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Pharmacy Medication Update: Dementia

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Title: Pharmacy Medication Update: Dementia


1
Pharmacy Medication Update Dementia
  • Megan J. Ehret, PharmD, MS, BCPP
  • Associate Professor University of Connecticut

2
Objectives
  • Describe the clinical presentation and diagnostic
    criteria for dementia and mild cognitive
    impairment.
  • Describe the treatment guidelines and landmark
    clinical trials for the treatment of dementia.
  • Select an evidenced-based drug therapy regimen
    for stabilizing symptoms of dementia.
  • Identify essential information to discuss during
    patient education about the drug therapy of
    dementia.

3
Prevalence/Clinical Course
  • 2-4 of population over 65 years old
  • Increases with age
  • AD accounts for 60 of all dementias in the
    elderly
  • Gradual onset and is slowly progressive
  • Cognition is affected early on with impairment in
    motor, behavioral, and sensory functioning
    occurring later
  • Time to onset to death 8-10 years
  • Loss of 3-4 points/year on MMSE

4
Risk Factors
  • Degeneration of cholinergic neurons
  • Cortical atrophy
  • Presence of neurofibrillary tangles
  • Accumulation of neuritic plaques
  • Increasing age
  • Down Syndrome
  • Head trauma
  • Depression
  • Lower educational level

5
DSM 5 Diagnostic Criteria- Alzheimers Disease
  • Must meet criteria for major or mild
    neurocognitive disorder
  • Cognitive decline from baseline in 1/5
    Attention, Executive Function, Learning and
    Memory, Language, Perceptual-Motor, or Social
    Cognition)
  • Cognitive impairment is slow and gradual

DSM 5 2013
6
Signs and Symptoms of AD
  • Loss of early memory- progresses to loss of
    long-term memory
  • Final stages gait abnormalities, motor
    disturbances, decline in communication abilities,
    dependent on others

7
Objective Signs of AD
  • Amyloid Beta Peptide-
  • Imagining is appropriate in pts. with persistent
    mild cognitive impairment, pts. with core AD with
    atypical or unusual course, and progressive
    dementia with early age onset (lt65)
  • MRI- Cortical atrophy
  • MMSE- 3-4 point loss
  • MoCA- Rapid screening instrument for mild
    cognitive dysfunction
  • Total score is 30 gt26 is normal
  • Genetic Testing- APOE4, presenilins 1 and 2
  • Controversial

Alzheimers Association/Society of Nuclear
Medicine and Molecular Imagining 2013
8
Mini-Mental State Exam (MMSE)
9
(No Transcript)
10
Other Rating Scales
  • Alzheimers Disease Assessment Scale (ADAS)
  • Evaluate the severity of dysfunction in
    cognition, and non-cognitive behaviors over time
  • Severe Impairment Battery
  • Used to detect cognitive function in severe
    dementia
  • Neuropsychiatric Inventory
  • Assesses behavioral problems in dementia
  • Behavioral Pathology in Alzheimers Disease
    (BEHAVE-AD)
  • Assess behavioral symptoms and measure outcomes
    in treatment studies

11
Treatment Guidelines
12
Non-Pharmacological Treatment
13
Therapies and Plans
  • Increase enjoyable activities
  • Redirect and refocus
  • Increase social activities for the patient
  • Eliminate sources of conflict and frustration
  • Assess the pt.'s caregiver for signs and symptoms
    of depression

14
Pharmacological Treatment
15
General Approach
  • First line treatment Cholinesterase Inhibitors,
    memantine can also be used in moderate to severe
    dementia
  • Second line treatment addition of memantine to
    cholinesterase inhibitors
  • Medications have been shown to only temporarily
    slow the progression of the disease
  • Switching between cholinesterase inhibitors is
    well tolerated and provides therapeutic benefit
    if previous agent lacked efficacy or tolerability

16
Cholinesterase Inhibitors
  • Inhibit the cholinesterase (AChE)
  • Enzyme responsible for hydrolysis of
    acetylcholine
  • Elevates concentrations of acetylcholine for
    synaptic transmission in the CNS
  • Thought to improve memory and cognition

