Alzheimer's Disease

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Alzheimer's Disease

  1. 1. Alzheimer’s Disease By Theodore Graphos
  2. 2. Patient Case
  3. 3. CaseOverviewDemographics • 83 y/o • FemaleSituation Contacted by phone to follow-up on INR results  A-fib  Seen by Pharmacy Services for warfarin management
  4. 4. CaseHPI Recently diagnosed with Alzheimer’s Disease • Repeats herself • Tells the same stories repeatedly • Problems with medication adherence ▫ Repeat doses ▫ Missed doses ▫ Forgets schedule Her son is her primary caretaker
  5. 5. CasePMH Medical Surgical • Alzheimer’s Disease • BiV-PPM (Medtronic®) [Mar-11] • A-fib, paroxsymal • Cholecystectomy [Aug-10] • Sick sinus syndrome • Adenocarcinoma, colon – • Heart failure Polypectomy [Aug-10] • Hypertension • Cataracts, bilateral • GERD • Urinary incontinence • Chronic anemia • Depression • Insomnia • Fatigue • Diverticulosis • Meningioma [Jun-10] • Adenocarcinoma [Aug-10]
  6. 6. CasePMH Medical Surgical • Alzheimer’s Disease • BiV-PPM (Medtronic®) [Mar-11] • A-fib, paroxsymal • Cholecystectomy [Aug-10] • Sick sinus syndrome • Adenocarcinoma, colon – • Heart failure Polypectomy [Aug-10] • Hypertension • Cataracts, bilateral • GERD • Urinary incontinence • Chronic anemia • Depression • Insomnia • Fatigue • Diverticulosis • Meningioma [Jun-10] • Adenocarcinoma [Aug-10]
  7. 7. CasePMH Medical Surgical • Alzheimer’s Disease • BiV-PPM (Medtronic®) [Mar-11] • A-fib, paroxsymal • Sick sinus syndrome • Cholecystectomy [Aug-10] • Heart failure • Adenocarcinoma, colon – • Hypertension Polypectomy [Aug-10] • GERD • Cataracts, bilateral • Urinary incontinence • Chronic anemia • Depression • Insomnia • Fatigue • Diverticulosis • Meningioma [Jun-10] • Adenocarcinoma [Aug-10]
  8. 8. CasePMH Medical Surgical • Alzheimer’s Disease • BiV-PPM (Medtronic®) [Mar-11] • A-fib, paroxsymal • Cholecystectomy [Aug-10] • Sick Sinus Syndrome • Adenocarcinoma, colon – • Heart failure Polypectomy [Aug-10] • Hypertension • Cataracts, bilateral • GERD • Urinary incontinence • Chronic anemia • Depression • Insomnia • Fatigue • Diverticulosis • Meningioma [Jun-10] • Adenocarcinoma [Aug-10]
  9. 9. CaseFHx/SHx/AllergiesSocial Hx • Alcohol: Rarely • Smoking: Unknown • Caffeine: OccasionalFamily Hx • Father: Deceased (59) – Kidney failure • Mother: Deceased (74) – Complications of diabetesAllergies Substance Reaction Furosemide Rash, but can tolerate if given w/ diphenhydramine Hydrochlorothiazide Skin rashes Nitrofurantoin Pruritic rash on legs, trunk, and upper extremities Sulfa drugs
  10. 10. CaseVitals 7/26/11 • Patient is experiencing Ht 5’ 4” unexplained weight-loss • HR is controlled by PPM Wt 112 lbs BMI 19.2 (18.5-25) BP 119/59 (<120/80 mmHg) HR 69 (60-100 bpm) RR 16 (12-20 rpm)
  11. 11. CaseLabs 9/20/11 INR 1.9 L • INR is subtherapeutic (2-3) • Patient is anemic 7/27/11 ▫ Low RBC, Hgb, Hct RBC 3.58 L ▫ Borderline macrocytic (4.0-5.2 /L) ▫ Borderline anisocytosis Hgb 10.9 L (12.5-16.0 g/dL) • Renal impairment Hct 33.1 L (36-46 %) ▫ Low Scr, eGFR MCV 93 (81.0-97.4 fL) RDW-CV 14.4 (11.7-14.4 %) SCr 1.27 H (0.6-1.2 mg/dL) eGFR 39 L (106-132 mL/min)
  12. 12. CaseLabs 7/27/11 Albumin • No vitamin B12 or folate (3.5-5.5 g/dL) 4.1 deficiency K+ 4.1 (3.5-5.1 mEq/L) • Digoxin levels are high, but Ca2+ 9.3 not toxic (9.0-10.5 mg/dL) Vitamin B12 756 (211-946 pg/mL) Folate > 20 (> 3 ng/mL) 1/27/11 Digoxin (0.5-2.2 ng/mL) 1.2 (0.5-1 ng/mL) 7/22/09 DEXA (T-score) Spine: +1.4 (> -1.0) Femur: -1.1
