What are the available drug treatments for Alzheimer's disease, including their side effects?

From the Guidelines

Alzheimer's disease treatments primarily focus on managing symptoms and slowing disease progression, with current FDA-approved medications including cholinesterase inhibitors and memantine, which should be chosen based on tolerability, adverse effect profile, ease of use, and cost of medication, as evidence is insufficient to compare the effectiveness of different pharmacologic agents for the treatment of dementia 1.

Current Treatments

• Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) increase acetylcholine levels in the brain to improve cognitive function, typically prescribed at starting doses of 5-10mg daily for donepezil, 1.5-6mg twice daily for rivastigmine, and 4-12mg twice daily for galantamine.
• Memantine, an NMDA receptor antagonist, regulates glutamate activity and is typically prescribed at 5-20mg daily.

Side Effects

• Cholinesterase inhibitors commonly cause gastrointestinal side effects like nausea, vomiting, and diarrhea, along with possible dizziness, headaches, and sleep disturbances.
• Memantine may cause potential dizziness, confusion, and headaches.

Newer Treatments

• Aducanumab and Lecanemab target amyloid plaques and may slow cognitive decline but carry risks of brain swelling (ARIA) and microhemorrhages, requiring careful monitoring with MRI scans.

Treatment Plans

• Treatment plans should be individualized based on disease stage, overall health, and potential drug interactions.
• Non-pharmacological approaches like cognitive stimulation, physical exercise, and caregiver support remain essential components of comprehensive Alzheimer's care.
• Regular follow-up appointments are necessary to monitor effectiveness and manage side effects.

Key Considerations

• The choice of pharmacologic agents should be based on tolerability, adverse effect profile, ease of use, and cost of medication, as recommended by the American College of Physicians and the American Academy of Family Physicians 1.
• The combination of Memantine and Donepezil is recommended for severe AD in several countries, including the US, China, and Japan 1.

From the FDA Drug Label

The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving 10 mg/day and twice the placebo rate, are largely predicted by donepezil hydrochloride’s cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue, and anorexia. Table 1 Most Common Adverse Reactions Leading to Discontinuation in Patients with Mild to Moderate Alzheimer’s Disease Adverse Reaction Placebo (n=355) % 5 mg/day Donepezil Hydrochloride (n=350) % 10 mg/day Donepezil Hydrochloride (n=315) % Nausea 1 1 3 Diarrhea 0 <1 3 Vomiting <1 <1 2 Table 3 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received either donepezil hydrochloride 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. Table 3 Clinical Trials in Mild to Moderate Alzheimer’s Disease Adverse Reaction Placebo (n=355) % Donepezil Hydrochloride (n=747) % Percent of Patients with any Adverse Reaction 72 74 Nausea 6 11 Diarrhea 5 10 Headache 9 10 Insomnia 6 9 Pain, various locations 8 9 Dizziness 6 8 Accident 6 7 Muscle Cramps 2 6 Fatigue 3 5 Vomiting 3 5 Anorexia 2 4 Ecchymosis 3 4 Abnormal Dreams 0 3 Depression <1 3 Weight Loss 1 3 Arthritis 1 2 Frequent Urination 1 2 Somnolence <1 2 Syncope 1 2 Severe Alzheimer’s Disease (Donepezil hydrochloride 5 mg/day and 10 mg/day) The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving donepezil hydrochloride and at twice or more the placebo rate, are largely predicted by donepezil hydrochloride’s cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis Table 4 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received donepezil hydrochloride 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. Table 4 ease Body System/Adverse Reaction Placebo (n=392) % Donepezil Hydrochloride (n=501) % Percent of Patients with any Adverse Reaction 73 81 Accident 12 13 Infection 9 11 Diarrhea 4 10 Anorexia 4 8 Vomiting 4 8 Nausea 2 6 Insomnia 4 5 Ecchymosis 2 5 Headache 3 4 Hypertension 2 3 Pain 2 3 Back Pain 2 3 Eczema 2 3 Hallucinations 1 3 Hostility 2 3 Increase in Creatine Phosphokinase 1 3 Nervousness 2 3 Fever 1 2 Chest Pain <1 2 Confusion 1 2 Dehydration 1 2 Depression 1 2 Dizziness 1 2 Emotional Lability 1 2 Hemorrhage 1 2 Hyperlipemia <1 2 Personality Disorder 1 2 Somnolence 1 2 Syncope 1 2 Urinary Incontinence 1 2

Common Side Effects of Donepezil:

• Nausea
• Diarrhea
• Insomnia
• Vomiting
• Muscle cramp
• Fatigue
• Anorexia
• Ecchymosis
• Headache
• Dizziness
• Accident
• Infection
• Hypertension
• Pain
• Back Pain
• Eczema
• Hallucinations
• Hostility
• Increase in Creatine Phosphokinase
• Nervousness
• Fever
• Chest Pain
• Confusion
• Dehydration
• Depression
• Emotional Lability
• Hemorrhage
• Hyperlipemia
• Personality Disorder
• Somnolence
• Syncope
• Urinary Incontinence

Donepezil Treatment for Alzheimer's Disease: Donepezil hydrochloride is used to treat mild, moderate, and severe Alzheimer's disease. The effectiveness of donepezil hydrochloride in the treatment of patients with moderate to severe Alzheimer’s disease was established in studies employing doses of 10 mg/day and 23 mg/day.

Dosage and Administration: The recommended dosage of donepezil hydrochloride is 10 mg administered once daily. The dosage may be increased to 10 mg/day after a minimum of 4 weeks if the patient is tolerating the 5 mg/day dose.

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From the Research

Alzheimer's Drug Treatments

• Cholinesterase inhibitors (ChEIs) are a class of medications approved for the treatment of mild-to-moderate Alzheimer's disease (AD) 3.
• ChEIs, such as donepezil, galantamine, and rivastigmine, have proven efficacy in improving cognition, behavior, activities of daily living, and global functioning in mild-to-moderate AD 3.
• Memantine, an N-methyl-D-aspartate receptor antagonist, is also used in the treatment of AD, often in combination with ChEIs 4, 5.

Side Effects of ChEIs

• Common side effects of ChEIs include gastrointestinal, cardiorespiratory, extrapyramidal, genitourinary, and musculoskeletal symptoms, as well as sleep disturbances 3.
• Side effects are generally dose-related and most problematic during dose titration 3.
• Few clinically significant drug-drug interactions with ChEIs have been identified 3.

Switching Between ChEIs

• Switching between ChEIs may be considered for patients who experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues 6, 5.
• Approximately 50% of patients experiencing a lack/loss of efficacy with donepezil respond to subsequent treatment with rivastigmine 6.
• Rivastigmine is well tolerated, and the occurrence of safety/tolerability problems with donepezil is not predictive of similar problems with rivastigmine 6.

Combination Therapy

• Combination therapy with ChEIs plus memantine may be effective in stabilizing cognitive scores and affective functions in AD patients 4.
• The addition of memantine to ChEI therapy may result in significant improvements in cognitive and affective functions, particularly in older AD patients 4.
• However, the benefits of combination therapy may vary depending on the specific ChEI and patient population 4.

Treatment Strategies

• Dose up-titration and switching between ChEIs may help to improve response to ChEI treatment and address issues such as lack/loss of efficacy or safety/tolerability in patients with AD 5.
• Early initiation and persistent exposure to AD therapy may lead to delays in nursing home admission and significantly slower rates of cognitive and functional impairment 7.
• Regular monitoring for potential serious side effects of ChEI therapy is recommended, particularly in patients with advanced disease 7.