Download Alzheimer’s Disease: Update on Evidence

Alzheimer’s Disease:
Update on Evidence-Based
Treatment Guidelines
Debra Cherry, PhD
Freddi Segal-Gidan, PA-C, PhD
Bradley R. Williams, PharmD, CGP
On behalf of the California Workgroup on Guidelines for
Alzheimer’s Disease Management
Objectives
Identify the typical signs and symptoms
associated with Alzheimer’s disease and other
dementias.
Discuss the roles of cholinergic manipulation
and NMDA inhibition in the treatment of
Alzheimer’s disease symptoms.
Recognize behavior disturbances commonly
displayed by patients with dementia.
Develop a therapeutic strategy for treating
agitated behaviors in Alzheimer’s disease.
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 don’t always help.” She admits to
reading less than she used to; she also drives
less because “traffic is such a problem.”
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 it’s not as
much fun as it used to be.”
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
Dementia Warning Signs
Task
Example
Memory decline
Forgetfulness
Difficulty performing
familiar tasks
Bill paying, shopping
Disorientation
Getting lost in familiar places
Impaired judgment
Inviting strangers into the
home
Impaired abstract
Driving skills
thinking, problem-solving
Dementia Warning Signs
Task
Example
Misplacing things
Losing valuable items in the
home
Mood or behavior
change
New-onset irritability, unusual
habits or activities
Personality change
Withdrawn, increased
socialization
Loss of initiative
Lost interest in hobbies
What signs and symptoms
are present in Mrs. R. L.
that suggest that she may
have a dementia?
AD Management
Assessment
Treatment
Patient & Family Education &
Support
Legal Considerations
Assessment
Cognitive status
Daily function
Concurrent medical conditions
Medications
Behavior symptoms and mood
Living arrangements
Support system
Assessing Cognition
Test
Items/Score
Domains
Folstein Mini-Mental
Status Exam
19 items
30 points
Multi-dimensional
Mini-Cog
2 items
5 points
3-item recall
Clock drawing
Blessed OrientationConcentration-Memory
6 items
28 points
Orientation,
concentration, recall
Cognitive Assessment
Screening Instrument
25 items
100 points
Multi-dimensional
Assessing Function:
Activities of Daily Living (ADL)
Self-feeding
Dressing
Ambulation
Toileting
Bathing
Transfer from bed
to toilet
Continence
Grooming
Communication
Assessing Function:
Instrumental 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)
Concurrent Conditions
Chronic disease
Ability to manage
Impact on function
Delirium
New problems
Infection
Cancer
Medications & Cognition
Anticholinergics
Benzodiazepines
Sleep aids
Antipsychotics
Narcotics
Muscle relaxants
NSAIDs
Anti-arrhythmics
Antihypertensives
Cimetidine
Corticosteroids
Hypoglycemic
agents
Behavior and Mood
Agitation
Restlessness
Irritability
Aggression
Psychosis
Delusions
Paranoia
Hallucinations
Depression
Withdrawal
Sleep disturbances
Appetite changes
Apathy
Loss if interest
Living Arrangements
Declining ability for self-care
Patient autonomy vs. need for care
Safety issues
Rugs, appliances
Driving
Abuse and neglect
Dependence
Caregiver stress
Support System
Spouse
Ability to care for patient
Family
Community support
Alzheimer’s Association
Religious or other groups
Health care resources
Advance directives
How would you evaluate
Mrs. R. L. regarding her
condition?
What concerns do you
have regarding her care
and situation?
Treatment Strategies
Early diagnosis
Family education
Early treatment intervention
Effective management of
concurrent conditions
Ongoing caregiver support
Pharmacists Can…
Serve as an information resource
Local Alzheimer’s Association chapters
www.alz.org
1.800.272.3900
MedicAlert + Safe Return program
Social service agencies
Senior centers
Adult day care
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
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
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
ChEI Adverse Reactions (%)
Nausea
Vomiting
Diarrhea
Donepezil
4-24
1-15
4-17
Rivastigmine
8-58
5-38
7-17
Galantamine
6-37
4-21
2-12
Wt/App
Dizziness
Insomnia
2-19
NR
8-18
3-18
6-27
NR
6-12
4-19
NR
Musc
Headache
6-8
9-12
NR
7-20
NR
6-11
-Kaduszkiewicz, et al., BMJ 2005;331:321-327
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
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?
