By: Bezie Kebede(B.

pharm, MSc)
Email: [email protected]/[email protected]
 Learning objectives
2

After you completed this session, you are expected to:

 Define Alizimer’s disease
 Identify risk factors
 Describe pathophysiology
 Know diagnostic approach
 Determine treatment protocol
 Compare and contrast efficacy of different class of drugs
 Know how to monitor ADR and manage it
 Introduction
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 Alzheimer disease (AD) is characterized by progressive cognitive decline

including
◼ memory loss, disorientation, and impaired judgment and learning.
 It is a diagnosis of exclusion
 There is no single symptom unique to AD
◼ diagnosis relies on a thorough patient history.
 There is no cure for AD; however, drug treatment can slow symptom
progression.
 Family members of AD patients are profoundly affected by the increased
dependence of their loved ones as the disease progresses.
 Introduction
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 Various classifications of dementia include

 dementia of the Alzheimer type, vascular dementia, and

 dementia due to human immunodeficiency virus (HIV) disease,

 head trauma, Parkinson disease, Huntington disease,

 Epidemiology
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 AD is the most common type of dementia, affecting an estimated 5.2

million Americans in 2014.
 It is the sixth leading cause of death across all age groups in the United
States
 the fifth leading cause of death for individuals 65 years of age and older.
 The prevalence of AD increases with age.
 Of those affected, one in nine are 65 years of age or older, and 1/3 are 85
years of age or older.
 It is projected that by the year 2050, there will be a threefold increase
in prevalence,
 Epidemiology
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 yielding potentially 13.8 million AD patients due to a population

increase in persons older than 65 years.
 The severity of AD also correlates with increasing age and is classified as
mild, moderate, or severe.
 The mean survival time is reported to be approximately 6 years from
the onset of symptoms.
 age at diagnosis, severity of AD, and other medical conditions affect survival
time.
 Prevalence in Ethiopia? (33.3%) HIV-associated dementia
 Etiology
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 It is unknown;
➢ genetic factors may contribute to errors in protein
synthesis
➢ resulting in the formation of abnormal proteins involved in
pathogenesis.
 Early onset, accounts for approximately 1% of all AD.
 This type is usually familial and follows an autosomal
dominant pattern in approximately 50% of cases of early-
onset AD.
 Etiology
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 Mutations in three genes,

 presenilin 1 on chromosome 14(young children)

 amyloid precursor protein (APP) on chromosome 21

 presenilin 2 on chromosome 1

◼ lead to an increase in the accumulation of amyloid beta (Aβ) in the

brain
• oxidative stress, neuronal destruction, and the clinical syndrome of AD.
 The genetic basis for the more common late-onset AD appears more complex.
 Genetic susceptibility is more sporadic, and it may be more dependent on
environmental factors.
 Etiology
9

 The apolipoprotein E (apo E) gene on chromosome 19 has been

identified as a strong risk factor for late-onset AD.
 There are three variants of apo E
▪ however, carriers of two or more of the apo E4 allele have an earlier
onset of AD (~ 6 years earlier) compared with non carriers.
Environmental factors
 family history, female gender, and

 vascular risk factors(such as diabetes, hypertension, heart

disease, and current smoking).
 decreased reserve capacity of the brain, head injury
 Down syndrome, depression, mild cognitive impairment
 Pathophysiology
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Amyloid Cascade Hypothesis

 Amyloid plaques are extracellular lesions found in the brain and
cerebral vasculature.
 Plaques largely consist of Aβ.
 Aβ peptides consisting of 36 to 43 amino acids are produced via
processing of a larger protein.
 amyloid cascade hypothesis states that there is an imbalance between the
 production and clearance of Aβ peptides
◼ aggregation that causes accumulation of Aβ ultimately leading to AD.
 Pathophysiology
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Neurofibrillary Tangles(NFTs)
 NFTs are commonly found in the cells of the hippocampus and
cerebral cortex in persons with AD and are composed of
abnormally hyper-phosphorylated tau protein.
 Tau protein provides structural support to microtubules, the cell’s
transportation and skeletal support system.
 Pathophysiology
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❑ When tau filaments undergo abnormal phosphorylation at a specific site,

✓ they cannot bind effectively to microtubules, and the microtubules collapse.
❑ Without an intact system of microtubules, the cell cannot function
properly and eventually dies.
❑ The density of the NFTs correlates with the severity of the dementia.
❑ NFTs are found in other dementing illnesses besides AD, and may
represent a common method by which various inciting
factors culminate in cell death.
 Pathophysiology
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Inflammation/immunologic hypothesis
❑ brain amyloid deposition associated with

❑ release of cytokines, nitric oxide, and other radical species, and

complement factors that can both injure neurons and promote ongoing
inflammation.
❑ local inflammatory and immunologic alterations.
❑ inflammation is relevant to AD neuro-degeneration
 Pathophysiology
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Cholinergic Hypothesis:
❑ Neuronal damage can be seen in conjunction with plaque
structures.
❑ degeneration results in a variety of neurotransmitter deficits,
❑ with cholinergic abnormalities being the most prominent.
❑ Loss of cholinergic activity correlates with AD severity.
❑ In the late stage of AD, the number of cholinergic neurons is
reduced
❑ loss of nicotinic receptors in the hippocampus and cortex.
❑ acetylcholine, glutamate, serotonin, and NE
 Clinical presentation
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 memory loss
 Aphasia
 Apraxia
 Agnosia
 disorientation, and impaired executive function.
 depression, psychotic symptoms, aggression, motor hyperactivity
 uncooperativeness, wandering, and combativeness.
 Patients become increasingly unable to care for themselves.
 Stages of Alzheimer’s Disease
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 Diagnosis
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 History and physical examination

