The fundamental unit of excitable tissue is the nerve cell (Fig. 18.1). The major parts of the nerve cell include the cell body, the nucleus, dendrites, and the axon. The lipoprotein nerve cell membranes of the axon and to a lesser degree the dendrites are involved in electrical activity. Most of the axons in the body are covered with a discontinuous insulating substance, called myelin (Fig. 18.2), with gaps determined by the size and function of the nerve (nodes of Ranvier).

The physiological basis for nerve conduction is the movement of sodium and potassium ions across the axonal membrane through ion channels (Fig. 18.3). Sodium channels exist in three states: resting, activated (open), or inactivated. The sodium channels allow movement of sodium only in the open state, while potassium moves freely, achieving electrical neutrality and determining the electrical charge intracellularly, with sodium restricted to the extracellular side when the sodium channels are closed. The result is that sodium is the predominant extracellular cation and potassium the predominant intracellular cation. Following chemical, mechanical, or electrical stimuli, movement of sodium occurs into the cell via open sodium channels causing depolarization. At a given threshold (−55 mV) an action potential occurs and this segment of the axon causes depolarization of adjacent axonal membrane (neural conduction). The electrical neutrality is rapidly restored by egress of potassium outside the cell, inactivation of voltage-gated sodium channels, and the balance restored by energy-dependent sodium/potassium ATPase (transports three sodium ions out of the cell for every two potassium ions it transports inside the cell). In axons covered with myelin (myelinated nerves), the depolarization occurs at the nodes of Ranvier, with sodium movement at one node causing opening of the sodium channels at the adjacent node.

Conduction block occurs when this process is interrupted by sodium channel blockade, which can be reversible or nonreversible. Clinical conduction block with local anesthetics occurs exclusively in the reversible group, with irreversible block occurring with pesticides and animal venom. All reversible sodium channel block occurs on the intracellular side of the sodium channel (Fig. 18.4). For physiologic reasons, local anesthetics are delivered on the extracellular side, because intraneural injection into the axon would cause damage to the nerve cell membrane. This means that the molecule chosen must be capable of diffusing across the axonal membrane (lipid solubility), and occupy the open face of the sodium channel on the intracellular side (ionic bonding). The crossing of the neural membrane occurs at the Nodes of Ranvier in myelinated axons, and blockage of consecutive nodes increases the probability of conduction block. This is the reason why conduction block occurs quickly in smaller, unmyelinated (C) nerve fibers and slowest in the larger myelinated (A) nerve fibers (Table 18.2).

The prototype local anesthetic agent has four structural elements that contribute to function (Fig. 18.5). They are all amphipathic molecules, which means that within the molecule there are elements with different purposes. All local anesthetics are weak bases, manufactured and stored at acid pH as sodium (or carbonate) salts. The largest element is the hydrophobic side of the molecule which creates lipid solubility. On the opposite side of the molecule is the hydrophilic element, allowing for ionic activity. The hydrophilic side is a tertiary amine for all commercially available local anesthetics except benzocaine (a secondary amine). The hydrophobic and the hydrophilic elements are linked via an intermediate chain of between 3 and 7 carbon equivalents in size. Within the intermediate chain is a bond (either amide or ester) that determines the type of molecule and its metabolism in the body. The amino amides originate from and are metabolized to anilines whereas the amino esters are related to para-aminobenzoic acid (PABA).

Lipid solubility is determined by the size of the hydrophobic element of the molecule, but also by aliphatic substitutions on the intermediate chain and the hydrophilic element. Lipid solubility determines the potential for the molecule to cross the axonal membrane, and hence determines the potency and toxicity. More lipid solubility means more potency and potential for central nervous system (CNS) toxicity.

Protein binding is an indirect measure of the potential for the molecule to remain embedded in the substance of the axonal membrane. The greater the protein binding affinity of a given local anesthetic, the longer the duration of conduction block with that agent. Because lipid solubility is an important determinant of protein binding, potency and duration of local anesthetics are usually similar, that is, highly potent agents also have a long duration of conduction block.

The pK_a of the molecule is determined by the tertiary amine, the ionic signature. The pK_a is the pH for a given molecule at which the cationic (ionic) and base (unionized) forms are in equal concentrations. Commercial local anesthetics have pK_a between 7.6 and 9.3 and are manufactured as sodium salts at an acid pH (5.0–5.5, unless manufactured with epinephrine which requires storage at a pH less than 3.0 to prevent spontaneous hydrolysis of the epinephrine). In the bottle/vial, the majority of the molecules are cationic (>1,000:1).

The properties of local anesthetics that describe their unique clinical characteristics include speed of onset of action, potency, duration of action, and toxicity.

Onset of action of a local anesthetic can be enhanced by using a higher dose, higher concentration, and a pK_a which is close to the physiologic pH (more availability of the unionized form). Speed of onset of conduction block is the time from injection of the solution to interruption of neural activity. This is determined by the need for the solution to be injected extracellularly, the time for a substantial number of molecules to cross the axonal membrane and occupy the sodium channels. The solution injected is predominately cationic, and the cation has very limited potential to cross the lipid membrane. Extracellular buffering (mostly bicarbonate) raises the pH from 5.0 to physiologic, where the cation/base ratio increases to about 70:30. Some of the base then begins to cross the cell membrane to the intracellular side. Once on the intracellular side, the base rapidly converts to the cationic state because of the more acidic intracellular pH, which rapidly occupies the sodium channels. The latency to onset is determined first by the distance of injection to the nerve cell membrane (accuracy of the person performing the block, and the hydrophilic properties of the agent), and secondly by the cation/base ratio. The higher the concentration of the base, the faster the onset of conduction block. Since the base concentration at acid pH is less as the pK_a increases, the speed of onset of action is inversely proportionate to pK_a. For example, the pK_a of lidocaine is 7.6 and bupivacaine is 8.3, with lidocaine having a substantially increased speed of onset of action. This is also the physiologic basis for pre-block alkalinization of a local anesthetic solution with bicarbonate to increase the speed of onset of action.

Potency of a local anesthetic is directly related to the amount of the base that ultimately crosses the axonal membrane, and to the lipid solubility of the base form of the agent. The potency increases in direct proportion to lipid solubility. The local anesthetic with the least lipid solubility is procaine and it has the lowest potency. Conversely, bupivacaine has the highest lipid solubility and is the most potent local anesthetic available commercially.

The duration of action of a local anesthetic is determined by the affinity of the agent to remain embedded in the axonal membrane. The axonal membrane is a hydrophobic, lipoprotein environment. The duration of a given agent is best estimated by the protein binding of the agent, although it is also influenced by lipid solubility. As protein binding increases, so does the duration of action. In general, as the lipid solubility increases, so does protein binding and hence duration of action of the local anesthetic. For example, the least protein bound agent is 2-chloroprocaine, which also has the shortest duration of action. Conversely, etidocaine and bupivacaine have the highest protein binding potential and also the longest duration of action.

Local anesthetics besides being available as injectable solutions are also available for topical application of eyes (absorbed via the mucous membranes), and for dermal anesthesia (EMLA cream). Systemic absorption of local anesthetics is determined by site of injection, dose, addition of vasoconstrictor, and pharmacologic profile of the local anesthetic. The uptake of local anesthetic into the blood from greatest to least is IV > tracheal > intercostal > caudal > paracervical > epidural > brachial > sciatic > subcutaneous. Toxicity of local anesthetics is directly related to the potency and lipid solubility of the drug. More highly toxic drugs have a smaller gap between the therapeutic and the toxic dose (therapeutic index).