Local Anesthetics: Chemistry and Structure-Activity Relationship

Local anesthetics, or LAs, are drugs that induce a temporary loss of sensation in a limited body area, preventing pain during a medical procedure.  

Injectable LAs are administered subcutaneously or into the subarachnoid spaces. Surface anesthetics are applied superficially on scraped skin or mucous membranes on different sites like the nose and mouth.

Chemically, LAs are amphiphilic molecules, consisting of a hydrophilic amine and a lipophilic aromatic ring joined by ester or amide linkage.

Ester-linked-LAs, like procaine, are readily hydrolyzed by plasma esterases. So, their numbing effect is short and less intense.

In contrast, amide-linked LAs like lidocaine are more stable and have a prolonged anesthetic effect.

LAs work by reversibly blocking sodium ion channels in nerves, transiently inhibiting the transmission of sensory and motor impulses.
As weak bases, LAs remain partially unionized at the physiological pH and can cross the lipid bilayer.

Once inside the axon, they ionize and block the receptors of the sodium ion channels to stop impulse transmission.
The hydrophobic binding sites shield the LAs from metabolism while enhancing their potency and anesthesia duration.