoral numbness / tinnitus
Definitive Rx of LAST	20% Intralipid
LA safe in liver disease (ester)	Chloroprocaine

Recently asked / exam angle

• Intralipid dose and mechanism (lipid sink) — bolus 1.5 mL/kg of 20% emulsion — repeatedly asked single-best-answer.
• Order of nerve fibre block — "which is blocked first/last?" (B first, Aα motor last; pain before motor clinically).
• Maximum safe dose calculation — given body weight and % solution, calculate max volume (lignocaine 3 mg/kg plain, 7 with adrenaline). Know mg/mL conversions.
• Site of action of LA on Na⁺ channel — intracellular/inner pore, binds open & inactivated states (use-dependent block).
• Ester vs amide identification and metabolism (plasma esterase vs liver); PABA allergy.
• Adrenaline contraindicated in end-arteries (digits, penis, pinna).
• Bupivacaine 0.75% contraindicated in obstetrics; ropivacaine/levobupivacaine safer.
• EMLA composition (lignocaine + prilocaine) and methaemoglobinaemia treated with methylene blue.
• CC/CNS ratio low for bupivacaine — most dangerous.
• Effect of tissue pH/abscess on LA efficacy.

Rapid revision

1. Structure = aromatic ring + ester/amide link + amine; amides have two "i"s, esters one.
2. Esters → plasma pseudocholinesterase, metabolite PABA → allergy; amides → liver, allergy rare.
3. pKa → onset; lipid solubility → potency; protein binding → duration.
4. LAs block Na⁺ channels from inside, binding open/inactivated states → use-dependent block; resting potential unchanged.
5. Fibre block: B (autonomic) first → pain/temp → touch/pressure → motor (Aα) last; recovery reverse.
6. Lignocaine 3 mg/kg plain, 7 mg/kg with adrenaline; bupivacaine 2 → 3; prilocaine highest (6).
7. Cocaine = only vasoconstrictor LA; all others vasodilate.
8. Adrenaline prolongs block but is banned in end-arteries (fingers, toes, penis, ear, nose).
9. CNS toxicity precedes cardiac — circumoral numbness/tinnitus earliest; seizures then CVS collapse.
10. Bupivacaine = most cardiotoxic, low CC/CNS ratio, avoid 0.75% in obstetrics.
11. LAST treatment = 20% Intralipid 1.5 mL/kg bolus + 0.25 mL/kg/min; benzodiazepine for seizures; small-dose adrenaline; amiodarone not lignocaine.
12. Prilocaine/benzocaine → methaemoglobinaemia → methylene blue; EMLA = lignocaine + prilocaine; abscess (acidic) blunts LA action.