KEY POINTS

1. Local anesthetics block voltage-gated sodium channels by interrupting the initiation and propagation of impulses in axons, but they have a wide variety of other biologic actions, both desirable and undesirable.
2. The currently available local anesthetics are of two chemical classes: aminoesters and aminoamides.
3. The low potency and lack of specificity of the available local anesthetics are due in part to the structural constraint that they must have high solubility and diffuse rapidly in both aqueous environments and the lipid phases of biologic membranes.
4. Reversible protonation of the tertiary amine group makes local anesthetics uncharged at basic pH and charged at acid pH; the base forms are more soluble in lipid environments, whereas the acid forms are more soluble in aqueous environments.
5. Aminoesters are primarily metabolized by plasma esterases; aminoamides are metabolized primarily by hepatic cytochrome P450-linked enzymes.
6. The principal systemic toxicities of local anesthetics involve the heart (including atrioventricular conduction block, arrhythmias, myocardial depression, and cardiac arrest) and the brain (including irritability, lethargy, seizures, and generalized CNS depression). Hypoxemia and acidosis exacerbate these toxicities. Resuscitation after bupivacaine overdose is particularly difficult. Therefore, prevention of intravascular injection or overdose is crucial, and major nerve blockade should involve incremental, fractionated dosing.
7. Local anesthetics are directly toxic to nerve at the concentrations supplied in commercial solutions. Intraneural concentrations during regional anesthesia are generally (but not always) below the threshold for toxicity because of spread of solutions through tissues and diffusion gradients from injection sites into nerve. Injection into a constrained tissue space increases the risk of local toxicity.
8. Optimal use of local anesthetics in regional anesthesia requires an understanding of the individual patient's clinical situation; the location, intensity, and duration of regional anesthesia and analgesia required; anatomic factors affecting the deposition of drug near nerves; proper drug selection and dosing; and ongoing assessment of clinical effects after administration of local anesthetics.

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9. Recent efforts have led to the development of several new formulations for topical anesthesia. Single-stereoisomer (as opposed to a racemic mixture) formulations have been developed in an effort to reduce systemic toxicity and improve sensory selectivity.
10. Local anesthetics are increasingly being used for postoperative infusion and local and systemic administration in the management of chronic pain. Further research and development may lead to safe, more selective agents that can facilitate more prolonged administration in the setting of acute or chronic pain.