Two Chemical Classes
Amide Class
Amide Local Anesthetics
- Linkage: amide bond (-NH-CO-)
- Metabolism: liver (hepatic enzymes)
- Mnemonic: "i" before -caine (lidocaine, bupivacaine, ropivacaine)
- True allergy: extremely rare
- Most modern agents are amides
Ester Class
Ester Local Anesthetics
- Linkage: ester bond (-CO-O-)
- Metabolism: plasma pseudocholinesterase
- Allergy metabolite: para-aminobenzoic acid
- Generally shorter duration
- Examples: cocaine, procaine, chloroprocaine, tetracaine, benzocaine
Cross-Reactivity Rule
No cross-reactivity between amides and esters. Ester allergy is due to para-aminobenzoic acid metabolite. Amide reactions often due to methylparaben preservative in multi-dose vials — use preservative-free formulations. Safe to substitute across classes.
Pharmacokinetic Determinants
Three Key Properties
What Governs Potency, Duration, and Onset
| Property |
Effect |
High example |
Low example |
| Lipid solubility |
Higher = more potent, longer duration |
Bupivacaine |
Procaine |
| Protein binding |
Higher = longer duration |
Bupivacaine (~95%) |
Chloroprocaine |
| pKa near 7.4 |
More un-ionized at tissue pH = faster onset |
Lidocaine (7.9) |
Bupivacaine (8.1) |
High-Yield Individual Agents
Amide — Most Versatile
Lidocaine
- Intermediate duration and potency
- Most widely used local anesthetic
- Also Class Ib antiarrhythmic — sodium channel blockade in ventricular myocardium
- Used for infiltration, nerve blocks, epidural, spinal, topical, intravenous regional
Amide — Cardiotoxic
Bupivacaine
- Long duration, high protein binding (~95%)
- Preferred for epidural labor analgesia
- Cardiotoxic: "fast in, slow out" from cardiac sodium channels — cardiac arrest very difficult to resuscitate
- Never use for intravenous regional anesthesia
Amide — Safer Alternative
Ropivacaine
- Long duration, similar to bupivacaine
- Less cardiotoxic than bupivacaine
- More motor-sparing at lower concentrations
- Preferred in obstetric epidurals where long duration needed
Amide — Methemoglobinemia
Prilocaine
- Causes methemoglobinemia via metabolite ortho-toluidine
- Component of EMLA cream (with lidocaine) for topical skin anesthesia
- Risk clinically relevant in young infants
Ester — Unique Vasoconstrictor
Cocaine
- Only local anesthetic that causes vasoconstriction
- Blocks norepinephrine and dopamine reuptake
- Topical use only (nasal and pharyngeal procedures)
- Schedule II — high abuse potential
Ester — Topical / Methemoglobinemia
Benzocaine
- Topical use only — insoluble for injection
- Throat sprays, endoscopy topical anesthesia
- Causes methemoglobinemia with excessive use
- With prilocaine: two agents most associated with drug-induced methemoglobinemia in this class