Lipid solubility appears to be the most significant property of local anesthetic molecules in determining anesthetic potency. Local anesthetic molecules which are highly lipophilic easily penetrate nerve cell membranes and become intracellular, resulting in more blockades. For example, bupivacaine is considerably more lipid soluble and more potent than lidocaine.

Local anesthetics exist in ionized and nonionized forms, the proportions changed by pH of the environment. The nonionized portion is the form that is capable of diffusing across nerve membranes and blocking sodium channels. The nonionized form also has a faster onset of action due to fast diffusion. Local anesthetics differ in respect to the pH at which the ionized and nonionized forms are present at equilibrium (7.6–8.9). The more closely the equilibrium pH for a given anesthetic approximates the physiologic pH of tissues (i.e., 7.35–7.45), the more rapid the onset of action.

A decrease in pH shifts equilibrium toward the ionized form, delaying onset of action. This explains why local anesthetics are slower in onset of action and less effective in the presence of inflammation, which creates a more acidic environment with lower pH. By addition of sodium bicarbonate to certain local anesthetics, we may enhance the onset of action. Overalkalinization, however, can cause local anesthetic molecules to precipitate from solution [2].

Protein binding is related to the duration of action. The more firmly the local anesthetic binds to the protein of the sodium channel, the longer the duration of action. Poorly protein-bound agents, such as procaine, are readily washed out in in vitro experiments, and duration of local anesthetic blockade can be extremely short, whereas those which are highly protein bound, such as bupivacaine, are less easily washed out in in vitro experiments, and conduction blockade is interrupted for a longer period of time. The clinical activity of the agents which are more protein bound such as bupivacaine and etidocaine are associated with a longer duration of clinical anesthesia. The less well protein-bound agents such as procaine and chloroprocaine are associated with short duration of clinical activity.

Most local anesthetics, with the exception of cocaine, have a biphasic effect on vascular smooth muscle. At low doses, they cause vasoconstriction, and at high doses, they cause vasodilation via direct relaxation of peripheral arteriolar smooth muscle fibers. The more vasodilatory property the local anesthetic has, the faster the absorption and thus the shorter the duration of action of the local anesthetic. To counteract this vasodilatation, epinephrine is often included in local anesthetic solutions [3].

Na+ channels are heterotrimeric transmembrane proteins, consisting of α (Mr~260 kDa), β1 (36 kDa), and β2 (33 kDa) subunits. The α subunit contains four homologous domains (I–IV); each domain contains 6 α-helical transmembrane segments (S1–S6). The voltage sensor is located in the fourth transmembrane segment of each domain which is rich in positively charged residues. The loop between domains III and IV serves as an inactivation gate which folds to block the pore shortly after opening of the channel. The binding site for local anesthetics is located in the S6 transmembrane domain of segment IV close to the intracellular side of the membrane [4].

Na+ (sodium) channels can be found in three states. First, there is the closed state at potentials below –70 mV. The pore in the channel is occluded so that Na⁺ ions cannot pass from one side to the other. Second, the open state of the channel is initiated by depolarization of the transmembrane potential to the threshold potential (usually above –40 mV). In response to depolarization, the channel opens within a millisecond and allows Na⁺ ions to diffuse down their concentration gradient through the pore, causing an inward current and depolarizing the transmembrane potential even further, which continues a self‐driven depolarization [5].

This process underlies the upstroke of the action potential of most excitable cells. During channel opening the S4 segment twists back, driven by both the changed potential difference and intrinsic charge changes, which allow the outer pore mouth to expand, resulting in a 20° twist of the α‐helix. The third state follows activation during prolonged depolarization and is termed the inactivated state. The inactivated state was shown to be a nonconducting mode of the channel. The order of affinity of local anesthestics for different sodium channel states is open, inactivated, and lastly, resting. Thus, the open state of the sodium channel is the primary target of local anesthetic molecules. The blocking of propagated action potentials is therefore a function of the frequency of depolarization.

After administration of local anesthetics, molecules diffuse from the extraneural site toward the nerves. The rate of diffusion depends on several factors; the most significant of which is the concentration gradient. The greater the initial concentration of the local anesthetic, the faster is the diffusion of its molecules and the more rapid its onset of action. It is important to note that the fasciculi that are located near the surface of the nerve are termed mantle bundles and are reached by the local anesthetic first and blocked completely. The fasciculi found closer to the center of the nerve are called core bundles and are exposed to less concentrated anesthetic solution and delayed response [6].

Thus, small unmyelinated C fibers (pain) and small myelinated Aδ fibers (pain and temperature) are blocked before larger myelinated Aγ, Aβ, and Aα fibers (postural, touch, pressure, and motor signals). In large nerve trunks, motor nerves are usually located circumferentially and may be affected before the sensory fibers. In the extremities, proximal sensory fibers are located more circumferentially than distal sensory fibers. Thus, loss of sense may spread from proximal to distal part of the limb.

It is important to understand that nerves with higher firing frequency and more positive membrane potential are more sensitive to local anesthetic block because the charged (active form) local anesthetic molecules are more likely to access to the binding sites in the open Na+ channel and less likely to dissociate from its binding sites in the open or inactivated channels in comparison with the resting Na+ channels. Sensory fibers, especially pain fibers, have a high firing rate and relatively longer action potential duration than motor fibers and thus are more sensitive to lower concentrations of local anesthetics.

A significant difference exists between the onset times of various agents when blocks are done for peripheral nerves. In general, agents of intermediate potency have a more rapid onset than the more potent compounds do. Onset times of approximately 14 min for lidocaine and mepivacaine have been reported versus approximately 23 min for bupivacaine. Epinephrine will increase the duration of most local anesthetics for peripheral nerve blocks, but should not be used for ankle or digit blocks for risk of ischemia (Table 11.3).

When combining two local anesthetics for a given block, usually a short-acting local anesthetic for surgical anesthesia is used, with the combination of a long-acting agent for postoperative pain control. It is recommended to not use the maximum doses for two local anesthetics in combination, because the toxicities are additive [7].