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Alzheimers Disease: Update on EvidenceBased Treatment Guidelines

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Title: Alzheimers Disease: Update on EvidenceBased Treatment Guidelines


1
Alzheimers DiseaseUpdate on Evidence-BasedTrea
tment Guidelines
  • Debra Cherry, PhD
  • Freddi Segal-Gidan, PA-C, PhD
  • Bradley R. Williams, PharmD, CGP
  • On behalf of the California Workgroup on
    Guidelines for Alzheimers Disease Management

2
Objectives
  • Identify the typical signs and symptoms
    associated with Alzheimers disease and other
    dementias.
  • Discuss the roles of cholinergic manipulation and
    NMDA inhibition in the treatment of Alzheimers
    disease symptoms.
  • Recognize behavior disturbances commonly
    displayed by patients with dementia.
  • Develop a therapeutic strategy for treating
    agitated behaviors in Alzheimers disease.

3
Mrs. R. L.
Mrs. R. L. is a retired librarian who visits her
physician for a routine follow-up for her
osteoarthritis, GERD, and glaucoma. She has
enjoyed her 3 years of retirement, but reports
that recently her husband has been worried about
her memory. Mrs. L. states that she had started
writing reminder notes, which dont always
help. She admits to reading less than she used
to she also drives less because traffic is such
a problem.
4
Mrs. R. L.
Mr. L. reports that his wife often returns from
grocery shopping having forgotten to pick up
several things that she intended to buy. At
other times she will wander through the house,
looking in drawers or closets for items that she
had put away for safe-keeping. Although they
used to go out to dinner at least once a week,
they now go much less frequently because Mrs. L.
states that I just never know what to order, and
its not as much fun as it used to be.
5
Mrs. R. L.
  • Mrs. R. L.s medications include
  • Xalcom Drops 1 drop in each eye HS
  • (Latanoprost 0.005 Timolol 0.5)
  • Esomeprazole (Nexium) 20 mg daily
  • Acetaminophen 1 gm PRN arthritis pain
  • Unisom 2-3 times/week for insomnia

6
Dementia Warning Signs
7
Dementia Warning Signs
8
What signs and symptoms are present in Mrs. R. L.
that suggest that she may have a dementia?
9
AD Management
  • Assessment
  • Treatment
  • Patient Family Education Support
  • Legal Considerations

10
Assessment
  • Cognitive status
  • Daily function
  • Concurrent medical conditions
  • Medications
  • Behavior symptoms and mood
  • Living arrangements
  • Support system

11
Assessing Cognition
12
Assessing Function Activities of Daily Living
(ADL)
  • Self-feeding
  • Dressing
  • Ambulation
  • Toileting
  • Bathing
  • Transfer from bed to toilet
  • Continence
  • Grooming
  • Communication

13
Assessing FunctionInstrumental ADL (IADL)
  • Writing
  • Reading
  • Cooking
  • Cleaning
  • Shopping
  • Doing laundry
  • Climbing stairs
  • Using telephone
  • Managing medication
  • Managing money
  • Ability to perform outside work
  • Ability to travel (public transportation)

14
Concurrent Conditions
  • Chronic disease
  • Ability to manage
  • Impact on function
  • Delirium
  • New problems
  • Infection
  • Cancer

15
Medications Cognition
  • Anticholinergics
  • Benzodiazepines
  • Sleep aids
  • Antipsychotics
  • Narcotics
  • Muscle relaxants
  • NSAIDs
  • Anti-arrhythmics
  • Antihypertensives
  • Cimetidine
  • Corticosteroids
  • Hypoglycemic agents

16
Behavior and Mood
  • Agitation
  • Restlessness
  • Irritability
  • Aggression
  • Psychosis
  • Delusions
  • Paranoia
  • Hallucinations
  • Depression
  • Withdrawal
  • Sleep disturbances
  • Appetite changes
  • Apathy
  • Loss if interest

17
Living Arrangements
  • Declining ability for self-care
  • Patient autonomy vs. need for care
  • Safety issues
  • Rugs, appliances
  • Driving
  • Abuse and neglect
  • Dependence
  • Caregiver stress

18
Support System
  • Spouse
  • Ability to care for patient
  • Family
  • Community support
  • Alzheimers Association
  • Religious or other groups
  • Health care resources
  • Advance directives

19
How would you evaluate Mrs. R. L. regarding her
condition? What concerns do you have regarding
her care and situation?
20
Treatment Strategies
  • Early diagnosis
  • Family education
  • Early treatment intervention
  • Effective management of concurrent conditions
  • Ongoing caregiver support

21
Pharmacists Can
  • Serve as an information resource
  • Local Alzheimers Association chapters
  • www.alz.org
  • 1.800.272.3900
  • MedicAlert Safe Return program
  • Social service agencies
  • Senior centers
  • Adult day care

