Local Anesthetics: Spinal Afferents and Local Anesthetic Mechanisms of Action
Local anesthetics cause temporary loss of pain sensation without loss of consciousness by blocking conduction along sensory nerve fibers. Some selectivity for pain afferents is achieved partly by using the agent close to target neurons. All currently used drugs block voltagedependent Na+ channels in excitable cells, which decreases the likelihood of an action potential. The target site of the drugs is on the cytoplasmic side of the neuron membrane, so drug molecules must pass through the membrane.
They are both lipophilic and hydrophilic and are weak bases (amides or esters) that exist in equilibrium between ionized (hydrophilic) and nonionized (lipophilic) forms. The latter diffuse more readily through the membrane; the former diffuse more readily through cytoplasm. Esters are metabolized by plasma cholinesterases; amides are hydrolyzed in the liver. Because they act on all excitable cells, local anesthetics can cause toxicity, including fatal cardiovascular effects or seizures.