17
Donepezil (Aricept)
  • Treatment of mild to severe AD
  • Mild to moderate 5mg daily may increase to 10mg
    daily after 4-6 weeks, may increase to 23mg daily
    after gt3 months
  • Moderate to severe same as above
  • 23mg greater benefit in cognition, but not global
    functioning higher rates of GI adverse events

18
Donepezil
  • Warnings/Precautions
  • Peptic ulcer disease and GI bleeding monitor for
    GI bleeding especially in those who are higher
    risk
  • Weight Loss
  • Adverse Events
  • Nausea, vomiting, and diarrhea administer
    medication with food reduce dose
  • Vagotonic effects slows conduction through SA
    and AV nodes resulting in bradycardia
  • Insomnia Give medication in morning

19
Rivastigmine (Exelon)
  • Treatment of mild, moderate, and severe AD,
    treatment of Parkinsons Disease Dementia
  • 1.5mg twice daily, may increase by 3mg daily
    every 2 weeks based on tolerability max dose
    6mg twice daily
  • Patch 4.6mg/24hrs daily, may titrate to
    9.5mg/24hrs, then to 13.3mg/24hrs (verify that
    old patch has been removed prior to applying a
    new patch)
  • If dosing is interrupted for more than 3 days,
    pt. needs to be restarted on initial dose
  • Same warnings/precautions

20
Galantamine (Razadyne)
  • Mild to moderate AD
  • IR or solution 4mg twice daily for 4 weeks,
    then 8mg twice daily for gt4 weeks, if tolerated
    than 12mg twice daily
  • ER 8mg once daily for 4 weeks, then 16mg daily
    for gt4 weeks, if tolerated than 24mg daily
  • Same warnings/precautions

21
Memantine (Namenda)
  • Treatment of moderate to severe AD
  • Low to moderate, uncompetitive,
    N-methyl-D-aspartate (NMDA) receptor antagonist
  • Glutamate is an amino acid which may contribute
    to the pathogenesis of AD by over-stimulating the
    NMDA receptor
  • Short acting 5mg/day for 1 week, 5 mg twice
    daily for 1 week, 5 mg in the AM and 10mg in the
    PM for one week, then 10mg twice daily
  • Long acting 7mg/day for 1 week, 14mg/day for 1
    week, 21mg/day for 1 week, then 28mg/day

22
Memantine
  • Use with caution in patients with seizure
    disorders, hepatic impairment, or mild-moderate
    renal impairment
  • Most common adverse effects dizziness, headache,
    hallucinations, insomnia, confusion, and
    constipation

23
Duration of Therapy
  • Controversial
  • If no efficacy seen within 3 months of therapy at
    maximum dose, switching should be attempted
  • Both immediate switching and a 7-14 day wash our
    has been done good tolerability and efficacy

24
Dietary Supplements
25
Vitamin E
  • Late 1990s recommended due to its antioxidant
    effect
  • Decrease the accumulation of free radicals
  • Evidence on prevention is mixed
  • Adverse effects impaired hemostatis, fatigue,
    nausea, diarrhea, abdominal pains, falls
  • Meta-analysis high-dose can increase mortality
  • Not recommended

26
Nutraceuticals/Supplements
  • Ginkgo Biloba increase blood flow, decrease
    blood viscosity, antagonize platelet-activating
    factor receptors, increase anoxia tolerance,
    inhibit monoamine oxidase, antioxidant
  • Side effects nausea, vomiting, diarrhea,
    headaches, dizziness, palpitations, restlessness,
    weakness

27
Nutraceuticals/Supplements
  • Omega-3 large, prospective, placebo-controlled
    trial in AD subjects
  • Primary study endpoints negative

28
Medical Food
  • Axona
  • Modification of medium-chain triglyceride
    formulation
  • Contains mixtures of C5-C12 fatty acids
  • Converted to betahydroxybutyrate oxidative
    phosphorylation substrate by neuron mitochondria
    supports brain bioenergetics
  • Supported by trials of 40 mg /day for 45 days

29
Behavioral and Psychological Symptoms in Dementia
30
Diagnostic Criteria
  • No specific diagnostic criteria
  • Could be met for impulse control disorders,
    obsessive-control disorder, and bipolar disorder

