Cholinergic Pharmacology
Acetylcholine signaling through nicotinic and muscarinic receptors, and drugs that modify cholinergic transmission.
## Acetylcholine Synthesis and Degradation
Acetylcholine (ACh) is synthesized from choline and acetyl-CoA by choline acetyltransferase (ChAT). After release, ACh is rapidly hydrolyzed by acetylcholinesterase (AChE) in the synaptic cleft. The choline is recaptured by a high-affinity choline transporter (CHT1) for resynthesis.
Central cholinergic neurons originate primarily in the nucleus basalis of Meynert (projecting to cortex) and the pedunculopontine nucleus (projecting to thalamus). These pathways are critical for attention, learning, and memory.
## Nicotinic Receptors
Nicotinic ACh receptors (nAChRs) are pentameric ligand-gated cation channels. Key subtypes:
- **Neuromuscular junction (NMJ)** -- alpha-1 containing; blocked by non-depolarizing muscle relaxants (rocuronium) or activated then desensitized by succinylcholine
- **Autonomic ganglia** -- alpha-3/beta-4; targeted by ganglionic blockers (hexamethonium, historical)
- **CNS** -- alpha-4/beta-2 (most abundant); alpha-7 (linked to cognition); varenicline is a partial agonist at alpha-4/beta-2 for smoking cessation
## Muscarinic Receptors
Five subtypes (M1-M5), all GPCRs:
- **M1** (Gq) -- cortex, hippocampus; memory and cognition
- **M2** (Gi) -- heart; slows heart rate (vagal tone)
- **M3** (Gq) -- smooth muscle, glands; bronchoconstriction, secretions
- **M4** (Gi) -- striatum; emerging antipsychotic target (xanomeline)
- **M5** (Gq) -- substantia nigra; least characterized
## Key Drug Classes
- **Cholinesterase inhibitors** -- donepezil, rivastigmine, galantamine for Alzheimer's; neostigmine, pyridostigmine for myasthenia gravis
- **Muscarinic antagonists** -- atropine (nonselective), ipratropium (inhaled for COPD), oxybutynin (M3, overactive bladder), scopolamine (motion sickness)
- **Nicotinic agents** -- varenicline (partial agonist for smoking cessation), succinylcholine (depolarizing NMJ blocker)
- **Cholinomimetics** -- bethanechol (M3 agonist for urinary retention), pilocarpine (M3 agonist for glaucoma)
## Key Takeaways
- AChE rapidly terminates cholinergic signaling; its inhibition is the basis of Alzheimer's symptomatic treatment
- Nicotinic receptors are ion channels mediating fast transmission at the NMJ and ganglia
- Muscarinic receptors are GPCRs with organ-specific distribution enabling selective drug targeting
- Anticholinergic burden from polypharmacy is a common cause of cognitive impairment in elderly patients