Local Anaesthetics

Classification

Esters(procaine, cocaine, benzocaine, tetracaine): plasma pseudocholinesterase hydrolysis — RAPID, short duration, PABA metabolite → allergic potential. Amides(lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine): hepatic CYP450 — SLOWER, longer duration, RARE true allergy. Mnemonic: “-i-” before “-caine” = amide(lidoca-i-ne).

Mechanism

Block voltage-gated Na+ channels from INTRACELLULAR side → prevent Na+ influx/AP rising phase → reversible sensory(then motor) loss.

Two-step requirement: cross membrane UNCHARGED → re-equilibrate to CHARGED form intracellularly to bind. Weak bases, pKa~physiological. → ↓effectiveness in infected/inflamed(acidic) tissue — acidic environment shifts more drug to charged/impermeant form → less crosses membrane (dental abscess harder to anaesthetize).

Use-dependence: binds preferentially to OPEN/INACTIVATED Na+ channels → rapidly-firing pain fibres accumulate more block than quiescent fibres. PLUS separate fibre-diameter effect: small/less-myelinated(Aδ,C = pain/temp) blocked at LOWER concentration than large/myelinated(Aα/Aβ = motor/proprioception). BOTH mechanisms contribute — don’t conflate into just one.

Added Vasoconstrictor (Adrenaline)

3 distinct reasons: (1)↓systemic absorption→↑duration (2)↓peak plasma conc→↓systemic toxicity (3)↓local bleeding→better surgical field. NEVER for digits/ears/nose/penis (end-arteries, no collateral supply) → ischaemic necrosis risk.

Systemic Toxicity

CNS toxicity FIRST (lower plasma conc than cardiac): perioral numbness/tingling, tinnitus, metallic taste, light-headedness(early, subjective) → visual disturbance, twitching → SEIZURES(higher conc) → then global depression(incl. respiratory) at even higher conc. Paradox: early seizures = preferential block of INHIBITORY cortical pathways before excitatory ones at lower conc.

Cardiovascular toxicity: Na+ block in myocardium → ↓conduction(wide QRS, arrhythmia) → high conc → myocardial depression/collapse. BUPIVACAINE = disproportionately cardiotoxic vs its CNS toxicity — “fast-in, slow-out” binding kinetics(slow dissociation from cardiac Na+ channels) → accumulates across beats → cardiac arrest with LITTLE preceding CNS warning, hard to resuscitate. IV LIPID EMULSION(“lipid rescue”) = specific antidote for bupivacaine/lipophilic LA cardiotoxicity(sequesters drug into expanded lipid phase, pulls from cardiac tissue).

Methaemoglobinaemia: specific to PRILOCAINE(+benzocaine) — metabolite(o-toluidine) oxidizes Fe2+→Fe3+ Hb → ↓O2 carriage. Rx: IV methylene blue(accelerates MetHb reduction via NADPH-MetHb reductase).

Allergy: genuinely more common with ESTERS(PABA=antigen). Reported “allergy” often actually vasovagal/adrenaline reaction, not true ester allergy. If genuine → switch to AMIDE(minimal cross-reactivity, different allergenic determinant).

Clinical Relevance

Ester/amide split directly predicts duration+allergy potential+which drug is safe after a reported reaction — not taxonomic trivia. Bupivacaine’s cardiotoxicity-before-CNS pattern is a DIRECT consequence of its binding kinetics, not arbitrary memorization — understanding WHY predicts that lipid rescue (not just standard ACLS) is the specific needed intervention.

Classification

By chemical linkage between the aromatic (lipophilic) end and the amine (hydrophilic) end of the molecule — this linkage determines the route of metabolism, which is itself the single most clinically important classification fact:

Esters: procaine, cocaine, benzocaine, tetracaine — metabolized by plasma pseudocholinesterase (rapid hydrolysis, short duration, and the source of para-aminobenzoic acid, PABA, a metabolite responsible for the class’s characteristic allergic potential).
Amides: lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine — metabolized hepatically (by CYP450 enzymes), slower than ester hydrolysis, longer duration, and genuinely rare true allergy (the “-i-” in the drug name before “-caine” is the traditional mnemonic for amides: lidoca-i-ne, bupivaca-i-ne).

Mechanism of Action

Local anaesthetics block voltage-gated Na⁺ channels from the intracellular side of the neuronal membrane, preventing the Na⁺ influx that generates the action potential’s rising phase — without an action potential, the impulse cannot propagate past the blocked segment, producing reversible loss of sensation (and, at higher concentrations, motor function) in the innervated area.

The molecule must first cross the neuronal membrane in its uncharged (non-ionized) form to reach its binding site on the internal face of the Na⁺ channel, then re-equilibrate to its charged form intracellularly to actually bind and block the channel — this two-step requirement (cross while uncharged, bind while charged) is why local anaesthetics are weak bases with a pKa near physiological pH, and why effectiveness in infected/inflamed tissue is reduced: the acidic environment of infected tissue shifts more of the drug into its charged, membrane-impermeant form, meaning less drug crosses the membrane to reach its intracellular binding site — a frequently tested, clinically real limitation (a dental abscess is harder to anaesthetize than intact tissue for exactly this reason).

