Anaes · Local anaesthetic pharmacology

Local anaesthetic chemistry: amide and ester

Also known as Amide vs ester local anaesthetics · Local anaesthetic structure-activity · Voltage-gated sodium channel blockers

Local anaesthetics reversibly block nerve conduction by inhibiting voltage-gated sodium channels in a use-dependent fashion, and every agent shares a three-part structure (a lipophilic aromatic ring, an ester or amide linkage, and a hydrophilic tertiary amine) that classifies it as an ESTER (cocaine, procaine, chloroprocaine, amethocaine), metabolised by plasma cholinesterases to para-aminobenzoate (PABA) and so carrying a higher allergy risk, or an AMIDE (lidocaine, bupivacaine, ropivacaine, prilocaine), metabolised by hepatic CYP450 enzymes with rare true allergy. They are weak bases (pKa about 7.6 to 8.9): the un-ionised lipid-soluble form crosses the nerve membrane and the ionised form binds the channel from inside, so onset depends on pKa and tissue pH and is reduced in inflamed or acidotic tissue (ion trapping). Potency tracks lipid solubility and duration tracks protein binding, so bupivacaine is potent and long-acting while lidocaine has a faster onset. Small myelinated and unmyelinated sensory fibres block before large motor fibres, and adrenaline prolongs duration (but must be avoided in end-arterial territories). These fundamentals are reinforced by the recent reviews of Galata (2026) on LA hypersensitivity, Little (2026) on local-only anaesthesia, Copur (2026) on LA dosing, Ogu (2026) on bupivacaine formulation, Chooklin (2026) on LA clinical use and de Souza (2026) on regional analgesia adjuvants.