Procaine, Tetracaine and Benzocaine

Mechanism

Mechanism of action

Local anesthetics prevent the generation and conduction of the axonal action potential by physically blocking the voltage-gated sodium channels (Na_v1.5, Na_v1.7, Na_v1.8) inside the cell pore.

To bind actively, the molecule must pass through the lipid bilayer of the axon in its neutral, non-ionized form (free base). Once in the acidic axoplasmic cell cytoplasm, it again acquires a hydrogen proton to become its positively charged soluble ionized cationic form, which binds reversibly to the receptor located in the pore S6 subunit of the sodium channel, blocking the massive entry of sodium and stabilizing the membrane potential.

This ionization balance according to the Henderson-Hasselbalch law explains why in inflamed tissues with extreme local acidosis (such as an abscess, pH ≈ 6.0), the fraction of free neutral free base decreases drastically, drastically reducing the axonal penetration capacity of the anesthetic and its local clinical efficacy.

Benzocaine and Acquired Methemoglobinemia

Benzocaine is an ester-type anesthetic widely used in sprays for topical application to the pharyngeal mucosa prior to diagnostic endoscopies. Its metabolism generates oxidative metabolites of the amino group that have the ability to oxidize the ferrous iron (Fe²⁺) of the hemoglobin molecules of red blood cells to its inactive ferric state (Fe³⁺), forming methemoglobin. Methemoglobin is unable to transport oxygen reversibly and shifts the hemoglobin dissociation curve to the left, inducing severe tissue hypoxia that is not reversed with normal supplemental oxygen. Rescue treatment: Methylene Blue (1 - 2 mg/kg IV at 1%).

Clinical

Clinical Characteristics and Use

• Procaine: Low potency and short duration (30 - 45 minutes). Its main metabolite, para-aminobenzoic acid (PABA), has a high allergenic potential, explaining the high incidence of historically associated anaphylactic reactions.
• Tetracaine: High potency and long duration. Of wide historical use for hyperbaric spinal anesthesia in combination with glucose solutions.
• Metabolism: Hydrolyzed quickly and immediately by the enzyme plasma cholinesterase (pseudocholinesterase), which drastically limits its bioavailability and reduces the risk of direct systemic toxicity due to accumulation.