Download Memory Medications

Pharmacology: Pharmacotherapy for Alzheimer’s Disease and Dementia (Bannon)
OVERVIEW OF ALZHEIMER’S DISEASE AND OTHER DEMENTIAS:

Dementia:
Definition: loss of memory and other intellectual abilities serious enough to interfere with daily life
Prevalence: one of the most important age-related medical problems (30-35% of people aged 80-90)
Types of Dementia:
o Alzheimer’s Disease: accounts for 50-70% of all dementias
o Other Types:

Vascular dementia: post-stroke, multi-infarct (more precipitous course)
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Mixed dementia: more common than previously thought

Lewy Body dementia: PD plus dementia (Lewy bodies in the midbrain, cortex etc.)
 Progressive dementia with:
o Fluctuating cognition
o Many features of PD
o REM sleep disturbances
o Detailed visual hallucinations
o Autonomic instability
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Others:
 Parkinson’s Disease
 Frontotemporal dementia
 CJD
 Huntington’s Disease
 Other neurological diseases
General Treatment Point: fewer treatment s are approved for non-AD dementias; however, AD treatments may
be beneficial
Mild Cognitive Impairment:
o Cognitive decline greater than expected for one’s age and educational level (measured using a
cognitive scale)
o May not significantly interfere with ADLs
o Associated with an increased risk of AD (pre-dementia or transitional state to AD)

Clinical Features and Course of AD:
General: progressive and fatal disease with gradual onset of impairment (death in 6-12 years)
Course:
o Short term memory impacted first
o Followed by loss of other cognitive abilities (ability to calculate, use common tools- ideomotor apraxia)
o No effect on distant memories, altertness or motor function until very advanced stage of disease
Cause of Death: most comply due to complications of immobility (ie. pneumonia, pulmonary embolism)

Pathophysiology of AD:
Marked atrophy of cerebral cortex: uneven loss of cortical and subcortical neurons innervating the cortex (ie.
basal forebrain cholinergic cells)
Plaques and tangles in hippocampus and associative cortex: the abundance of these generally correlated with
cognitive impairment
o Senile Plaques: due to accumulation of beta-amyloid protein; accompanied by degenerating neuronal
processes
o Neurofibrillary Tangles: microtubule breakdown associated with hyperphosphorylated tau protein

Causes of AD:
Most common cause: idiopathic
Genetic Forms (~10% of cases):
o Defect in APP
o Defect in AP processing proteins (presnilins- PS1 and PS2)
o Lipid transporter apolipoprotein E4 is a risk factor
PHARMACOTHERAPIES:

Cholinesterase Inhibitors:
Basis: loss of ACh in cholinergic neurons of the basal forebrain innervating the cortex in AD; ChE inhibitors
prolong half-life of ACh
Efficacy: provide MODEST improvements in cognition and global functions, as well as some transiet stabilization
of the disease; do NOT slow ultimate progression of disease (not disease modifiying)
-
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Donepezil:
o Use:

Mild, moderate and severe AD

MCI

PD with dementia

Lewy body dementia

Vascular dementia
o MOA: reversible AChE inhibitor
o Pharmacokinetics:

Long half-life: once-daily dosing (convenient)

Metabolism: hepatic (CYP2D6/3A4)- watch for potential DDIs
o Side Effects: occur especially during dose escalation; all tend to decrease over time

GI (N/V/D)

Muscle cramps

Bradycardia

Urinary incontinence
Rivastigmine:
o Use:

Mild to moderate AD

PD with dementia

Lewy body dementia
o MOA: reversible, non-competitive inhibitor of AChE (also inhibits butyrylcholinesterase)
o Pharmacokinetics:

Shorter Half-Life: BID dosing

Transdermal patch: also available (good absorption)

Metabolism: ChE hydrolysis (no drug-drug interactions)
o Side Effects/Efficacy: similar to donezepil
Galantamine:
o Use:

Mild to moderate AD

Vascular dementia
o MOA: reversible competitive inhibitor of AChE; also binds allosterically to nACh receptors
o Pharmacokinetics:

Shorter Half-Life: BID dosing; now also an extended release form

Metabolism: liver (CYP2D6/3A4)- some DDIs

Excretion: some also excreted unchanged
o Side Effects/Efficacy: similar to donezepil and rivastigmine
NMDA Receptor Antagonist (Memantine):
Use:
o Moderate to severe AD
o Vascular dementia
o May also help manage aggression/agitation
MOA: uncompetitive antagonist at NMDA receptors
o Only binds to R when it has already bound glutamate
o Therefore, use-dependent blockade of overly active NMDA that pass Ca++ and may lead to
excitotoxicity (ie. more activate neurons more likely to be targeted)
Pharmacokinetics:
o Dosing: BID
o Excretion: unchanged in the urine (no metabolism)
Efficacy: similar to ChE inhibitors
Side Effects: generally safe and well-tolerated
o Headaches, dizziness, confusion
Treatment of Behavioral and Psychotic Symptoms:
Remember to look for drug interactions and medical problems (ie. discomfort): if outbursts, emotional distress,
restlessness, hallucinations, delusions etc.
Off-Label Use of Drugs: must use caution
o Antidepressants: mood/irritability
o Anxiolytics: anxiety/restlessness
o
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Antipsychotics: formerly used for agitation, but now a black box warning of an increased risk of death
due to heart attack, pneumonia or other infection from use

