Pharmacodynamics—Local anesthetics stop the propagation of action potentials in nerve axons by preventing the influx of sodium through voltage-gated sodium channels in the axon membrane. Other actions of local anesthetics (eg, effects on other voltage-gated ion channels and ligand-gated ion channels) may be important for their analgesic action and/or for undesired side effects.
Chemistry—Local anesthetics are weak bases with 3 structural parts: a hydrophilic end and a lipophilic end linked by an amino ester or an amino amide bond. The bond is the basis for classifying local anesthetics into 2 groups: the amino esters and the amino amides. Optical isomers of local anesthetics with an asymmetric carbon atom usually differ in potency, duration of action, and toxicity.
Expression of local anesthetic action—In vitro, there generally is a positive correlation between molecular weight of local anesthetic molecules and lipophilicity, protein binding, duration of action, potency, and toxicity; there is an inverse relation with speed of onset. In vivo expression of local anesthetic action is dependent on other factors as well, such as injection site, dose, intrinsic vasoactivity, and formulation. The manifestation of sensory versus motor block varies and is dependent on many factors, including the agent and type of block performed.
Pharmacokinetics—Local anesthetics usually are injected near the target site instead of relying on systemic circulation to carry them there (except, eg, intravenous regional anesthesia and treatment of certain neuropathic pain states). Barriers to the diffusion of local anesthetics to their target vary and are dependent on injection site (eg, epidural vs intrathecal), influence dose, speed of onset, and duration of action. Local anesthetics that reach systemic circulation are widely distributed in the body. Hydrolysis of the amino ester bond by esterases in blood is the primary biotransformation process for amino ester-linked local anesthetics. Hepatic extraction and biotransformation are important elimination and biotransformation pathways for amino amide-linked local anesthetics.
Toxicity—Local anesthetic toxicity can be categorized as allergic, tissue, cardiovascular, central nervous system, and methemoglobinemia. Clinically, manifestations of local anesthetic systemic toxicity do not occur in a predictable order, and which occur and how soon after local administration are variable. Concerns about cardiovascular toxicity related to bupivacaine have driven a search for long-acting local anesthetics with less cardiotoxic action.
Formulation—Substances are sometimes added to local anesthetic formulations to preserve the molecules, to prevent microbial growth, to prevent systemic absorption, to enhance and/or prolong local anesthetic action, and to enhance spread of the local anesthetic.
Local anesthetics are widely used to prevent or treat acute pain; to treat inflammatory, cancer, and chronic pain; and for diagnostic and prognostic purposes. Drugs classified as local anesthetics reversibly block action potential propagation in axons by preventing the sodium entry that produces the potentials.1 However, other actions of these drugs, such as anti-inflammation by interaction with G-protein receptors2 and analgesic effect in the spinal cord by blocking postsynaptic ionotropic receptor function mediated by extracellular receptor-activated kinase,3 also are thought to be relevant to their use to prevent or ...