1. Effectiveness & Use of
Cholinesterase Inhibitors in
Dementia
Dr. Donna Kay Buna, Pharm D
Dr. Dean Foti, MD, FRCP(C)
February 22, 2012
Some graphs are not included in this handout
because of copyright

2. Disclosures for Dr. Buna
• Paid honorarium from MSD, Glaxo and
Pfizer

3. Disclosures for Dr. Dean Foti
• Honoraria for speaking
engagements
• Consultant for Canadian
Advisory Boards
• No stock or financial
interests
• Novartis Canada
• Pfizer Canada

4. Learning Objectives
• Role of medications in management of Mild
Cognitive Impairment (MCI) and dementia
• Understand when initiation,
discontinuation, or switching of
cholinesterase inhibitors is appropriate

5. Outline
•
•
•
•
Overview of the drugs, benefits, expectations
Optimizing therapy
Counseling Points
Stopping, switching and when to avoid using
them
• Lots of time for questions!

6. The prevalence of dementia will triple by 2031!
Chertkow H. Diagnosis & treatment of dementia: Introduction. CMAJ
2008;178(3):316.
dkbuna 2010

7. Pharmacotherapy
• Cholinesterase Inhibitors
– Donepezil (Aricept®)
– Rivastigmine (Exelon®)
– Galantamine (Reminyl®)
• Memantine (Ebixa®)- NMDA antagonist
dkbuna 2010

8. Mechanism of
Action
Cholinesterase
Inhibitors
Adapted Figure 1.Beyond the Cholinergic Hypothesis: Do Current Drugs
Work in AD? CNS Neuroscience & Therapeutics 2010;16:235-245.
ChAT=choline acetyltransferase
Ach=acetylcholine
AChE=acetylcholinesterase
VAChT= vesicles of ChAT
nα7AChR= nicotinic Ach receptor
M1AChR= muscarinic receptor
HACU= high affinity choline transporter
AChEI=acetylcholinesterase inhibitor

9. Donepezil
5 & 10mg regular tablets
5 & 10mg rapidly disintegrating tablets
• First CHEI on the market – August 1997
• Indicated for mild, moderate and severe AD
• Starting dose 2.5-5mg and titrate up to maximum of 10mg
daily
• Extensively metabolized to 4 metabolites; 2 active; minor
substrates for Cytochrome P450 – 2D6 & 3A4 – not
usually clinically significant drug interactions.
• No dose adjustments necessary in hepatic or renal
dysfunction
• Best tolerated of the 3 available

10. Rivastigmine
1.5, 3, 4.5 and 6mg
capsules
2mg/ml solution
Also available generically –
PMS, Ratio, Sandoz, Teva
 Approved in Canada since ~ 2000
 Inhibits both ACHE and BuCHE-”pseudo-irreversible”
 Indicated for mild to mod AD and mild to mod Parkinson’s
dementia
 Start 1.5mg twice daily, increase by 3mg/day q4 weeks to MAX
of 12mg/day
 Minimally involved in cytochrome P450 systems , so reduced
risk of drug interactions
 No dose adjustment in renal or hepatic disease

11. • Exelon 5 – 5 cm2 patch
contains 9mg base – release
4.6mg/ 24 hours
• Exelon 10 – 10 cm2 patch
contains 18mg base –
releases 9.5mg/24 hours
Introduced in 2007
Indicated for mild to mod AD
Improved tolerability over oral formulation- 3x
fewer reports N/V IDEAL Study*
Health Canada warning April 2010
*IDEAL. Int J Geriatr Psych
2007;22:456-67.

13. • Galantamine
• 8, 16, 24mg ER
tablets
• Generic - Patriot
 Introduced in 2001, indicated for mild-mod AD
 Unique dual mechanism-reversible competitor inhibitor ACHE AND
allosteric modulator of nicotinic receptor
 Start with 8mg ER daily and titrate up to 8mg to MAX 24mg/day
 Extensively metabolized by cytochrome P450 – 2D6 and 3A4 to
metabolites of low activity
 Hepatic insufficiency; Max dose 16mg/day in mod disease (C-P 7-0)
and not recommended in severe disease (C-P 10-15)
 Renal insufficiency: Max dose 16mg/day in mod disease; not
recommended in severe disease (CrCL < 10 mL/min)

14. Canadian Dementia Guidelines 2007
14.Recommendations regarding the use of
cholinesterase inhibitors
a) All three cholinesterase inhibitors available
in Canada are modestly efficacious for mild
to moderate AD. They are all viable
treatment option for most patients with mild
to moderate AD. (Grade A, Level I)

15. Efficacy-Cognitive Improvement
benefit
Lanctot et al, CMAJ, 2003
no benefit

16. Mod-Severe AD: Donepezil v. Placebo
Activities of Daily Living
Donepeziln=134
Placebo n=140
125
129
121
126
(134)
(140)
Feldman et al 2000

17. Galantamine Reduces Caregiver Time
by One Hour per Day in Mild-Mod AD
30
*
20
Change From
Baseline in
Daily Time
Spent
Assisting With
ADL (min)
10
0
–10
–20
–30
–40
–50
*P < .05 vs baseline.
Sano M, Wilcock GK et al., Int J Ger Psy, 2003:942-50.

