What causes blue feet in patients taking Donepezil (acetylcholinesterase inhibitor)?

Donepezil and Blue Feet: Potential Causes and Management

Blue feet in patients taking donepezil are most likely due to peripheral vascular effects caused by the medication's cholinergic properties, which can lead to vasodilation and potentially result in blood pooling in the extremities.

Mechanism and Causes

Donepezil is an acetylcholinesterase inhibitor commonly used for treating mild to moderate Alzheimer's disease. Several mechanisms may contribute to blue discoloration of the feet in patients taking this medication:

1. Cardiovascular Effects:

   • Donepezil has known cardiovascular effects including:
     • Decreased heart rate (bradycardia) 1
     • Prolonged PR interval on ECG 1
     • Potential for complete atrioventricular block in rare cases 2
   • These cardiac effects may lead to decreased peripheral perfusion, resulting in bluish discoloration of the extremities

2. Vascular Effects:

   • Cholinergic stimulation can cause peripheral vasodilation
   • This may lead to blood pooling in the lower extremities
   • In patients with pre-existing vascular disease, this effect may be more pronounced

3. Orthostatic Hypotension:

   • Donepezil has been associated with orthostatic hypotension 1
   • This can cause blood pooling in the feet when standing, leading to bluish discoloration

Risk Factors

Patients at higher risk for developing blue feet while on donepezil include:

• Elderly patients (most Alzheimer's patients are elderly)
• Patients with pre-existing cardiovascular disease
• Those taking concomitant medications with negative chronotropic effects 1
• Patients with peripheral vascular disease
• Those with higher doses of donepezil (10mg vs 5mg) 3

Clinical Evaluation

When a patient on donepezil presents with blue feet, evaluate for:

• Vital signs, particularly heart rate and blood pressure (including orthostatic measurements)
• Peripheral pulses
• Temperature of the affected extremities
• Other signs of decreased perfusion
• ECG to assess for bradycardia or heart block
• Medication review for potential drug interactions

Management Considerations

Based on the Mayo Clinic Proceedings guideline on polypharmacy management in older adults 3:

1. Consider Deprescribing:

   • Cholinesterase inhibitors like donepezil have adverse effects including cardiovascular effects
   • They may lack long-term benefit, particularly in advanced dementia
   • Deprescribing should be considered if adverse effects occur

2. Dose Adjustment:

   • Consider reducing the dose from 10mg to 5mg daily
   • This may reduce adverse effects while maintaining some therapeutic benefit

3. Alternative Medications:

   • Consider switching to rivastigmine patch which may have a different side effect profile 4
   • For patients with significant vascular risk factors, rivastigmine may be preferred over donepezil 4

4. Monitoring:

   • Regular cardiovascular monitoring for patients on donepezil
   • Particular attention to heart rate and blood pressure
   • ECG monitoring if symptoms suggest cardiac involvement

Important Caveats

• Blue feet could also be a sign of more serious vascular or cardiac conditions unrelated to donepezil
• Donepezil has not been specifically associated with blue discoloration of extremities in major clinical trials, suggesting this may be a rare side effect or related to underlying conditions
• Sudden onset of blue extremities warrants urgent medical evaluation to rule out acute vascular compromise

Prevention

• Start with lower doses (5mg) and titrate slowly
• Monitor cardiovascular parameters regularly
• Educate patients and caregivers about potential side effects
• Be cautious when combining donepezil with other medications that affect heart rate or blood pressure

In summary, while blue feet in patients taking donepezil may be related to the medication's cardiovascular effects, thorough evaluation is necessary to determine the exact cause and appropriate management strategy.