What medications can cause anticholinergic syndrome?

Medications That Cause Anticholinergic Syndrome

Anticholinergic syndrome can be caused by numerous medication classes including antihistamines, tricyclic antidepressants, antipsychotics, muscle relaxants, overactive bladder agents, antiemetics, benzodiazepines, opioids, and anesthetic agents—with diphenhydramine, cyclobenzaprine, oxybutynin, promethazine, prochlorperazine, and tricyclic antidepressants being among the most common culprits. 1, 2, 3, 4

Major Drug Classes and Specific Agents

Antihistamines

• First-generation H1 antihistamines are strongly anticholinergic and frequently cause central nervous system effects 1
  • Diphenhydramine is commonly abused recreationally for sedative and hallucinogenic effects at high doses and should be avoided in older adults 1, 2, 3
  • Hydroxyzine and chlorpheniramine cause sedation and cognitive decline, particularly in elderly patients 1
  • Cyproheptadine has extended anticholinergic and antiserotonergic activities 1
  • Promethazine has antihistaminergic and anticholinergic effects causing CNS depression and extrapyramidal symptoms 1, 3

Muscle Relaxants and Antispasmodics

• Cyclobenzaprine has strong anticholinergic properties and is sometimes misused recreationally 1, 2, 3
• Benztropine is an anticholinergic agent that contributes to anticholinergic burden and should be avoided entirely in elderly patients with Alzheimer's disease receiving antipsychotics 2, 5

Overactive Bladder Medications

• Oxybutynin should be avoided in older adults due to strong anticholinergic effects causing sedation, confusion, and delirium 1, 3

Antidepressants

• Tricyclic antidepressants have high anticholinergic properties that induce delirium 1, 3, 4
• Paroxetine has high anticholinergic properties 1, 3

Antipsychotics and Antiemetics

• Phenothiazines produce anticholinergic effects 4, 6
• Prochlorperazine is a dopamine receptor antagonist with anticholinergic effects, extrapyramidal symptoms, and can rarely cause neuroleptic malignant syndrome 1, 3
• Butyrophenones can induce central cholinergic blockade 6

Gastrointestinal Medications

• Histamine2-receptor antagonists such as cimetidine are associated with increased postoperative delirium 1, 3, 6

Anesthetic Agents

• Opioids (particularly meperidine), benzodiazepines, ketamine, etomidate, propofol, nitrous oxide, and halogenated inhalation anesthetics can cause central anticholinergic syndrome 1, 6, 7, 8
• Scopolamine (hyoscine) in overdose causes CNS depression and anticholinergic syndrome 9
• Atropine and other belladonna alkaloids directly produce anticholinergic effects 4, 8

Sedatives

• Benzodiazepines including midazolam can induce central cholinergic blockade 1, 6, 8

Clinical Recognition

The classic presentation follows 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

Central Manifestations

• Agitated delirium with visual hallucinations, confusion, disorientation, anxiety, and seizures 2, 5, 4
• CNS depression ranging from stupor to coma and respiratory depression 4, 6, 7

Peripheral Manifestations

• Dry mucous membranes and hot, dry, erythematous skin 2, 5
• Mydriasis (dilated pupils) 2, 5, 4
• Tachycardia and mild hyperthermia 2, 5, 4
• Hypoactive or absent bowel sounds and urinary retention 2, 5, 4

Critical Management Considerations

Physostigmine 0.5-1 mg IV in adults (0.01-0.02 mg/kg in children) produces dramatic reversal of anticholinergic effects within minutes and is the specific antidote. 5, 4, 7

Immediate Actions

• Discontinue all offending anticholinergic medications immediately 5
• Use benzodiazepines as first-line treatment for agitation, not antipsychotics which worsen anticholinergic effects 2, 5
• Avoid physical restraints as they exacerbate hyperthermia and worsen lactic acidosis 2

Special Populations at Risk

• Older adults are particularly vulnerable due to baseline cognitive impairment and reduced physiologic reserve 3, 5, 10
• Patients taking multiple anticholinergic drugs experience cumulative "anticholinergic burden" adversely affecting cognition, functional status, and activities of daily living 3, 10
• Younger children and those with developmental disabilities may experience paradoxical behavioral disinhibition 3

Common Pitfalls

• Anticholinergic effects can persist longer than plasma drug levels, so symptoms may continue even after drug levels decline 5
• The syndrome occurs in 1-40% of postanesthetic cases depending on diagnostic criteria and drug combinations used 6, 8
• Over-the-counter medications and herbal supplements can cause anticholinergic syndrome and must be considered in the differential diagnosis 9