What are the clinical manifestations, common offending drugs, and management of anticholinergic toxicity, particularly in older adults?

Anticholinergic Effects: Clinical Manifestations, Offending Drugs, and Management

Deprescribe strongly anticholinergic medications in older adults immediately, as they cause cognitive decline, delirium, falls, and functional impairment through broad muscarinic receptor blockade that is poorly tolerated in aged patients. 1

Clinical Manifestations

The anticholinergic toxidrome presents with a classic constellation remembered by the mnemonic "Red as a beet, dry as a bone, hot as a hare, blind as a bat, mad as a hatter, full as a flask." 2

Pathognomonic features include:

• Dry mucous membranes and hot, dry, erythematous (flushed) skin 2, 3
• Mydriasis (dilated pupils) 3
• Agitated delirium with visual hallucinations (the "mad as a hatter" component) 2, 3
• Hypoactive or absent bowel sounds 2, 3
• Mild hyperthermia with tachycardia and hypertension 2, 3
• Urinary retention (the "full as a flask" component) 4

Spectrum of Severity in Older Adults

Peripheral anticholinergic effects in elderly patients include:

• Dry mouth leading to communication difficulty, malnutrition, dental caries, and increased respiratory infection risk 4
• Blurred vision and impaired accommodation causing falls and accidents 1, 4
• Constipation progressing to fecal impaction 1, 4
• Urinary hesitancy progressing to urinary retention 1, 4
• Increased heart rate precipitating or worsening angina 4
• Impaired thermoregulation with inability to sweat, leading to life-threatening hyperthermia 4

Central nervous system effects range from subtle to severe:

• Sedation and decreased alertness 1
• Mild confusion and inability to concentrate 4
• Cognitive impairment and decline in activities of daily living (ADL) scores 1
• Frank delirium 2, 5
• Increased risk of dementia with chronic exposure 6

Common Offending Drugs

High-risk anticholinergic medications that must be deprescribed in older adults include: 1

First-Generation Antihistamines

• Diphenhydramine (commonly abused recreationally for sedative and hallucinogenic effects at high doses) 1, 2
• Hydroxyzine (causes impaired driving performance, worsened by cellular phone use) 1

Muscle Relaxants

• Cyclobenzaprine (strong anticholinergic properties, sometimes misused) 1, 2
• Metaxalone 1

Overactive Bladder Agents

• Oxybutynin (adds to anticholinergic burden and cognitive impairment, especially problematic in elderly women with OAB) 1, 6
• Other antimuscarinic agents for OAB that cross the blood-brain barrier 6

Other Anticholinergic Agents

• Benztropine (contributes to anticholinergic burden) 2
• Tricyclic antidepressants (monitor for QRS widening on ECG) 3
• Antipsychotics (typical agents like chlorpromazine and haloperidol; atypical agents like quetiapine, risperidone, olanzapine) 1

Critical point: One-third to one-half of medications commonly prescribed for older people have anticholinergic activity, and the cumulative "anticholinergic burden" from multiple medications causes more harm than single agents. 7, 5

Management Approach

Acute Anticholinergic Toxidrome

Immediate supportive care with continuous cardiorespiratory monitoring is essential. 3

Step 1: Stabilization and monitoring

• Continuous cardiac monitoring for dysrhythmias 3
• Core temperature monitoring 3
• Serial ECGs to monitor for QRS widening (suggesting tricyclic antidepressant co-ingestion) 3

Step 2: Symptomatic treatment

• Benzodiazepines are first-line for agitation (NOT antipsychotics, which worsen anticholinergic effects) 2, 3
• Aggressive cooling measures if temperature rises 3
• IV fluid resuscitation for hypotension 3
• Activated charcoal if patient can safely swallow or has protected airway 3

Step 3: Antidote consideration

• Physostigmine is the specific antidote producing dramatic reversal within minutes, but reserve for life-threatening complications only 2, 3

Critical pitfall to avoid: Never use physical restraints in anticholinergic toxidrome—they exacerbate hyperthermia and worsen lactic acidosis. 2, 3

Chronic Anticholinergic Burden Management

Deprescribing strategy for older adults:

Step 1: Identify all anticholinergic medications

• Use the Anticholinergic Drug Scale or anticholinergic cognitive burden scale (updated 2012) to quantify burden 1, 8
• Calculate Drug Burden Index showing cumulative effects on cognition, functional status, and ADL scores 1

Step 2: Prioritize deprescribing based on risk

• Target medications with strong anticholinergic properties first (diphenhydramine, cyclobenzaprine, oxybutynin) 1
• Consider patient functionality, support needs, living situation, and care plans 1
• Account for increased blood-brain barrier permeability in elderly 6

Step 3: Substitute with safer alternatives when treatment still needed

• For overactive bladder: Switch to trospium chloride (quaternary amine less likely to cross blood-brain barrier) or mirabegron (beta-3 agonist with no anticholinergic effects) 6
• For allergic rhinitis: Use second-generation antihistamines (fexofenadine, loratadine, desloratadine) that do not cause sedation at recommended doses 1
• For rhinorrhea despite other treatments: Use topical anticholinergic agents rather than systemic agents 1
• For behavioral symptoms: Use redirection and non-pharmacological approaches 1

Step 4: Avoid dangerous dosing strategies

• Do NOT use AM/PM regimen combining second-generation antihistamine in morning with first-generation at bedtime—first-generation agents dosed at bedtime still cause significant daytime drowsiness and performance impairment due to prolonged half-lives 1

Special Considerations in Older Adults

Elderly patients are uniquely vulnerable because:

• Physiological and pathophysiological changes with aging increase sensitivity to anticholinergic effects 4
• Decline in acetylcholine physiology associated with aging is further blocked by anticholinergics 1
• Increased blood-brain barrier permeability allows greater CNS penetration 6
• Comorbid conditions (increased intraocular pressure, benign prostatic hypertrophy, preexisting cognitive impairment) increase complication risk 1
• Higher risk of falls, fractures, subdural hematomas 1
• Polypharmacy creates pharmacodynamic and pharmacokinetic drug interactions heightening anticholinergic effects 4

Documented outcomes of anticholinergic burden in elderly:

• Injurious falls 1
• Episodes of confusion or delirium 1
• Emergency department visits and hospitalizations 1
• Increased mortality risk 6
• Decline in cognition, functional status, and ADL scores 1
• Increased caregiver burden and costs 4