Cholinergic Pharmacology: Muscarinic/Nicotinic Receptors and Cholinesterase Inhibitors

Cholinergic Neurotransmission: Synthesis, Release, and Breakdown

Synthesis: \text{AcCoA} + \text{Choline} \rightarrow \text{ACh} via choline acetyltransferase. Storage in vesicles; Ca2+-dependent release.
Degradation: acetylcholinesterase (AChE) breaks ACh into choline + acetate; choline recycled via choline transporter.
Modulators: Botulinum toxin inhibits ACh release; Hemicholinium inhibits choline uptake; Vesamicol inhibits vesicular packaging; AChE inhibitors increase synaptic ACh.
Autonomic terminals contain ACh and receptors; pre- and post-synaptic sites shape signaling.

Nicotinic receptors (nic): ligand-gated Na+/K+ channels at neuromuscular junction and autonomic ganglia; presynaptic nicotinic receptors facilitate ACh release during sustained activity.
Muscarinic receptors (mus): G-protein-coupled; subtypes M1, M3, M5 (excitatory) and M2, M4 (inhibitory).
Receptor locations (overview):
- CNS and autonomic ganglia (N/nicotinic and M1/CNS-associated)
- Heart, smooth muscle, exocrine glands (M2, M3)
- Endothelium (NO-mediated vasodilatation via M3)

M1, M3, M5: Excitatory (CNS, gastric parietal cells; gastric acid secretion; glandular and smooth muscle effects)
M2, M4: Inhibitory (heart)
Cardiac effects: M2-mediated negative chronotropy, dromotropy, bathmotropy, inotropy.
Vascular: No direct parasympathetic innervation; ACh can cause NO-mediated vasodilatation if present in circulation.
Glands: increased secretions (salivary, gastric, nasopharyngeal, tear, sweat glands).
Lungs: bronchoconstriction and increased bronchial secretions (parasympathetic innervation via vagal pathways).
GI tract: increased motility and secretions; sphincter relaxation.
Urogenital: detrusor contraction; sphincter relaxation; urination.
Eye: miosis and accommodation via M3; improved drainage of aqueous humor (glaucoma therapy).

Ocular effects (M3): miosis, accommodation; improved aqueous humor drainage (glaucoma therapy).
Cardiac effects (M2): negative chronotropy, dromotropy, bathmotropy, inotropy.
Vascular effects (M3): endothelium NO-mediated vasodilatation; indirect parasympathetic tone.
Pulmonary effects (M3): bronchoconstriction; increased bronchial secretions.
GI effects (M1, M3): increased motility; sphincter relaxation; increased secretions (salivary, gastric).
Urogenital effects (M3): detrusor contraction; sphincter relaxation → urination.
Glands (M3): increased secretions from nasopharyngeal, tear, and sweat glands (sweat via sympathetic cholinergic fibers).

Glaucoma: Pilocarpine 1-2\%
Supraventricular arrhythmia: Bethanechol
Atonic diseases (paralytic ileus, atonic bladder, congenital megacolon): Bethanechol (rare)
Dry mouth/eyes (Sjögren, radiation therapy): Cevimeline (selective M3 agonist)

Enzymes: \text{Acetylcholinesterase} \ (\text{AChE})\ and \text{Butyrylcholinesterase} \ (\text{BuChE})\
- AChE: main substrate is acetylcholine; localized in synaptic cleft and cholinergic terminals.
- BuChE: substrates include butyrylcholine, acetylcholine; widespread (plasma, skin, GI tract, liver, brain).
- Inhibitors: block both enzymes, increasing ACh at all cholinergic sites.
Duration categories:
- Short-acting: Edrophonium (quaternary ammonium; peripheral; binds active site) — diagnosis of myasthenia gravis.
- Intermediate-acting: Carbamates (carbamoyl esters) — hydrolyzed slowly. Examples: Physostigmine (tertiary amine, CNS/peripheral), Neostigmine, Pyridostigmine, Demecarium.
- Clinical uses: glaucoma, ileus, MG, reversing tubocurarine, atropine intoxication, Alzheimer's disease (some agents).
- Irreversible organophosphates: pesticides (parathion, malathion); nerve agents (tabun, sarin, soman). Phosphorylate AChE; pralidoxime reactivates (if given early).

Reversible inhibitors: hydrolysis and restoration of AChE; effects are temporary.
Irreversible inhibitors: covalent phosphorylation; prolonged AChE inactivation; reactivation requires pralidoxime or new enzyme synthesis; duration of action days to weeks.
Actions: M and N effects (muscarinic and nicotinic) with indirect ACh elevation at all cholinergic synapses.

Diarrhea, Urination, Miosis, Bronchorrhea/Bronchospasm, Emesis, Lacrimation, Salivation, Sweating, Lethargy, (and) Seizures (if CNS involved).
Clinical significance: excess ACh at muscarinic and nicotinic receptors following overdose of cholinesterase inhibitors or nerve agents.

Immediate steps: decontamination; atropine IV to block muscarinic effects
Pralidoxime (2-PAM) within ~6\text{ hours} to reactivate AChE (especially for organophosphates)
No specific antagonist for nicotinic effects; manage with supportive care and, if necessary, ventilatory support
After stabilization, continue atropine as needed to control muscarinic symptoms.

ACh reduces blood pressure via vasodilation (muscarinic effect).
At higher doses, after atropine blockade of muscarinic effects, ACh can cause tachycardia and BP increase via sympathetic (nicotinic) ganglionic stimulation and adrenaline release from adrenal medulla.

ACh acts at 4 sites: post-ganglionic parasympathetic endings (M), autonomic ganglia (N), NMJ (N), CNS (M, N).
Receptors and signaling:
- Nicotinic: Na+/K+ channel opening; depolarization at NMJ and ganglia.
- Muscarinic: G-protein-coupled; diverse organ effects (M1–M5).
Therapeutic and toxicology implications rely on modulating ACh levels or receptor activation at specific sites.