Dementia notes feb 2012

337 views

Published on

Published in: Health & Medicine, Sports
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
337
On SlideShare
0
From Embeds
0
Number of Embeds
4
Actions
Shares
0
Downloads
10
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Dementia notes feb 2012

  1. 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. 2. Disclosures for Dr. Buna • Paid honorarium from MSD, Glaxo and Pfizer
  3. 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. 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. 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. 6. The prevalence of dementia will triple by 2031! Chertkow H. Diagnosis & treatment of dementia: Introduction. CMAJ 2008;178(3):316. dkbuna 2010
  7. 7. Pharmacotherapy • Cholinesterase Inhibitors – Donepezil (Aricept®) – Rivastigmine (Exelon®) – Galantamine (Reminyl®) • Memantine (Ebixa®)- NMDA antagonist dkbuna 2010
  8. 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. 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. 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. 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.
  12. 12. • 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)
  13. 13. 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)
  14. 14. Efficacy-Cognitive Improvement benefit Lanctot et al, CMAJ, 2003 no benefit
  15. 15. 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
  16. 16. 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.
  17. 17. 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
  18. 18. ChEI’s: Use Across Dementias • Mild - Moderate AD • Moderate - Severe AD • Dementia with Lewy Bodies & Parkinson Disease Dementia • Vascular/Mixed Dementia
  19. 19. Which ChEI to use for mild-moderate AD? • All equal efficacy • Ask patient and family: Pill or Patch? • Influences: – Familiarity – Cost – Side effect profile
  20. 20. 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
  21. 21. Early VS Late Treatment “Defining optimal treatment”. Alzheimer’s & Dementia 2011;7:177-184.
  22. 22. High Dose vs Low Dose “Defining optimal treatment”. Alzheimer’s & Dementia 2011;7:177-184
  23. 23. Lower dose Start with “Rescue” Later “Defining optimal treatment”. Alzheimer’s & Dementia 2011;7:177-184
  24. 24. 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
  25. 25. Counseling Point Symptomatic, not curative Higher Function Outcome Can delay progression Time Symptomatic No Treatment Lower Function dkbuna 2010
  26. 26. 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.
  27. 27. 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
  28. 28. 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
  29. 29. 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
  30. 30. 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
  31. 31. The Declining Patient • Consider alternate medication when: – significant clinical progression – caregiver dissatisfaction – medication intolerance • Treatment Options – Switch ChEI’s – Memantine (combined with ChEI > monotherapy)
  32. 32. 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
  33. 33. 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
  34. 34. When not to use ChEIs? • Normal Aging • Mild Cognitive Impairment • Frontal-temporal lobar dementias (eg Pick’s disease)
  35. 35. 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
  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. Questions • Please type your questions below in the Q&A box

×