Indirect-Acting Cholinergic Agonists: Mechanism of Action

Recall that indirect-acting cholinergic agonists inhibit AChE enzymes. This prevents hydrolysis of acetylcholine in the synapse and potentiates cholinergic activity at post-synaptic neurons or neuromuscular junctions.

The active site of the enzyme has a choline-binding anionic and a catalytic esteratic subsite.

Reversible inhibitors such as simple alcohols bearing quaternary ammonium groups interact electrostatically with the enzyme. As the enzyme–inhibitor complex is less stable and reversible, such agents have a brief duration of action.

Reversible inhibitors that are carbamoyl esters transfer their carbamoyl group to the serine hydroxyl group of the esteratic subsite. As the carbamoylated enzyme is more stable and undergoes slow hydrolysis, these drugs have a medium duration of action.

Organophosphates, however, interact covalently and phosphorylate the serine residue. This forms an irreversible complex resulting in a long-lasting effect of the drug.

The phosphorylated enzyme's stability is enhanced through the process called aging. Here, one of the alkyl group is lost which further strengthens the phosphorus–enzyme bond.