Cholinergic Pharmacology

Cholinergic pharmacology deals with drugs that mimic, augment, or block the action of acetylcholine (ACh) — the universal transmitter of the parasympathetic system, all autonomic ganglia, the somatic neuromuscular junction, and the adrenal medulla. This is a high-yield, mechanism-driven chapter where receptor subtype, drug lipophilicity, and reversibility of enzyme inhibition decide the answer.

Cholinergic Transmission — the synapse

Acetylcholine is synthesised from choline + acetyl-CoA by choline acetyltransferase (ChAT) in the cytoplasm, then packaged into vesicles by the vesicular ACh transporter (VAChT). The rate-limiting step is choline uptake by the high-affinity sodium-dependent transporter, which is blocked by hemicholinium. Vesicular packaging is blocked by vesamicol, and calcium-dependent exocytotic release is blocked by botulinum toxin (cleaves SNARE proteins). Released ACh is rapidly hydrolysed in the synaptic cleft by acetylcholinesterase (AChE / true cholinesterase) to choline and acetate; choline is then recaptured.

High-yield: Hemicholinium blocks choline uptake, vesamicol blocks vesicular storage, botulinum toxin blocks ACh release, and AChE inhibitors prolong ACh action — know each block point.

There are two cholinesterases: AChE (true/specific, found at synapses and RBCs, substrate-specific) and butyrylcholinesterase / pseudocholinesterase (plasma, liver; hydrolyses succinylcholine, procaine, ester local anaesthetics). Low pseudocholinesterase → prolonged succinylcholine apnoea.

Cholinergic Receptors — classification

Receptors are divided into muscarinic (G-protein coupled) and nicotinic (ligand-gated ion channels).

Receptor	Type / coupling	Main location	Effect of activation
M1	Gq → ↑IP3/DAG	CNS, gastric parietal/ECL cells, autonomic ganglia	↑ Gastric acid, CNS excitation, memory
M2	Gi → ↓cAMP, ↑K⁺	Heart (SA/AV node)	Bradycardia, ↓conduction, ↓atrial contractility
M3	Gq → ↑IP3/DAG	Smooth muscle, glands, eye, endothelium	Contraction (gut, bladder), secretion, miosis, NO-mediated vasodilation
M4 / M5	Gi (M4), Gq (M5)	CNS	Modulatory, M5 on cerebral vessels & dopamine
Nm	Nicotinic (ion channel)	Skeletal muscle NMJ	Muscle contraction
Nn	Nicotinic (ion channel)	Autonomic ganglia, adrenal medulla, CNS	Ganglionic transmission, catecholamine release

High-yield: Odd-numbered muscarinic receptors (M1, M3, M5) are Gq (excitatory, ↑IP3); even (M2, M4) are Gi. M2 in heart is the classic "vagal brake."

A mnemonic for muscarinic effects — "DUMBBELSS": Diarrhoea, Urination, Miosis, Bradycardia/Bronchospasm, Bronchorrhoea, Emesis, Lacrimation, Salivation, Sweating. (Sweat glands are sympathetic anatomically but use ACh on muscarinic receptors — hence muscarinic agonists cause sweating.)

Direct-acting Cholinomimetics

These directly stimulate cholinergic receptors. They are divided into choline esters (bethanechol, carbachol, methacholine) and natural alkaloids (pilocarpine, muscarine, arecoline).

Drug	Muscarinic	Nicotinic	AChE-resistant?	Key clinical use
Acetylcholine	+++	+++	No (rapidly destroyed)	None therapeutic (intraocular miosis)
Bethanechol	+++	–	Yes	Post-op/neurogenic urinary retention, post-op ileus
Carbachol	++	++	Yes	Glaucoma (topical), intraoperative miosis
Methacholine	+++	–	Partial	Bronchial challenge test for asthma
Pilocarpine	+++	–	Yes (alkaloid)	Glaucoma, xerostomia (Sjögren, post-radiation)

High-yield: Bethanechol is selective for the bladder and gut (muscarinic, no nicotinic), AChE-resistant, used for atonic bladder and post-op ileus — but contraindicated in mechanical obstruction, peptic ulcer, asthma, and hyperthyroidism (risk of arrhythmia).

High-yield: Pilocarpine causes miosis and ciliary muscle contraction → opens the trabecular meshwork → used in acute angle-closure glaucoma. It is also the drug of choice for xerostomia in Sjögren syndrome and post-radiation. Cevimeline is an M3-selective alternative.

Methacholine challenge test: A patient with normal spirometry but suspected asthma inhales increasing methacholine; a ≥20% fall in FEV1 confirms bronchial hyper-responsiveness.

Anticholinesterases (Indirect-acting Cholinomimetics)

These inhibit AChE, increasing ACh at all cholinergic synapses. They are classed by chemistry and reversibility.