18. Initiating Cholinesterase Therapy:
It’s all about expectations
•
•
•
•
20 % will improve noticeably
50 % will remain unchanged
20 % will continue to worsen
10-15 % are intolerant
Expect the majority to remain unchanged

19. ChEI’s: Use Across Dementias
• Mild - Moderate AD
• Moderate - Severe AD
• Dementia with Lewy Bodies &
Parkinson Disease Dementia
• Vascular/Mixed Dementia

20. Which ChEI to use for
mild-moderate AD?
• All equal efficacy
• Ask patient and family: Pill or Patch?
• Influences:
– Familiarity
– Cost
– Side effect profile

21. Optimizing Therapy
• Early vs Late start
• Hi dose vs low dose
• Low dose start with high dose
“rescue” later
• Adherence
• Counseling – set expectations; ensure
adherence

22. Early VS Late Treatment
“Defining optimal treatment”. Alzheimer’s & Dementia
2011;7:177-184.

23. High Dose vs Low Dose
“Defining optimal treatment”. Alzheimer’s & Dementia
2011;7:177-184

24. Lower dose Start with “Rescue” Later
“Defining optimal treatment”. Alzheimer’s & Dementia
2011;7:177-184

25. Compliance/Adherence
• Average treatment duration 4-5 months
• Susceptible to poor compliance – age,
comorbidities, memory deficits, pill
burden
• Educate patient/family/caregiversestablish expectations
• Ensure a follow-up plan

26. Counseling Point
Symptomatic, not curative
Higher
Function
Outcome
Can delay progression
Time
Symptomatic
No Treatment
Lower
Function
dkbuna 2010

27. Counseling point
Some respond, some don’t
Responder
Non-Responder
(Continued
worsening)
25%
25%
50%
Average response
= mild improvement
or same for 1 year
(Brain Cancer)
Super Responder
(Much better)
dkbuna 2010
Dalziel B. Dementia Newsletter for Physicians 2008; 6(4):3-4.

28. Counseling Point
How do you know if it is working?
• What target symptoms are important to
the patient & their family?
– A- ADL, functional measure
– B-behavioral
– C-cognitive
• Document at baseline
• Persist for the duration to realize long
term benefits.
dkbuna 2010

29. Counseling Point
Watching for side effects
• Start low, titrate up if tolerated
• Visit physician at 4-6 weeks to assess
• Common side effects:
–
–
–
–
–
N/V, diarrhea
Anorexia with weight loss
Sleep disturbances
Muscle/leg cramps
Syncope/dizziness
dkbuna 2010

30. Counseling Point
6 month Follow-up
• Assess if it is working
• Compare to baseline
• Documentation required to continue
coverage
• Key components:
– FMMSE still between 10-26
– GDS still between 4 & 6
– Global assessment
dkbuna 2010

31. How long to continue
ChEI’s in Alzheimer Disease?
• No specific reason to discontinue if function &
behaviour reasonable
• NOT correct that only effective for 6-12 months
• Trial discontinuation not recommended
• Consider discontinuation when limited
contribution to self-care and interactions

32. The Declining Patient
• Consider alternate medication when:
– significant clinical progression
– caregiver dissatisfaction
– medication intolerance
• Treatment Options
– Switch ChEI’s
– Memantine (combined with ChEI > monotherapy)

33. Should you change ChEI’s?
• Generally not too helpful in gradually declining
patient on prolonged therapy
• Switch ChEI’s when:
– Intolerant due to side effects
– Significant early progression: ‘nonresponder’
– family strongly requests and is motivated

34. How to Switch ChEI’s
• Generally no wash out period required
when switching for declining patient
– Usual titration schedule for new medication
– When changing from high dose donepezil or
rivastigmine, start at galantamine ER 16mg
• Combining ChEI’s not recommended
• When switching for tolerability issues, wait
about one week for resolution of s/e’s

35. When not to use ChEIs?
• Normal Aging
• Mild Cognitive Impairment
• Frontal-temporal lobar dementias
(eg Pick’s disease)

36. MCI Definition
Mild Cognitive Impairment
•
•
•
•
•
Memory complaint
Objective memory impairment
Normal general cognitive function
Activities of daily living generally intact
Not demented
Petersen et al., Neurology, 2001

37. MCI Becoming Dementia
• MCI is a high risk state for future dementia
– 10 % per year over the first 5 years
• 30 % stay the same
• 20 % of MCI may revert to normal

38. Should MCI patients be treated
with cholinesterase inhibitors?
• Generally Not
• Clinical trials with all 3 ChEI’s negative
• …..but……
– Positive early results from donepezil MCI trial
– Some patients are very amnestic and have early
AD but do not meet the criteria for dementia

39. Summary
• ChEI’s have modest but significant
benefits in meaningful outcomes to
patients and families across a spectrum
of dementia severities and types
• Tolerability and formulation of ChEI’s
vary between patients – try different
ones

40. Questions
• Please type your questions below in the Q&A
box