What is the recommended dosing for cholinesterase inhibitors (e.g. donepezil) and N-methyl-D-aspartate receptor antagonists (e.g. memantine) in patients with Alzheimer's dementia?

Recommended Dosing for Cholinesterase Inhibitors and Memantine in Alzheimer's Dementia

For optimal management of Alzheimer's dementia, donepezil should be initiated at 5 mg daily for 4-6 weeks, then increased to 10 mg daily if well-tolerated, while memantine should be started at a low dose and titrated to 20 mg daily for moderate-to-severe disease. 1

Cholinesterase Inhibitors Dosing

Donepezil

• Initial dose: 5 mg once daily in the evening, just prior to retiring 2
• Titration: After 4-6 weeks, increase to 10 mg daily if well-tolerated 2
• Maximum dose:
  • Mild to moderate Alzheimer's: 10 mg daily 2
  • Moderate to severe Alzheimer's: 23 mg daily (only after at least 3 months on 10 mg daily) 2
• Administration: Can be taken with or without food; 23 mg tablet should not be split, crushed, or chewed 2

Rivastigmine

• Initial dose: 1.5 mg twice daily (3 mg/day) 3
• Titration: Increase by 1.5 mg twice daily (3 mg/day) every 4 weeks as tolerated 3
• Maximum dose: 6 mg twice daily (12 mg/day) 3
• Administration: Take with food to reduce gastrointestinal side effects 3

Galantamine

• Initial dose: 4 mg twice daily (8 mg/day) with morning and evening meals 3
• Titration: After 4 weeks, increase to 8 mg twice daily (16 mg/day) for at least 4 weeks 3
• Maximum dose: 12 mg twice daily (24 mg/day) based on individual response and tolerability 3
• Administration: Take with meals to minimize gastrointestinal side effects 3

N-methyl-D-aspartate (NMDA) Receptor Antagonist Dosing

Memantine

• Initial dose: Start low and gradually titrate 1
• Target dose: 20 mg daily for moderate to severe Alzheimer's disease 1
• Administration: Once daily dosing

Combination Therapy

For moderate to severe Alzheimer's disease, combination therapy with donepezil and memantine provides greater improvement than donepezil alone, with benefits including enhanced cognitive function, improved behavioral symptoms, and better global function 1.

Monitoring and Assessment of Response

• Beneficial response to cholinesterase inhibitors should be determined from:

  • Physician's global assessment
  • Primary caregiver's report
  • Neuropsychological assessment or mental status questionnaire
  • Evidence of behavioral or functional changes 3

• Observation for 6-12 months is usually necessary to assess potential benefit 3

• Cholinesterase inhibitors should be discontinued if:

  • Side effects develop and do not resolve
  • Adherence is poor
  • Deterioration continues at the pretreatment rate after 6-12 months 3

Side Effects Management

Cholinesterase Inhibitors

• Common side effects include nausea, vomiting, diarrhea, anorexia, and dizziness 1
• Most side effects are mild and transient, primarily affecting the gastrointestinal system 4
• Taking medication with food can reduce gastrointestinal side effects 3

Memantine

• Generally better tolerated than cholinesterase inhibitors 1
• Side effects include dizziness, headache, confusion, and constipation 1
• Withdrawal rates due to adverse events are similar to placebo 1

Important Clinical Considerations

1. Realistic Expectations: Benefits of both medications are modest; managing expectations with patients and caregivers is essential 1

2. Regular Assessment: Regular monitoring of cognitive function using appropriate tools is necessary to evaluate response 1

3. Medication Selection: Donepezil is often recommended as first-line treatment for mild to moderate dementia due to its once-daily dosing and favorable side effect profile 1, 4

4. Switching Medications: Patients who do not respond to one cholinesterase inhibitor may respond to another 3

5. Tacrine Considerations: Tacrine is considered a second-line agent due to hepatotoxicity (occurring in 40% of treated patients) and the need for four-times-daily dosing 3

By following these dosing recommendations and monitoring protocols, clinicians can optimize the management of cognitive symptoms in patients with Alzheimer's dementia while minimizing adverse effects.