autonomic pharmacology · cholinergic system
Cholinergic Neuroeffector Pharmacology
Receptor activation, inhibition, and clinical integration — high‑yield for USMLE
⚡ Synthesis, storage, and release of ACh
- Choline uptake: Na⁺‑dependent transporter (similar to SGLT)
- Rate‑limiting step: choline acetyltransferase (ChAT)
- Vesicular storage: protons exchanged for ACh (vesicular transporter)
- Release: Ca²⁺‑dependent exocytosis at the neuroeffector junction
- Termination: acetylcholinesterase (AChE) hydrolyzes ACh → choline + acetate
- Choline reuptake: high‑affinity, recycled for new synthesis
⏳ Botulinum toxin: prevents vesicle docking & release (cleaves SNARE proteins)
🧪 Hemicholinium: blocks choline reuptake → depletes ACh
Choline →
ChAT →
ACh →
Vesicle →
exocytosis →
AChE →
choline
🔬 Cholinergic receptor families
- Muscarinic (M1–M5) — GPCR, slow response
- M1, M3, M5: Gq → PLC ↑ → IP₃ / DAG / Ca²⁺
- M2, M4: Gi → adenylyl cyclase ↓ → cAMP ↓
- Nicotinic (N) — ligand‑gated ion channel, fast response
- NN: autonomic ganglia, adrenal medulla
- NM: neuromuscular junction (skeletal muscle)
| Receptor | Coupling | Effector |
|---|---|---|
| M1, M3, M5 | Gq | ↑ PLC → IP₃, DAG, Ca²⁺ |
| M2, M4 | Gi | ↓ adenylyl cyclase → ↓ cAMP |
| NN, NM | ion channel | Na⁺/K⁺ flux → depolarisation |
⚠️ N receptors desensitise rapidly with sustained agonist exposure
💊 Muscarinic receptor agonists
- Bethanechol — M‑selective (no CNS)
- Uses: postoperative ileus, neurogenic urinary retention
- Methacholine — M > N, diagnostic for bronchial hyperreactivity
- Pilocarpine / Cevimeline — M‑selective
- Xerostomia (Sjögren, radiation), glaucoma (pilocarpine topical)
- ACh — rapidly hydrolysed, no clinical use
📌 Pilocarpine: direct M agonist, lowers IOP by increasing aqueous outflow
🧪 Acetylcholinesterase inhibitors (indirect agonists)
- Edrophonium — short acting, diagnostic for myasthenia gravis
- Physostigmine — tertiary amine, enters CNS
- Glaucoma, atropine overdose (antidote)
- Neostigmine / Pyridostigmine — quaternary, no CNS
- Ileus, urinary retention, myasthenia gravis, reverse NM blockade
- Donepezil / Rivastigmine — lipid soluble, CNS, Alzheimer disease
- Organophosphates — irreversible, lipid soluble
- Insecticides (malathion, parathion), nerve agents (sarin)
| Drug | Properties | Key use |
|---|---|---|
| Edrophonium | short acting | myasthenia gravis diagnosis |
| Physostigmine | tertiary, CNS | atropine OD, glaucoma |
| Neostigmine | quaternary, no CNS | ileus, reversal of NM block |
| Donepezil | lipophilic, CNS | Alzheimer disease |
⚠️ Organophosphate toxicity: muscarinic + nicotinic excess. Atropine for muscarinic effects; pralidoxime (2‑PAM) to reactivate AChE (must be given before aging).
- Toxicity features: salivation, lacrimation, urination, diarrhoea, bradycardia, bronchoconstriction, muscle fasciculations → paralysis
🚫 Muscarinic receptor antagonists
- Atropine — prototype, tertiary amine (CNS entry)
- Effects (dose‑dependent): ↓ secretions, mydriasis, cycloplegia, tachycardia, hyperthermia, sedation, urinary retention
- Antidote for AChE inhibitor poisoning (muscarinic effects)
- Ipratropium / Tiotropium — inhalational, no CNS, asthma/COPD
- Scopolamine — motion sickness, sedation, short‑term memory block
- Oxybutynin — overactive bladder (urge incontinence)
- Benzatropine / Trihexyphenidyl — lipid soluble, parkinsonism, EPS
🧠 Atropine overdose: “hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter” — supportive + physostigmine if severe
⚡ Nicotinic receptor antagonists
- Ganglion blockers — hexamethonium, mecamylamine
- Block both SANS and PANS ganglia → loss of autonomic tone
- Effects: vasodilation, hypotension, reflex tachycardia (blocked), constipation, urinary retention, anhidrosis
- Neuromuscular blockers — see anaesthetics section
- Non‑depolarising (e.g., rocuronium) vs depolarising (succinylcholine)
| System | Effect of ganglion blockade |
|---|---|
| Arterioles | vasodilation (↓ SANS tone) |
| Heart (SA node) | tachycardia (loss of PANS tone) |
| GI tract | ↓ motility → constipation |
| Bladder | urinary retention |
| Sweat glands | anhidrosis (loss of SANS) |
🩺 Clinical pearls & high‑yield facts
- Alzheimer disease: loss of cholinergic neurons in nucleus basalis of Meynert → AChE inhibitors (donepezil) provide modest symptomatic benefit
- Atropine: order of effects — secretions ↓, mydriasis, tachycardia, hyperthermia, CNS excitation
- Physostigmine crosses BBB; neostigmine does not — useful for central anticholinergic syndrome
- Organophosphate poisoning: “SLUDGE” (salivation, lacrimation, urination, diarrhoea, GI upset, emesis) + muscle twitching
- Pralidoxime (2‑PAM): reactivates AChE only before “aging” (covalent bond stabilises)
- Dual innervation: PANS dominates heart (SA/AV), pupil, GI, bladder; SANS dominates vascular tone & sweat glands
📌 Exam trap: myasthenia gravis — edrophonium (short) improves; atropine is used for cholinergic crisis (overmedication with AChE inhibitors)