dimentpharmnotes24revenge Flashcards

Syndrome of brain disorders
• Slowly ↓ memory &
reasoning
• Erodes independence

• Impairment in cognition that
impairs ability to function on
a daily basis

597,300 Canadians
living with dementia
in 2020

Results in great personal strain for
those with dementia & their
caregivers
• 55% Canadians with dementia live at
home
• Causes > disability than other diseases
• Severe financial burden for family &
caregivers ($10.4 billion out of pocket
expenses)
• Caregiver stress → ↓ health

1 in 4 require assistance with ADLs
• 1 in 4 exhibit behaviors
• 1 in 4 experience symptoms of depression
• 1 in 4 hospitalized over 3 months
• 1 in 5 visit emergency over 3 month

•Diet
• Physical activity
• Assess & manage hearing loss
• Sleep
- Manage sleep apnea
- Avoid sleep deprivation
- Good sleep hygiene
• Increase or maintain
engagement in cognitively
stimulating exercises
• Social engagement
• Minimize exposure to
anticholinergic medications
• Annual influenza vaccination

• ↓ cognition
• Usually memory
• Executive function
preserved
• Maintains ability
to carry out IADLs

-alzheimers

-lewy body dementia

-vascular dementia

-frontotemporal dementia

-others; parkinson's, huntington's,

-mixed dementias

-Tau Hypothesis

-Cholinergic Hypothesis

-Beta-amyloid hypothesis

Additional Hypotheses
• Inflammatory
• Oxidative stress
• Serotonergic
• others

dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with advanced age and Alzheimer's disease

it is pathological accumulations of amyloid-β, a peptide fragment of a membrane protein called amyloid precursor protein, that act as the root cause of AD and initiate its pathogenesis

Plaques
• Block neurotransmission
• Promote inflammation → neuron death
• Weaken blood vessels
• Initiates phosphorylation of tau proteins

• ↓ β-amyloid
production
• Prevent β-amyloid
aggregation
• ↑ removal of β-
amyloid
• Active vaccines
• Passive vaccines

The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs. Tau protein is a highly soluble microtubule-associated protein (MAP).

• Non-functioning microtubules
• Apoptosis

• Gradual onset
• ↓ cognition from baseline
• Amnestic deficits
- Impaired learning &
short term memory
deficits
• Executive dysfunction
-Reasoning, judgment,
problem solving
• Not due to any other cause

• Associated with cerebrovascular risk
factors & disease
• Abrupt onset
• Stepwise decline
• Temporal relationship between
vascular insult & cognitive decline

• Spontaneous parkinsonism
• Early, recurrent visual hallucinations
• Falls
• Orthostatic hypotension
• Antipsychotic sensitivity

• Insidious onset with slow progression
• Two primary types
• Semantic
• ↓ ability to verbalize
• Behavioral
• Disinhibition, repetitive behavior
• Social consequences
• Marital-family, occupation, social
problems

Four question approach
1. Is there a memory
problem?
2. Is function impacted?
3. What is the cause of the
memory problem?
4. What can we do?

• Interview patient
• Obtain collateral information (without patient present)
• Ask about memory
• Types of problems – specific examples
• Forgetting appointments, repetitive questions
• Changes in activities – activities or hobbies dropped
• Course of changes
• DON’T ACCEPT “IT’S BECAUSE OF MY/THEIR AGE”

• MMSE
- Favors educated
- Hearing & vision
- > 3 points “true change”
• MoCA
- Language, visuospatial ability, memory & recall, abstract thinking
http://www.mocatest.org/
- Now requires licensure
- Alternatives include RUDAS,
..>Tests memory, visuospatial orientation, praxis, visuoconstructional drawing, language & judgement
• BCRS
-Concentration, recent & remote memory

Functional assessment staging tool (FAST)

Types of assistance
• None
• Supervision
• Prompting
• Minimal hands-on care
• Total hands-on care
• Distinguish what can be done from what
is done

• Instrumental ADLs
• Managing money
• Managing
medications
• Driving
• Cooking
• Housekeeping
• Laundry
• Using telephone
• Basic ADLs
• Dressing
• Grooming
• Bathing
• Feeding
• Toileting

mild=4

moderate=5

severe=6

very severe= 7

I ADLS

R-epetitive dressing

A DLS: a) difficulty dressing

b)bathing

c) toileting

d) incontinence

N o speech and step

??(edit )

delirium onset=sudden(hr to days) while dementia is gradual

duration

delirium =short day to weeks

dementia= chronic

delirium= attention is impaired , in dementia its usually unaffected.

