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Treatment for Alzheimer’s Disease


Treatment for Alzheimer s Disease Maenne Okunola June 2011 UGA COP: Pharm D. Candidate Preceptor: Dr. Ali Rahimi Treatment Goal Currently there is no current ... – PowerPoint PPT presentation

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Title: Treatment for Alzheimer’s Disease

Treatment for Alzheimers Disease
  • Maenne Okunola
  • June 2011
  • UGA COP Pharm D. Candidate
  • Preceptor Dr. Ali Rahimi

Treatment Goal
  • Currently there is no current therapy to treat
    Alzheimers disease. Current therapy is aimed at
    prolonging the patients cognitive function and
    secondary goals include symptomatically treating
    psychiatric and behavioral abnormalities
  • Current therapy has not been shown to prolong
    life, cure AD, halt or reverse the
    pathophysiological degradation of the disease

Natural Disease Progression
  • Alzheimers Disease Assessment Scale-Cognition
    (ADAS-cog) scores worsen by an average of 4
    points over 6 months and 7 points over 1 year
  • 4 points represents a clinically significant
  • In clinical practice a Mini Mental Status
    Examination (MMSE) is used due to time
    requirements of the ADAS-cog
  • An untreated patient has an average decline of
    2-4 points per year

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Brain Comparison
Ideal Treatment
  • Improving symptomatic decline by improving
    cognitive function, daily activities, and
  • Current therapy
  • Arrests the neurodegenerative molecular process
  • Research needed

Treatment Algorithm
  • Cholinesterase Inhibitor
  • NMDA Antagonist
  • Cholinesterase Inhibitor NMDA antagonist
  • Titrate doses to recommended maintenance therapy
    as tolerated
  • Symptomatic approach is used to treat behavioral

Cholinesterase Inhibitors
Cholinesterase Inhibitors
  • Donepezil (Aricept)- used in mild to severe
  • Galantamine (Razadyne)- used in mild to moderate
  • Rivastigmine (Exelon)- used in mild to moderate
  • Combination of more than one cholinesterase
    inhibitor is not recommended
  • Choice of therapy often selected based on ease of
    use for the patient, cost and safety issues
  • Switching can occur if patients are not
    tolerating the initial treatment or a treatment
  • If MMSE decline is greater than 2-4 points in one
    year changing therapy is warranted

Cholinesterase Inhibitors
  • Donepezil, Rivastigmine and Galantamine
  • All show similar efficacy and adverse event
    profiles with gastrointestinal complaints being
    the most common symptom
  • Dose titration over several months can help
    tolerability of urinary incontinence, dizziness,
    headache, syncope, bradycardia, muscle weakness,
    salivation and sweating
  • Abrupt discontinuation is discouraged due to
    worsening of cognition or behavioral problems in
    some medications
  • Avoid use with anti-cholinergic medications which
    is especially important when trying to treat
    behavioral abnormalities.

Cholinesterase Inhibitors Mechanism of Action
  • Donepezil- specifically and reversibly inhibits
  • Rivastigmine- inhibits both butylcholinesterase
    and acetylcholinesterase
  • Galantamine- selective, competitive, reversible
    acetylcholinesterasse inhibitor and also enhances
    the action of acetylcholine on nicotinic
  • Clinical relevance is unknown

NMDA Antagonist
N-methyl-D Aspartate (NMDA) Antagonist
  • Memantine- used in moderate to severe disease
  • Not recommended in early stages of the disease
  • Only NMDA-antagonist available
  • Blocks glutamatergic neurotransmission by
    antagonizing NMDA receptors
  • Glutamate an excitatory neurotransmitter in the
  • Most common side effects include constipation,
    confusion, dizziness, headache, hallucinations,
    coughing, and hypertension

Dosage Forms
  • Galantamine (Razadyne)- capsule, tablet, and
  • Donepezil (Aricept)- tablet (oral disintegrating
  • Rivastigmine (Exelon)- capsule, patch, and
  • Memantine (Namenda)- tablet and solution

Treatment for Non-cognitive Symptoms
  • Psychosis
  • Disruptive behavior
  • Depression
  • Environmental interventions then pharmacological
  • Limited clinical data therefore, treatment is
  • General guidelines reduced doses, close
    monitoring closely, slow dose titrations, and
    careful documentation
  • Cholinesterase inhibitors and memantine should be
    considered as first line therapy in patients with
    behavior abnormalities in the beginning stages of

  • Haloperidol
  • Olanzapine
  • Quetiapine
  • Risperidone
  • Ziprasidone
  • Treatment of psychosis hallucinations,
    delusions, suspicions
  • Treatment of disruptive behaviors Agitation and
  • Not FDA approved

Concern with Antipsychotics
  • Worsening cognitive impairment, oversedation,
    falls, tardive dyskinesia, neuroleptic malignant
    syndrome, hyperlipidemia, weight gain, diabetes
    mellitus, cerebrovascular accidents
  • A dose reduction or discontinuation should be
    considered periodically in patients
  • Physical restraints should be limited to patients
    who pose imminent harm to themselves or others.