22
Helping Families Manage Meds
  • Evaluate risk for additional, drug-induced
    cognitive impairment (e.g., anticholinergics)
  • Explain potential adverse effects
  • Instruct families how to monitor
  • Assess the ability of patients and caregivers to
    adhere to a medication regimen
  • Adherence aids
  • Simplify medication regimen

23
Disease Modifying Approaches
  • Cholinergic manipulation
  • Cholinesterase inhibitors
  • All agents block acetylcholinesterase activity
  • Rivastigmine also blocks butyrylcholinesterase
  • Galantamine stimulates cholinergic receptors
  • NMDA antagonist
  • Reduces glutamate activity
  • Regulates calcium entry into cells

24
Available Agents
  • Donepezil (Aricept)
  • Starting dose is therapeutic
  • CYP1A2 substrate
  • Galantamine (Razadyne)
  • Initial dose is not therapeutic
  • Probably first to go generic
  • Rivastigmine (Exelon)
  • Patch reduces GI effects
  • Renal excretion

25
ChEI Adverse Reactions ()
-Kaduszkiewicz, et al., BMJ 2005331321-327
26
Principles for ChEI Use
  • Initial treatment upon diagnosis or 6-months
    duration of AD symptoms
  • Evaluate for ADR after 2-4 weeks
  • Evaluate for effectiveness every 6 months
  • Switch if poor tolerance, or continued decline
  • Discontinue prior to surgery

27
Is Mrs. R. L. an appropriate candidate for
treatment with a cholinesterase inhibitor? How
should her treatment (both drug and non-drug) be
started and monitored?
28
Counseling Points
  • Effects on cognition are very mild
  • May stabilize or slow decline for 6-12 months
  • May improve independence, self-care
  • Gastrointestinal effects are prominent
  • May slow heart rate

29
The Evidence Suggests
-Kaduszkiewicz, et al., BMJ 2005331321-327
30
Memantine
  • Uncompetitive NMDA receptor antagonist
  • Increased glutamate release in CNS produces
    excitotoxic reactions and cell death
  • Prominent in areas affected by dementias
  • Calcium ion channels are affected
  • Moderate affinity for receptor avoids toxicity
    associated with ketamine, etc.

31
Memantine (Namenda)
  • Approved for use in moderate, severe AD
  • Monotherapy
  • With ChEI
  • Availability
  • 5 10 mg tablets
  • 10 mg/5 mL solution
  • Dosing
  • 5 mg/day for 1 week
  • Increase by 5 mg/day in weekly intervals to 10 mg
    twice daily
  • 10 mg/day maximum with renal impairment
  • May be taken without regard to meals
  • Renal elimination as unchanged drug

32
Memantine Adverse Effects
  • gt 5 incidence in clinical trials
  • Agitation (less than for placebo)
  • Diarrhea
  • Insomnia
  • 5 incidence
  • Dizziness
  • Headache
  • Hallucinations

33
Memantine
  • Effects in moderate AD
  • Slower decline in overall function and in loss of
    activities of daily living
  • No significant effect on cognition
  • Systematic reviews have reported small to no
    clinically relevant effect

34
Principles for Memantine Use
  • Treat upon reaching mild to moderate AD symptoms
  • Typically used as adjunct to ChEI
  • Evaluate for ADR after 2-4 weeks
  • Evaluate for effectiveness every 6 months
  • Discontinue prior to surgery

35
Behavior Symptoms
  • Most difficult for both patients and caregivers
  • Behavior symptoms contribute to
  • Patient distress
  • Caregiver burnout
  • Excess disability
  • Institutionalization

36
Treatment Recommendations
  • Treat behavioral symptoms and mood disorders
    using
  • Non-pharmacologic approaches, such as
    environmental modification, task simplification,
    appropriate activities, etc.
  • IF non-pharmacological approaches prove
    unsuccessful, THEN use medications, targeted to
    specific behaviors, if clinically indicated. Note
    that side effects may be serious and significant.

37
Treatment Increase Level of Function and Delay
Disease Progression
  • Behavioral interventions
  • Adult day services
  • Exercise and recreation
  • Medications

38
Behavioral Symptoms as AD Progresses
100
Agitation
80
Diurnal Rhythm
60
Depression
Irritability
Prevalence ( of patients)
Wandering
Social Withdrawal
Aggression
40
Mood Change
Anxiety
Hallucinations
Paranoia
20
Socially Unacceptable
Delusions
Suicidal Ideation
Accusatory
Sexually Inappropriate
0
40
30
20
10
0
10
20
30
Months Before Diagnosis Months After
Diagnosis
Jost BC, Grossberg GT. J Am Geriatr Soc.
1996441078-1081.
39
Mrs. R. L.
Mrs. R. L. starts to realize she has
Alzheimers disease. She becomes depressed. She
is dysphoric, has lost her appetite, and feels
helpless and hopeless. Her husband reports that
he is becoming frustrated and doesnt know how to
help her.
40
What is your assessment of Mrs. L.s
condition? Is she a candidate for antidepressant
treatment? What should be done to assist her
her husband?
41
Mood Changes
  • Depressed mood
  • Dysphoria secondary to dementia
  • Concurrent major depression
  • Cognition, behavior, co-morbid conditions
    influence management
  • Connect her to the Alzheimers Association for
    support activities

