Pharmacology chapters
Cholinergic and anticholinergic drugs
Drugs that copy, boost or block acetylcholine: cholinergic receptors, direct agonists (bethanechol, pilocarpine), anticholinesterases (neostigmine, pyridostigmine, physostigmine), organophosphate poisoning and its treatment, muscarinic blockers (atropine and others) and neuromuscular blockers.
- Acetylcholine acts on muscarinic (G protein: M1 nerves/stomach, M2 heart (slows it), M3 glands, smooth muscle, eye) and nicotinic receptors (ion channels at ganglia and the neuromuscular junction); it is broken down by acetylcholinesterase.
- Anticholinesterases: neostigmine/pyridostigmine (quaternary, do not enter brain: myasthenia gravis, reversing non-depolarising block), physostigmine (tertiary, enters brain: atropine poisoning), edrophonium (very short: diagnosis); organophosphates inhibit the enzyme irreversibly → SLUDGE + bradycardia, miosis, bronchorrhoea, fasciculations and paralysis; treat with atropine (muscarinic effects) and pralidoxime early (reactivates the enzyme before "ageing").
- Atropine blocks muscarinic receptors: dry mouth, tachycardia, mydriasis with cycloplegia, urinary retention, hot dry skin, delirium ("dry as a bone, red as a beet, blind as a bat, mad as a hatter, hot as a hare"); antidote physostigmine.
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Acetylcholine basics
- Made from choline + acetyl-CoA by choline acetyltransferase; stored in vesicles; release needs calcium (blocked by botulinum toxin).
- Broken down rapidly by acetylcholinesterase into choline and acetate.
- Released at: all autonomic ganglia, parasympathetic post-ganglionic endings, sympathetic fibres to sweat glands, the neuromuscular junction, the adrenal medulla and the brain.
Cholinergic receptors
| Receptor | Type | Main sites | Effects |
|---|---|---|---|
| M1 | Gq | Nerves, stomach (parietal cell regulation), CNS | Gastric acid, memory |
| M2 | Gi | Heart | ↓ heart rate and AV conduction |
| M3 | Gq | Glands, smooth muscle, eye, endothelium | Secretions, bronchoconstriction, gut motility, bladder contraction, miosis, accommodation, vasodilation (via nitric oxide) |
| Nicotinic N_N (ganglionic) | Ion channel | Autonomic ganglia, adrenal medulla | Ganglionic transmission |
| Nicotinic N_M (muscle) | Ion channel | Neuromuscular junction | Skeletal muscle contraction |
Muscarinic effects (the parasympathetic picture)
- Eye: miosis (sphincter pupillae), accommodation for near vision (ciliary muscle), lower intraocular pressure.
- Heart: bradycardia, slowed AV conduction.
- Lungs: bronchoconstriction, more secretions.
- Gut: more motility and secretions, sphincters relax.
- Bladder: detrusor contracts, sphincter relaxes → urination.
- Glands: sweating, salivation, tears.
Direct-acting cholinergic agonists
| Drug | Notes | Uses |
|---|---|---|
| Bethanechol | Muscarinic; resists cholinesterase | Urinary retention (post-operative), gut atony |
| Carbachol | Muscarinic and nicotinic | Miosis in eye surgery |
| Pilocarpine | Muscarinic; tertiary | Glaucoma (especially acute angle-closure), dry mouth (Sjögren) |
| Methacholine | Muscarinic | Bronchial challenge test for asthma |
Pilocarpine contracts the ciliary muscle and sphincter pupillae, opening the trabecular meshwork and pulling the iris from the drainage angle.
Anticholinesterases (indirect agonists)
They block acetylcholinesterase, so acetylcholine builds up at muscarinic and nicotinic sites.