31
Signs and Symptoms
  • Physically aggressive agitation pushing, biting,
    kicking, spitting
  • Physically nonaggressive behavior pacing,
    wondering, inappropriate voiding, undressing
  • Verbally aggressive behavior screaming, yelling,
    cursing
  • Verbally nonaggressive behavior requesting
    attention, repetitively calling out
  • Most common apathy, delusions,
    aggression/agitation, anxiety, psychomotor
    disturbance, irritability, sleep/wake
    disturbance, depression, disinhibition,
    hallucinations

32
Risk Factors/ Prevalence
  • Can occur in up to 60 of demented patients in
    community dwelling and 80 in long term care
    facilities
  • 1/3 of mildly-impaired dementia pts., 2/3 of
    moderate impairment pts.
  • After 5 yrs. w/dementia 90 with have one BPSD
  • Risk of developing varies
  • Fronto-temporal dementias, LBD, vascular
    dementia, Huntingtons disease more likely to
    experience BPSD symptoms

33
Clinical Course
  • Depression, apathy, social withdrawal can be
    noticed several years before diagnosis of
    dementia
  • As dementia progresses frequency and intensity
    of agitation and aggression worsen
  • At end stages of dementia, episodes of agitation
    and aggression may diminish

34
Treatment Guidelines
  • Rule out psychological and psychosocial causes
    for change in behavior
  • Elimination of causative factors and psychosocial
    intervention are treatments of choice
  • Medication therapy can be recommended
  • Hyperactivity syndrome and psychosis
    risperidone, olanzapine, quetiapine,
    aripiprazole, citalopram, trazodone, and
    carbamazepine
  • Valproic acid and lithium should be avoided lack
    of evidence

World Federation of Societies of Biological
Psychiatry 2011
35
Non-Pharmacological Treatment
  • Treatment of choice
  • Recognizing, redirecting, and diffusing the
    neuropsychiatric behavior
  • Intervene early
  • Stay calm- avoid arguing or trying to reason with
    the patient
  • Wondering
  • Environmental modifications
  • Providing activities
  • Electronic alarms
  • Safety Plans

36
Non-Pharmacological Treatment
  • Sleep disturbances
  • Strive for consistent bedtimes
  • Limit daytime napping
  • Restrict use of alcohol and caffeinated beverages
  • Reduce light levels, changes in temperature, and
    nighttime noises
  • Avoid changes in daily routines
  • Other therapies
  • Music therapy
  • Light therapy
  • Massage therapy
  • Multisensory Stimulation

37
Pharmacological Treatment
38
Antipsychotics
  • Evidence is high to support the use of
    antipsychotics for BPSD
  • Second Generation Antipsychotics
  • Over 37 trials risperidone, olanzapine,
    quetiapine, aripiprazole
  • Limited to no data clozapine, ziprasidone,
    paliperidone, iloperidone, asenapine, lurasidone
  • Range 2 days to 1 year endpoints were not
    standardized

Dementia Psychosis Agitation
Aripiprazole
Olanzapine /-
Quetiapine /- /-
Risperidone
39
SHIFT IN RISK PERCEPTION OF ANTIPSYCHOTICS
Current Medical Realities
Past Areas of Concern
Diabetes
TD
Weight Gain
Prolactin
Tardive Dyskinesia
Hyperlipidemia
Insulin Resistance
Sedation
Weight Gain
Insulin Resistance
Hyper- lipidemia
Coronary Heart Disease
Sedation
CHD
Prolactin
40
SIDE EFFECTS OF ATYPICAL ANTIPSYCHOTICS
CLOZ RIS OLZ QUE
ZIP ARIP
0/
0/

