What is the pathophysiology of anticholinergics?

Pathophysiology of Anticholinergics

Primary Mechanism of Action

Anticholinergics competitively block acetylcholine at muscarinic receptors, thereby inhibiting parasympathetic nervous system activity throughout the body. 1, 2 This competitive inhibition prevents acetylcholine accumulation at muscarinic receptor sites, leading to widespread effects across multiple organ systems. 1

Receptor-Level Pathophysiology

• Muscarinic receptor blockade is the fundamental mechanism, with acetylcholine being a critical modulator of interactions among most other central neurotransmitters. 3
• The blockade occurs at five muscarinic receptor subtypes (M1-M5), though anticholinergics vary in their receptor selectivity and tissue distribution. 2
• Quaternary ammonium compounds (like ipratropium) cannot cross the blood-brain barrier due to their charged structure, limiting effects to peripheral tissues. 2
• Tertiary amines (like oxybutynin, diphenhydramine) readily cross the blood-brain barrier and block central muscarinic receptors, producing both peripheral and central nervous system effects. 1, 4

Organ System Effects

Peripheral Parasympathetic Blockade

• Exocrine glands: Reduced lacrimation, salivation, and perspiration through blockade of muscarinic stimulation of secretory glands. 1
• Gastrointestinal tract: Decreased motility and secretions by blocking vagal (parasympathetic) tone, which can lead to constipation and gastric retention. 4
• Bladder: Reduced detrusor muscle contractions through muscarinic blockade, decreasing urinary frequency but potentially causing retention. 1, 4
• Cardiovascular: Tachycardia results from blockade of vagal tone on the sinoatrial node. 5
• Eyes: Mydriasis (pupil dilation) and cycloplegia (loss of accommodation) from blockade of pupillary constrictor and ciliary muscles. 5

Central Nervous System Effects

• Cognitive impairment occurs when anticholinergics cross into the CNS and block central cholinergic neurotransmission, which is essential for memory and attention. 1, 4
• The clinical syndrome includes agitation, hallucinations, disorientation, confusion, delirium, or conversely stupor and coma—collectively termed central anticholinergic syndrome (CAS). 5, 3
• Age-related decline in baseline cholinergic function makes elderly patients particularly vulnerable, as anticholinergics further reduce already diminished acetylcholine activity. 5, 1

Dose-Dependent and Cumulative Effects

Anticholinergic Burden

• Multiple medications with anticholinergic properties create cumulative effects even when individual drugs have modest antimuscarinic activity. 6, 7
• This "anticholinergic burden" is associated with progressive decline in cognition, functional status, and activities of daily living scores in older patients. 5
• One-third to one-half of medications commonly prescribed to older adults possess some degree of anticholinergic activity. 6

Classic Toxidrome Presentation

The anticholinergic toxidrome demonstrates the full pathophysiologic spectrum when receptor blockade is extensive: 5

• Hyperthermia ("hot as a hare") from impaired sweating
• Dry mucous membranes ("dry as a bone") from reduced secretions
• Flushed skin ("red as a beet") from cutaneous vasodilation
• Mydriasis ("blind as a bat") from pupillary dilation
• Delirium ("mad as a hatter") from central effects
• Urinary retention ("full as a flask") from bladder dysfunction
• Hypoactive or absent bowel sounds from reduced GI motility 5
• Tachycardia from loss of vagal tone 5

Clinical Implications of Pathophysiology

Therapeutic Applications

• Bronchodilation occurs through blockade of vagally mediated bronchial smooth muscle tone, though efficacy varies among patients. 5
• Nerve agent poisoning: Atropine serves as the gold standard antidote by blocking excessive muscarinic receptor stimulation from acetylcholine accumulation caused by cholinesterase inhibition. 1

Adverse Effect Profile

• The broad, non-selective muscarinic receptor blockade produces predictable adverse effects including dry mouth, blurred vision, tachycardia, confusion, constipation, urinary retention, and hyperthermia. 1, 4
• Heat prostration (fever and heat stroke) can occur in high environmental temperatures due to impaired thermoregulation from decreased sweating. 4
• Risk of urinary retention is particularly high in patients with bladder outflow obstruction. 4
• Gastric retention and paralytic ileus may develop, especially in patients with gastrointestinal obstructive disorders or ulcerative colitis. 4