  13. 13. Case Medications Medication Strength Qty Form Frequency Indication Triamcinolone acetonide 0.1% - Cream Once daily to rash Rash Oxybutynin 24hr (Ditropan XL®) 15 mg 1 Tablet Daily Urinary incontinence Potassium chloride 10 mEq / 7.5 mL Liquid Daily Potassium balance Pantoprazole (Protonix®) 40 mg 1 Tablet Daily GERD Digoxin 0.125 mg 1 Tablet Daily CHF Bumetanide (Bumex®) 1 mg 1 Tablet Daily CHF Warfarin (Coumadin®) 2.5 mg 2.5 mg daily, except 3.75 mg on Wed A-fib Lisinopril 5 mg 1 Tablet Daily HTN, CHF Carvedilol 6.25 mg 1 Tablet Twice daily CHF, HTN Centrum Silver Chewables® - 1 Tablet Daily None  Patient tried Namenda® once some time in July, but “did not like the way it made her feel.”  Patient also tried Aricept® once, but did not like it because it made her feel like a "zombie."
  14. 14. Alzheimer’s Disease
  15. 15. AD Description Alzheimer’s disease (AD) is a common age-related, chronic debilitating neurodegenerative condition that is associated with progressive cognitive decline and profound neuronal loss.
  16. 16. AD Epidemiology • Most common form of dementia in the elderly ▫ 10% of those >65 y/o ▫ 50% of those >85 y/o • 4.5 million affected in the US • 18 million affected world-wide
  17. 17. AD History • Discovered in 1907 • Two pathologic alterations ▫ Neuritic plaques ▫ Neurofibrillary tangles • Full pathology is still unknown Dr. Alois Alzheimer
  18. 18. AD Pathology Neuritic plaques • β-amyloid protein (Aβ) ▫ Breakdown product of a membrane-bound protein • Imbalance between the production and clearance of Aβ peptides resulting in aggregation that causes accumulation of Aβ and ultimately leading to AD (Amyloid Cascade Hypothesis) • While Aβ sequestered in plaques was at first believed to represent the critical toxic species, more recent versions of the hypothesis assume Aβ that is not sequestered in plaques actually drives the disease. Neurofibrillary Tangles (NFTs) • Tau protein ▫ Provide stability to microtubules ▫ Mostly found in neuronal cells ▫ Become hyperphosphorylated in AD
  19. 19. AD Pathology [ The Amyloid Cascade Hypothesis ]
  20. 20. NMDAantagonists ChEI
  21. 21. AD Clinical Presentation Cognitive • Memory loss (poor recall and losing items) • Aphasia (circumlocution and anomia) • Apraxia • Agnosia • Disorientation (impaired perception of time and unable to recognize familiar people) • Impaired executive function Noncognitive • Depression, psychotic symptoms (hallucinations and delusions) • Behavioral disturbances (physical and verbal aggression, motor hyperactivity, uncooperativeness, wandering, repetitive mannerisms and activities, and combativeness) Functional • Inability to care for self (dressing, bathing, toileting, and eating)
  22. 22. AD Staging Stages of Alzheimers Disease Mild Patient has difficulty remembering recent events. Ability to manage finances, (MMSE score 26–18) prepare food, and carry out other household activities declines. May get lost while driving. Begins to withdraw from difficult tasks and to give up hobbies. May deny memory problems. Moderate Patient requires assistance with activities of daily living. Frequently (MMSE score 17–10) disoriented with regard to time (date, year, season). Recall for recent events is severely impaired. May forget some details of past life and names of family and friends. Functioning may fluctuate from day to day. Patient generally denies problems. May become suspicious or tearful. Loses ability to drive safely. Agitation, paranoia, and delusions are common. Severe Patient loses ability to speak, walk, and feed self. Incontinent of urine and (MMSE score 9–0) feces. Requires care 24 hours a day, 7 days a week.