 Medical and medication hx
 AD is a clinical diagnosis
 based on identified symptoms and difficulty with activities of daily living
revealed by patient and caregiver interviews.
 laboratory tests
 (serum B12, folate, thyroid panel, CBC, serum electrolytes, and
liver function tests)
 Imaging tests: MRI, CT
 Treatment
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Goals of Treatment:
❑ to maintain functioning as long as possible,

❑ with a secondary goal to treat the psychiatric and behavioral

sequelae.
 For mild to moderate AD, consider use of a cholinesterase inhibitor,
and
 For moderate to severe AD, consider adding memantine, and titrate
to maintenance dose.
 Alternatively, consider memantine or cholinesterase inhibitor alone.
 Treat behavior symptoms with support and behavior interventions,
and use pharmacological management only if necessary.
 Treatment
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Non- pharmacologic
 behavioral interventions
 Sleep disturbances, wandering, agitation, and aggression
 Patient awareness about the course of
 illness, prognosis, available treatments, legal decisions, and quality-
of-life issues.
 stress-management techniques and support group options, should also be
discussed.
 exercise, light therapy, music therapy, reminiscence therapy, aroma therapy,
relaxation techniques
 Treatment
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 identify the symptom, causative factors, and adapt the caregiving

environment to remedy the situation
 Environmental triggers may include noise, glare, an insecure space, and
too much background distraction, including television.
 It is important to monitor for pain, hunger, thirst, constipation, full
bladder, fatigue, infections, skin irritation, comfortable temperature,
fears, and frustrations.
 Treat co-morbid condition
 Creating a calm environment and removing stressors and triggers is key
21
Treatment
Pharmacologic
 Pharmacotherapy for Cognitive Symptoms

 Cholinesterase inhibitors and NMDA-receptor antagonists

 The latest treatment guidelines recommend the use of cholinesterase
inhibitors for AD, with no preference for a specific agent.
 Donepezil, rivastigmine, and galantamine are indicated in mild to moderate AD
 Renal impairment
 When switching from one cholinesterase inhibitor to another, 1 week
washout is generally sufficient.
 Treatment
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 treatment should be continued with the initial medication throughout

the course of the illness.
 Three medications have similar efficacy in mild to moderate AD, and
duration of benefit lasts 3 to 12 months.
 Because of their short half-lives, if rivastigmine or galantamine
treatment is interrupted for several days or longer,
◼ retitrate starting at the lowest dose.
 The most frequent adverse effects include
➢ mild to moderate GI symptoms, urinary incontinence, dizziness, headache,
syncope, bradycardia, muscle weakness, salivation, and sweating.
 Abrupt discontinuation can cause worsening of cognition and
behavior in some patients.
 Treatment
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Other drugs
 Memantine blocks glutamatergic neurotransmission by antagonizing
◼ N-methyl-d-aspartate receptors, which may prevent excitotoxic
reactions.
 It is used as monotherapy and in combination with a cholinesterase
inhibitor.
 It is indicated for treatment of moderate to severe AD
 Dosing must be adjusted in patients with renal impairment.
 It is usually well tolerated
 constipation, confusion, dizziness, and headache.
 Guidelines recommend low-dose aspirin in AD patients with significant
brain vascular disease.
 Treatment
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 Treatment
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 Trials do not support the use of estrogen to prevent or treat

dementia.
 Vitamin E is under investigation for prevention of AD and is not
recommended for treatment of AD.
 Because of the incidence of side effects and a lack of supporting
evidence,
o neither NSAIDs nor prednisone is recommended for treatment or
prevention of AD.
 Trials of statin drugs have not shown significant benefit in
prevention or treatment of AD.
 Treatment
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Pharmacotherapy for noncognitive symptoms

 targets psychotic symptoms, inappropriate or disruptive
behavior, and depression.
 Use environmental interventions first and pharmacotherapy only
when necessary
 identify and correct underlying causes of disruptive behaviors
when possible
 start with reduced doses and titrate slowly

 monitor closely

 periodically attempt to taper and discontinue medication

 document carefully.
27

Antipsychotics
 Antipsychotic medications have traditionally been used for disruptive
behaviors and neuropsychiatric symptoms,
 but the risks and benefits must be carefully weighed.

◼ A meta-analysis found that only 17% to 18% of dementia patients

showed a modest treatment response with atypical antipsychotics.
 Antipsychotic treatment should rarely be continued beyond 12 weeks.
 Treatment
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 Treatment
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Antidepressants
 Depression and dementia share many symptoms, and the diagnosis of
depression can be difficult, especially later in the course of AD.
 SSRI is usually given to depressed patients with AD, and the best
evidence is for sertraline and citalopram.
 Tricyclic antidepressants are usually avoided.
Miscellaneous Therapies
 Use of benzodiazepines is not advised except on an “as needed”
basis for infrequent episodes of agitation.
 Carbamazepine, valproic acid, and gabapentin may be alternatives,
but evidence is conflicting.
 Evaluations of therapeutics outcomes
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 At baseline interview both patient and caregiver,

▪ identify target symptoms; define therapeutic goals; and document
cognitive status,
▪ physical status, functional performance, mood, thought processes, and
behavior.
 Daily activity of the patient should be evaluated
 Observe the patient carefully for potential side effects, monitored and
documented.
 Assess for drug effectiveness and adherence to regimen
 Consider dose adjustments after a month of treatment
 Several months to 1 year of treatment may be required to determine whether
therapy is beneficial.