Which drugs have the highest anticholinergic activity?

Drugs with the Highest Anticholinergic Effects

First-generation antihistamines, tricyclic antidepressants, and certain antipsychotics demonstrate the strongest anticholinergic activity, with amitriptyline, atropine, clozapine, dicyclomine, doxepin, L-hyoscyamine, thioridazine, and tolterodine showing anticholinergic activity exceeding 15 pmol/mL atropine equivalents at typical therapeutic doses. 1

Medications with Highest Anticholinergic Burden

Very High Anticholinergic Activity (>15 pmol/mL atropine equivalents)

• Tricyclic antidepressants: Amitriptyline and doxepin demonstrate the highest anticholinergic activity among antidepressants, exceeding 15 pmol/mL at therapeutic doses 1
• Antipsychotics: Clozapine and thioridazine show very high anticholinergic effects, with activity >15 pmol/mL 1
• Anticholinergic agents: Atropine, dicyclomine, L-hyoscyamine, and tolterodine all exceed 15 pmol/mL anticholinergic activity 1

High Anticholinergic Activity (5-15 pmol/mL atropine equivalents)

• First-generation antihistamines: Diphenhydramine demonstrates anticholinergic activity of 5-15 pmol/mL, and the American Geriatrics Society specifically recommends avoiding it in older adults due to strong anticholinergic effects causing sedation, confusion, delirium, falls, and hospitalizations 2, 1
• Antipsychotics: Chlorpromazine and olanzapine show 5-15 pmol/mL anticholinergic activity 1
• Tricyclic antidepressants: Nortriptyline (a secondary amine) has lower but still significant anticholinergic activity of 5-15 pmol/mL 1
• Urinary antispasmodics: Oxybutynin demonstrates 5-15 pmol/mL activity, and the American Geriatrics Society recommends avoiding it in older adults 2, 1
• Selective serotonin reuptake inhibitors: Paroxetine has high anticholinergic properties among SSRIs, with 5-15 pmol/mL activity 3, 1

Additional High-Risk Anticholinergic Medications

• Antiemetics: Prochlorperazine and promethazine should be avoided in older adults due to high anticholinergic properties 2
• Muscle relaxants: Cyclobenzaprine is identified by the American Geriatrics Society as having strong anticholinergic effects 2
• Other antihistamines: Cyproheptadine has extended anticholinergic activity plus antiserotonergic effects, making it particularly problematic 3

Clinical Significance and Mechanism

First-generation antihistamines are particularly problematic because they cross the blood-brain barrier and block central muscarinic receptors, leading to cognitive effects, whereas newer agents like tiotropium have limited systemic absorption and minimal CNS penetration. 4

Why First-Generation Agents Are More Problematic

• First-generation antihistamines penetrate the CNS and block both central H1 histaminergic and M1 muscarinic receptors, explaining their greater effectiveness for rhinorrhea but also their worse side effect profile 3
• The anticholinergic effects cannot be eliminated by bedtime-only dosing due to prolonged plasma half-lives and active metabolites 3, 5
• Concomitant use with other CNS-active substances like alcohol and sedatives further enhances performance impairment 3

Cumulative Anticholinergic Burden

• Patients taking multiple anticholinergic drugs experience "anticholinergic burden" that adversely affects cognition, functional status, and activities of daily living scores 2
• Two-thirds of older adults in mental health services are prescribed medications with anticholinergic properties, and 23% have regimens with high anticholinergic burden (AEC score ≥3) 6
• High anticholinergic burden often results from combinations of commonly prescribed psychotropics with individual modest anticholinergic activity (AEC scores of 1-2) rather than single highly anticholinergic agents 6

High-Risk Populations

Older adults are particularly vulnerable to anticholinergic adverse effects due to age-related decline in baseline cholinergic function, pre-existing comorbidities like prostatic hypertrophy and elevated intraocular pressure, and cognitive impairment. 3, 4, 5

• The American Geriatrics Society specifically recommends avoiding strongly anticholinergic medications entirely in elderly patients with Alzheimer's disease receiving antipsychotics 5
• Anticholinergic drugs can cause paradoxical behavioral disinhibition, especially in younger children and those with developmental disabilities 2
• Polypharmacy is associated with increased anticholinergic burden in advanced cancer patients, likely reflecting increasing use of medications with anticholinergic activity for symptom control 3

Common Pitfalls

• Psychotropic medications are particularly likely to demonstrate anticholinergic activity, with each drug classification (antipsychotic, antidepressant, cardiovascular) having at least one medication with significant anticholinergic effects 1
• Many drugs not traditionally classified as anticholinergics possess anticholinergic activity, including antidepressants, antipsychotics, antihistamines, antispasmodics, bronchodilators, antiarrhythmics, and skeletal muscle relaxants 7, 8
• One-third to one-half of medicines commonly prescribed for older people have anticholinergic activity 9