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Classify cholinergic drugs. Describe their pharmacological actions, uses and adverse effects. Add a note on organophosphorus poisoning.

Pharmacology · 2nd Professional — Para-Clinical

Classification of Cholinergic Drugs

Group	Drugs	Notes
Directly acting — choline esters	Acetylcholine, methacholine, carbachol, bethanechol	Acetylcholine is useless clinically (destroyed instantly); bethanechol is resistant to cholinesterase and acts mainly on the gut and bladder
Directly acting — alkaloids	Pilocarpine, muscarine, arecoline	Pilocarpine is used topically in glaucoma and orally for xerostomia
Indirectly acting — reversible anticholinesterases	Neostigmine, physostigmine, pyridostigmine, edrophonium, donepezil, rivastigmine	Inhibit acetylcholinesterase, so acetylcholine accumulates
Indirectly acting — irreversible	Organophosphates — malathion, parathion, dyflos; nerve gases (sarin)	Phosphorylate the enzyme; recovery needs new enzyme synthesis

Pharmacological Actions

System	Muscarinic effects
Eye	Miosis (circular muscle of iris); spasm OF accommodation (ciliary muscle) with blurring for distance; reduced intraocular pressure by opening the trabecular meshwork
Cardiovascular	Bradycardia, reduced AV conduction and atrial force; vasodilatation and hypotension through endothelial nitric oxide (M3), even though vessels have no cholinergic innervation
Respiratory	Bronchoconstriction and increased bronchial secretion
Gastrointestinal	Increased motility, tone and secretion; sphincters relax; may cause colic, nausea and diarrhoea
Urinary	Detrusor contracts, trigone and sphincter relax — promotes voiding
Glands	Increased salivation, lacrimation and sweating
Nicotinic (with anticholinesterases)	Initial fasciculations then weakness and paralysis from persistent depolarisation; ganglionic stimulation

CLINICAL PEARL

Acetylcholine dilates vessels that have no cholinergic nerve supply at all. It acts on M3 receptors on vascular endothelium, releasing nitric oxide, which diffuses to the smooth muscle. Remove the endothelium and the same dose causes constriction — the experiment that led to the discovery of endothelium-derived relaxing factor.

Therapeutic Uses

Indication	Drug	Rationale
Glaucoma	Pilocarpine (topical)	Ciliary muscle contraction opens the trabecular meshwork and improves aqueous outflow; also used to break an attack of angle-closure
Myasthenia gravis	Neostigmine, pyridostigmine (treatment); edrophonium (diagnosis, brief action)	More acetylcholine competes for the reduced number of receptors
Post-operative urinary retention and paralytic ileus	Bethanechol, neostigmine	Stimulates detrusor and bowel; obstruction must be excluded first
Reversal of neuromuscular blockade	Neostigmine with glycopyrrolate or atropine	Reverses non-depolarising blockers; the antimuscarinic prevents bradycardia and secretions
Alzheimer disease	Donepezil, rivastigmine, galantamine	Cross the blood–brain barrier and raise central acetylcholine; symptomatic benefit only
Atropine and antimuscarinic poisoning	Physostigmine	A tertiary amine, so it crosses into the CNS and reverses the central delirium — neostigmine, a quaternary compound, does not
Dry mouth after radiotherapy; Sjogren syndrome	Pilocarpine, cevimeline	Stimulates residual salivary tissue

Organophosphorus Poisoning

Common and important in India, from agricultural insecticide, often self-poisoning
Mechanism — irreversible phosphorylation of acetylcholinesterase; "ageing" makes the bond permanent after some hours, after which oximes no longer work
Muscarinic features — mnemonic "dumbbells": Diarrhoea, Urination, Miosis, Bronchospasm, Bradycardia, Emesis, Lacrimation, Lethargy, Salivation
Nicotinic features — fasciculations, weakness, paralysis, tachycardia and hypertension from ganglionic stimulation
CNS features — anxiety, confusion, convulsions, coma, central respiratory depression
Death is from respiratory failure — bronchial secretions, bronchospasm, respiratory muscle paralysis and central depression acting together
Treatment — decontamination, airway and ventilation; atropine in large repeated doses titrated to dry secretions; pralidoxime to reactivate the enzyme, given early before ageing; diazepam for convulsions
Intermediate syndrome — proximal muscle weakness 24 to 96 hours later, needing ventilation; and delayed polyneuropathy weeks later

Muscarinic and Nicotinic Effects Compared

Feature	Muscarinic effects	Nicotinic effects
Receptor	G-protein coupled (M1–M5)	Ligand-gated ion channel (NN, NM)
Sites	Smooth muscle, cardiac muscle, glands, endothelium	Autonomic ganglia, adrenal medulla, neuromuscular junction
Effects	Bradycardia, bronchoconstriction, secretions, gut and bladder contraction, miosis	Fasciculation then paralysis; ganglionic stimulation with tachycardia and hypertension
Blocked by	Atropine	Not blocked by atropine — requires pralidoxime and ventilation
In poisoning	The "dumbbells" picture	Muscle weakness and respiratory failure — what actually kills

This is why atropine alone is not enough in organophosphorus poisoning — it treats only half the syndrome, and a patient can be pink, dry and still dying of respiratory muscle paralysis

Adverse Effects and Contraindications

Adverse effects — predictable extensions of the muscarinic actions: salivation, sweating, colic, diarrhoea, bradycardia, hypotension, bronchospasm, blurred vision, urinary urgency
Contraindicated in bronchial asthma (bronchoconstriction), peptic ulcer (acid secretion), intestinal or urinary obstruction (perforation risk), hyperthyroidism and coronary insufficiency
Cholinergic crisis in myasthenia — excessive anticholinesterase causes weakness that mimics a myasthenic crisis; the edrophonium test distinguishes them, since it improves myasthenic weakness and worsens cholinergic weakness

Applied Aspects

Give pralidoxime early — once ageing has occurred it is ineffective, so time matters more than dose
Atropine dosing in poisoning is far larger than textbook doses, often many milligrams repeated, and is guided by clearing chest secretions rather than by a fixed schedule
Exclude mechanical obstruction before giving bethanechol or neostigmine for retention or ileus, or perforation may result
Anticholinesterases used topically in glaucoma cause miosis and dim vision, particularly troublesome at night and in cataract
Protective equipment and safe storage of pesticides would prevent most Indian cases; this is a public health problem as much as a clinical one
Physostigmine, not neostigmine, for central antimuscarinic delirium — the tertiary/quaternary distinction determines which drug can act in the brain
Pilocarpine remains useful in acute angle-closure glaucoma, where pupillary constriction pulls the iris away from the drainage angle
Anticholinesterases for Alzheimer disease give modest and temporary benefit; they do not alter the underlying disease, and expectations must be set honestly with families
Bethanechol is resistant to cholinesterase and acts mainly on gut and bladder with little cardiovascular effect, which is why it is preferred for retention and ileus
Mushroom poisoning of the muscarinic type responds to atropine, while the more dangerous Amanita phalloides type does not and causes hepatic failure — the distinction matters

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