What is the mechanism of action of commonly used anticholinergic drugs?

Mechanism of Action of Commonly Used Anticholinergic Drugs

Anticholinergic drugs work by competitively blocking muscarinic acetylcholine receptors at postganglionic parasympathetic nerve terminals, preventing acetylcholine from binding and thereby inhibiting parasympathetic nervous system activity throughout the body. 1

Core Pharmacological Mechanism

Anticholinergics function as competitive antagonists at muscarinic receptors, meaning their blockade can be overcome by increasing acetylcholine concentrations at the receptor site 1. The fundamental mechanism involves:

• Competitive inhibition where the drug binds to muscarinic receptors without activating them, physically preventing acetylcholine from accessing these sites 1
• Surmountable antagonism that can be reversed by anticholinesterase agents which increase acetylcholine levels by preventing its enzymatic breakdown 2, 1
• Receptor selectivity variation among different anticholinergic agents, though most clinical doses are non-selective across muscarinic receptor subtypes 3

Muscarinic Receptor Subtypes and Tissue Distribution

The muscarinic receptor system includes five subtypes (M1-M5), with M1, M2, and M3 being the most clinically relevant 3:

• M1 receptors predominate in the central nervous system and are involved in cognitive function 4
• M2 receptors are found primarily in cardiac tissue where they mediate vagal control of heart rate 3
• M3 receptors are located in smooth muscle (bronchi, bladder, gastrointestinal tract), exocrine glands (salivary, lacrimal), and the eye (pupillary constrictor and ciliary muscles) 3

Most anticholinergics used clinically show greater affinity for M1 receptors than M2 receptors, though at therapeutic doses they block all subtypes non-selectively. 4

Organ System Effects Based on Mechanism

Cardiovascular System

• Vagal blockade at cardiac M2 receptors causes tachycardia by removing parasympathetic restraint on the sinoatrial node 3, 1
• Small doses may paradoxically cause initial bradycardia due to transient central stimulation before peripheral blockade predominates 1
• Atropine abolishes reflex vagal cardiac slowing and can reverse bradycardia from cholinesterase inhibitors 1

Respiratory System

• Bronchodilation occurs through M3 receptor blockade on bronchial smooth muscle, removing vagally-mediated bronchoconstriction 2, 3
• Vagal tone provides the dominant control of airway smooth muscle via acetylcholine release onto M3 receptors 5
• Reduced bronchial secretions result from blocking parasympathetic stimulation of submucosal glands 3

Secretory Glands

• Blockade of M3 receptors on exocrine glands reduces salivation, lacrimation, and perspiration 3, 1
• This mechanism explains the characteristic dry mouth, dry eyes, and anhidrosis seen with anticholinergic use 3

Ocular Effects

• M3 receptor blockade in the iris causes mydriasis (pupil dilation) by preventing pupillary constrictor muscle contraction 3
• Ciliary muscle paralysis (cycloplegia) impairs accommodation, causing blurred near vision 3

Gastrointestinal and Genitourinary Systems

• Smooth muscle M3 receptor blockade reduces motility, causing constipation and potentially ileus 3
• Bladder detrusor muscle relaxation from M3 blockade helps with urinary incontinence but can cause urinary retention 3

Central Nervous System

• First-generation anticholinergics cross the blood-brain barrier and block central M1 receptors, causing cognitive effects including confusion, delirium, and memory impairment 3, 6
• Newer quaternary ammonium compounds (like ipratropium and tiotropium) are poorly absorbed and have minimal CNS penetration due to their ionized structure 2

Commonly Used Anticholinergic Drugs and Their Mechanisms

Atropine

• The prototypical non-selective muscarinic antagonist that blocks all muscarinic receptor subtypes 1
• Used as the "gold standard" for nerve agent intoxication because it reverses muscarinic overstimulation from acetylcholine accumulation 3
• Does not affect nicotinic receptors at the neuromuscular junction, so it cannot reverse the paralysis from excessive nicotinic stimulation 3

Ipratropium Bromide

• A quaternary ammonium compound with poor systemic absorption that acts locally on nasal and bronchial mucosa 2
• Effectively reduces rhinorrhea by blocking M3 receptors on nasal glands but has minimal effect on congestion 2
• Does not alter physiologic nasal functions like mucociliary clearance or sense of smell 2

Tiotropium

• A long-acting muscarinic antagonist with limited systemic absorption and minimal CNS penetration 2, 3
• Provides 24-hour bronchodilation in asthma and COPD through sustained M3 receptor blockade 2
• The quaternary structure prevents crossing biological membranes, reducing systemic anticholinergic side effects 2

Neuromuscular Blocking Agents (NMBAs)

While technically acting on nicotinic rather than muscarinic receptors, understanding their mechanism provides context:

• Nondepolarizing NMBAs (pancuronium, vecuronium, rocuronium) are competitive antagonists at nicotinic receptors on the motor endplate 2
• Depolarizing NMBAs (succinylcholine) act as agonists, causing sustained depolarization and paralysis 2
• Acetylcholinesterase inhibitors (neostigmine, pyridostigmine) reverse nondepolarizing blockade by increasing acetylcholine concentration to compete with the NMBA 2

Clinical Implications and Adverse Effects

Predictable Side Effects from Mechanism

The broad muscarinic receptor blockade produces a characteristic toxidrome 3:

• Dry mouth, blurred vision, mydriasis
• Tachycardia
• Urinary retention
• Constipation or ileus
• Hyperthermia (from inability to sweat)
• Confusion and delirium (with CNS-penetrating agents)

Vulnerable Populations

• Elderly patients are particularly susceptible due to age-related decline in baseline cholinergic function 3, 6
• "Anticholinergic burden" from multiple medications adversely affects cognition, functional status, and activities of daily living 6
• Paradoxical behavioral disinhibition can occur in young children and those with developmental disabilities 6

Disease-Specific Considerations

• Myasthenia gravis patients show increased sensitivity to anticholinergics due to fewer acetylcholine receptors 2
• Burn patients demonstrate resistance to nondepolarizing agents due to receptor up-regulation 2

Receptor Selectivity and Drug Development

While traditional anticholinergics like atropine are non-selective, newer agents attempt M1 or M3 selectivity to minimize cardiac (M2) side effects. 4 However, at therapeutic doses, most agents lose their selectivity and block multiple receptor subtypes 3. Drugs like scopolamine, trihexyphenidyl, and biperiden show greater M1 selectivity than ethopropazine, though clinical significance remains uncertain 4.