42
Antidepressants
43
Mrs. R. L.
Some time has passed and Mr. L. is concerned
about changes in his wifes behavior. She
becomes agitated, especially in the late
afternoon and leaves the house. She says she is
going home and gets more agitated when he reminds
her that she is in her home.
44
Evaluating Behaviors
  • Rapid onset requires search for medical cause
  • Pain, infection, adverse drug effect
  • Identify problem
  • A Antecedents / triggers
  • B - Behavior be specific
  • C Consequences / reinforcers

45
What may be triggering Mrs. L.s behavior? What
does this behavior mean to her? How should these
symptoms be managed?
46
Common Causes of Behaviors
  • Health
  • Difficult tasks
  • Confusing environment
  • Communication breakdown
  • Patients perceptions of the situation

47
Behavior Management Principles
  • Non-drug management generally provides better
    results
  • Assess likelihood that pharmacotherapy will be
    beneficial
  • Target medication to specific behavior
  • Avoid caregiver interpretation of PRN orders
  • Consider the patient's health status
  • Consider drug pharmacokinetic and
    pharmacodynamic properties

48
Non-drug Strategies
  • Avoid startling patient
  • Dont argue incorrect statements
  • Employ distractions
  • Safety-proof living areas
  • One-step commands

49
Specific Behaviors
50
Specific Behaviors
51
Mrs. R. L.
Mrs. R. L. has begun a daily exercise program
and late afternoon agitation is now less of an
issue. However, at night she awakens and becomes
agitated. She believes someone is trying to
break into the house. When her husband tries to
reassure her, she gets angry and strikes out at
him.
52
What non-drug strategies are appropriate to
manage Mrs. L.s current behaviors? Is drug
therapy appropriate, and if so, how should it be
initiated?
53
Managing Anxiety
  • Reassure, dont ignore
  • Distract - engage person in other activities
  • Music, simple tasks, hobby-type activities
  • Simplify the environment
  • Cover windows and mirrors use night lights

54
Anxiolytics
  • Short-term use for anxiety in early stages
  • Benzodiazepine use is discouraged
  • Use short-acting agents, if necessary
  • Trazodone 25 mg is an effective agent for anxiety
    or insomnia
  • Periodically re-assess need
  • Taper BZDP downward to avoid seizures

55
Managing Aggression
  • Identify the cause (noise, fear, etc.)
  • Focus on the persons feelings
  • Avoid getting angry or upset
  • Simplify the environment to limit distractions
  • Music, exercise, etc. as a soothing activity
  • Shift the focus to another activity

56
Antipsychotic Agents
  • Effective for acute aggressive episodes
  • Some benefit for delusions, hallucinations
  • Bedtime dose for initial treatment
  • Very low doses often sufficient
  • Discontinue periodically to assess continued need
  • Increased risk for stroke, weight gain

57
Antipsychotic Agents
58
Atypical Agents
  • Divalproex
  • Useful for aggression or anger unrelated to
    anxiety, psychosis or depression
  • Starting dose 125 mg BID
  • Maximum dose 625 mg BID
  • Nausea, GI disturbances are most prominent ADR
  • Tremor, weight gain, hair loss, drowsiness

59
Mrs. R. L.
Mr. L. is no longer able to care for his wife due
to his decline in health. Mrs. L. is placed in
the locked dementia section of an assisted living
facility. She rarely speaks, gets up frequently
during the night and wanders into other
residents rooms, disrupting their sleep. During
the day, she paces the hall. She battles with
staff who attempt to assist her with bathing and
hygiene.
60
Mrs. R. L.
She has fallen twice, once fracturing her wrist.
At her last evaluation, her MMSE score was 7/30
and her CDR was 3/5. Current medications
include Donepezil 10 mg HS Memantine 10 mg
BID Esomeprazole 20 mg daily Amlodipine 10 mg
daily HCTZ 12.5 mg daily Zolpidem 10 mg HS
PRN Quetiapine 50 mg BID for combativeness Vicod
in 1 tablet q4h PRN pain
61
What factors are contributing to her current
behaviors? What changes, if any, do you
recommend in her medication regimen?
62
Summary
  • Early diagnosis is essential
  • The pharmacist should
  • Evaluate ALL medications
  • Refer to community resources
  • Work with the patient and caregivers
  • Ensure medication regimens are simple
  • Minimize medication changes, and avoid changes
    during transition times
  • Communicate with all health care providers

63
Questions?
Questions?
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