How do muscarinic (muscarinic) agonists and antagonists work?

Mechanism of Action of Muscarinic Agents

Muscarinic agonists work by binding to and activating muscarinic acetylcholine receptors (M1-M5 subtypes), mimicking the action of acetylcholine to stimulate parasympathetic responses, while muscarinic antagonists competitively block these same receptors to prevent acetylcholine binding and inhibit parasympathetic activity. 1, 2

Muscarinic Agonists

Receptor Binding and Activation

• Muscarinic agonists are cholinergic parasympathomimetic agents that bind to muscarinic receptors and exert broad pharmacologic effects with predominant muscarinic action. 1
• These agents activate muscarinic receptors distributed throughout both peripheral and central nervous systems, regulating various cholinergic functions. 3

Physiological Effects by Organ System

Exocrine Glands:

• Muscarinic agonists increase secretion by exocrine glands including sweat, salivary, lacrimal, gastric, pancreatic, and intestinal glands, as well as mucous cells of the respiratory tract. 1
• In salivary glands, muscarinic agonists activate M3 receptors on secretory acinar cells to stimulate secretion and cause contraction of myoepithelial cells. 4
• Pilocarpine produces dose-related increases in unstimulated salivary flow with onset at 20 minutes, peak effect at 1 hour, and duration of 3-5 hours. 1

Ocular Effects:

• Muscarinic agonists act mainly via M3 receptors to cause contraction of the iris sphincter, ciliary muscle, and trabecular meshwork, while increasing aqueous humor outflow facility. 4
• When applied topically to the eye, these agents cause miosis, spasm of accommodation, and may cause transitory rise in intraocular pressure followed by more persistent fall. 1

Smooth Muscle:

• Dose-related smooth muscle stimulation of the intestinal tract causes increased tone, motility, spasm, and tenesmus. 1
• Bronchial smooth muscle tone may increase, and tone and motility of urinary tract, gallbladder, and biliary duct smooth muscle may be enhanced. 1

Bladder Function:

• In the urinary bladder, parasympathetic nervous system maintains normal function by contracting detrusor smooth muscle via M3 receptors and providing indirect "re-contraction" via M2 receptors through reduction in adenylate cyclase activity. 5

Receptor Subtype Specificity

• Cevimeline binds to muscarinic receptors as a cholinergic agonist, with metabolism primarily by CYP2D6 and CYP3A3/4 isozymes. 6
• Pilocarpine's neuroprotective effects on retinal neurons are largely mediated through M1-selective muscarinic receptors, as demonstrated by abolishment with M1-selective antagonist pirenzepine. 7

Muscarinic Antagonists

Mechanism of Receptor Blockade

• Muscarinic antagonists are competitive antagonists that bind to muscarinic receptors and prevent acetylcholine from binding, thereby blocking parasympathetic activity. 2
• Tolterodine is a competitive muscarinic receptor antagonist with high specificity for muscarinic receptors, showing negligible activity for other neurotransmitter receptors or cellular targets such as calcium channels. 2

Respiratory Applications

• In the airways, muscarinic antagonists like tiotropium inhibit acetylcholine release at the receptor level by binding to M2 and M3 muscarinic receptors lining the airway, producing bronchodilation. 8
• Vagal-mediated tone through released acetylcholine at motor nerve endings is responsible for both resting and bronchoconstrictive airway responses in asthma and COPD. 8
• Parasympathetic activity is the dominant reversible component in COPD patients, as sympathetic terminals on airway smooth muscle cells are rare or nonexistent. 8

Urinary Bladder Effects

• Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors, making antagonists effective for treating overactive bladder. 2
• Tolterodine's main effects include increase in residual urine (reflecting incomplete bladder emptying) and decrease in detrusor pressure, consistent with antimuscarinic action on the lower urinary tract. 2

Multiple Receptor Locations

• Muscarinic receptors exist at three key bladder locations: detrusor smooth muscle (direct contraction), urothelium (release of inhibitory factors), and prejunctionally on nerve terminals (M1 facilitates transmitter release while M2/M4 inhibit release). 5

Clinical Implications

Therapeutic Benefits

• Long-acting muscarinic antagonists reduce risk of acute COPD exacerbations, improve quality of life, increase exercise capacity, and demonstrate acceptable safety profiles. 8
• The American College of Chest Physicians recommends long-acting muscarinic antagonists over placebo (Grade 1A) and over long-acting β-agonists (Grade 1C) for preventing moderate to severe COPD exacerbations. 8

Common Pitfalls

• Potential side effects of muscarinic antagonists include dry mouth, urinary retention, and glaucoma due to widespread distribution of muscarinic receptors. 8
• Muscarinic agonists like bethanechol have not been demonstrated effective for underactive detrusor function in urinary retention, contrary to historical use. 9
• Atropine produces unwanted side-effects including dilated pupils, blurred vision, light sensitivity, and dry mouth due to non-selective muscarinic receptor blockade. 3

Pharmacokinetic Considerations

• Pilocarpine is highly protein-bound (primarily to α1-acid glycoprotein) with mean elimination half-life of 0.76-1.35 hours depending on dose. 1
• Tolterodine is extensively metabolized by liver via CYP2D6, forming the active 5-hydroxymethyl metabolite that contributes significantly to therapeutic effect. 2
• Food intake increases pilocarpine bioavailability by 53% but does not affect active metabolite levels in extensive metabolizers. 1