Cholinergic Pharmacology

The rate-limiting step is not synthesis itself but the availability of choline. Choline must be transported into the nerve terminal from the synaptic cleft by a high-affinity choline transporter. When neuronal firing increases, transporter activity rises to meet the higher demand.

Inside the terminal, choline acetyltransferase transfers an acetyl group from acetyl-coenzyme A to choline, producing acetylcholine. This enzyme is the defining marker of cholinergic neurons. In Alzheimer disease, choline acetyltransferase activity is reduced in the cortex and hippocampus, reflecting loss of cholinergic neurons from the basal forebrain — the mechanistic rationale for treating Alzheimer disease with acetylcholinesterase inhibitors.

Newly synthesized acetylcholine is packaged into synaptic vesicles. Storage protects it from cytoplasmic degradation and positions it for rapid calcium-triggered release.

When an action potential arrives at the nerve terminal, voltage-gated calcium channels open. The resulting calcium influx triggers fusion of vesicles with the presynaptic membrane and release of acetylcholine into the synaptic cleft.

Acetylcholinesterase in the synaptic cleft then rapidly hydrolyzes acetylcholine into choline and acetate. Choline is recycled back into the terminal for resynthesis.

Because termination depends entirely on enzymatic hydrolysis — not reuptake of intact transmitter — inhibiting acetylcholinesterase prolongs and amplifies every cholinergic signal simultaneously.

All five subtypes fall into one of two groups. M1, M3, and M5 couple to Gq proteins, activating pathways that raise intracellular calcium and produce excitatory responses. M2 and M4 couple to Gi proteins, which reduce cellular excitability. The odd-even pattern — odd subtypes are Gq, even subtypes are Gi — is a reliable organizing principle for the whole receptor family.

Non-selective muscarinic antagonists such as atropine and scopolamine block all five subtypes, producing the full anticholinergic syndrome: tachycardia, mydriasis, dry mouth, urinary retention, constipation, and — with central nervous system penetration — confusion and delirium.

Selective M3 antagonists limit adverse effects by targeting specific tissues. Darifenacin and solifenacin target M3 in the bladder for overactive bladder, with reduced cardiac and central nervous system effects. Ipratropium and tiotropium are inhaled M3 antagonists producing bronchodilation in chronic obstructive pulmonary disease and asthma with minimal systemic absorption. Benztropine and trihexyphenidyl target M1 and M4 in the striatum for Parkinson disease tremor.

Overstimulation from acetylcholinesterase inhibitor toxicity or organophosphate poisoning produces simultaneous overstimulation of muscarinic and nicotinic receptors at all sites in the body.