Counseling Points
Effects on cognition are very mild
May stabilize or slow decline for 6-12
months
May improve independence, selfcare
Gastrointestinal effects are
prominent
May slow heart rate
The Evidence Suggests…
-Kaduszkiewicz, et al., BMJ 2005;331:321-327
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.
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
Memantine Adverse Effects
> 5% incidence in clinical trials
Agitation (less than for placebo)
Diarrhea
Insomnia
5% incidence
Dizziness
Headache
Hallucinations
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
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
Behavior Symptoms
Most difficult for both patients and
caregivers
Behavior symptoms contribute to:
Patient distress
Caregiver burnout
Excess disability
Institutionalization
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.
Treatment: Increase Level of Function
and Delay Disease Progression
Behavioral interventions
Adult day services
Exercise and recreation
Medications
Behavioral Symptoms as
AD Progresses
Prevalence (% of patients)
100
Agitation
80
60
Depression
Irritability
Wandering
Social
Withdrawal
40
Diurnal
Rhythm
Paranoia
Anxiety Mood
Change
0
–40
–30
Accusatory
–20
–10
Hallucinations
Socially Unacceptable
Delusions
Sexually Inappropriate
20
Suicidal
Ideation
Aggression
0
Months Before Diagnosis
Jost BC, Grossberg GT. J Am Geriatr Soc. 1996;44:1078-1081.
10
20
30
Months After Diagnosis
Mrs. R. L.
Mrs. R. L. starts to realize she has
Alzheimer’s 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 doesn’t
know how to help her.
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?
Mood Changes
Depressed mood
Dysphoria secondary to dementia
Concurrent major depression
Cognition, behavior, co-morbid
conditions influence management
Connect her to the Alzheimer’s
Association for support & activities
Antidepressants
Drug
Start
Max/day
10 mg
30 mg
5 mg
20 mg
Paroxetine
10 mg
30 mg
Sertraline
25 mg
150 mg
Mirtazapine
7.5 mg
30 mg
Trazodone
25 mg
100 mg
Citalopram
Escitalopram
Mrs. R. L.
Some time has passed and Mr. L. is
concerned about changes in his wife’s
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.
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
What may be triggering Mrs. L.’s
behavior?
What does this behavior mean
to her?
How should these symptoms be
managed?
Common Causes of
Behaviors
Health
Difficult tasks
Confusing environment
Communication breakdown
Patient’s perceptions of the situation
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
Non-drug Strategies
Avoid startling patient
Don’t argue incorrect statements
Employ distractions
Safety-proof living areas
One-step commands
Specific Behaviors
Problem
Apathy
Irritability
Agitation
Wandering
Mood disorders
Strategy
Stimulation/Activities
Simple tasks
Breakdown tasks to simple steps
Redirection and distraction
Visual cues
Exercise in safe places to wander
Enroll in Medic-Alert® + Safe Return
Exercise
®
Specific Behaviors
Problem
Strategy
Disturbed sleep
Sleep hygiene practices
Daytime stimulation
Reduced evening stimulation
Psychotic
symptoms
Reassurance
Distraction, rather than confrontation
Remove triggers (e.g., mirrors)
Appetite
problems
Offer simple, finger foods
Remove distractions from dining area
Soothing music during meals
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.
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?
Managing Anxiety
Reassure, don’t ignore
Distract - engage person in other
activities
Music, simple tasks, hobby-type
activities
Simplify the environment
Cover windows and mirrors; use night
lights
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
Managing Aggression
Identify the cause (noise, fear, etc.)
Focus on the person’s 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
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
Antipsychotic Agents
Drug
Start (HS)
Max/day
5 mg
20 mg
10-25 mg
100 mg
Haloperidol
0.5 mg
4 mg
Olanzapine
2.5 mg
15 mg
Quetiapine
25 mg
200 mg
Risperidone
0.25 mg
3 mg
Aripiprazole
Clozapine
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
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.
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
Vicodin 1 tablet q4h PRN pain
What factors are contributing to her
current behaviors?
What changes, if any, do you
recommend in her medication
regimen?
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
Questions?…
Questions?…