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Alzheimer’s Disease Update on Evidence-Based Treatment Guidelines by SupremeLord

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									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
Identify the typical signs and symptoms
associated with Alzheimer’s disease and other
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
                           Bill paying, shopping
familiar tasks
Disorientation             Getting lost in familiar places
                           Inviting strangers into the
Impaired judgment
Impaired abstract
                          Driving skills
thinking, problem-solving
    Dementia Warning Signs
        Task                     Example

                     Losing valuable items in the
Misplacing things
Mood or behavior     New-onset irritability, unusual
change               habits or activities
                     Withdrawn, increased
Personality change

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
Patient & Family Education &
Legal Considerations
Cognitive status
Daily function
Concurrent medical conditions
Behavior symptoms and mood
Living arrangements
Support system
           Assessing Cognition
           Test        Items/Score          Domains
Folstein Mini-Mental   19 items      Multi-dimensional
Status Exam            30 points
Mini-Cog               2 items       3-item recall
                       5 points      Clock drawing
Blessed Orientation-   6 items       Orientation,
Concentration-Memory   28 points     concentration, recall

Cognitive Assessment   25 items      Multi-dimensional
Screening Instrument   100 points
     Assessing Function:
Activities of Daily Living (ADL)
Self-feeding     Bathing
Dressing         Transfer from bed
Ambulation       to toilet
Toileting        Continence
   Assessing Function:
 Instrumental ADL (IADL)
Writing         Climbing stairs
Reading         Using telephone
Cooking         Managing medication
Cleaning        Managing money
Shopping        Ability to perform
Doing laundry   outside work
                Ability to travel (public
 Concurrent Conditions
Chronic disease
 Ability to manage
Impact on function
New problems
Medications & Cognition
Anticholinergics   NSAIDs
Benzodiazepines    Anti-arrhythmics
Sleep aids         Antihypertensives
Antipsychotics     Cimetidine
Narcotics          Corticosteroids
Muscle relaxants   Hypoglycemic
    Behavior and Mood
Agitation          Depression
  Restlessness       Withdrawal
  Irritability       Sleep disturbances
  Aggression         Appetite changes
Psychosis          Apathy
  Delusions          Loss if interest
   Living Arrangements
Declining ability for self-care
  Patient autonomy vs. need for care
Safety issues
  Rugs, appliances
Abuse and neglect
  Caregiver stress
      Support System
 Ability to care for patient
Community support
 Alzheimer’s Association
 Religious or other groups
Health care resources
Advance directives
How would you evaluate
Mrs. R. L. regarding her

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
   MedicAlert + Safe Return program
 Social service agencies
   Senior centers
   Adult day care
Helping Families Manage
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 (%)
               Donepezil        Rivastigmine   Galantamine
Nausea           4-24               8-58           6-37
Vomiting         1-15               5-38           4-21
Diarrhea         4-17               7-17           2-12
Wt/App           2-19               3-18           6-12
Dizziness         NR                6-27           4-19
Insomnia         8-18                NR             NR
Musc              6-8                NR             NR
Headache         9-12               7-20           6-11
-Kaduszkiewicz, et al., BMJ 2005;331:321-327
 Principles for ChEI Use
Initial treatment   Evaluate for
upon diagnosis or   effectiveness every
6-months            6 months
duration of AD        Switch if poor
symptoms              tolerance, or
                      continued decline
Evaluate for ADR
after 2-4 weeks     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
May improve independence, self-
Gastrointestinal effects are
May slow heart rate
   The Evidence Suggests…

-Kaduszkiewicz, et al., BMJ 2005;331:321-327
Uncompetitive NMDA receptor
  Increased glutamate release in CNS
  produces excitotoxic reactions and cell
    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     Dosing
moderate, severe AD       5 mg/day for 1 week
  Monotherapy             Increase by 5 mg/day
  With ChEI               in weekly intervals to
                          10 mg twice daily
                          10 mg/day maximum
  5 & 10 mg tablets       with renal impairment
  10 mg/5 mL solution
                        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)
5% incidence
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            Evaluate for
 reaching mild to      effectiveness every
 moderate AD           6 months
 symptoms              Discontinue prior
   Typically used as   to surgery
   adjunct to ChEI
 Evaluate for ADR
 after 2-4 weeks
   Behavior Symptoms
Most difficult for both patients and
Behavior symptoms contribute to:
  Patient distress
  Caregiver burnout
  Excess disability
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
Behavioral Symptoms as
    AD Progresses
Prevalence (% of patients)

                             60                                      Rhythm
                                                  Depression                          Irritability

                                             Social                                                   Wandering         Aggression
                             40              Withdrawal               Anxiety Mood
                                                                              Change                             Hallucinations
                             20                                                                 Socially Unacceptable
                                            Suicidal                                           Delusions
                                            Ideation                                                 Sexually Inappropriate
                                   –40      –30        –20           –10          0              10              20         30

                                         Months Before Diagnosis                        Months After Diagnosis

Jost BC, Grossberg GT. J Am Geriatr Soc. 1996;44:1078-1081.
          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
    Drug       Start    Max/day
Citalopram     10 mg     30 mg
Escitalopram    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
          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

What does this behavior mean
to her?

How should these symptoms be
    Common Causes of
Difficult tasks
Confusing environment
Communication breakdown
Patient’s perceptions of the situation
  Behavior Management
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                     Strategy
                 Simple tasks
Irritability     Breakdown tasks to simple steps
Agitation        Redirection and distraction
                 Visual cues
Wandering        Exercise in safe places to wander
                 Enroll in Medic-Alert® + Safe Return ®
Mood disorders
           Specific Behaviors
    Problem                     Strategy
                  Sleep hygiene practices
Disturbed sleep   Daytime stimulation
                  Reduced evening stimulation
                  Distraction, rather than confrontation
                  Remove triggers (e.g., mirrors)
                  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
  Music, simple tasks, hobby-type
Simplify the environment
  Cover windows and mirrors; use night
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
Music, exercise, etc. as a soothing
Shift the focus to another activity
  Antipsychotic Agents
Effective for acute aggressive episodes
Some benefit for delusions,
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
Aripiprazole     5 mg        20 mg
Clozapine      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
       Atypical Agents
  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
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


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