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Treatment for Alzheimer’s Disease
Maenne OkunolaJune 2011UGA COP: Pharm D. CandidatePreceptor: Dr. Ali Rahimi
Treatment Goal
Currently there is no current therapy to treat Alzheimer’s disease. Current therapy is aimed at prolonging the patient’s 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
Alzheimer’s 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 change 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
Brain Comparison
Ideal Treatment
Improving symptomatic decline by improving cognitive function, daily activities, and behavior 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 symptoms
Cholinesterase Inhibitors
Cholinesterase Inhibitors
Donepezil (Aricept)- used in mild to severe disease Galantamine (Razadyne)- used in mild to moderate disease Rivastigmine (Exelon)- used in mild to moderate disease 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 failure 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
acetylcholinesterase Rivastigmine- inhibits both butylcholinesterase and
acetylcholinesterase Galantamine- selective, competitive, reversible
acetylcholinesterasse inhibitor and also enhances the action of acetylcholine on nicotinic receptors
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
brain Most common side effects include constipation,
confusion, dizziness, headache, hallucinations, coughing, and hypertension
Dosage Forms
Galantamine (Razadyne)- capsule, tablet, and solution
Donepezil (Aricept)- tablet (oral disintegrating tablet)
Rivastigmine (Exelon)- capsule, patch, and solution
Memantine (Namenda)- tablet and solution
Treatment for Non-cognitive Symptoms Psychosis Disruptive behavior Depression Environmental interventions then pharmacological therapy Limited clinical data; therefore, treatment is empirical 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 AD
Antipsychotics
Haloperidol Olanzapine Quetiapine Risperidone Ziprasidone Treatment of psychosis: hallucinations, delusions,
suspicions Treatment of disruptive behaviors: Agitation and
aggression 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.
Antidepressants
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 depression
Anticonvulsants
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
EducationPreparationCommunication
Educating patient and family at the time of diagnosis 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 discomfort
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
Caregivers
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 caregiver
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
Interventions
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 therapy
Behavioral Management
Sleep disturbances Wandering Urinary Incontinence Agitation Aggression May be useful to try this before beginning
drug therapy
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 dementia
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 AD
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 daily
May be more promising for symptomatic treatment of Alzheimer’s 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 Alzheimer’s disease as compared with Placebo- Currently Phase III
60 mg orally titrated up to 140 mg
Immune Globulin Intravenous (Human), 10% (IGIV, 10%) 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 trial
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.aoa.gov www.nia.nih/gov/alzheimers www.alzforum.org www.aarp.gov www.thefamilycaregiver.org www.ec-online.net
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
Resources
http://www.gammagardliquid.com/about-gammagard-liquid/dosage-administration.html
http://www.nlm.nih.gov/medlineplus/druginfo/natural/1003.html
cdc.gov www.ncbi.nlm.nih.gov www.novartis.com www.alz.org www.clinicaltrials.gov
Resources
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://www.guideline.gov.
Dipiro J,Talbert R, Yee G., Matzke G, Wells B, Posey L. Pharmacotherapy: A Pathophysiologic Approach. 7th. New York: McGraw-Hill, 2008. 1051-1066
B Vitamins, Homocysteine, and Neurocognitive Function in the Elderly. American Journal of Clinical Nutrition. February 2000;71(2):614s-620s. Accessed June 15, 2011.