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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.

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Treatment for Alzheimer’s Disease

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  1. Treatment for Alzheimer’s Disease Maenne Okunola June 2011 UGA COP: Pharm D. Candidate Preceptor: Dr. Ali Rahimi

  2. 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

  3. 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

  4. Brain Comparison

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

  6. 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

  7. Cholinesterase Inhibitors

  8. 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

  9. 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.

  10. 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

  11. NMDA Antagonist

  12. 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

  13. 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

  14. 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

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

  16. 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.

  17. 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

  18. Anticonvulsants • Carbamazepine • Valproic Acid • Treatment of agitation or aggression

  19. 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

  20. Key Non-pharmacological Methods • Education • Preparation • Communication

  21. 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

  22. 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

  23. 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

  24. 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

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

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

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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 Therapies in the Pipeline

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

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

  39. Helpful links • www.aoa.gov • www.nia.nih/gov/alzheimers • www.alzforum.org • www.aarp.gov • www.thefamilycaregiver.org • www.ec-online.net

  40. 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

  41. 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

  42. 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.

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