  23. 23. AD Diagnosis Progressive change in MMSE memory or functionClinical diagnosis made mostly DSM-IV criteriaby ruling out other possibilities Dementia AHRQ guidelines• DSM-IV-TR Medication-induced Medication review AHRQ guidelines dementia• National Institutes of Health-Alzheimer’s Disease Hypothyroidism and Related Disorders Abnormal lab tests Abnormal physical exam Abnormal B12 Deficiency AAN guidelines Systemic illness Association (NIH-ADRDA) ▫ Published in 2011 Vascular dementia Abnormal Hydrocephalus ▫ Used mostly for research CT or MRI/Optional Tumors NINDS criteria purposes Subdural hematoma Yes DSM-IV criteria Depressed mood Depression AHRQ guidelines NINCDS-ADRDA Alzheimer’s disease Atypical disorders criteria Refer for assessment
  24. 24. AD Prognosis & Treatment GoalsPrognosis • Cannot cure or prevent Alzheimer’s ▫ Current therapy does not affect the progression of the disease • Survival following diagnosis is typically 4 to 6 yearsTreatment Goals • Treat cognitive symptoms • Treat psychiatric and behavioral sequelae • Preserve cognitive functioning as long as possible
  25. 25. AD Non-pharmacologic therapy • Disease-state education Table 63-3 Basic Principles of Care for the Alzheimers Patient • Consider vision, hearing, or other sensory impairments. • End-of-life planning • Find optimal level of autonomy and adjust expectations for patient performance over time. • Handling behavioral • Avoid confrontation. Remain calm, firm, and supportive if the patient symptoms becomes upset. • Maintain a consistent, structured environment with stimulation level • Caring for the caregiver appropriate to the individual patient. • Provide frequent reminders, explanations, and orientation cues. Employ guiding, demonstration, and reinforcement. • Reduce choices, keep requests and demands of the patient simple, and avoid complex tasks that lead to frustration. • Bring sudden declines in function and the emergence of new symptoms to professional attention.
  26. 26. AD Pharmacologic therapy Only 5 FDA-Approved Drugs Drug name Brand name Approved For FDA Approved Cholinesterase Inhibitors (ChEIs) Galantamine Razadyne® Mild to moderate 2001 Rivastigmine Exelon® Mild to moderate 2000 Donepezil Aricept® All stages 1996 Tacrine Cognex® Mild to moderate 1993 NMDA Antagonists Memantine Namenda® Moderate to severe 2003
  27. 27. AD Cholinesterase InhibitorsActions Galantamine Oral: 4 mg BID (Razadyne®) (up to 12 mg BID) Oral, ER: 8 mg daily ACh (up to 24 mg daily) Choline + Acetic acid Rivastigmine Oral: 1.5 mg BID (Exelon®) (up to 6 mg BID) Patch: 4.6 mg/24 hr, 9.5 mg/24 hr • Increase concentration of Ach Donepezil Oral: 5, 10, or 23 mg daily • Improve alertness and cognitive (Aricept®) activity
  28. 28. AD Cholinesterase InhibitorsAdverse Reactions Galantamine Oral: 4 mg BID Related to cholinergic effects… (Razadyne®) (up to 12 mg BID) Oral, ER: 8 mg daily • N/V/D Most common (up to 24 mg daily) • Dizziness Rivastigmine Oral: 1.5 mg BID • Headache (Exelon®) (up to 6 mg BID) • Urinary incontinence Patch: 4.6 mg/24 hr, 9.5 mg/24 hr • Fatigue • Sweating Donepezil Oral: 5, 10, or 23 mg daily (Aricept®) • Salivation • Bradycardia • Personality changes
  29. 29. AD Cholinesterase InhibitorsPrecautions Galantamine Oral: 4 mg BID (up to 12 mg BID) • Renal/hepatic impairment (Razadyne®) Oral, ER: 8 mg daily (up to 24 mg daily) • Cardiac conduction abnormalities Rivastigmine Oral: 1.5 mg BID (up to 6 mg BID) • Peptic ulcer disease (Exelon®) Patch: 4.6 mg/24 hr, 9.5 mg/24 hr • COPD/asthma • Seizures Donepezil Oral: 5, 10, or 23 mg daily (Aricept®) • Urinary tract obstructions
