What are anticholinergic effects?

What Are Anticholinergic Effects?

Anticholinergic effects are adverse reactions that occur when medications block acetylcholine receptors, resulting in both peripheral symptoms (dry mouth, blurred vision, constipation, urinary retention) and central nervous system manifestations (confusion, memory impairment, delirium, and in severe cases, coma). 1, 2

Mechanism of Action

Anticholinergic effects occur when drugs block the action of acetylcholine at muscarinic receptors throughout the body. 2 Acetylcholine is normally rapidly broken down by the enzyme acetylcholinesterase, but when anticholinergic drugs occupy these receptor sites, they prevent acetylcholine from exerting its normal physiological effects. 2

Clinical Manifestations

Peripheral (Body-Wide) Effects

The peripheral anticholinergic syndrome produces predictable symptoms related to blocking acetylcholine in various organ systems: 2, 3

• Dry mouth and dry eyes due to decreased salivary and lacrimal gland secretion 1
• Blurred vision and mydriasis (dilated pupils) from impaired accommodation 2, 3
• Constipation from diminished gastrointestinal motility 1, 2
• Urinary retention and difficulty with micturition 1, 2, 3
• Tachycardia (rapid heart rate) 2, 3
• Decreased sweating leading to dry skin and potential hyperthermia 2, 3
• Reduced secretions in the pharynx, bronchi, and nasal passages 2

Central Nervous System Effects

Central anticholinergic effects are particularly concerning as they can significantly impact cognition, function, and safety, especially in older adults: 1, 4

• Mild effects: Anxiety, confusion, disorientation, memory problems 2, 3
• Moderate effects: Delirium, hallucinations, agitation, hyperactivity 2, 3
• Severe effects: Stupor, coma, seizures, medullary paralysis, and potentially death 2, 3
• Cognitive impairment including decreased alertness and performance impairment that can persist even without subjective awareness of drowsiness 1, 4

Common Medications That Cause Anticholinergic Effects

Many medications produce anticholinergic effects either as their primary mechanism or as unwanted side effects: 1, 2

Medications with Strong Anticholinergic Properties

• First-generation antihistamines: Diphenhydramine, hydroxyzine, promethazine 1, 4
• Tricyclic antidepressants 2
• Phenothiazines and other antipsychotics (particularly low-potency agents like chlorpromazine) 1, 2
• Muscle relaxants: Cyclobenzaprine 4
• Belladonna alkaloids: Atropine, scopolamine 2, 3
• Urinary antispasmodics: Oxybutynin 4

Medications with Moderate Anticholinergic Properties

• Antiemetics: Promethazine, prochlorperazine 1
• Some benzodiazepines 3
• Certain opioids 3

Special Populations at High Risk

Older Adults

Older adults are particularly vulnerable to anticholinergic effects and should be approached with extreme caution when considering these medications: 1, 4

• More sensitive to psychomotor impairment and cognitive effects 1, 4
• Higher risk of falls, fractures, and subdural hematomas 1, 4
• More susceptible to complications from anticholinergic effects due to comorbidities (glaucoma, benign prostatic hypertrophy, preexisting cognitive impairment) 1, 4
• The American Geriatrics Society Beers Criteria specifically identifies many anticholinergic medications as potentially inappropriate for adults 65 years and older 4
• Associated with increased emergency department visits, hospitalizations, and healthcare costs 4

Children and Adolescents

• May have difficulty communicating concerns about side effects due to developmental issues 1
• Can experience paradoxical CNS stimulation with first-generation antihistamines 1
• May have impaired learning and school performance with first-generation antihistamines 1

Anticholinergic Burden

The cumulative effect of taking multiple medications with anticholinergic properties—termed "anticholinergic burden"—significantly increases the risk of adverse outcomes: 4, 5

• Approximately one-third of independent-living older adults and half of those in long-term care facilities take medications with anticholinergic properties that may be unnecessary 4
• The cumulative anticholinergic burden is associated with cognitive decline, functional decline, increased fall risk, and higher mortality 4, 6
• Long-term use has been consistently linked with increased risk of dementia and death in older people 6, 7

Clinical Management Considerations

Diagnosis of Anticholinergic Syndrome

The diagnosis is often made by process of exclusion and confirmed by dramatic reversal of symptoms within minutes following intravenous administration of physostigmine (a centrally active anticholinesterase agent). 2, 3 The differential diagnosis must exclude hypoxia, electrolyte disturbances, hypoglycemia, and other metabolic or neurological causes. 3

Prevention and Risk Reduction

When anticholinergic medications must be used, implement these strategies to minimize harm: 1, 4

• Prefer second-generation antihistamines (fexofenadine, loratadine, desloratadine) over first-generation agents, as they do not cause sedation at recommended doses and have minimal anticholinergic effects 1
• Use the lowest effective dose for the shortest duration possible 4
• Regularly review medication regimens to identify and reduce anticholinergic burden, particularly in older adults 4
• Consider topical anticholinergic agents (when treating conditions like overactive bladder) rather than systemic ones to minimize cognitive side effects 1, 4
• Avoid prophylactic use unless specifically indicated for patients at high risk of acute dystonias 1

Important Caveats

• Do not use an AM/PM dosing strategy (combining a second-generation antihistamine in the morning with a first-generation agent at bedtime) as first-generation antihistamines dosed only at bedtime can still cause significant daytime drowsiness and performance impairment due to prolonged plasma half-lives 1
• Concomitant use with other CNS-active substances (alcohol, sedatives, antidepressants) further enhances performance impairment 1, 4
• Driving and occupational safety: Workers and drivers taking first-generation antihistamines show impaired performance and are more likely to be involved in accidents 1
• Duration of action: The anticholinergic effects of physostigmine reversal are relatively short (45-60 minutes), so repeated dosing may be necessary 2