  • Citalopram
  • Escitiolopram
  • Fluoxetine
  • Paroxetine
  • Sertraline
  • Venlafaxine
  • Trazadone
  • Treatment of depression poor appetite, insomnia,
    hopelessness, anhedonia, withdrawal, suicidal
    thoughts, agitation, or anxiety
  • As many as 50 of AD patients suffer from

  • Carbamazepine
  • Valproic Acid
  • Treatment of agitation or aggression

Standard of treatment
  • None exists
  • Duration of treatment ranges from clinician to
    clinician. May be months to years
  • No clear standard of care for dosing from
    clinical trials
  • No clear standard of when to discontinue therapy
    in very severe stages of AD
  • Many clinicians do discontinue therapy when the
    patient becomes bed ridden

Key Non-pharmacological Methods
  • Education
  • Preparation
  • Communication

  • Educating patient and family at the time of
  • Discussion of the course of illness
  • Expectations from treatment
  • Legal and financial planning including a durable
    power of attorney
  • Quality of life issues
  • Re-enforcing the importance of communication
    between the patient and family members
  • Decreasing environmental triggers and personal

Non-Pharmacological Interventions
  • Physical well-being
  • Increased overall well being
  • Stimulation oriented treatments recreational
    activity, art therapy, music therapy, pet therapy
    and aromatherapy may be useful, but lack of
    sufficient evidence to validate effectiveness but
    used in clinical practice

  • Find time to rest, relax and tend to personal
    affairs because stress will impact the health and
    quality of life of both the patient and the
  • Help patients to discover a structured level of
    autonomy using reminders and explanations
  • Be aware of signs and symptoms of decline
  • Knowing when to institutionalize a patient

  • Patients should be assessed every 3-6 months
  • Patients may need to stop driving even at mild
    levels of treatment
  • Sleep disturbances common in people with
    dementia, proper sleep hygiene should be
    implemented before beginning pharmacological

Behavioral Management
  • Sleep disturbances
  • Wandering
  • Urinary Incontinence
  • Agitation
  • Aggression
  • May be useful to try this before beginning drug

Epidemiological Correlations
  • Brain Vascular Health
  • Lipid lowering agents
  • Non inflammatory agents
  • Vitamin B 6, B12 and B12 deficiency
  • Hyerhomocysteinemia

Brain Vascular Health
  • New studies have evidence brain vascular disease
    plays an important role in the progression of
  • Brain vascular disease may accelerate deposition
    of beta amyloid plaques and increase amyloid
    toxicity to neurons and the neural synapses
  • Brain vascular health includes managing blood
    pressure, glucose, cholesterol and homocysteine.
  • Elevated homocysteine levels correlate with
    decreased performance on cognitive tests
  • Importance of stating physically, mentally, and
    socially active

Folate, Vitamin B12, Vitamin B6
  • Defects in these vitamins are associated with
    neurological and psychological dysfunction
  • In elderly patients there is increased concern of
    satiety, atrophic gastritis, and decreased
    function of the olfactory functions
  • Increased homocysteine has a direct correlation
    with a deficiency and these vitamins

Estrogen Therapy
  • Epidemiological studies post menopausal women who
    took estrogen replacement therapy had a lower
    incidence of AD
  • Studies did not show an improvement in behavioral
    or functional outcomes when estrogen used to
    treat cognitive decline
  • Estrogen has a risk of stroke and other
    cardiovascular events

Anti-inflammatory Agents
  • Epidemiological studies suggest patients on
    anti-inflammatory agents have a lower incidedence
    of AD
  • Treatment less than 2 years proved beneficial in
    some patients
  • Clinical studies does not show evidence of
    cognitive benefit and tolerability was an issue