Reversible
| Drug | Structure | Uses |
|---|---|---|
| Edrophonium | Quaternary; very short acting (minutes) | Formerly the Tensilon test for myasthenia gravis |
| Neostigmine | Quaternary: does not cross the blood-brain barrier | Myasthenia gravis, reversal of non-depolarising neuromuscular block, post-operative urinary retention and ileus |
| Pyridostigmine | Quaternary; longer-acting | Myasthenia gravis (drug of choice for symptoms) |
| Physostigmine | Tertiary: crosses the blood-brain barrier | Atropine (anticholinergic) poisoning; glaucoma |
| Donepezil, rivastigmine, galantamine | Centrally acting | Alzheimer disease |
For atropine poisoning, use physostigmine (it reaches the brain and reverses delirium); neostigmine stays outside the brain.
Myasthenic vs cholinergic crisis: too little drug (myasthenic crisis) and too much (cholinergic crisis: excess secretions, fasciculations, weakness) both cause weakness; the response to a short-acting anticholinesterase was used to tell them apart.
Irreversible: organophosphates
Organophosphates (insecticides such as malathion, parathion, chlorpyrifos; nerve agents such as sarin) bind acetylcholinesterase covalently. Over time the bond becomes permanent: "ageing". Pesticide poisoning (from swallowing or farm exposure) is a common emergency in Pakistan.
Features (excess acetylcholine everywhere):
- Muscarinic: DUMBELS / SLUDGE: Diarrhoea, Urination, Miosis (pinpoint pupils), Bradycardia and Bronchorrhoea and Bronchospasm, Emesis, Lacrimation, Salivation and sweating.
- Nicotinic: muscle fasciculations, cramps, then weakness and paralysis (including respiratory muscles); tachycardia and hypertension may occur (ganglionic stimulation).
- CNS: confusion, seizures, coma, respiratory depression.
Treatment:
- Airway, breathing, circulation; remove contaminated clothes and wash skin; staff protect themselves.
- Atropine IV in large, repeated doses until secretions dry (chest clear), heart rate adequate and blood pressure acceptable. Atropine treats muscarinic effects only; it does not reverse muscle weakness. Pupil size is not the target.
- Pralidoxime (an oxime) reactivates acetylcholinesterase if given early, before ageing; it helps the nicotinic effects (muscle weakness).
- Diazepam for seizures; ventilation if needed.
Atropine treats the muscarinic effects; pralidoxime reactivates the enzyme and helps the nicotinic muscle weakness. Pralidoxime is not useful for carbamate poisoning in the same way.
Antimuscarinic (anticholinergic) drugs
| Drug | Main uses |
|---|---|
| Atropine | Bradycardia (symptomatic), organophosphate poisoning, pre-anaesthetic (dry secretions), with neostigmine (to block its muscarinic effects) |
| Hyoscine (scopolamine) hydrobromide | Motion sickness (patch); sedation; amnesia |
| Hyoscine butylbromide | Gut and biliary colic (antispasmodic); does not enter brain |
| Ipratropium, tiotropium (inhaled) | COPD and asthma (bronchodilation) |
| Tropicamide (short), cyclopentolate, homatropine, atropine (longest) | Eye examination: mydriasis and cycloplegia (for refraction in children) |
| Oxybutynin, tolterodine, solifenacin | Overactive bladder (urge incontinence) |
| Benztropine, trihexyphenidyl (benzhexol) | Parkinsonism and drug-induced extrapyramidal effects |
| Glycopyrrolate | Reduces secretions; used with neostigmine; does not enter brain |
Effects and atropine poisoning
Atropine blocks muscarinic effects, giving the opposite of the parasympathetic picture. The classic description:
- "Dry as a bone": dry mouth, no sweating.
- "Red as a beet": flushed skin (vasodilation).
- "Blind as a bat": mydriasis and cycloplegia (blurred near vision).
- "Mad as a hatter": confusion, delirium, hallucinations.
- "Hot as a hare": hyperthermia (no sweating; children are vulnerable).
- Also tachycardia, urinary retention, constipation.
