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Pharm Exam 2 > Bannon: Alzheimer's Disease and Dementia > Flashcards

Bannon: Alzheimer's Disease and Dementia Flashcards

1
Q

Dementia

Definition:
Prevalence:

A

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)

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2
Q

What accounts for 50-70% of all dementias?

A

Alzheimer’s Disease

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3
Q

Other Types of Dementia

Vascular dementia:
Mixed dementia:

A

Vascular dementia: post-stroke, multi-infarct (more precipitous course)

Mixed dementia: more common than previously thought

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4
Q

Other Types of Dementia

Others:

A

Others:

  • Parkinson’s Disease
  • Frontotemporal dementia
  • CJD
  • Huntington’s Disease
  • Other neurological diseases
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5
Q

Other Types of Dementia

Lewy Body dementia:

A 
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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6
Q

Dementia

General Treatment Point:

A

General Treatment Point: fewer treatments are approved for non-AD dementias; however, AD treatments may be beneficial

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7
Q

Dementia

Mild Cognitive Impairment: (3)

A

Cognitive decline greater than expected for one’s age and educational level (measured using a cognitive scale)

May not significantly interfere with ADLs

Associated with an increased risk of AD (pre-dementia or transitional state to AD)

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8
Q

Clinical Features and Course of AD

General:
Course:
Cause of Death:

A

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)

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9
Q

Pathophysiology of AD

Marked atrophy of cerebral cortex:

A

Marked atrophy of cerebral cortex: uneven loss of cortical and subcortical neurons innervating the cortex (ie. basal forebrain cholinergic cells)

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10
Q

Pathophysiology of AD

Plaques and tangles in hippocampus and associative cortex:

Senile Plaques:

Neurofibrillary Tangles:

A

Plaques and tangles in hippocampus and associative cortex: the abundance of these generally correlated with cognitive impairment

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11
Q

Pathophysiology of AD

Senile Plaques:
Neurofibrillary Tangles:

A

Senile Plaques: due to accumulation of beta-amyloid protein; accompanied by degenerating neuronal processes

Neurofibrillary Tangles: microtubule breakdown associated with hyperphosphorylated tau protein

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12
Q

Causes of AD:

Most:
Genetic form:

A

Most common cause: idiopathic

Genetic Forms (~10% of cases):
o Defect in APP
o Defect in APP processing proteins (presnilins- PS1 and PS2)
o Lipid transporter apolipoprotein E4 is a risk factor

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13
Q

Cholinesterase Inhibitors

Basis:

A

Basis: loss of ACh in cholinergic neurons of the basal forebrain innervating the cortex in AD; ChE inhibitors prolong half-life of ACh

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14
Q

Cholinesterase Inhibitors

Efficacy:

A

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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15
Q

Donepezil

Use: (5)
MOA:

A

Use:

  • Mild, moderate and severe AD
  • MCI
  • PD with dementia
  • Lewy body dementia
  • Vascular dementia

MOA: reversible AChE inhibitor

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16
Q

Cholinesterase Inhibitors: (3)

A

Donepezil
Rivastigmine
Galantamine

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17
Q

Donepezil

Half life:
Metabolism:

A

Long half-life: once-daily dosing (convenient)

Metabolism: hepatic (CYP2D6/3A4)- watch for potential DDIs

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18
Q

Donepezil

Side Effects: (4)

A

Side Effects: occur especially during dose escalation; all tend to decrease over time

  • GI (N/V/D)
  • Muscle cramps
  • Bradycardia
  • Urinary incontinence
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19
Q

Rivastigmine

Use: (3)

A
  • Mild to moderate AD
  • PD with dementia
  • Lewy body dementia
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20
Q

Rivastigmine

MOA:

A

MOA: reversible, non-competitive inhibitor of AChE (also inhibits butyrylcholinesterase)

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21
Q

Rivastigmine

Half-life:
Patch:
Metabolism

A

Shorter Half-Life: BID dosing

Transdermal patch: also available (good absorption)

Metabolism: ChE hydrolysis (no drug-drug interactions)

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22
Q

Rivastigmine

Side Effects/Efficacy

A

Side Effects/Efficacy: similar to donezepil

  • GI (N/V/D)
  • Muscle cramps
  • Bradycardia
  • Urinary incontinence
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23
Q

Galantamine

Use: (2)

A

Mild to moderate AD

Vascular dementia

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24
Q

Galantamine

MOA:

A

MOA: reversible competitive inhibitor of AChE; also binds allosterically to nACh receptors

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25
Q

Galantamine

Shorter Half-Life:
Metabolism:
Excretion:

A

Shorter Half-Life: BID dosing; now also an extended release form

Metabolism: liver (CYP2D6/3A4)- some DDIs

Excretion: some also excreted unchanged

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26
Q

Galantamine

Side Effects/Efficacy:

A

Side Effects/Efficacy: similar to donezepil and rivastigmine

  • GI (N/V/D)
  • Muscle cramps
  • Bradycardia
  • Urinary incontinence
27
Q

NMDA Receptor Antagonist (Memantine)

Use: (3)

A

o Moderate to severe AD
o Vascular dementia
o May also help manage aggression/agitation

28
Q

NMDA Receptor Antagonist (Memantine)

MOA:

A

MOA: uncompetitive antagonist at NMDA receptors

Only binds to R when it has already bound glutamate

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)

29
Q

NMDA Receptor Antagonist (Memantine)

Dosing:
Excretion:

A

o Dosing: BID

o Excretion: unchanged in the urine (no metabolism)

30
Q

NMDA Receptor Antagonist (Memantine)

Efficacy:
Side Effects:

A

Efficacy: similar to ChE inhibitors

Side Effects: generally safe and well-tolerated
o Headaches, dizziness, confusion

31
Q

Treatment of Behavioral and Psychotic Symptoms

Remember to look for:

A

Remember to look for drug interactions and medical problems (ie. discomfort): if outbursts, emotional distress, restlessness, hallucinations, delusions etc.

