Nerves in both the central nervous system (CNS) and peripheral nervous system are differentiated by the presence or absence of a myelin sheath that is interrupted at short intervals by specialized regions called nodes of Ranvier.

Nerve fibers are commonly classified according to their size, conduction velocity, and function (Table 21-1).

Transmission of electrical impulses along cell membranes is the basis of signal transduction. Energy necessary for the propagation and maintenance of the electric potential is maintained on the cell surface by ionic disequilibria across the permeable cell membrane. The resting membrane potential (about −60 to −70 mV) is predominantly attributable to a difference in the intracellular and extracellular concentrations of potassium and sodium ions.

The flow of ions responsible for action potentials is mediated by a variety of channels and pumps, the most important of which are the voltage-gated sodium channels. (Nine isoforms of voltage-gated sodium channels have been identified.)

It is widely accepted that local anesthetics induce anesthesia and analgesia through direct interactions with the sodium channels. (They reversibly bind the intracellular portion of voltage-gated sodium channels.)

Application of local anesthetics typically produces a concentration-dependent decrease in the peak sodium current.

Local anesthetics block peripheral nerves by disrupting the transmission of action potentials along nerve fibers. Only about 1% to 2% of the injected local anesthetics ultimately penetrate into the nerve to reach the site of action (voltage-gated sodium channels).

The degree of nerve blockade depends on the local anesthetic’s concentration and volume (needed to suppress the regeneration of nerve impulses over a critical length of nerve fiber).

Not all sensory and motor modalities are equally blocked by local anesthetics (sequential disappearance of temperature sensation, proprioception, motor function, sharp pain, and last light touch). This differential blockade had been thought to be simply related to the diameter of the nerve fiber (smaller fibers are inherently more susceptible to drug blockade than large fibers), but this does not appear to be universally true. In this regard, small nerve fibers require a shorter length (<1 cm)
exposed to local anesthetic for block to occur than do large fibers.

Most clinically relevant local anesthetics are made up of a lipid-soluble, aromatic benzene ring connected to an amide group via either an amide or ester moiety.

The type of linkage divides the local anesthetics into aminoesters (metabolized in the liver or by plasma cholinesterase) and aminoamides (metabolized in the liver).

All clinically used local anesthetics are weak bases that can exist as either the lipid-soluble, neutral form or as the charged, hydrophilic form. The combination of pH and pKa of the local anesthetic determines how much of the compound exists in each form (Table 21-2).

A ratio with high concentration of the lipid-soluble form favors entry into cells because the main pathway for entry is by passive absorption of lipid-soluble form through the cell membrane. Clinically, alkalization of the anesthetic solution increases the ratio of the
lipid-soluble form to the cationic form, thereby facilitating drug entry.

Anesthetic activity and potency are affected by the stereochemistry of local anesthetics.

Epinephrine added to the local anesthetic solution may prolong the local anesthetic block, increase the intensity of the block and decrease systemic absorption of the local anesthetic.

Opioids (especially buprenorphine) added to the local anesthetic solution placed into the epidural or subarachnoid space result in synergistic analgesia and anesthesia without increasing the risk of toxicity.

α₂-Adrenergic agonists such as clonidine produce synergistic analgesia via supraspinal and spinal adrenergic receptors. Clonidine also has direct inhibitory effects on peripheral nerve conduction (A and C nerve fibers).

Steroids. Combined with intermediate- to long-acting local anesthetics, dexamethasone extends the duration of analgesia by approximately 50% after utilization of the supraclavicular or interscalene approach for brachial plexus block (Fig. 21-1).