Cholinergic agonists

Overview
Cholinergic agonists are drugs that stimulate cholinergic receptors by mimicking the action of acetylcholine (ACh). They can act directly by binding to and activating muscarinic or nicotinic receptors, or indirectly by inhibiting cholinesterase enzymes, thereby increasing endogenous ACh levels. Their effects span the parasympathetic nervous system, somatic neuromuscular junctions, and certain areas of the central nervous system.

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Classification

1. Direct-Acting Cholinergic Agonists – Bind to and activate ACh receptors

   • Muscarinic receptor agonists (parasympathomimetics):

     • Examples: Bethanechol, Pilocarpine, Cevimeline, Methacholine, Carbachol

     • Primary effects: Smooth muscle contraction (GI, bladder), increased glandular secretions, miosis, bronchoconstriction, reduced heart rate

   • Nicotinic receptor agonists:

     • Examples: Nicotine, Varenicline (partial agonist), Succinylcholine (neuromuscular depolarizing blocker but initially stimulates nicotinic receptors)

     • Primary effects: Skeletal muscle contraction (NMJ), stimulation of autonomic ganglia and adrenal medulla

2. Indirect-Acting Cholinergic Agonists – Inhibit acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE)

   • Reversible inhibitors: Neostigmine, Pyridostigmine, Physostigmine, Edrophonium, Donepezil, Rivastigmine, Galantamine

   • Irreversible inhibitors: Echothiophate, Organophosphates (malathion, parathion), nerve agents (sarin, VX)

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Therapeutic Uses

• Ophthalmology: Pilocarpine, Carbachol, Echothiophate for glaucoma (reduce intraocular pressure by increasing aqueous humor outflow)

• GI & Urinary Disorders: Bethanechol for non-obstructive urinary retention or GI atony

• Xerostomia (Dry Mouth): Pilocarpine, Cevimeline for Sjögren’s syndrome or post-radiation dryness

• Neuromuscular Disorders: Neostigmine, Pyridostigmine for myasthenia gravis; reversal of non-depolarizing neuromuscular block

• Alzheimer’s Disease: Donepezil, Rivastigmine, Galantamine to improve cognitive symptoms

• Smoking Cessation: Nicotine replacement, Varenicline

• Diagnostic Uses: Methacholine challenge test for bronchial hyperreactivity

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Contraindications (general for muscarinic agonists)

• Asthma or COPD (risk of bronchospasm)

• Bradycardia, hypotension

• Coronary artery disease (due to reduced cardiac output)

• Peptic ulcer disease (increased gastric acid secretion)

• Urinary or GI tract obstruction

• Hyperthyroidism (risk of atrial fibrillation)

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Adverse Effects (muscarinic stimulation)

• Common: Sweating, flushing, salivation, lacrimation, rhinorrhea, abdominal cramps, diarrhea, nausea, vomiting, urinary urgency, miosis, blurred vision

• Cardiovascular: Bradycardia, hypotension

• Respiratory: Bronchoconstriction, increased secretions

• With nicotinic agonists: Muscle cramps, fasciculations, hypertension (ganglionic stimulation), tachycardia, CNS stimulation

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Drug Interactions

• Anticholinergics (e.g., atropine, scopolamine, TCAs, antihistamines) antagonize effects

• Other cholinergic drugs (including cholinesterase inhibitors) increase risk of cholinergic toxicity

• Beta-blockers: Additive bradycardia risk with muscarinic agonists

• Neuromuscular blockers: Succinylcholine effects prolonged with cholinesterase inhibitors