32
Q

Off-Label Use of Drugs: must use caution

Antidepressants:
Anxiolytics:

A

Antidepressants: mood/irritability
Anxiolytics: anxiety/restlessness

33
Q

Off-Label Use of Drugs: must use caution

Antipsychotics:

A

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

34
Q

Special Case of Lewy Body Dementia

A

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)
35
Q

Hospital Delirium

Population:
Description:

A

Population: elderly hospital patients (not previously demented)

Description: sudden state of confusion accompanied by hallucinations and agitation

36
Q

Hospital Delirium

Cause:

A 
-	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
37
Q

Hospital Delirium

Results: (3)

A

o Hinders recovery and extends hospitalization
o Leads to placement in nursing home or rehab
o Increases likelihood of death or subsequent dementia

38
Q

Hospital Delirium

Prevention: (4)

A

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

39
Q

AD Neuroimaging Initiative

Collaborative Effort:

A

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

40
Q

AD Neuroimaging Initiative

Florbetapir F-18 PET Imaging:

A

Florbetapir F-18 PET Imaging: detects plaques and predicts beta-amyloid deposits seen at autopsy; now FDA approved as a diagnostic test for AD

41
Q

New Therapeutics (Disease Modification): (2)

A

Anti-Amyloid Therapies

Anti-Tau/Tangles Therapy

42
Q

Anti-Amyloid Therapies: (3)

A

Increasing Aβ Clearance (Immunotherapy)
Decreasing Aβ Generation
Disruption of Amyloid Aggregation

43
Q

Anti-Amyloid Therapies
Increasing Aβ Clearance (Immunotherapy)

Active Vaccination:

A

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?)

44
Q

Anti-Amyloid Therapies
Increasing Aβ Clearance (Immunotherapy)

Passive Immunization:

A

Passive Immunization: with humanized monoclonal Ab against Aβ (bapineuzumab)
- Worked in animal model and now in phase 3 clinical trials

45
Q

Anti-Amyloid Therapies

Decreasing Aβ Generation: (2)

A

Inhibition of BACE1

Inhibition of γ-Secretase

46
Q

Anti-Amyloid Therapies
Decreasing Aβ Generation

Inhibition of γ-Secretase Agents: (2)

A

Semagecestat

Novel Targeting via γ-Secretase Activating Protein (GSAP)

47
Q

Anti-Amyloid Therapies
Decreasing Aβ Generation
Inhibition of γ-Secretase

Semagecestat:

A

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)

48
Q

Anti-Amyloid Therapies
Decreasing Aβ Generation
Inhibition of γ-Secretase

Novel Targeting via γ-Secretase Activating Protein (GSAP):

A

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

49
Q

Anti-Amyloid Therapies

Disruption of Amyloid Aggregation: (2)

A

Arenflurbril and Tramiprosate

PTB2 (Modulator of Copper and Zinc)

50
Q

Anti-Amyloid Therapies
Disruption of Amyloid Aggregation

Arenflurbril and Tramiprosate:

A

Arenflurbril and Tramiprosate: amyloid-targeting drugs that showed some activity at reducing amyloid levels, but not clinical effect in phase 3 trials

51
Q

Anti-Amyloid Therapies
Disruption of Amyloid Aggregation

PTB2 (Modulator of Copper and Zinc):

A

PTB2 (Modulator of Copper and Zinc): showed clinical benefit and decreased CSF amyloid in phase 2

52
Q

Anti-Tau/Tangles Therapy

Tau Protein:
Targeting:

A

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

53
Q

Anti-Tau/Tangles Therapy

AL-108 (NAP):

A
  • 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
54
Q 
Anti-Tau/Tangles Therapy
Methylthioninium Chloride (Methylene Blue):
A

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)

55
Q

Anti-Tau/Tangles Therapy

Lithium and Valproic Acid:

A
  • Both inhibit glycogen synthase kinase 3 (may be involved in tau hyperphosphorylation)
  • Clinical trials of both are currently underway
56
Q

Risk and Protective Factors and Related Interventions

Non-Modifiable Risk Factors:

A

o Age
o Genetics
o Head injury
.

57
Q

Risk and Protective Factors and Related Interventions

Modifiable Risk Factors: (5)

A 
o	Obesity
o	Diabetes
o	HTN
o	Hypercholesterolemia
o	Alcohol intake and smoking
58
Q

Risk and Protective Factors and Related Interventions

Protective Factors:: (2)

A

o Cognitive reserve (education, occupation, mental activities)
o Physical activity

59
Q

Risk and Protective Factors and Related Interventions

Related Interventions:

A

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

60
Q

Current View of Management of AD Patients

Early Diagnosis:

A

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

61
Q

Current View of Management of AD Patients

Lifestyle Issues and Nonpharmacological Interventions: (4)

A

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

62
Q

Current View of Management of AD Patients
Optimization of Pharmacotherapy

% that discontinue:
What decreases GI effects?

A

~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

63
Q

Current View of Management of AD Patients
Optimization of Pharmacotherapy

Switch to another ChEI after:
Combination therapy of ChEI and memantine may:

A

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

Pharm Exam 2 (13 decks)

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