/0


Low Blood Pressure
Dry mouth, constipation
0
0
0
/
0

Tremors, stiffness, endocrine problems
0
/0
0
0/
/
0
0
0


/-

Sedation
-/
-/




Weight gain
0
0




Lipids
0
0




Blood sugar
CLOZ clozapine RIS risperidone OLZ
olanzapine QUET quetiapine ZIP ziprasidone
ARIP aripiprazole Adapted from Nasrallah HA,
Mulvihill T. Ann Clin Psychiatry.
2001(Dec)13(4)215-227
41
WEIGHT GAIN ATYPICAL ANTIPSYCHOTICS
Data for Package Labels
42
LIPID ABNORMALITIES
Data from product labels
43
ADA/APA CONSENSUS CONFERENCE ON ANTIPSYCHOTIC
DRUGS AND OBESITY AND DIABETES SUMMARY
Drug Weight Gain Risk for Diabetes Worsening Lipid Profile
Clozapine (Clozaril)
Olanzapine (Zyprexa)
Risperidone (Risperdal) Paliperidone (Invega) /- /-
Quetiapine (Seroquel) /-
Aripiprazole (Abilify) /- - -
Ziprasidone (Geodon) /- - -
increase effect - no effect D
discrepant results. Newer drugs with limited
long-term data.
44
ADA/APA CONSENSUS CONFERENCE ON ANTIPSYCHOTIC
DRUGS AND OBESITY AND DIABETES SUMMARY
Baseline 4 wk 8 wk 12 wk Quarterly Annually Q5yr
Weight X X X X X X
BP X X X
Fasting Glucose X X X
Waist Circumference X X
Fasting Lipid X X X
45
Antipsychotics
  • Typical Antipsychotics
  • 5 clinical trials comparing the efficacy of
    haloperidol to a SGA
  • Average haloperidol dose per day 2-4 mg
  • No difference in efficacy with haloperidol versus
    a SGA

46
Adverse Events- Black Box Warning
  • WARNINGS INCREASED MORTALITY IN ELDERLY PATIENTS
    WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDALITY
    AND ANTIDEPRESSANT DRUGS

47
Black Box Warning Cerebrovascular Accidents
  • Cerebrovascular Adverse Events, Including Stroke,
    in Elderly Patients with Dementia-Related
    Psychosis
  • In placebo-controlled trials with risperidone,
    aripiprazole and olanzapine in elderly subjects
    with dementia, there was a higher incidence of
    cerebrovascular adverse events (cerebrovascular
    accidents and transient ischemic attacks)
    including fatalities compared to placebo-treated
    subjects

48
Risk Factors for Stroke
  • Beyond Control
  • Advancing age, risk doubles after age 55 years
  • Male gender
  • African-American
  • Family history of diabetes
  • Family history of stroke or
  • TIA
  • May be altered
  • Medical
  • Hypertension
  • Atrial fibrillation
  • Elevated cholesterol
  • Coronary Heart Disease
  • Sleep Apnea
  • Lifestyle
  • Smoking
  • Obesity
  • Excessive Alcohol

Source National Stroke Association
49
Antidepressants
  • Mixed studies
  • Trazodone gt haloperidol
  • Fluoxetine haloperidol
  • Sertraline gt placebo agitation
  • Citalopram- mixed studies
  • Fluvoxamine perphenazine gt perphenazine alone
  • All studies showed similar adverse event
    profiles studies were relatively short in
    duration, lacked randomization, and small number
    of pts.

50
Mood Stabilizers
  • One meta-analysis and 5 RTCs did not support
    efficacy of valproic acid in treating
    aggression, agitation, or psychosis
  • Carbamazepine one meta-analysis and 3 trials
    efficacy in treatment of agitation and aggression
    compared to placebo placebo was better tolerated
  • Oxcarbazepine failed trial
  • Lamotrigine, gabapentin, topiramate case reports
    or case series

51
Cholinesterase Inhibitors
  • AChE inhibitors can improve BPSD
  • If AChE inhibitors are tapered Worsening of
    BPSD symptoms can occur

52
Memantine
  • Naturalistic, small, open-labeled studies
  • Modest improvement in BPSD and overall good
    tolerability

53
General Recommendations
  • Do not discontinue or change the dose of
    treatment without discussion with health care
    provider
  • Reduce/eliminate risk for strokes and diabetes
  • What matters most
  • Symptom relief
  • Reduced care giver burden
  • Increase quality of life
  • Avoidance of unacceptable risks
  • Improved functional status
  • Risk reduction and cost of care

54
Conclusion
55
Key Concepts
  • Etiology is unknown
  • Current pharmacotherapy neither cures or arrests
    the pathology
  • Pharmacotherapy focuses on 3 areas
  • Cognition
  • Behavioral and psychiatric symptoms
  • Functional ability
  • Pharmacotherapy may reduce the total cost of
    treating AD by delaying cognitive decline and
    time to nursing home placement
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