LOC(delirium)=up and down while in dementia its usually unaffected

delirium thoughts disorganized , dementia's are impaired.

course

delirium=fluctuating, dementia=stable

memory(delirium)= reduced as well as in dementia

Acute confusion
• New confusion in someone who was
normal before
OR
• Worsening confusion in someone who was forgetful before or previously
diagnosed with dementia.

Important to understand baseline cognition
• Baseline MMSE (6th vital sign?)
• Collateral history from family – those that know patient well

• Confusion Assessment Method
• Acute onset & fluctuating course
AND
• Inattention
AND
• Disorganized thinking
OR
• Change in level of consciousness

• Consider depression
• Depression can cause some symptoms of
dementia
• Executive dysfunction
• Depression can also be presenting
symptom of dementia
• If apathy, low mood, poor
appetite/weight loss, early morning
awakening are present AND prominent
consider trial of antidepressant

< 10% patients seen in clinic
• < 50% actually reverse
• Common causes
• Medications – sedatives, anticholinergic
burden
• Depression
• Hypothyroidism & B12 deficiencies are
usually coincidental rather than causative

• Non-pharmacologic interventions
• Address safety issues – e.g. driving, wandering
• Caregiver support
• Community resources – refer ALL
patients/caregivers to Alzheimer Society
• Medico-legal issues
• While still have capacity to do so, appoint:
• Substitute decision maker
• Power of attorney for finances

Pharmacologic interventions
• Cholinesterase inhibitors
- Donepezil
- Galantamine
- Rivastigmine
• NMDA receptor antagonist
- Memantine
• Aducanumab
- Anti-beta amyloid
- Recently available in US – controversial
- Not approved by Health Canada

• Vascular Cognitive Impairment
• Treatment of hypertension in
vascular MCI
• If > 140/90
• Receive guideline
recommended treatments for
primary/secondary stroke
prophylaxis as appropriate
• Use of ASA not recommended
• Brain imaging → white
matter lesions of
presumed vascular origin
+/- stroke history

cholinesterase inhibitors (ChEIs)

efficacy/effectiveness

AD + another pathology

• AD + Vascular component
• PDD
• LBD
• Change to CCCDTD5 – use of
ChEIs may be considered for
vascular dementia

• ChEI’s inhibit AChEsterase activity
• ↑ ACh

ChEIs – DO THEY WORK?
• Evidence in mild-moderate AD
• Cochrane Library Systematic Review

Some data supporting use of donepezil in moderate to severe disease
(Black et al. Neurology 2007; 69:459-69, Winblad et al, Lancet 2006)
• Short duration, does not address issue of when to discontinue
• Donepezil is approved for moderate to severe disease
• Some evidence in PDD and LBD
• Cochrane Library Systematic Review

Some get better
Some stabilize
Some get worse

donepezil- slower titration

Rivastigmine -Gi upset-PO issues

galantamine-some require 32 mg daily

• Why
• Poorly tolerated due to adverse effects
• Poor response in early disease
• Generally only switch once

?

-Miosis

-COPD NOT a contraindication
Respiratory outcomes similar between ChEI users & non-users
Bradycardia & syncope
– Bradycardia – 6.9 vs 4.4 events/1000 pt years
– Syncope 31.5 vs 18.6 event/1000 pt years
GI upset – nausea & vomiting

• Insomnia
• Take donepezil & galantamine in morning
• If PO rivastigmine – 2nd dose no later than 4-6 pm
• Agitation
• Urge type urinary incontinence??
• Leg cramps – most common with donepezil
• Health Canada warning – rhabdomylosis with donepezil
• Overall risk is low – warning based on 1 Canadian case report + 88 internationally
• 1 per 1667 prescriptions based on Ontario study (Fleet JL, et al. CMAJ 2019 September 16;191:E1018-24. doi: 10.1503/cmaj.190337)
• Risk appears greater with donepezil compared to galantamine or rivastigmine
• Consider monitoring parameters to identify rhabdomylosis

