Author(s): Lillye Anderson, Ken Solt

1. Introduction. Local anesthetics are a group of drugs which cause a reversible loss of sensation by blocking nerve conduction. This is accomplished through tissue infiltration, topical application, peripheral nerve blocks and neuraxial anesthesia techniques. The first local anesthetic used clinically was cocaine, isolated from the coca plant. Modern local anesthetics are sodium channel blockers derived from the cocaine molecule.

2. Chemistry. Local anesthetics are composed of a terminal amine attached to an aromatic ring via an ester or amide linkage. Local anesthetics are weak bases with both charged (protonated) and uncharged (unprotonated) forms at physiologic pH ~7.4. Only uncharged molecules can cross the lipid bilayer to block sodium channels intracellularly.

   1. Esters.Benzocaine, cocaine, chloroprocaine, procaine, and tetracaine. Ester hydrolysis is catalyzed by pseudocholinesterase and the degradation product is p-aminobenzoic acid (PABA).

   2. Amides.Bupivacaine, etidocaine, lidocaine, mepivacaine, prilocaine, and ropivacaine. The amide linkage is cleaved through initial N-dealkylation followed by hydrolysis, which occurs primarily in the liver. The elimination half-life for most amide local anesthetics is 2 to 3 hours.

3. Mechanism of action

   1. Local anesthetics inhibit voltage-gated Na⁺ channels (NaV) by binding to the intracellular pore of NaV. To enter the cell, the uncharged molecule must traverse the lipid bilayer through passive nonionic diffusion.

   2. Local anesthetics block nerve conduction by inhibiting sodium influx and impairing the propagation of action potentials.

   3. Physiochemical properties of the local anesthetics affect neural blockade.

      1. Lipid solubility. More lipophilic local anesthetics exhibit increased potency because they more easily permeate nerve membranes. Higher lipid solubility also leads to prolonged duration of action.

      2. pK_a. Agents with a lower pK_a will have faster onset since a greater fraction of the drug will exist in the uncharged form.

      3. pH of the drug solution. Higher pH will accelerate the onset by increasing the proportion of molecules in the uncharged form.

      4. Drug concentration. Higher concentrations will accelerate onset owing to mass effect.

   4. Differential blockade of nerve fibers

      1. Peripheral nerves are classified according to size and function (Table 19.1). Local anesthetics block conduction based on the number of NaV channels, with thin, myelinated fibers more susceptible to blockade than thick, unmyelinated fibers.

         
         TABLE 19.1 Classification of Nerve Fibers

         Class	Myelin	Diameter (μm)	Local Anesthetic Sensitivity	Function
         A-α	+++	12–20	++	Motor
         A-β	+++	5–12	++	Touch/pressure
         A-γ	++	1–4	+++	Proprioception/motor tone
         A-δ	++	1–4	+++	Pain/temperature
         B	+	1–3	++	Preganglionic autonomic
         C	–	0.5–1	+	Pain/temperature

      2. Local anesthetics block sensitivity to pain and temperature first, followed by fine touch. Finally, motor function is impaired. However, this differential blockade is imperfect (eg, it is nearly impossible to produce a full sensory block without impairing motor function).

      3. Sequence of block progresses in the following order: Sympathetic ≥ pain and temperature ≥ proprioception ≥ fine touch and pressure ≥ motor.

   5. Pathophysiologic factors affecting the neural block

      1. Decreased cardiac output reduces the plasma and tissue clearance of local anesthetics, increasing plasma concentrations and the potential for toxicity.

      2. Severe hepatic disease may prolong the duration of action of amides.

      3. Reduced cholinesterase activity. Newborns, pregnant patients and patients with atypical cholinesterase or cholinesterase deficiency may have decreased clearance of ester-type anesthetics, but this is not usually associated with toxicity.

      4. Fetal acidosis may cause ion-trapping (eg, accumulation of ionized local anesthetic in the fetal circulation) potentially resulting in fetal toxicity. This is more likely with amides not cleared rapidly by maternal liver enzymes.

      5. Sepsis, malignancy, and cardiac ischemia can increase plasma levels of α₁-acid glycoprotein, an acute phase reactant with high affinity for amide local anesthetics, decreasing the plasma concentration of unbound local anesthetics.

4. Commercial preparations. In most commercial preparations, the pH is adjusted with hydrochloric acid or sodium hydroxide to a final value of 4 to 6. Solutions with epinephrine are adjusted to pH 3 to 4 to minimize the degradation of epinephrine.

   1. Antimicrobial preservatives. Methylparaben or other paraben derivatives are used as antiseptic agents for multidose vials. Preservative-free solutions are used for neuraxial anesthesia to avoid the neurotoxic effects of preservatives.

   2. Epinephrine. Epinephrine is often added to prolong the duration of nerve blocks and to act as a marker for intravascular injection (see Section II.B).

   3. Antioxidants (sodium metabisulfite, sodium ethylenediaminetetraacetic acid [EDTA]) are added to mixtures containing epinephrine to slow oxidization.

   4. Liposomal bupivacaine. Bupivacaine liposome injectable suspension, marketed under the trade name Exparel was designed for slow release of bupivacaine from liposomes to prolong its local anesthetic effects and reduce toxicity. It is approved by the US Food and Drug Administration

      (FDA) for TAP block, interscalene block, adductor canal block and popliteal block as well as for local infiltration at the surgical site.