Aromatic Group (Lipophilic End):
Typically, a benzene ring, responsible for lipophilicity, enabling penetration of nerve cell membranes.
Potency is proportional to lipid solubility, influencing membrane penetration.
Intermediate Chain (Linker):
Connects the aromatic group to the ionizable group and determines metabolism and duration of action.
A) Ester-linked Anesthetics:
Metabolized by plasma cholinesterases.
Higher risk of allergic reactions.
B) Amide-linked Anesthetics:
Metabolized in the liver.
Lower allergy risk and longer duration of action.
Ionizable Group (Hydrophilic End):
Usually a tertiary amine, contributing to hydrophilicity.
Degree of ionization affects onset of action:
Non-ionized form penetrates membranes.
Ionized form blocks sodium channels inside nerves, causing anesthesia.
Additional SAR Factors:
Stereochemistry: Enantiomers may differ in activity and toxicity (e.g., bupivacaine).
Intermediate Chain Length: Longer chains generally increase duration of action.
Aromatic Ring Substituents: Lipophilic groups enhance potency, while hydrophilic groups may reduce it.