• Doesn’t make sense to concomitantly use drugs with anticholinergic activity
• Attenuate therapeutic effect? (Lu CJ & Tune LE Am J Geriatr Psychiatry
2003;11:458-61)
• Cholinergic agents (e.g. pyridostigmine) have
potential to enhance adverse effects
• Exacerbate adverse effects via different mechanism (e.g. bradycardia)
• Beta-blockers
• Digoxin

• Applies to Donepezil& Galantamine
• Metabolism via CYP2D6 and CYP3A4
• Implications
-Inhibition of CYP2D6 and/or CYP3A4
...>↑ serum concentrations → ↑ adverse effects
- Slow metabolizers of CYP2D6
...>Should be partially accounted for by intact CYP3A4
but potential for:
↑serum concentrations → ↑adverse effects
• Induction of CYP3A4
• Potential for ↓ serum concentrations → ↓
effectiveness
• Fast metabolizers of CYP2D6
• Potential for ↓serum concentrations → ↓
effectiveness

• ChEIs + memantine is safe but insufficient
evidence to recommend for or against
• Domino-AD – combination therapy no better than
single therapy (NEJM 2012;366:893-903)

Cautions : Active seizure disorder
D/C -if skin rash presents

Indications AD – approved
LBD – off label
PDD – off label
VD – off label

Agitation, confusion, dizziness, fatigue,
N/V

Appropriate indications
• AD, PDD, LBD or VD
• Should be deprescribed if MCI or FTD
• Clinically meaningful worsening of
cogntion/function in past 6 months not due to other medical conditions or environmental factors
• No clinically meaningful benefit observed at any time during treatment
• Severe or end-stage
• Intolerable adverse effects
• Non-adherence safety risk or unable to assess effectiveness

Why would you not start the ChEI
desprescribing process for 6 to 8 weeks
following admission to a long-term care
facility?
• Time to settle into facility
• If new onset or exacerbation of
behavioral sx’s
• Is it due to new environment or is
it due to discontinuation of the
ChEI?

↓ β-amyloid
production
• Prevent β-amyloid
aggregation
• ↑ removal of β-
amyloid
• Active vaccines
• Passive vaccines

• Aducanumab
• Health Canada application withdrawn
• Controversial FDA approval
• Lecanemab
• Approved by US FDA
• Awaiting approval by
Health Canada
• Donanemab
• Awaiting approval in US & Canada

• Amyloid related imaging abnormalities-edema (ARIA-E)
- Also includes microhemorrhages (ARIA-H)
...> Consideration of concomitant use with anticoagulants, antiplatelet agents, NSAIDs, SSRIs
- More common with higher doses & APOE4 positive
• Homozygotes > heterozygotes
• While biologically plausible benefit many questions remain:
• Is the effect size clinically detectable?
• Are the effects reproducible?
• Is the Canadian Health Care system equipped to provide aducanamab?
• Requires specialist-based evaluation & monitoring
• Availability of specialized equipment (PET scans)
• Invasiveness of monitoring
• Including lumbar puncture
• Regular MRI scanning
• Capacity for monthly infusions

• Common behaviours in dementia
• Agitation, aggression, restlessness,
wandering, disinhibition, repetition,
insomnia
• Other common issues in dementia
• Depression, apathy, anxiety, personality
changes, psychosis –
hallucinations/delusions,

cohen-mansfield agitation inventory

-important to define the problem behavior, especially when documenting

1. physically non-aggressive -generally restless, pacing

verbally non agressive -negativism, constant requests for help, repetition.

physically aggressive- hitting, pushing, scratching, grabbing things.

verbally aggressive-verbally threatening, cursing.