Reversible inhibitors

• Edrophonium — ultra-short acting (binds reversibly to anionic site); used historically for the Tensilon test (diagnosis of myasthenia gravis) and to differentiate myasthenic from cholinergic crisis.
• Neostigmine — quaternary (charged) → poor CNS penetration; carbamylates the enzyme. Uses: myasthenia gravis, reversal of non-depolarising neuromuscular blockade, post-op ileus/urinary retention. Has direct nicotinic action at NMJ.
• Physostigmine — tertiary amine → crosses BBB. It is the antidote for central anticholinergic (atropine, antihistamine, TCA, datura) toxicity.
• Pyridostigmine — longer acting; mainstay oral therapy of myasthenia gravis; also pre-treatment prophylaxis against nerve-gas (soman).
• Donepezil, rivastigmine, galantamine — central-acting, used in Alzheimer's disease. Tacrine is obsolete (hepatotoxic).

High-yield: Neostigmine = quaternary = no CNS entry; Physostigmine = tertiary = crosses BBB. Physostigmine treats central antimuscarinic poisoning. Neostigmine is used for myaesthenia/NMJ-block reversal and to treat Ogilvie syndrome (acute colonic pseudo-obstruction).

Irreversible inhibitors — Organophosphates & Carbamates

Organophosphates (parathion, malathion, diazinon, nerve agents — sarin, tabun, soman, VX) phosphorylate the esteratic site forming a stable covalent bond. Over hours this undergoes "ageing" — loss of an alkyl group makes the inhibition permanent and oxime-resistant.

High-yield: Once the OP–enzyme complex "ages," pralidoxime is ineffective — hence oximes must be given early. Soman ages fastest (minutes); echothiophate is a therapeutic OP used in glaucoma.

Organophosphate Poisoning — high-yield emergency

Mechanism: Irreversible AChE inhibition → ACh accumulation → muscarinic + nicotinic + CNS overstimulation.

Clinical features

• Muscarinic (DUMBBELSS): miosis (pinpoint pupils), bronchorrhoea/bronchospasm, salivation, lacrimation, sweating, vomiting, diarrhoea, bradycardia, urination.
• Nicotinic: fasciculations, muscle weakness, paralysis, tachycardia, hypertension, mydriasis (variable).
• CNS: anxiety, seizures, coma, respiratory depression.

High-yield: Death in OP poisoning is due to respiratory failure — combination of bronchorrhoea/bronchospasm (muscarinic), diaphragmatic weakness (nicotinic), and central respiratory depression. "The killer is the airway and the lungs."

Management — stepwise approach:

1. Decontaminate (remove clothes, wash skin) + secure Airway/Breathing/Circulation → 2. Atropine (competitive muscarinic blocker) titrated to drying of secretions and clear chest, not to pupils or heart rate → 3. Pralidoxime (2-PAM) reactivates AChE at the nicotinic NMJ (relieves muscle weakness) — give early before ageing → 4. Benzodiazepine (diazepam) for seizures.

High-yield: Atropine reverses muscarinic and central effects but NOT nicotinic (skeletal muscle weakness/fasciculations). Pralidoxime is needed for the nicotinic component. The atropine end-point is clear chest and dry secretions.

Atropine vs Pralidoxime

Feature	Atropine	Pralidoxime (2-PAM)
Action	Blocks muscarinic receptors	Reactivates phosphorylated AChE
Covers muscarinic	Yes	–
Covers nicotinic	No	Yes (NMJ)
Covers CNS	Yes (some)	Poor (charged, limited entry)
Time-critical	Less	Yes — must precede ageing

Intermediate syndrome: 24–96 h after acute cholinergic crisis — proximal muscle, neck flexor, and respiratory muscle weakness; not improved by oximes/atropine — needs ventilatory support. OPIDN (organophosphate-induced delayed neuropathy): 1–3 weeks later, distal sensorimotor polyneuropathy due to inhibition of neuropathy target esterase (NTE) — independent of AChE.

Carbamate poisoning

Carbamates (carbaryl, propoxur, and the drugs neostigmine/physostigmine) carbamylate AChE but the bond is spontaneously reversible (no ageing) and they penetrate CNS poorly. Therefore carbamate poisoning is milder, self-limiting, treated with atropine; pralidoxime is generally not required and may even be relatively contraindicated in carbaryl poisoning.

Myasthenia Gravis — applied pharmacology

Autoantibodies against postsynaptic nicotinic ACh receptors at the NMJ. AChE inhibitors (pyridostigmine first-line symptomatic) increase ACh availability.

