What is the mechanism of action of anticholinergics?

Mechanism of Action of Anticholinergics

Anticholinergics work by blocking muscarinic receptors, preventing acetylcholine from binding to these receptors and thereby inhibiting parasympathetic nervous system activity. 1

Primary Mechanism

• Anticholinergics are muscarinic receptor antagonists that competitively and reversibly block the binding of acetylcholine to muscarinic receptors (M1-M5) 1
• They prevent the accumulation of acetylcholine at muscarinic receptors, thereby inhibiting parasympathetic nervous system stimulation 2
• The blockade of muscarinic receptors, particularly M3 receptors in the airways, leads to bronchodilation by preventing acetylcholine-induced smooth muscle contraction 1

Receptor Specificity

• Different anticholinergic medications have varying affinities for the five muscarinic receptor subtypes (M1-M5) 1
• Some anticholinergics like tiotropium have similar affinity to all muscarinic receptor subtypes 1
• Newer selective anticholinergics like pirenzepine preferentially block specific receptor subtypes (e.g., M1 receptors) to achieve targeted effects with fewer side effects 3

Tissue-Specific Effects

• In the airways: Blockade of M3 receptors on smooth muscle prevents bronchoconstriction, making anticholinergics effective bronchodilators for conditions like COPD and asthma 4
• In the gastrointestinal tract: Anticholinergics reduce gastric acid secretion and smooth muscle contractions 3
• In the urinary tract: Blockade of muscarinic receptors reduces bladder contractions, helping with urinary incontinence 2
• In secretory glands: Anticholinergics reduce excessive lacrimation, salivation, and perspiration by blocking muscarinic stimulation 2

Central vs. Peripheral Effects

• First-generation anticholinergics can cross the blood-brain barrier and block central muscarinic receptors, leading to cognitive effects 2
• Newer anticholinergics like tiotropium have limited systemic absorption (only about 7% when inhaled) and minimal central nervous system penetration 2
• The central anticholinergic effects are particularly concerning in older adults, contributing to cognitive impairment and delirium 5

Clinical Applications

• Respiratory conditions: Anticholinergics like tiotropium are first-line bronchodilators for COPD as they block the only reversible component of airway obstruction in this condition 4
• Gastrointestinal disorders: Anticholinergics reduce gastric acid secretion and smooth muscle spasms 3
• Urinary incontinence: They reduce bladder contractions by blocking muscarinic receptors 2
• Nerve agent poisoning: Atropine is the "gold standard" treatment for nerve agent intoxication as it blocks the muscarinic receptor overstimulation caused by acetylcholine accumulation 2

Adverse Effects Related to Mechanism

• The broad muscarinic receptor blockade results in predictable side effects summarized as "dry as a bone, blind as a bat, red as a beet, mad as a hatter, hot as a hare" 2
• These effects include dry mouth, blurred vision, tachycardia, confusion, and hyperthermia 2
• In older adults, anticholinergic burden (cumulative effect of multiple medications with anticholinergic properties) can significantly impair cognition, functionality, and increase fall risk 6
• Anticholinergic medications are particularly problematic in elderly patients due to age-related decline in cholinergic function 2

Pharmacodynamic Considerations

• The bronchodilation following inhalation of anticholinergics like tiotropium is predominantly a site-specific effect 1
• The competitive and reversible nature of muscarinic antagonism has been demonstrated with human and animal receptors 1
• In preclinical studies, the prevention of methacholine-induced bronchoconstriction by tiotropium was dose-dependent and lasted longer than 24 hours 1

Understanding the mechanism of action of anticholinergics is crucial for appropriate clinical use and minimizing adverse effects, particularly in vulnerable populations like the elderly.