How are cholinergic drugs classified?
Cholinergic (parasympathomimetic) drugs act on the transmitter that runs the parasympathetic nervous system, acetylcholine (ACh). There are two broad groups: direct-acting agonists, which bind and activate (mainly muscarinic) receptors, and indirect-acting agents (anticholinesterases), which block acetylcholinesterase and so increase ACh at the receptors.
| Group | Subgroup | Drugs |
|---|---|---|
| Direct-acting | Choline esters | Acetylcholine, methacholine, carbachol, bethanechol |
| Direct-acting | Natural alkaloids | Muscarine, pilocarpine, cevimeline |
| Indirect — reversible | Anticholinesterases | Physostigmine, neostigmine, pyridostigmine, edrophonium; rivastigmine, donepezil, galantamine (for dementia) |
| Indirect — irreversible | Organophosphates | Echothiophate, parathion, malathion, diazinon, nerve agents (tabun, sarin, soman) |
Which receptors does acetylcholine act on, and what are the effects?
| Receptor | Where | Effect of stimulation |
|---|---|---|
| M1 | Gastric parietal cells; CNS | Gastric secretion; CNS stimulation |
| M2 | Heart; visceral smooth muscle | Bradycardia, slowed AV conduction (SA nodal hyperpolarisation) |
| M3 | Smooth muscle, exocrine glands, bladder; blood vessels | Contraction of smooth muscle (gut, bladder detrusor, bronchi), glandular secretion, miosis, vasodilation |
| Nicotinic (Nm, Nn) | CNS, adrenal medulla, autonomic ganglia, neuromuscular junction | Ganglionic stimulation; skeletal-muscle twitching then paralysis at higher doses |
- Heart: bradycardia (even arrest), AV block; atrial fibrillation or flutter can be provoked by uneven vagal innervation of the atrium.
- Vessels: dilation, fall in BP and flushing.
- Gut and bladder: increased tone and peristalsis, relaxed sphincters — cramps, evacuation, voiding.
- Lungs: bronchoconstriction (can precipitate asthma) and increased secretions.
- Glands: salivation, sweating, lacrimation, gastric and tracheobronchial secretions.
- Eye: pilocarpine drops contract the iris sphincter (miosis) and cause spasm of accommodation.
- CNS: acetylcholine given IV does not cross the blood–brain barrier; drugs that do enter the brain give stimulation followed by depression.
What are the clinical uses of cholinergic drugs?
| Condition | Drug and note |
|---|---|
| Myasthenia gravis | First-line symptomatic therapy: pyridostigmine (preferred over neostigmine for its longer duration) |
| Reversal of non-depolarising neuromuscular block | Neostigmine, preceded or accompanied by atropine or glycopyrrolate to block muscarinic effects |
| Postoperative and postpartum non-obstructive urinary retention; hypotonic neurogenic bladder | Bethanechol (also neostigmine for retention) |
| Open-angle glaucoma | Pilocarpine, carbachol — raise aqueous outflow; now third-choice add-on miotics |
| Intra-ocular surgery | Carbachol as an intra-ocular miotic |
| Breaking iris–lens adhesions | Alternating atropine (mydriatic) and pilocarpine (miotic) |
| Alzheimer dementia (mild to moderate) | Donepezil, rivastigmine, galantamine |
| Dry mouth in Sjögren syndrome | Cevimeline (approved); pilocarpine |
| Anticholinergic poisoning (atropine, scopolamine, diphenhydramine) | Physostigmine — only for toxic, life-threatening delirium |
| Acute colonic pseudo-obstruction; neurotoxic snakebite | Neostigmine (off-label / when antivenom unavailable or ineffective) |
| Neurogenic orthostatic hypotension | Pyridostigmine (facilitates ganglionic transmission) |
| Parameter | Value |
|---|---|
| Dose | 0.03 to 0.07 mg/kg IV (up to 5 mg), the higher dose when the first twitch is only just above 10% of baseline |
| When | After the first twitch on the nerve stimulator is above 10% of baseline, or a second twitch is present |
| Onset and duration | Peak effect at 7 to 10 minutes; duration about 55 to 75 minutes |
| Co-drug | Glycopyrrolate or atropine, to attenuate muscarinic effects |
How are anticholinesterases used in myasthenia gravis?
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction, with antibodies against the nicotinic acetylcholine receptor, MuSK or LRP4. About 10% of patients have a thymoma. Anticholinesterases are symptomatic treatment: they stop ACh breakdown so that more transmitter reaches the reduced number of receptors.
- Pyridostigmine bromide is the usual first-line drug and is preferred over neostigmine because of its longer duration of action. It is oral; parenteral in those who cannot swallow.
- Ambenonium chloride can be used if bromide causes GI intolerance.
- MuSK-positive MG responds poorly to these drugs and may need higher doses.
- Patients still symptomatic need immunosuppression: glucocorticoids and azathioprine first line; ciclosporin, methotrexate, mycophenolate, cyclophosphamide and tacrolimus second line.