Use-dependence (frequency-dependent block): local anaesthetics bind preferentially to Na⁺ channels in their open/inactivated state rather than the resting state, so rapidly firing neurons (pain fibres, which fire at high frequency) accumulate more block than quiescent ones — part of why sensory (particularly pain and temperature) fibres are blocked before motor fibres at a given local anaesthetic concentration, alongside the genuine anatomical fact that smaller-diameter, less-myelinated fibres (Aδ and C fibres carrying pain/temperature) are blocked at lower concentrations than larger, more heavily myelinated fibres (Aα/Aβ carrying motor/proprioception) — both a fibre-diameter effect and a use-dependence effect contribute to this differential block, and conflating “small fibres block first” with only one of the two mechanisms is a common incomplete answer.

Added Vasoconstrictors

Adrenaline (epinephrine) is commonly co-administered with a local anaesthetic (never with agents used for digit/appendage blocks — see below) for three genuinely distinct, all examinable reasons: (1) local vasoconstriction slows systemic absorption, prolonging the duration of local action; (2) the same reduced systemic absorption lowers peak plasma concentration and therefore systemic toxicity risk for a given local dose; (3) reduced local bleeding improves the surgical/procedural field. Adrenaline-containing local anaesthetic must never be used for digits, ears, nose, or penis (“end-arteries”/terminal circulation) — vasoconstriction in a vascular bed with no collateral supply can cause ischaemic necrosis, a specific, high-yield contraindication.

Adverse Effects and Systemic Toxicity

Systemic toxicity occurs when plasma concentration rises too high (accidental intravascular injection, exceeding maximum safe dose, or rapid absorption from a highly vascular injection site) and reflects the drug’s Na⁺-channel-blocking action extending beyond the local site to the CNS and cardiovascular system:

CNS toxicity (generally occurs at lower plasma concentrations than cardiac toxicity, i.e. CNS symptoms are usually the earlier warning): perioral numbness and tingling, tinnitus, metallic taste, and light-headedness first (early, subjective, easy to miss if not asked about) → progressing to visual disturbance, muscle twitching → generalized seizures at higher concentration. The paradox worth remembering: early excitatory CNS symptoms (seizures) occur because local anaesthetics preferentially block inhibitory cortical pathways before excitatory ones at lower concentrations — at higher concentrations, global CNS depression (including respiratory depression) follows.
Cardiovascular toxicity: Na⁺ channel blockade in the myocardium slows cardiac conduction (widened QRS, arrhythmia) and, at high concentration, causes myocardial depression and cardiovascular collapse. Bupivacaine is disproportionately cardiotoxic relative to its CNS toxicity compared with other amides (it binds cardiac Na⁺ channels with much slower dissociation kinetics — “fast-in, slow-out” — so it accumulates in the myocardium across successive beats), meaning cardiac arrest can occur with comparatively little preceding CNS warning, and resuscitation from bupivacaine-induced cardiac arrest is notoriously difficult (IV lipid emulsion (“lipid rescue”) is a specific, examinable resuscitation measure for bupivacaine — and other lipophilic local anaesthetic — cardiotoxicity, thought to work by sequestering the lipophilic drug into an expanded intravascular lipid phase, pulling it away from cardiac tissue).
Methaemoglobinaemia: specifically associated with prilocaine (and benzocaine) — a metabolite (o-toluidine for prilocaine) oxidizes haemoglobin’s iron from Fe²⁺ to Fe³⁺, impairing O2 carriage; treated with IV methylene blue, which accelerates methaemoglobin reduction back to haemoglobin via NADPH-methaemoglobin reductase.
Allergy: genuinely more common with esters (PABA metabolite is the antigenic culprit) — a patient reporting a prior “allergic reaction” to a dental local anaesthetic is more likely to have had a vasovagal or adrenaline-related reaction than a true ester allergy, but if genuine ester allergy is confirmed/suspected, switching to an amide is the appropriate response (cross-reactivity between the two classes is minimal to absent, since the allergenic determinant differs).

Clinical Relevance

The ester/amide split is not a taxonomic curiosity — it directly predicts duration of action, allergic potential, and even which drug is safe to reach for in a patient with a reported prior local anaesthetic reaction. Bupivacaine’s cardiotoxicity-before-CNS-toxicity pattern, specifically, is the kind of fact that looks like memorization but is actually a direct consequence of its distinctive Na⁺-channel binding kinetics — understanding why it’s disproportionately cardiotoxic (not just that it is) is what lets a student also predict that lipid rescue, not just standard ACLS, is the specific intervention needed.

Uncharged-vs-charged form crossing the neuronal membrane to reach the intracellular Na⁺ channel binding site, and why acidic/infected tissue reduces effectiveness.
Differential nerve fibre blockade by diameter/myelination (Aδ/C pain fibres blocked before Aα/Aβ motor fibres).
CNS-toxicity-before-cardiotoxicity concentration gradient, with bupivacaine’s disproportionate cardiotoxicity marked as an exception.