Lipid Lowering Agents
  • Epidemiological studies and AD show a correlation
    between higher midlife total cholesterol rates
    and AD
  • Correlation between people on lipid lowering
    therapy and lower incidences' of AD
  • Pravastatin and lovastatin but not simvastatin
    were associated with a lower incidence of AD
  • More trials are needed to address the impact of
    cognitive benefit, the duration of treatment,
    class effect, and optimal dosing for its role in
  • Role of therapy should remain for people with
    indications for their use

Therapies in the Pipeline
  • Vitamin E
  • Atomexetine
  • IGIV 10
  • Thiazolidinediones (anti-inflammatory effects)
  • Over 900 studies occurring now phase 1-4 and
  • Ginkgo Biloba
  • Huperzine A
  • Semagacestat (LY450139)
  • Coenzyme Q10
  • Acupuncture
  • Over 100 studies phase 3

Vitamin E
  • Antioxidant- may be useful because of the
    accumulation of free radicals associated with AD
  • Favorable side effect profile and low cost
  • Impaired hemostasis, fatigue, nausea, diarrhea,
    abdominal pain, and thinning of the blood
  • Increased mortality in older patients
  • Doses above 400 international units per day
    should be avoided in patients with AD
  • May be beneficial in combination with Selegeline
    Phase III study-PREADVISE- examining anti-oxidant
    effects of Selegeline

Ginkgo Biloba
  • Increased blood flow, decreased viscosity of the
    blood, antagonizing platelet activating factor
    receptors, increased tolerance to anoxia,
    inhibiting monoamine oxidase, anti-infective
    properties, preventing damage of membranes caused
    by free radicals
  • If used for dementia should be used as soon as
    deterioration of cognitive functioning occurs
  • Side effects are typically mild and rare
  • Herbal products are typically poorly standardized

Huperzine A
  • An alkyloid isolated from the Chinese club moss,
    Huperzia serrata
  • Reversibly inhibits acetylcholinesterase and is
    administered orally in doses 50-200 mcg 2-4 times
  • May be more promising for symptomatic treatment
    of Alzheimers disease
  • Promising product from clinical studies, but lack
    of product purity
  • Concurrent use with other available
    cholinesterase inhibitors should be avoided

Semagacestat (LY450139)
  • Inhibiting the enzyme gamma-secretase lowers the
    production of beta amyloid. Semagacestat
    (LY450139) a functional gamma-secretase inhibitor
    lowers the beta amyloid in the blood and spinal
    fluid in humans.
  • Effect of LY450139 a gamma-secretase inhibitor on
    the progression of Alzheimers disease as
    compared with Placebo- Currently Phase III
  • 60 mg orally titrated up to 140 mg

Immune Globulin Intravenous (Human), 10 (IGIV,
  • A Randomized, Double-Blind, Placebo-Controlled,
    Two Dose-Arm, Parallel Study of the Safety and
    Effectiveness of Immune Globulin Intravenous
    (Human), 10 (IGIV, 10) for the Treatment of
    Mild to Moderate Alzheimer's Disease Phase III
  • The purpose of this study is to determine whether
    IGIV, 10 treatment, administered at two
    different doses results in a significantly
    slower rate of decline of dementia symptoms in
    subjects with mild to moderate (AD).
  • Approved in 2005 for primary immunodeficiency

Coenzyme Q10
  • A natural antioxidant in the body
  • Role of therapy currently being explored, but
    limited clinical trials in humans for AD

Helpful links
  • www.nia.nih/gov/alzheimers

Economic Impact
  • US health care cost is greater than 100 billion
  • Annual cost for caring for an individual with
    advanced AD is approximately 50,000
  • According to CDC, there is 231,900 patients in
    nursing homes with AD which accounts for 15.5 of
    the nursing home population
  • 4th leading cause of death in adults

  • http//
  • http//

  • National Guideline Clearinghouse (NGC). Guideline
    synthesis Management of Alzheimer's disease and
    related dementias. In National Guideline
    Clearinghouse (NGC). Rockville (MD) 2006 Nov
    (revised 2010 Sep). cited 2011 June 13.
    Available http//
  • Dipiro J,Talbert R, Yee G., Matzke G, Wells B,
    Posey L. Pharmacotherapy A Pathophysiologic
    Approach. 7th. New York McGraw-Hill, 2008.
  • B Vitamins, Homocysteine, and Neurocognitive
    Function in the Elderly. American Journal of
    Clinical Nutrition. February 200071(2)614s-620s.
    Accessed June 15, 2011.