  30. 30. AD Cholinesterase InhibitorsInteractions Galantamine Oral: 4 mg BID (up to 12 mg BID) Cholinergics (Razadyne®) Oral, ER: 8 mg daily • Postoperative ileus (up to 24 mg daily) • Urinary retention Rivastigmine Oral: 1.5 mg BID (Exelon®) (up to 6 mg BID) Patch: 4.6 mg/24 hr, Anticholinergics 9.5 mg/24 hr • Urinary incontinence Donepezil Oral: 5, 10, or 23 mg • Parkinson’s (Aricept®) daily • COPD/asthma • 1st gen antihistamines
  31. 31. AD Cholinesterase InhibitorsMonitoring Galantamine Oral: 4 mg BID (Razadyne®) (up to 12 mg BID) • Mental status Oral, ER: 8 mg daily (up to 24 mg daily) • Cholinergic side-effects Rivastigmine Oral: 1.5 mg BID • Renal & hepatic function (Exelon®) (up to 6 mg BID) Patch: 4.6 mg/24 hr, 9.5 mg/24 hr Donepezil Oral: 5, 10, or 23 mg (Aricept®) daily
  32. 32. AD NMDA antagonistsActions • Blocks postsynaptic N-methyl- D-aspartate (NMDA) (i.e. Memantine Oral: 5 mg/day (up to 20 mg/day) (Namenda®) glutamate) receptors Oral, ER: 7 mg daily (up to 28 mg daily) • Prevents excitatory neurotoxicity • Improves signal transduction
  33. 33. AD NMDA antagonistsAdverse Reactions • Constipation • Confusion Memantine (Namenda®) Oral: 5 mg/day (up to 20 mg/day) • Dizziness Oral, ER: 7 mg daily (up to 28 mg daily) • Headache • Hallucinations • Coughing • Hypertension
  34. 34. AD NMDA antagonistsPrecautions • Cardiovascular disease • Renal impairment Memantine (Namenda®) Oral: 5 mg/day (up to 20 mg/day) • Seizures Oral, ER: 7 mg daily (up to 28 mg daily)
  35. 35. AD NMDA antagonistsInteractions • No significant drug interactions Memantine Oral: 5 mg/day (up to 20 mg/day) (Namenda®) Oral, ER: 7 mg daily (up to 28 mg daily)
  36. 36. AD NMDA antagonistsMonitoring • Mental status • Blood pressure Memantine (Namenda®) Oral: 5 mg/day (up to 20 mg/day) • Renal function Oral, ER: 7 mg daily (up to 28 mg daily)
  37. 37. AD Unproven therapies • Estrogen ▫ Lower incidence of AD in women receiving HRT • NSAIDs ▫ Prevent damage from neuroinflammation • Statins ▫ Apolipoprotein E (ApoE) linked to AD • Vitamin E ▫ Antioxidant to counter oxidative stress * None of the therapies above have shown success in clinical trails *
  38. 38. AD Secondary therapies • Antipsychotics ▫ Used to treat behavioral symptoms ▫ Most of benefit for their neuroleptic effects ▫ Use non-pharmacologic approaches first • Benzodiazepines ▫ Also used to treat behavioral symptoms and agitation ▫ May worsen cognition ▫ Can increase fall risk • Antidepressants ▫ Depression is a common comorbidity in AD ▫ Citalopram and sertraline have the most evidence to support their use • Anticonvulsants ▫ Used for mood-stabilization ▫ Not enough evidence to recommend use
  39. 39. Back to our case…
  40. 40. CaseA & P 1. Alzheimer’s Disease • No remaining pharmacologic options • Monitor cognitive capacity and recommend lifestyle modifications as necessary • Continually assess impact on adherence to other medications (especially warfarin) • Suggest resources for the son/caregiver
  41. 41. CaseA & P 2. A-fib • CHADS2 = 3 ▫ Lifetime anticoagulation with warfarin is therefore appropriate in this patient • Patient’s INR is still subtherapeutic ▫ Increased weekly dose by 7% 3. Heart failure • Receiving recommended pharmacotherapy for Stage C heart failure • Well-controlled at this time 4. Hypertension • BP is stable and at goal • Note that low diastolic BP could reduce cerebral perfusion and worsen AD
