Download Chapter 16 Cholinesterase Inhibitors

Chapter 22
Alzheimer’s Disease
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Alzheimer’s Disease







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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
2
Pathophysiology

Degeneration of neurons


Early in hippocampus
• Memory
Later in cerebral cortex
• Speech, perception, reasoning, and other higher
functions
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
3
Pathophysiology

Reduced cholinergic transmission


Levels of acetylcholine (ACh) 90% below normal
• Important neurotransmitter
• Critical to forming memories
Loss of cholinergic function not the whole story
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
4
Pathophysiology

Beta-amyloid and neuritic plaques



Form outside of neurons
Spherical bodies composed of beta-amyloid core
Neurofibrillary tangles and tau


Form inside neurons
See Figure 22-1
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
5
Fig. 22-1. Histologic changes in Alzheimer’s disease.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
6
Pathophysiology

Apolipoprotein E4 (apoE4)


Endoplasmic reticulum–associated binding
protein


May also contribute to AD
Present in high concentrations in AD patients
Homocysteine

Elevated plasma levels of homocysteine
associated with increased risk for AD
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
7
Risk Factors

Major risk factors



Advancing age
Family history
Possible risk factors









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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
8
Symptoms






Memory loss
Confusion
Feeling disoriented
Impaired judgment
Personality changes
Difficulty with self-care
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
9
Symptoms




Behavior problems (wandering, pacing,
agitation, screaming)
“Sundowning”
Inability to recognize family members
Inability to communicate
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
10
Progressive Symptoms


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.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
11
Diagnosis


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.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
12
Diagnosis


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:



MRI: atrophy of brain areas
PET: altered patterns in the brain
Cerebrospinal fluid analysis: presence of
abnormal proteins
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
13
Drug Therapy



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).
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
14
Drug Therapy

Neuronal receptor blocker


Memantine
Cholinesterase inhibitors




Donepezil
Galantamine
Rivastigmine
Tacrine
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
15
Drug Therapy

Treatment of AD with these drugs can yield
improvement that is statistically significant but
clinically marginal.


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.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
16
Drug Therapy


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.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
17
Drug Therapy

Cholinesterase inhibitors





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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
18
Drug Therapy

Cholinesterase inhibitors (cont’d)

Adverse effects
• Cholinergic side effects
• GI
• Dizziness
• Headache
• Bronchoconstriction
• Liver injury (tacrine)
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
19
Drug Therapy

Memantine (Namenda, Namenda XR)




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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
20
Fig. 22-2. Memantine mechanism of action.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
21
Other Treatments

Drugs for neuropsychiatric symptoms




Symptoms experienced by 80% of AD patients
Include agitation, aggression, delusions,
hallucinations
Atypical antipsychotics
SSRIs for depression (not AD symptoms)
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
22