Myasthenic crisis vs Cholinergic crisis

Feature	Myasthenic crisis	Cholinergic crisis
Cause	Undertreatment / infection	Overdose of anticholinesterase
Pupils	Normal	Miosis (pinpoint)
Secretions	Normal	Excess (salivation, sweating)
Fasciculations	Absent	Present
Edrophonium (Tensilon) test	Improves	Worsens
Treatment	↑ AChE inhibitor, plasmapheresis/IVIG	Stop drug, atropine, support

High-yield: Edrophonium improves myasthenic crisis but worsens cholinergic crisis — the classic differentiating test. Atropine should be at the bedside before the test.

Alzheimer's Disease

Loss of cholinergic neurons (nucleus basalis of Meynert) → cholinergic deficit hypothesis. Centrally-acting reversible AChE inhibitors — donepezil (once daily, long t½), rivastigmine (also inhibits butyrylcholinesterase; available as patch), galantamine (also allosteric nicotinic modulator) — give modest symptomatic benefit. Memantine (NMDA antagonist) is added in moderate-severe disease. Cholinergic adverse effects: nausea, diarrhoea, bradycardia, syncope (caution with sick sinus/AV block).

Glaucoma — cholinergic role

In glaucoma, cholinomimetics (pilocarpine, carbachol, echothiophate) contract the ciliary muscle and pull on the scleral spur → open the trabecular meshwork → ↑aqueous outflow → ↓IOP. Topical AChE inhibitors are now largely superseded by prostaglandin analogues and beta-blockers, but pilocarpine remains useful in acute angle-closure to break the attack via miosis.

Adverse effects & contraindications (summary flow)

Excess muscarinic stimulation → bradycardia, hypotension, bronchospasm, increased secretions, abdominal cramps, urinary urgency, miosis, blurred vision, sweating.

Contraindications to cholinomimetics: bronchial asthma/COPD, peptic ulcer disease, coronary insufficiency, mechanical GI/urinary obstruction, hyperthyroidism (arrhythmia risk).

Key differentials & exam traps

• Nicotinic vs muscarinic: Atropine blocks only muscarinic. To block ganglia use ganglion blockers (hexamethonium, trimethaphan, mecamylamine); to block NMJ use curare-type (tubocurarine, atracurium) or depolarising (succinylcholine).
• Reversal of NMJ blockade: Neostigmine reverses non-depolarising block; it worsens phase-I depolarising (succinylcholine) block. Sugammadex specifically reverses rocuronium/vecuronium by encapsulation (not a cholinesterase mechanism).
• Direct vs indirect agonist: Direct agonists act even when nerve is degenerated; indirect (anti-AChE) need endogenous ACh.

Recently asked / exam angle

• Pinpoint pupils + excessive secretions + farmer/pesticide exposure → OP poisoning; treat with atropine + pralidoxime; atropine end-point = drying of secretions, not pupil size.
• Drug crossing BBB to treat atropine/datura poisoning → physostigmine (tertiary amine).
• Why pralidoxime fails if given late → ageing of the phosphorylated enzyme.
• Antidote that reverses nicotinic features in OP poisoning → pralidoxime (atropine does not).
• Drug of choice for post-op non-obstructive urinary retention / atonic bladder → bethanechol.
• Bronchial provocation test agent → methacholine.
• M2 receptor — Gi-coupled, cardiac, mediates vagal bradycardia.
• Rivastigmine — only AChE inhibitor also inhibiting butyrylcholinesterase, available as transdermal patch.
• Sweat gland innervation paradox — sympathetic cholinergic (muscarinic) → explains sweating with cholinomimetics and dry skin with atropine.
• Galantamine — dual action (AChE inhibition + nicotinic allosteric modulation).

Rapid revision

1. ACh synthesis rate-limiting step = choline uptake (blocked by hemicholinium); release blocked by botulinum toxin.
2. Odd muscarinic (M1/M3/M5) = Gq/↑IP3; even (M2/M4) = Gi/↓cAMP.
3. M2 = cardiac bradycardia; M3 = glands, smooth muscle, miosis, NO vasodilation.
4. Bethanechol — bladder/gut selective, AChE-resistant; for urinary retention & ileus.
5. Pilocarpine — glaucoma + xerostomia (Sjögren); causes miosis.
6. Neostigmine quaternary (no CNS); physostigmine tertiary (crosses BBB, antidote for atropine poisoning).
7. Pyridostigmine = first-line symptomatic myasthenia gravis.
8. OP poisoning: pinpoint pupils, DUMBBELSS, death from respiratory failure; Rx atropine + pralidoxime + diazepam.
9. Atropine covers muscarinic/CNS; pralidoxime covers nicotinic — must precede ageing (soman ages fastest).
10. Edrophonium improves myasthenic, worsens cholinergic crisis.
11. Alzheimer's: donepezil, rivastigmine (also BuChE, patch), galantamine; add memantine in moderate-severe.
12. Carbamate poisoning is milder (reversible, no ageing); pralidoxime usually unnecessary.