Cholinergic Pharmacology covers cholinergic pharmacology for INI CET (AIIMS PG).
Cholinergic Transmission:
- Acetylcholine (ACh) synthesized from: Acetyl-CoA + Choline (via Choline Acetyltransferase — ChAT)
- Stored in: Vesicles (via VMAT — vesicular monoamine transporter, though ACh uses VAChT)
- Released on depolarization: Ca²⁺-dependent exocytosis
- Degradation: Acetylcholinesterase (AChE) — rapidly hydrolyzes ACh → Acetate + Choline (choline recycled)
Cholinergic Receptors:
- Muscarinic receptors (GPCR — 5 subtypes M₁-M₅):
- M₁: CNS, gastric parietal cells (acid secretion) — blocked by atropine
- M₂: Heart (decreases HR, conduction velocity) — blocked by atropine
- M₃: Exocrine glands (salivary, lacrimal, bronchial), smooth muscle (bronchoconstriction), vascular endothelium (NO release → vasodilation) — blocked by atropine
- Nicotinic receptors (Ligand-gated ion channels — Na⁺/K⁺):
- Nm (muscular): NMJ (skeletal muscle) — blocked by non-depolarizing agents (rocuronium, vecuronium) and depolarizing agent (succinylcholine)
- Nn (neural): Autonomic ganglia (both sympathetic and parasympathetic) — blocked by ganglion blockers (trimethaphan, hexamethonium)
Cholinergic Agonists:
- Direct-acting: ACh (too short-acting for clinical use), Carbachol (cholinoester — resistant to AChE, used in glaucoma), Bethanechol (M₃ selective — urinary retention), Pilocarpine (M₃ — glaucoma, xerostomia)
- Indirect-acting (AChE inhibitors): Prevent ACh breakdown → accumulate ACh at synapses
- Reversible: Physostigmine (crosses BBB — CNS effects), Neostigmine (quaternary amine — does NOT cross BBB), Donepezil, Rivastigmine, Galantamine (used in Alzheimer’s)
- Irreversible: Organophosphates (insecticides — nerve agents sarin, soman), Echothiophate (glaucoma)
Organophosphate Poisoning:
- Irreversible AChE inhibition → excess ACh → overstimulation of all cholinergic receptors
- SLUDGE/DUMBBELS effects: Salivation, Lacrimation, Urination, Defecation, GI upset, Emesis / Diarrhea, Urination, Miosis, Bronchospasm/bronchorrhea, Bradycardia, Lacrimation, Excitation/Sweating
- Treatment: Atropine (competitive muscarinic antagonist — reverses muscarinic effects) + Pralidoxime (2-PAM — reactivates AChE if given before “aging” occurs)
Muscarinic Antagonists (Anticholinergics):
- Atropine: Non-selective M blocker; used in bradycardia (increases HR), GI spasms, ophthalmology (mydriasis/cycloplegia), antidote for organophosphate poisoning; side effects: dry mouth, urinary retention, constipation, confusion (crosses BBB), mydriasis
- Ipratropium: Inhaled M₃ blocker for COPD/asthma
- Tiotropium: Long-acting inhaled anticholinergic for COPD
- Scopolamine: CNS effects (antiemetic for motion sickness — crosses BBB)
- Glycopyrrolate: Quaternary amine — does not cross BBB; used in anesthesia (reduces secretions)
⚡ Exam Tip for INI CET (AIIMS PG): Atropine is the antidote for organophosphate poisoning (muscarinic excess). Pralidoxime reactivates AChE. Neostigmine (AChE inhibitor) is used to reverse non-depolarizing NMJ blockade — but must be given with an anticholinergic (glycopyrrolate) to prevent muscarinic effects.