If these must be used, use the lowest dose possible for a trial period and ONLY after
behavioral measures have been tried
Special Case of Lewy Body Dementia:
o Difficult to manage

Very high risk of adverse responses to APDs (sedation, parkinsonism, neuroleptic malignant
syndrome)- use clozapine if needed

PD drugs also an issue (ChEI may help)
Hospital Delirium:
Population: elderly hospital patients (not previously demented)
Description: sudden state of confusion accompanied by hallucinations and agitation
Cause: unclear; many apparent triggers
o Infection (ie. pneumonia)
o Surgery
o Catheter insertion
o Some mediations
o Sleep interruption for tests
o Lack of eyeglasses or dentures
Results:
o Hinders recovery and extends hospitalization
o Leads to placement in nursing home or rehab
o Increases likelihood of death or subsequent dementia
Prevention:
o Adjust schedules to allow patients more sleep
o ensure the patient has eyeglasses, dentures and hearing aids
o Remove catheter and IV when feasible
o Increase physical and cognitive exercise
AD Neuroimaging Initiative:
Collaborative Effort: recruited MCI and AD patients and controls and looked for biomarkers
o Combination of memory tests, PET scans and CSF amyloid predicts very early stage AD
Florbetapir F-18 PET Imaging: detects plaques and predicts beta-amyloid deposits seen at autopsy; now FDA
approved as a diagnostic test for AD
New Therapeutics (Disease Modification):
Anti-Amyloid Therapies:
o Increasing Aβ Clearance (Immunotherapy):

Active Vaccination: worked well in mouse models but still in human trials
 Postmortem tissue of 2 patients in the trial show no amyloid plaques but still died
of severe end-stage dementia (amyloid hypothesis?)

Passive Immunization: with humanized monoclonal Ab against Aβ (bapineuzumab)
 Worked in animal model and now in phase 3 clinical trials
o Decreasing Aβ Generation:

Inhibition of BACE1

Inhibition of γ-Secretase:
 Semagecestat: passed phase I and II trials but halted in phase III
o Did not slow progression of AD but rather caused dose-dependent
decrease in cognitive function and ADLs compared to placebo
o Also caused an increased risk for skin cancer
o One problem with this approach is this enzyme affects production of ~20
proteins (some of which have critical brain functions- Notch, cadherins)
 Novel Targeting via γ-Secretase Activating Protein (GSAP):
o GSAP is a targeting protein that determines that enzymes substrates
o If inhibited or genetically inactivated, AD model mice we normal with no
plaques
o Renews hope for γ-secretase related therapeutics
o Disruption of Amyloid Aggregation:

Arenflurbril and Tramiprosate: amyloid-targeting drugs that showed some activity at
reducing amyloid levels, but not clinical effect in phase 3 trials


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PTB2 (Modulator of Copper and Zinc): showed clinical benefit and decreased CSF amyloid in
phase 2
Anti-Tau/Tangles Therapy:
o General:

Tau Protein: stabilizes neuronal microtubules in axons; hyperphosphorylation leads to
formation of paired helical filaments that disrupt axons

Targeting: targeting of tau has been the scientific minority in terms of drug development
o AL-108 (NAP):

Derived from neuroprotective protein

In phase 2 trials, intranasal administration dose-dependently improved short-term recall and
working memory in MCI

Reduces tangles and plaques in animal models
o Methylthioninium Chloride (Methylene Blue):

In phase 2 trials, showed cognitive benefit over 4 year period (major issues with trial have
been raise)

Postulated to work clinically by disrupting tau-mediated tangle formation (disrupts tau-tau
binding)
o Lithium and Valproic Acid:

Both inhibit glycogen synthase kinase 3 (may be involved in tau hyperphosphorylation)

Clinical trials of both are currently underway
Risk and Protective Factors and Related Interventions:
Non-Modifiable Risk Factors:
o Age
o Genetics
o Head injury
Modifiable Risk Factors:
o Obesity
o Diabetes
o HTN
o Hypercholesterolemia
o Alcohol intake and smoking
Protective Factors:
o Cognitive reserve (education, occupation, mental activities)
o Physical activity
Related Interventions:
o Despite the above information, RCTs have not shown a benefit of the following on the development of
Alzheimer’s Disease:

Antihypertensives, statins, B vitamins, omega-3, ginkgo biloba, antioxidants, cognitive
interventions
Current View of Management of AD Patients:
Early Diagnosis: of MCI and identification of subtype should now allow earlier intervention in AD
o Amnesic MCI: conversion rate to AD is 50% over 2.5 years
Lifestyle Issues and Nonpharmacological Interventions:
o Brighter lights
o Modify physical layout of space
o Use of activities and food with positive emotional content (persists even with memory impairment)
o Stress management and support for caregiver
Optimization of Pharmacotherapy:
o ~50% of patients on new AD medications with discontinue in 4 months due to side effects of
perceived/real lack of efficacy

Slower titration of ChEIs to decrease GI effects

Switch to another ChEI after 1 week washout period (50% of those who fail to respond to one
will respond to another)

Combination therapy of ChEI and memantine may help therapeutic and adverse effects
o If behavioral disturbances occur (as they often do in advanced AD), try lifestyle changes and
ChEI/memantine combinations BEFORE APDs