Local Anesthetics

Amide local anesthetics contain an amide linkage — a nitrogen-carbonyl bond (written as -NH-CO-) — between the aromatic ring and the intermediate chain. This linkage is chemically stable and resistant to hydrolysis in the bloodstream. As a result, amide local anesthetics must travel to the liver to be metabolized by hepatic enzymes. Onset is generally intermediate to slow compared to esters, and duration tends to be longer.

The amide class includes most of the agents in common clinical use today: lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, levobupivacaine, and etidocaine. A reliable mnemonic: all amide local anesthetics have the letter "i" appearing before the "-caine" suffix in their generic name — lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, etidocaine.

Ester local anesthetics contain an ester linkage — a carbonyl-oxygen bond (written as -CO-O-) — between the aromatic ring and the intermediate chain. This linkage is readily hydrolyzed in the plasma by pseudocholinesterase (also called plasma cholinesterase or butyrylcholinesterase — an enzyme circulating in the blood that breaks down ester bonds). Because metabolism occurs in the bloodstream rather than requiring hepatic processing, ester hydrolysis is generally rapid, which translates to shorter duration and lower systemic toxicity risk for most esters.

The ester class includes cocaine, procaine, chloroprocaine, tetracaine, and benzocaine. One product of ester hydrolysis is para-aminobenzoic acid, which is responsible for allergic reactions to ester local anesthetics — discussed in Section 2.

Allergic reactions to ester local anesthetics are more common than reactions to amides. The responsible antigen is not the ester drug itself but rather para-aminobenzoic acid — the product released when ester local anesthetics are hydrolyzed in the plasma. Para-aminobenzoic acid is a well-recognized allergen that can trigger immunoglobulin E-mediated hypersensitivity reactions ranging from urticaria (hives) to anaphylaxis.

Because all ester local anesthetics produce para-aminobenzoic acid on hydrolysis, cross-reactivity within the ester class is possible. A patient who has had an allergic reaction to procaine may react to tetracaine or chloroprocaine as well, since all three yield the same allergenic metabolite.

True immunoglobulin E-mediated allergy to amide local anesthetics is extremely rare. When a patient reports an adverse reaction after receiving an amide agent, the reaction is more often due to vasovagal syncope, anxiety, a systemic response to inadvertent intravascular injection of epinephrine (a drug sometimes added to local anesthetic solutions), or a reaction to the preservative in the multi-dose vial rather than to the amide itself.

The relevant preservative is methylparaben, which is structurally similar to para-aminobenzoic acid. Multi-dose vials of amide local anesthetics contain methylparaben as an antimicrobial preservative. A patient with ester allergy (and therefore para-aminobenzoic acid sensitivity) may react to methylparaben in a multi-dose amide formulation — not because the amide itself caused allergy, but because of structural similarity between methylparaben and para-aminobenzoic acid. The solution: use preservative-free single-dose vials of the amide agent in any patient with a history of ester allergy.

Amide and ester local anesthetics do not cross-react with each other. A patient with confirmed ester allergy can safely receive an amide local anesthetic (using a preservative-free formulation). A patient with a documented rare amide allergy can safely receive an ester agent. The two classes are pharmacologically distinct enough that allergy to one does not predict allergy to the other.

Local anesthetics with higher lipid solubility penetrate nerve membranes more readily and bind membrane proteins with greater affinity. Higher lipid solubility therefore correlates with higher intrinsic potency — less drug is needed to produce the same degree of blockade — and with longer duration of action, because the drug partitions into the lipid-rich myelin and membrane and is released slowly.

Bupivacaine is highly lipid-soluble and correspondingly potent and long-acting. Lidocaine is less lipid-soluble and produces intermediate potency and duration. Procaine is poorly lipid-soluble and is among the least potent and shortest-acting agents.

Local anesthetics bind to plasma proteins — primarily alpha-1 acid glycoprotein — and to proteins within the nerve membrane itself. A drug with high protein binding remains at the site of action longer because it dissociates slowly from protein binding sites. This is the primary determinant of duration of action independent of lipid solubility.

Bupivacaine is approximately 95% protein-bound, which contributes to its long duration. Lidocaine is approximately 65% protein-bound, producing an intermediate duration. Chloroprocaine is poorly protein-bound and is hydrolyzed rapidly by plasma pseudocholinesterase — its duration is the shortest of any local anesthetic in clinical use.

The acid dissociation constant (pKa) of a local anesthetic determines how much of the drug exists in the un-ionized (membrane-crossing) form at physiological tissue pH of 7.4. Drugs with a pKa closer to 7.4 have a larger un-ionized fraction at tissue pH, meaning more drug is immediately available to cross the nerve membrane. This produces faster onset.

Lidocaine has a pKa of 7.9 — relatively close to physiological pH — and has a faster onset than bupivacaine, whose pKa of 8.1 means a smaller un-ionized fraction at the same pH. Chloroprocaine has a pKa of 8.7, which would predict slow onset — but in practice it is used in high concentrations, which overcomes the ionization disadvantage and produces rapid clinical onset despite the unfavorable pKa.

Most local anesthetics cause vasodilation at clinical concentrations by relaxing vascular smooth muscle. Vasodilation increases blood flow at the injection site, accelerating systemic absorption of the drug and reducing the duration of local effect. This is why epinephrine (a drug that causes blood vessel constriction by activating alpha-1 receptors) is frequently added to local anesthetic solutions — it counteracts vasodilation, slows absorption, prolongs duration, and reduces peak plasma concentration.

Cocaine is the single exception among local anesthetics. Rather than causing vasodilation, cocaine produces vasoconstriction by blocking the reuptake of norepinephrine (a chemical messenger that stimulates blood vessels to contract) into nerve terminals, increasing norepinephrine concentration at vascular smooth muscle receptors. This intrinsic vasoconstrictive property makes cocaine uniquely useful for procedures involving nasal and pharyngeal mucosa, where simultaneous anesthesia and vasoconstriction reduce bleeding.