Based on their chemical structure, local anesthetics can be divided into ester-type drugs and amide-type drugs. Each local anesthetic has a lipophilic (hydrophobic) portion and a hydrophilic portion (Fig. 21-1). The hydrophilic portion, an amine that is a weak base, exists in both ionized and nonionized forms. The ionized, protonated form predominates at lower pH levels, and the nonionized, unprotonated form predominates at higher pH levels. Only the nonionized form can penetrate neuronal membranes to reach binding sites on the internal surface of sodium channels. Inflammation and acidosis decrease the pH of tissues, thereby increasing the ionization of local anesthetics. For this reason, local anesthetics are less effective in the presence of these conditions, necessitating larger doses.

Local anesthetics are formulated as hydrochloride salts with a pH less than 7, as the ionized molecule is more soluble and stable than the free base. Once injected, the local anesthetic solution is quickly buffered to the pH of the tissue.

The duration of action of local anesthetics can be short, medium, or long (Table 21-1). Because local anesthetics act directly at the site of administration, their duration of action is determined primarily by the rate of diffusion and absorption away from the site of administration. Diffusion and absorption, in turn, depend on the chemical properties of the anesthetics and on such factors as local pH and blood flow. In some formulations, epinephrine is added to prolong a local anesthetic’s duration of action by producing vasoconstriction and slowing its rate of absorption. Because of the risk of ischemia and necrosis, however, local anesthetics with epinephrine are not used to anesthetize tissues with end arteries, such as tissues of the fingers, toes, ears, nose, and penis.

After systemic absorption, ester-type local anesthetics are metabolized in the plasma by butyrylcholinesterases to p-aminobenzoic acid (PABA) derivatives. Amide-type local anesthetics undergo metabolism by hepatic P450 enzymes to yield polar metabolites. In both cases, the metabolites are excreted in the urine.

Mechanism of Action

Local anesthetics cause a reversible inhibition of action potential conduction by binding to the sodium channel and decreasing the nerve membrane permeability to sodium. The nonpolar, lipophilic form of the anesthetic molecule passes through the neuronal membrane and switches to the polar, hydrophilic form in the cytoplasm of the neuron. This cationic form of the anesthetic binds to the cytoplasmic side of the sodium channel protein and prolongs the inactivation state of the sodium channel (Fig. 21-2). With sodium channels blocked, action potentials cannot propagate along the neuronal fiber, and sensory input is lost.

Amide-Type Local Anesthetics

Lidocaine produces local anesthesia after topical or parenteral administration. The most widely used local anesthetic, it is available in a number of formulations. These include topical solutions and ointments, oral sprays, viscous gels for oral and laryngeal application, and various parenteral formulations. EMLA, a eutectic mixture of the local anesthetics lidocaine and prilocaine, is available as a cream to anesthetize intact skin to a depth of 5 mm. In pediatric patients, EMLA cream has been used for local anesthesia before venipuncture, intravenous cannulation, or circumcision. Lidocaine is also used for infiltration, nerve block, epidural, and spinal anesthesia. Lidocaine is also available as a transdermal patch (LIDODERM) approved for postherpetic neuralgia and widely used off label for conditions such as vertebral fractures.

Etidocaine has properties similar to those of lidocaine, but its duration of action is considerably longer. It is primarily used for infiltration and nerve block anesthesia.

Bupivacaine, mepivacaine, and ropivacaine have similar clinical uses but differ in their duration of action, as shown in Table 21-1. Bupivacaine has been the most widely used local anesthetic for obstetric anesthesia, but it causes cardiac depression more frequently than do many other local anesthetics. Bupivacaine is also available in a liposome-encapsulated formulation (EXPAREL) for long-acting analgesia in the treatment of postsurgical pain. Ropivacaine is a newer drug that may cause fewer cases of cardiac toxicity. Levobupivacaine is the isolated S(−)-stereoisomer of racemic bupivacaine, which is the active form of the chiral drug mixture. It is used in epidural anesthesia for labor and delivery.

Prilocaine is a congener of lidocaine. It is converted to O-toluidine, a toxic metabolite that can cause methemoglobinemia if it is allowed to accumulate. For this reason, prilocaine use is limited to topical and infiltration anesthesia.

Dibucaine is formulated in an ointment used to relieve the pain and itching of hemorrhoids (piles) and other problems in the rectal area.