Cholinergic Agonists

Cholinergic agonists directly activate acetylcholine receptors, mainly muscarinic receptors, and reproduce parasympathetic stimulation without needing cholinesterase inhibition. Clinical use is narrow: non-obstructive urinary retention, xerostomia, glaucoma and surgical miosis, and bronchial challenge testing.

Classification. Choline esters (bethanechol, carbachol, methacholine, acetylcholine) and alkaloids or synthetic agonists (pilocarpine, cevimeline). Acetylcholine is hydrolysed too quickly for systemic use. Nicotinic agonists such as nicotine and varenicline act on different receptors and are not part of this class.

Receptor selectivity. Bethanechol is almost purely muscarinic. Carbachol and methacholine have muscarinic activity, with carbachol also acting at nicotinic receptors. Pilocarpine is a partial muscarinic agonist with a predominant M3 effect. Cevimeline is selective for M1 and M3.

Mechanism. M1, M3 and M5 receptors couple to Gq, activating phospholipase C with inositol trisphosphate-mediated calcium release and protein kinase C activation. M2 and M4 couple to Gi, lowering cyclic AMP and opening potassium channels, which slows the sinoatrial node and atrioventricular conduction. Endothelial M3 stimulation releases nitric oxide and causes vasodilation even though most vessels lack parasympathetic innervation.

Organ effects. Eye: miosis and ciliary muscle contraction that opens the trabecular meshwork and lowers intraocular pressure. Heart: bradycardia and slowed atrioventricular conduction. Airways: bronchoconstriction and increased secretions. Gut: raised tone, motility and secretion. Bladder: detrusor contraction with sphincter relaxation. Glands: salivation, lacrimation and sweating.

Pharmacokinetics. Quaternary esters (bethanechol, carbachol, methacholine) are poorly and variably absorbed orally and do not enter the brain. Bethanechol is resistant to cholinesterase, begins to act within 30 to 90 minutes of an oral dose and lasts up to 6 hours. Pilocarpine and cevimeline are tertiary, absorbed orally and cross into the central nervous system. Pilocarpine is metabolised mainly by CYP2A6 and cevimeline by CYP2D6 and CYP3A4.

• Bethanechol: oral; muscarinic only; acts on detrusor and gut; no central effects. The only member used for bladder emptying.
• Pilocarpine: oral for dry mouth, topical for glaucoma; the only member with meaningful sweating, central and cardiovascular effects at oral doses.
• Cevimeline: oral for Sjogren syndrome dry mouth; M3 preference gives fewer cardiac effects than pilocarpine, but it carries similar cardiopulmonary cautions.
• Methacholine: inhaled only, for bronchoprovocation; not given systemically because of profound bronchoconstriction and bradycardia.
• Carbachol: intraocular 0.01% for miosis at cataract surgery, and topical drops for glaucoma in some regions. Resistant to cholinesterase, so it lasts longer than acetylcholine.
• Acetylcholine: intraocular for rapid miosis in surgery; effect is brief because of fast hydrolysis.

• Non-obstructive urinary retention: bethanechol 10 to 50 mg orally 3 to 4 times daily on an empty stomach. Use only after mechanical obstruction is excluded. Evidence of benefit is limited, and intermittent catheterisation is preferred for neurogenic retention. Never give intravenously or intramuscularly because of circulatory collapse and cardiac arrest.
• Dry mouth after head and neck radiotherapy: pilocarpine 5 mg orally 3 times daily, increased to 10 mg 3 times daily if tolerated. Cevimeline 30 mg orally 3 times daily is an alternative.
• Sjogren syndrome: pilocarpine 5 mg orally 4 times daily or cevimeline 30 mg 3 times daily. Judge response over 8 to 12 weeks and stop if there is none.
• Glaucoma: pilocarpine 1% to 4% drops up to 4 times daily. Now a later option behind prostaglandin analogues, beta blocker drops and others. After pressure-lowering therapy in acute angle closure, pilocarpine 2% draws the iris away from the angle.
• Methacholine challenge: inhaled in doubling concentrations until FEV1 falls by 20% (PC20). PC20 under 4 mg/mL supports asthma, 4 to 16 mg/mL is borderline and over 16 mg/mL makes asthma unlikely. A negative result has a high negative predictive value. Withhold bronchodilators beforehand.
• Selection: postoperative or postpartum retention is usually managed with catheterisation first. A cholinesterase inhibitor such as neostigmine is an alternative short-term option.

Contraindications. Asthma or active bronchospasm, severe COPD, bradycardia, atrioventricular block, hypotension, recent myocardial infarction, hyperthyroidism, peptic ulcer disease, mechanical gastrointestinal or urinary obstruction, epilepsy, parkinsonism. Pilocarpine by mouth is contraindicated in acute iritis and narrow-angle glaucoma. Methacholine challenge is avoided with FEV1 under 60% of predicted, recent myocardial infarction or stroke, uncontrolled hypertension and aortic aneurysm.

Adverse effects. Sweating, salivation, flushing, nausea, abdominal cramps, diarrhoea, urinary urgency, bradycardia, hypotension, bronchospasm, blurred vision and headache.

Overdose. Salivation, lacrimation, sweating, bradycardia, bronchospasm, vomiting and hypotension. Give atropine 0.6 mg intravenously, repeated every 2 to 5 minutes until muscarinic signs settle, and supportive care. Adrenaline is reserved for severe circulatory collapse or bronchospasm.

Interactions. Antimuscarinics oppose the effect. Beta blockers add bradycardia and bronchospasm risk. Other cholinergic agents and cholinesterase inhibitors add toxicity. Ganglion blockers with bethanechol can cause severe hypotension.

Monitoring. Heart rate, blood pressure, respiratory status and symptom response at each dose change. Pilocarpine dry mouth response is judged over weeks.

Special groups. Avoid in pregnancy unless benefit is clear. Older adults are more prone to bradycardia and falls. Pilocarpine needs reduced dosing in moderate hepatic impairment (5 mg 3 times daily at most) and is not advised in severe impairment.