Raising acetylcholine without touching the receptor
Recall that acetylcholine is destroyed within milliseconds by the enzyme acetylcholinesterase. A cholinesterase inhibitor works by enzyme inhibition: it stops that breakdown, so acetylcholine lingers and piles up. The receptor itself is untouched, yet the effect is a strong, body-wide cholinergic surge — an *indirect* parasympathomimetic. These drugs treat myasthenia gravis (where muscle nicotinic signalling is failing), reverse muscle relaxants after surgery, and slow the decline in some forms of dementia.
Blocking the muscle junction
At the skeletal muscle endplate, acetylcholine acts on the muscle nicotinic receptor. A neuromuscular blocker interrupts exactly this junction to produce surgical paralysis. There are two flavours. Non-depolarizing blockers are plain antagonists that sit on the nicotinic receptor and keep acetylcholine out — and because a cholinesterase inhibitor raises acetylcholine, it can out-compete them and reverse the block. Depolarizing blockers instead over-stimulate the receptor, locking the muscle in a refractory state; a cholinesterase inhibitor would make these *worse*, not better.
Acting on the nerve and the ganglion
Two more advanced classes act *upstream* of the organ. An adrenergic neuron blocker works inside the sympathetic nerve ending itself — it disrupts the storage or release of norepinephrine, so the nerve fires but little messenger comes out, lowering blood pressure. The ganglionic blocker is the bluntest tool of all: it blocks the nicotinic receptors at the ganglia where both branches relay, so it shuts down sympathetic *and* parasympathetic outflow at once.
Because ganglionic blockers knock out both branches together, their effects are an unpredictable mess of cholinergic and adrenergic loss — low blood pressure, dry mouth, blurred vision, retention, constipation all at once. They were among the first antihypertensives but are now largely historical, replaced by the precise, single-target drugs of guide 4. They remain a perfect closing lesson: the more selective a drug's target, the cleaner and more predictable its effect.