Misinterpretation
• Environment
• Caregiver
• Signals/clues
• Intimate care (dressing,
bathing, toileting,
feeding) # 1 cause of
aggression
• Delirium - ↑ confusion
• Pain – dental, skin
breakdown, MSK

• Fear
• Boredom
• Fatigue

• Resistance
• Opposition or
counteracting force that
is protective
• Attempt to protect from
perceived harm
• May be instinctual
reaction to not
understanding
environment or
expectations in the
context of cognitive
impairment
• Occurs in relation to
an action

• Aggression
• Angry & destructive
behaviour intended to
cause harm
• Aimed at domination
• Offensive action
• Occurs without
provocation

• Can be triggered by:
• Unmet needs
• Lack of understanding of person with
dementia
• Important to gather information
about the individual

• Responsive
• Psychosis – if distressing
• Physical aggression if
safety of individual or
others is compromised
• Depression
• Low mood, apathy,
amotivation
• Anxiety

• Less likely to respond
• Wandering
• Verbal non-aggression
• Uncooperative
• Frequent repetition
• Bothering others

1. assessment(id/describe target behavior)

2. rule out precipitating factors

3. trial non-pharmacologic interventions

4. if medn-responsive trial pharmacologic intervention

5-reassess and monitor on regular basis-behavioral tracking

trial dose reduction/discontinuation.

• Delirium related to acute illness
• e. g. Infection, heart failure,
metabolic abnormalities
• Pain – acute or chronic
• Some evidence to support “round
the clock” analgesia in chronic pain
• Medications
• Anticholinergic, sedatives,
corticosteroids, alcohol-nicotine-drug
withdrawal
• Environment

• Identify target symptoms
• Behavioural tracking is crucial
• Start medication that is appropriate to
the behaviour
• Start low – go slow
• Increase dose to benefit or side effects
• Some side effects mimic behaviour
• Re-evaluate & trial tapering doses

• Harm
• Health Canada warning 2005 - ↑
risk of death with atypicals
• 2005 meta-analysis - ↑ mortality
• ARI – 1.2%, NNH = 83
• Retrospective cohort x 15 yr
• Dose dependent ↑ cardiac death for
both atypical & conventional agents

Benefit
• Systematic review
• Aggression
• Risperidone > placebo
• Psychosis
• Risperidone, olanazepine>placebo
• ↑ dropouts with APs
• ↑ CVA with APs
• ↑EPS with APs
• 2nd systematic review
• Aggression
• Haloperidol > placebo
• ↑ ADE – sedation, EPS

Sedation, confusion, falls
• Hypotension
• EPS can be mistaken for worsening behaviour
• Tardive dyskinesia
• Weight gain, hyperglycemia

risperidone, olanzapine &
aripiprazole
– Quetiapine not appropriately dosed in clinical trials
• Insufficient evidence to recommend for or against
• Modest efficacy – be realistic in determining outcomes
– Re-evaluate over time
• Agents can be withdrawn without worsening of BPSD
(Cochrane Database Syst Rev. 2018 Mar 30;3:CD007726. doi:
10.1002/14651858.CD007726.pub3)cihi
• Balance risk/benefit ratio
– 1 patient death for every 9-25 who benefit (Schnieder, JAMA, 2005)
– Discussion with family/caregivers
• Palliative care model of dementia
– Consider
• Patient impact
• Caregiver impact
• Severity of symptoms – harm related to not treating

• SSRIs
• Depression, anxiety, some evidence for “agitation” & psychosis (citalopram –CitAD study)
• Leonpacher AK, et al Am J Psychiatry
2016 May 1;173(5):473-80
• SNRIs
• Depression with apathy
• Mirtazepine
• Depression with poor sleep & weight loss
• Allow 6-8 weeks at target dose

Non-Pharm interventions first
• Other classes when appropriate –
depression, anxiety
• Atypical antipsychotic agent for targeted
symptoms (e.g. hallucinations, delusions,
aggression) with severe behaviours causing
distress &/or harm
• Informed consent & documentation
• Monitor closely – behavioural tracking is
essential
• Trial dose reduction to discontinuation if
stable > 3 months

• Advocate for patient/caregiver
• Refer EVERY patient/caregiver to Alzheimer Society
• Support patients/caregivers in medication
management
• Recognize & assist with managing side effects
• Recognize & assist with managing clinically
important drug interactions
• Appropriate use of medications
• Goals of care
• Patient/caregiver values/preferences
• Support patient/caregivers through
deprescribing process when appropriate