Ganglionic Blocking Agents — Mechanism of Action

Hexamethonium ("C6")

• Channel blocker (open-channel block): Hexamethonium does not primarily occupy the cholinoceptor binding site. Instead, it enters and occludes the nicotinic ion channel after it opens, shortening the duration of current flow — the open channel either becomes blocked or closes prematurely.
• This blocks the initial excitatory postsynaptic potential (EPSP) and inhibits ganglionic transmission.
• It is a quaternary amine, poorly absorbed orally, and was the first drug used clinically for hypertension.

"Hexamethonium actually produces most of its blockade by occupying sites in or on the nicotinic ion channel, not by occupying the cholinoceptor itself." — Katzung's Basic and Clinical Pharmacology, 16th Ed.

Trimethaphan (Trimethapham)

• Competitive (orthosteric) antagonist: Trimethaphan competes directly with acetylcholine (ACh) at the nicotinic receptor binding site, analogous to how curare (tubocurarine) works at the neuromuscular junction.
• Blockade is surmountable by increasing ACh concentration.
• It is a short-acting, polar compound (no longer available for clinical use in most countries).

"Trimethaphan acts by competition with ACh, analogous to the mechanism of action of curare at the neuromuscular junction." — Goodman & Gilman's Pharmacological Basis of Therapeutics

Pempidine

• Pempidine is also a ganglionic blocker acting at nicotinic receptors in autonomic ganglia, with a mechanism similar to hexamethonium — nondepolarizing channel blockade at neuronal nicotinic receptors.
• It is a secondary amine (like mecamylamine), giving it better oral bioavailability than the quaternary ammonium agents.
• Used historically as an antihypertensive; now largely obsolete.

Summary Table