Causes: overdose of atropine or datura seeds, and drugs with strong anticholinergic effects (tricyclic antidepressants, antihistamines, antipsychotics). Antidote: physostigmine (with care).
Contraindications: angle-closure glaucoma (mydriasis blocks drainage), prostatic enlargement (urinary retention), paralytic ileus, tachyarrhythmias.
Neuromuscular blockers
| Feature | Depolarising: suxamethonium (succinylcholine) | Non-depolarising: atracurium, cisatracurium, vecuronium, rocuronium, pancuronium |
|---|---|---|
| Mechanism | Nicotinic agonist: depolarises then keeps the end-plate depolarised (phase I block); prolonged use causes phase II block | Competitive antagonists at the nicotinic receptor |
| Onset and duration | Fastest onset (about a minute), shortest duration (about 5–10 minutes): ideal for rapid sequence intubation | Slower onset (rocuronium is fast), longer action |
| Sign | Fasciculations first | No fasciculations |
| Reversal | Not reversed by neostigmine (made worse in phase I); broken down by plasma pseudocholinesterase | Neostigmine (with glycopyrrolate or atropine); sugammadex binds rocuronium and vecuronium |
| Key adverse effects | Hyperkalaemia (avoid in burns, crush injury, denervation, renal failure), malignant hyperthermia, prolonged apnoea in pseudocholinesterase deficiency, muscle pain, raised intraocular and intragastric pressure, bradycardia | Histamine release (older agents like tubocurarine; atracurium mildly); atracurium undergoes Hofmann elimination (independent of liver and kidney: useful in organ failure) |
Suxamethonium = fasciculations, hyperkalaemia, malignant hyperthermia, pseudocholinesterase deficiency. Atracurium = Hofmann elimination. Sugammadex reverses rocuronium.
Botulinum toxin blocks acetylcholine release (used for dystonia, spasticity, achalasia, cosmetic uses); dantrolene acts inside muscle (ryanodine receptor) and is not a neuromuscular blocker.
Expect: muscarinic receptor subtypes and effects, uses of bethanechol and pilocarpine, neostigmine vs physostigmine (quaternary vs tertiary), drugs for myasthenia gravis, features and treatment of organophosphate poisoning (atropine and pralidoxime, ageing), atropine effects and poisoning, contraindications of anticholinergics, uses of hyoscine, ipratropium, tropicamide and oxybutynin, and depolarising vs non-depolarising neuromuscular blockers with their reversal.
Quick revision
- M2 heart; M3 glands, smooth muscle, eye. Nicotinic: ganglia and NMJ.
- Bethanechol: urinary retention. Pilocarpine: glaucoma.
- Neostigmine/pyridostigmine: myasthenia (no CNS). Physostigmine: atropine poisoning (CNS).
- Organophosphates: SLUDGE + miosis + bradycardia + fasciculations; atropine + pralidoxime.
- Atropine: dry, red, blind, mad, hot; avoid in angle-closure glaucoma and BPH.
- Suxamethonium: fasciculations, hyperkalaemia, MH, pseudocholinesterase. Non-depolarisers reversed by neostigmine or sugammadex.
Written by The House Job from standard pharmacology references (Katzung's Basic and Clinical Pharmacology).
FAQ
How is organophosphate poisoning treated?
Decontamination and supportive care, large repeated doses of atropine until secretions dry, pralidoxime given early to reactivate cholinesterase, and diazepam for seizures.
Why is physostigmine used for atropine poisoning instead of neostigmine?
Physostigmine is a tertiary amine that crosses the blood-brain barrier and reverses the central effects; neostigmine is quaternary and does not enter the brain.
What are the features of atropine poisoning?
Dry mouth and skin, flushing, dilated pupils with blurred vision, fever, delirium, tachycardia and urinary retention.
How is a non-depolarising neuromuscular block reversed?
With neostigmine, given with glycopyrrolate or atropine, or with sugammadex for rocuronium and vecuronium.