Transcript Chapter 16 Cholinesterase Inhibitors

Chapter 22
Alzheimer’s Disease
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Alzheimer’s Disease
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Devastating illness
Progressive memory loss
Impaired thinking
Neuropsychiatric symptoms
Inability to perform routine tasks of daily living
Alzheimer’s disease (AD) affects 4.5 million
Americans
4th leading cause of death – 100,000 deaths
per year
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Pathophysiology
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Degeneration of neurons
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Early in hippocampus
• Memory
Later in cerebral cortex
• Speech, perception, reasoning, and other higher
functions
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Pathophysiology
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Reduced cholinergic transmission
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Levels of acetylcholine (ACh) 90% below normal
• Important neurotransmitter
• Critical to forming memories
Loss of cholinergic function not the whole story
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Pathophysiology
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Beta-amyloid and neuritic plaques
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Form outside of neurons
Spherical bodies composed of beta-amyloid core
Neurofibrillary tangles and tau
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Form inside neurons
See Figure 22-1
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Fig. 22-1. Histologic changes in Alzheimer’s disease.
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Pathophysiology
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Apolipoprotein E4 (apoE4)
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Endoplasmic reticulum–associated binding
protein
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May also contribute to AD
Present in high concentrations in AD patients
Homocysteine
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Elevated plasma levels of homocysteine
associated with increased risk for AD
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Risk Factors
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Major risk factors
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Advancing age
Family history
Possible risk factors
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Female
Head injury
Low educational level
Production of apoE4
High levels of homocysteine
Low levels of folic acid
Estrogen/progestin therapy
Nicotine in cigarette smoke
Sedentary lifestyle
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Symptoms
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Memory loss
Confusion
Feeling disoriented
Impaired judgment
Personality changes
Difficulty with self-care
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Symptoms
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Behavior problems (wandering, pacing,
agitation, screaming)
“Sundowning”
Inability to recognize family members
Inability to communicate
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Progressive Symptoms
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Symptoms typically begin after age 65 years,
but may appear as early as age 40 years.
Life expectancy from symptom onset may be
20 years or longer, but is usually 4 to 8 years.
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Diagnosis
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NINCDS and ADRDA criteria based on
patient’s age and clinical evaluation
Under the proposed new definition of AD, a
patient must have episodic memory
impairment plus at least one AD biomarker,
as determined by MRI scan, PET
neuroimaging, or CSF analysis. Note that
overt dementia need not be present.
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Diagnosis
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2007 international group of AD experts
proposed new diagnostic criteria for AD.
Added technologies and tests that provide
data for evaluation of characteristic changes
of AD:
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MRI: atrophy of brain areas
PET: altered patterns in the brain
Cerebrospinal fluid analysis: presence of
abnormal proteins
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Drug Therapy
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Goal of treatment is to improve symptoms
and reverse cognitive decline.
Available drugs cannot do this.
Five drugs are approved for AD dementia
(none are very effective).
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Drug Therapy
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Neuronal receptor blocker
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Memantine
Cholinesterase inhibitors
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Donepezil
Galantamine
Rivastigmine
Tacrine
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Drug Therapy
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Treatment of AD with these drugs can yield
improvement that is statistically significant but
clinically marginal.
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Equivalent to taking a “weight loss drug” and
losing ½ pound after 6 months of therapy
It is not recommended that all patients
receive these drugs because of the modest
benefits.
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Drug Therapy
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Cholinesterase inhibitors may delay or slow
progression of disease, but will not stop it.
Drugs that block cholinergic receptors (firstgeneration antihistamines, TCAs,
conventional antipsychotics) can reduce
responses to cholinesterase inhibitors.
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Drug Therapy
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Cholinesterase inhibitors
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Indicated for mild to moderate AD
Prevent breakdown of ACh
May help to slow progression of disease
Only three are recommended for use and have
equivalent benefits:
• Donepezil
• Galantamine
• Rivastigmine
Not recommended (causes liver damage):
• Tacrine
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Drug Therapy
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Cholinesterase inhibitors (cont’d)
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Adverse effects
• Cholinergic side effects
• GI
• Dizziness
• Headache
• Bronchoconstriction
• Liver injury (tacrine)
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Drug Therapy
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Memantine (Namenda, Namenda XR)
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First drug in a new class, the NMDA receptor
antagonists
Indicated for moderate to severe AD
Better tolerated than cholinesterase inhibitors
Adverse effects
• Dizziness
• Headache
• Confusion
• Constipation
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Fig. 22-2. Memantine mechanism of action.
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Other Treatments
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Drugs for neuropsychiatric symptoms
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Symptoms experienced by 80% of AD patients
Include agitation, aggression, delusions,
hallucinations
Atypical antipsychotics
SSRIs for depression (not AD symptoms)
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