- Imaging of the chest (CT or MRI) is done to look for thymoma.
| Feature | Myasthenic crisis | Cholinergic crisis |
|---|---|---|
| Cause | Under-treated MG; infection, surgery, menstruation, drugs that impair neuromuscular function (some antibiotics, quinidine, calcium channel blockers) | Excess anticholinesterase dose, or insecticide exposure |
| Weakness | Present | Present, with muscarinic features (secretions, miosis, bradycardia, diarrhoea) and fasciculations |
| Edrophonium 2 mg IV | Improves | Worsens |
| Management | Treat the precipitant; support breathing if needed | Atropine for muscarinic effects, pralidoxime for nicotinic toxicity, supportive care |
What are the adverse effects and contraindications?
Cholinergic drugs cause adverse effects in any organ under parasympathetic control: bradycardia and AV block, hypotension and flushing, cramps and diarrhoea, urinary urgency, bronchospasm, salivation, sweating and lacrimation, miosis. Anticholinesterases additionally cause fasciculations and, at high dose, neuromuscular blockade.
- Bronchial asthma / COPD
- Peptic ulcer disease (use with caution)
- Arrhythmias (especially atrial fibrillation) and coronary artery disease
- Angle-closure glaucoma
- Hyperthyroidism
- Intestinal resection or anastomosis; urinary obstruction
- Orthostatic hypotension; severe miosis
How do organophosphates poison, and how is it treated?
Organophosphates (OPs) are insecticides (parathion, malathion), nerve agents (sarin) and some herbicides. They are absorbed through the skin, lungs and gut. An OP phosphorylates the serine in the active site of acetylcholinesterase, forming a strong covalent bond — so ACh accumulates and overstimulates muscarinic, nicotinic and central receptors. Spontaneous regeneration is slow (hours to days). With time the bond undergoes aging and becomes irreversible; the time varies by compound. Respiratory failure — bronchorrhoea, bronchospasm, central depression and muscle weakness — is the commonest cause of death. Mortality worldwide is quoted as 2% to 25%.
| System | Features |
|---|---|
| Muscarinic | DUMBELS: salivation, lacrimation, urination, defecation, miosis, bronchorrhoea, bradycardia (sinus bradycardia on ECG) |
| Nicotinic | Fasciculations, myoclonic jerks, then flaccid paralysis from a depolarising block; hypertension, tachycardia, sweating |
| CNS | Anxiety, confusion, seizures, coma, central respiratory depression |
| Clues | Pinpoint pupils, a garlic or petroleum smell |
| Step | Detail |
|---|---|
| Safety and decontamination | Rescuers wear protective equipment; remove clothing; wash the skin with soap and water 3 times; do not delay urgent care for decontamination |
| Airway | Secure it early (bronchospasm, bronchorrhoea, seizures). Avoid succinylcholine — it is not metabolised normally and prolongs paralysis |
| Atropine | Competes with ACh at muscarinic receptors. 2 to 5 mg IV in adults (0.05 mg/kg in children); double the dose every 3 to 5 minutes until secretions clear and there is no bronchoconstriction — atropinisation (dry skin and mucosa, tachycardia, mydriasis, reduced secretions). Judge by heart rate, BP and respiratory status rather than pupils or skin |
| Pralidoxime (2-PAM) | Reactivates phosphorylated enzyme; works only before aging; give after atropine. WHO-based regimen: 30 mg/kg IV over 30 minutes, then 8 mg/kg/hour. Evidence for benefit is controversial |
| Seizures | Benzodiazepines |
| Disposition | Admit and monitor in ICU for at least 48 hours; those asymptomatic for 12 hours may be discharged |
What are the complications and scoring in OP poisoning?
- Intermediate syndrome: muscle weakness 24 to 96 hours after poisoning, after the cholinergic crisis has resolved. Proximal limb weakness and cranial nerve palsies can progress to respiratory failure with no cholinergic signs or fasciculations; consciousness preserved; can last weeks. Neck flexors are often affected first — examine them.
- Peradeniya Organophosphorus Poisoning (POP) scale: developed in India in 1993 to grade severity and predict prognosis, using six parameters — miosis, fasciculations, respiration, bradycardia, level of consciousness and seizures.
- Occupational monitoring: serum and red-cell cholinesterase at baseline and then every 30 days; a fall of more than 20% from baseline should trigger a review of work practices.
- Diagnostic trial: if OP poisoning is suspected, improvement after 0.6 to 1 mg atropine supports it, but severe poisoning can give a false negative.
What do exams ask about cholinergic drugs?
- Drug of choice in myasthenia gravis — pyridostigmine.
- Reversal of non-depolarising blockers — neostigmine with atropine or glycopyrrolate.
- Postoperative urinary retention — bethanechol (neostigmine).
- Antidote for anticholinergic poisoning — physostigmine.
- First drug in OP poisoning — atropine; endpoint atropinisation (secretions dry), not pupil size.
- Pralidoxime — only before aging; reactivates AChE; given after atropine.
- Muscle relaxant to avoid in OP poisoning — succinylcholine.
- Intermediate syndrome — 24 to 96 hours, proximal weakness, neck flexors first.
- Edrophonium — improves myasthenic crisis, worsens cholinergic crisis.
- Contraindications — asthma, COPD, peptic ulcer, arrhythmias, angle-closure glaucoma, urinary or intestinal obstruction.