Esters
Ester local anesthetics are metabolized rapidly in the plasma by the enzyme pseudocholinesterase (also known as plasma cholinesterase). The rate of hydrolysis varies significantly among different esters, which directly impacts their potential for toxicity. For example, chloroprocaine, the most rapidly hydrolyzed ester, has the lowest toxicity, whereas tetracaine, which is hydrolyzed much more slowly, is associated with a higher risk of toxicity.
A common byproduct of ester metabolism is para-aminobenzoic acid (PABA), which is excreted in the urine. PABA is a known allergen, and allergic reactions to ester local anesthetics are typically attributed to this metabolite rather than the parent compound itself, such as procaine. Individuals with a hereditary condition known as atypical pseudocholinesterase (found in about 1 in 2800 people) cannot metabolize ester anesthetics effectively, leading to prolonged drug action and a higher risk of toxicity. This condition also impairs the metabolism of other drugs like succinylcholine, a muscle relaxant commonly used during anesthesia, leading to prolonged apnea (breathing cessation) in affected individuals.
Amides
Amide local anesthetics undergo metabolism primarily in the liver, where they are broken down by the cytochrome P450 enzyme system. Unlike esters, the metabolism of amides is more complex and slower, which contributes to their longer duration of action. Amides such as lidocaine, mepivacaine, etidocaine, and bupivacaine are almost entirely metabolized in the liver, and the rate of their biotransformation is influenced by hepatic blood flow and liver function.
Prilocaine is metabolized primarily in the liver, but some metabolism also occurs in the lungs. Articaine, a hybrid local anesthetic with both ester and amide components, undergoes partial metabolism in the blood by plasma cholinesterase and partially in the liver, resulting in a shorter half-life compared to other amides. Patients with liver disease or reduced liver function may experience delayed metabolism of amides, leading to increased systemic levels and a higher risk of toxicity.
