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.