  42. 42. CaseA & P 5. Urinary incontinence • Anticholinergic effects of Ditropan XL® may cause agitation and confusion which would amplify her AD • However, no negative effects were recorded after initiating this medication 6. Chronic anemia • Check for s/sx of bleeding • Check serum iron, TBIC, t-sat, and ferritin w/ next lab draw 7. Meningioma/Colon caner • Patient has refused additional intervention • Monitor for s/sx of bleeding • Occasionally reassess patient’s interest in treatment
  43. 43. References1. Anderson HS, Brannon GE, Boswell LP, Feng J, Haddock JL, Schneider R. Alzheimer Disease [Internet]. Medscape Reference: Drugs, Disease & Procedures. 2011 ;Available from: http://emedicine.medscape.com/article/1134817-overview2. Chopra K, Misra S, Kuhad A. Neurobiological aspects of Alzheimerʼs disease. [Internet]. Expert opinion on therapeutic targets. 2011 May ;15(5):535-55.[cited 2011 Oct 5] Available from: http://www.ncbi.nlm.nih.gov/pubmed/213142313. Cummings JL. Alzheimerʼs disease. [Internet]. The New England journal of medicine. 2004 Jul 1;351(1):56-67.[cited 2011 Aug 10] Available from: http://www.ncbi.nlm.nih.gov/pubmed/152293084. Cummings JL, Frank JC, Cherry D, Kohatsu ND, Kemp B, Hewett L, et al. Guidelines for managing Alzheimerʼs disease: Part II. Treatment. [Internet]. American family physician. 2002 Jun 15;65(12):2525-34.[cited 2011 Oct 5] Available from: http://www.ncbi.nlm.nih.gov/pubmed/120862425. Geldmacher DS. Treatment guidelines for Alzheimerʼs disease: redefining perceptions in primary care. [Internet]. Primary care companion to the Journal of clinical psychiatry. 2007 Jan ;9(2):113-21.[cited 2011 Oct 5] Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1896294&tool=pmcentrez&rendertype=abstract6. Jackson-siegal J. Our current understanding of the pathophysiology of alzheimer’s disease. Advanced Studies in Pharmacy. 2005 ;2(4):126-135.7. Marchesi VT. Alzheimerʼs dementia begins as a disease of small blood vessels, damaged by oxidative-induced inflammation and dysregulated amyloid metabolism: implications for early detection and therapy. [Internet]. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2011 Jan ;25(1):5-13.[cited 2011 Jun 24] Available from: http://www.ncbi.nlm.nih.gov/pubmed/212057818. McNaull BBA, Todd S, McGuinness B, Passmore AP. Inflammation and anti-inflammatory strategies for Alzheimerʼs disease--a mini-review. [Internet]. Gerontology. 2010 Jan ;56(1):3-14.[cited 2011 Oct 5] Available from: http://www.ncbi.nlm.nih.gov/pubmed/197525079. Pereira C, Agostinho P, Moreira PI, Cardoso SM, Oliveira CR. Alzheimerʼs disease-associated neurotoxic mechanisms and neuroprotective strategies. [Internet]. Current drug targets. CNS and neurological disorders. 2005 Aug ;4(4):383-403.[cited 2011 Oct 5] Available from: http://www.ncbi.nlm.nih.gov/pubmed/1610155610. Slattum P, Swerdlow R, Massey-Hill A. Alzheimerʼs Disease. In: DiPiro J, Talbert R, Yee G, Matzke G, Wells B, Posey LM, editor(s). Pharmacotherapy: A Pathophysiologic Approach, Seventh Edition. McGraw-Hill; 2008. p. 1051-1066.11. Standridge JB. Vicious cycles within the neuropathophysiologic mechanisms of Alzheimerʼs disease. [Internet]. Current Alzheimer research. 2006 Apr ;3(2):95-108.[cited 2011 Oct 5] Available from: http://www.ncbi.nlm.nih.gov/pubmed/16611010

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