What is the pathophysiology of anticholinergics in the central and peripheral nervous system?

Pathophysiology of Anticholinergics

Anticholinergics competitively block acetylcholine at muscarinic receptors in both the central and peripheral nervous systems, preventing parasympathetic nervous system activation and causing predictable organ-specific effects based on the distribution of these receptors. 1

Core Mechanism of Action

Receptor Blockade and Neurotransmitter Interaction

• Anticholinergic drugs competitively inhibit acetylcholine at muscarinic receptors, preventing the normal binding and activation of these receptors by the endogenous neurotransmitter. 2
• This blockade occurs at both central (brain and spinal cord) and peripheral (autonomic ganglia, smooth muscle, cardiac muscle, secretory glands) sites where muscarinic receptors are expressed. 1
• The competitive nature means that higher concentrations of acetylcholine can potentially overcome the blockade, though therapeutic doses typically produce sustained receptor antagonism. 2

Blood-Brain Barrier Penetration

• First-generation anticholinergics (tertiary amines) readily cross the blood-brain barrier and block central muscarinic receptors, leading to cognitive and behavioral effects. 1
• Quaternary ammonium compounds do not cross into the central nervous system and produce only peripheral anticholinergic effects with a different adverse effect profile. 2
• Newer agents like tiotropium have limited systemic absorption and minimal central nervous system penetration, reducing central side effects. 1

Central Nervous System Effects

Neurotransmitter Modulation

• Acetylcholine plays a critical role in modulating interactions among most other central neurotransmitters, so its blockade has widespread neurological consequences. 3
• Central cholinergic blockade produces the central anticholinergic syndrome (CAS), which is identical to the central symptoms of atropine intoxication. 3
• Acetylcholine is involved in nociception through the endorphinergic and serotoninergic systems, explaining some analgesic interactions. 3

Clinical Manifestations in the CNS

• Central anticholinergic effects include agitation, seizures, restlessness, hallucinations, disorientation, anxiety, confusion, and delirium. 1, 4
• Depressive manifestations can also occur, including stupor, coma, and respiratory depression. 3
• In nerve agent intoxication (the opposite scenario with excess acetylcholine), accumulation of acetylcholine in the CNS causes anxiety, disorientation, general convulsions, and coma, demonstrating the importance of balanced cholinergic tone. 5

Peripheral Nervous System Effects

Cardiovascular System

• Blockade of vagal tone on the sinoatrial node causes tachycardia, as the parasympathetic brake on heart rate is removed. 1
• In contrast, excess acetylcholine (as in nerve agent poisoning) causes initial nicotinic sympathetic hyperstimulation followed by muscarinic activation with bradycardia, heart block, QT prolongation, arrhythmias, and hypotension. 5

Respiratory System

• Bronchodilation occurs through blockade of vagally mediated bronchial smooth muscle tone, though efficacy varies among patients. 1
• Anticholinergics reduce bronchorrhea and bronchospasm by preventing muscarinic receptor activation in the airways. 5

Ocular Effects

• Mydriasis (pupil dilation) results from blockade of the pupillary constrictor muscle. 1
• Cycloplegia (paralysis of accommodation) occurs from blockade of the ciliary muscles, causing blurred vision particularly for near objects. 1

Secretory Glands

• Anticholinergics reduce excessive lacrimation, salivation, and perspiration by blocking muscarinic stimulation of secretory glands. 1
• The blockade of parasympathetic stimulation of submucosal glands reduces glandular secretions throughout the body. 1
• This produces the characteristic "dry as a bone" presentation with dry mucous membranes and anhidrosis. 6

Gastrointestinal System

• Blockade of muscarinic receptors in the GI tract reduces smooth muscle motility, causing hypoactive or absent bowel sounds. 6
• This can lead to constipation and, in severe cases, ileus or urinary retention ("full as a flask"). 6
• In contrast, excess acetylcholine causes hypermotility with nausea, vomiting, abdominal cramps, and severe diarrhea. 5

Genitourinary System

• Muscarinic receptor blockade in the bladder reduces detrusor muscle contractions, which is therapeutically useful for urinary incontinence but can cause urinary retention in overdose. 1

Thermoregulation

• Anticholinergics impair sweating through blockade of muscarinic receptors on sweat glands (despite sweat glands being sympathetically innervated, they use acetylcholine). 1
• Combined with increased metabolic activity from agitation, this produces hyperthermia ("hot as a hare"). 6
• Hot, dry, erythematous skin ("red as a beet") results from peripheral vasodilation attempting to compensate for impaired sweating. 6

Tissue-Specific Pathophysiology

Neuromuscular Junction (Nicotinic vs. Muscarinic)

• Classic anticholinergics primarily block muscarinic receptors and have minimal effect on nicotinic receptors at the neuromuscular junction. 5
• In nerve agent poisoning (excess acetylcholine), nicotinic receptor overstimulation causes involuntary fasciculation followed by weakness and flaccid paralysis through a depolarization-like block. 5
• Visceral smooth muscle, cardiac muscle, and secretory glands are influenced through muscarinic hyperstimulation, while autonomic ganglia and skeletal muscle are affected through nicotinic mechanisms. 5

Eustachian Tube (Specialized Application)

• When applied to the Eustachian tube region, anticholinergics work through blockade of muscarinic receptors in the tubal mucosa, reducing glandular secretions and promoting mucosal edema. 1
• This narrows the abnormally patent tube lumen and restores valve competence in patulous Eustachian tube. 1

Age-Related Vulnerability

Elderly Population Pathophysiology

• Age-related decline in baseline cholinergic function makes elderly patients particularly vulnerable to anticholinergics, which further reduce already diminished acetylcholine activity. 4
• Older adults have reduced physiologic reserve and often baseline cognitive impairment, amplifying the impact of anticholinergic blockade. 4
• One-third to one-half of medicines commonly prescribed for older people have anticholinergic activity, creating cumulative burden. 7

Cumulative Anticholinergic Burden

Additive Effects

• Anticholinergic burden, measured by considering number, dose, and degree of anticholinergic activity of medicines, predicts adverse health and functional outcomes. 7
• Multiple medications with anticholinergic properties produce additive effects, even when individual drugs have modest anticholinergic activity. 7
• This cumulative burden is a predictor of cognitive and functional impairments, falls, and decline in activities of daily living. 4, 7

Clinical Toxidrome Pathophysiology

The Complete Anticholinergic Syndrome

• When receptor blockade is extensive, the full anticholinergic toxidrome demonstrates the complete pathophysiologic spectrum: hyperthermia, dry mucous membranes, hot/dry/erythematous skin, mydriasis, agitated delirium with visual hallucinations, hypoactive or absent bowel sounds, urinary retention, and tachycardia. 1
• The classic mnemonic captures the pathophysiology: "Red as a beet, dry as a bone, hot as a hare, blind as a bat, mad as a hatter, full as a flask." 6

Therapeutic Applications Based on Pathophysiology

Antidotal Use in Nerve Agent Poisoning

• Atropine is the "gold standard" treatment for nerve agent intoxication because it blocks muscarinic receptor overstimulation caused by acetylcholine accumulation. 1
• In nerve agent poisoning, acetylcholinesterase is irreversibly blocked, causing rapid accumulation of acetylcholine at muscarinic and nicotinic receptors with intense postsynaptic cholinergic stimulation. 5
• Atropine blocks the muscarinic effects (smooth muscle contraction, cardiac manifestations, hypersecretion) but does not address nicotinic effects at the neuromuscular junction, which require oximes. 5