Alzheimer’s Disease

1. Alzheimer’s Disease By: Carla Alexander, 4th Year Pharmacy Student March 17th, 2011

2. Overview • Definition • Prognosis • Pathophysiology • Symptoms • Treatment • Functional Tests • Exceptional Drug Status

3. Types of Dementia • Dementias: • Alzheimer’s Disease • Vascular Dementia • Mixed Type Dementia • Frontal Lobe Dementia • Dementia with Lewy Bodies • Most common form of dementia is Alzheimer's Disease (50-75%)

4. Definition • An acquired impairment in intellectual function, involving at least three of the following: • Memory • Emotion • Language • Eye-hand skills • Executive function (planning or completing activities • Impairment of cognitive function is sufficient to interfere with normal daily activities.

5. Characteristics of Alzheimer’s Disease • Chronic • Progressive neurodegenerative disorder • No cure to halt progression • Rate of failure is variable for each person • Prognosis: • Lasts 3-20years (4.5 yrs avg.) • Body is weakened by inactivity, muscle wasting and decreased immune function • Death usually due to secondary infection, such as pneumonia

6. Statistics • Significant impact on society economically. • Today, half a million Canadians have Alzheimer's disease or a related dementia. • 1 in 11 Canadians over the age of 65 currently has Alzheimer's disease or a related dementia. • One Canadian every five minutes will develop dementia this year. By 2038, this will become one person every two minutes • If nothing changes, the number of people living with Alzheimer's disease or a related dementia is expected to more than double

7. Pathophysiology • Not a normal part of aging • Acetylcholine (Ach) is crucial for nerve to nerve communication • Depleted in Alzheimer’s Disease • Protein plaques (amyloid, A-Beta) & neurofibrillary tangles (tau) • Normally present in brain • Over production and accumulation in Alzheimer’s Disease • Toxic to nerve cells • Nerve cells die and their connections with other nerve cells are lost; brain cells continue to die over time • Damage starts 10+ years before symptoms

8. Nerve cell damage due to amyloid beta protein and tau protein. Decreased ability to transmit signals in brain. Decreased concentration of Ach, used for nerve communication.

9. Loss of activity and physical structure of brain.

10. Symptoms • Three interrelated aspects: • Memory • Perception • Thought • As the disease progresses, a person will experience new symptoms and an increase in the severity of older symptoms • Loss of memory affects perception of events which affects thinking; thoughts not remembered, which then affects your behaviour

11. 90% of patients have behavioural and psychological symptoms • Currently, once an ability is lost, it won’t return.

12. Causes • No known, single cause of Alzheimer's disease. • However: • Inherited (Genes – APOEe4) • Head injuries • More frequent in women

13. Diagnosis • True diagnosis can only be found post mortem • Rule out treatable causes • Physical exam • Cognitive tests (MMSE, clock drawing, FAQ) • History • Nurse observations • Blood work • Brain Imaging (MRI, CT)- to detect shape and volume of brain regions

14. Rule out Treatable causes • Rule out if pain is underlying problem • As seniors age they become still, sore and hurt • People with dementia can’t express themselves very well which triggers agitation • Depression (Pseudo-dementia) • Delirium (drugs, infections-UTI causes delirium) • first check urine • Hypothyroidism • Vit. B12 deficiency • Alcoholism • Drugs & polypharmacy • Hard of hearing

15. Functional Tests • Cognitive impairment assessed using Mini-Mental State Examination (MMSE) • Orientation, learning, naming, drawing, judgment skills, clock drawing • Functional disability is measured with Functional Assessment Staging Tool (FAST), or Functional Activities Questionnaire (FAQ) • FAQ is required by SK drug plan • Rates 10 routine activities from normal (0) to dependent (3) • Lower the score, the better

16. Max score: 30 points

17. Staging Severity • Mild • has trouble with recent memory • have difficulty with certain complex functions such as using the telephone, or managing finances, taking medications or driving • During the mild stage, many people have difficulty controlling their emotions, and so can become irritable and short-tempered. • Moderate • no longer can do complex activities • care for themselves with prompting. • have difficulty learning anything new, they mix up details • begin to move slowly • Suspiciousness, judgment for personal safety is too impaired for them to be counted on.

18. Staging Severity • Severe • need more and more help with personal care • no longer can control their bowels or bladder • lose weight, and often even lose a sense of who they are • cannot speak in full sentences • delusional, a common delusion is that people are stealing from them; another is that where they live is no longer their house, and they will want to 'go home'. They can mistake their spouse for their mother, or a child for a spouse.

19. Non-Pharmaceutical Treatments • Often sufficient to make a noticeable improvement in the target symptoms • Distraction • Avoid confrontation, clear and respectful communication • Safe, familiar environment without hazards (prevent falls) • Label items • No diet restrictions; snacks help • Exercise/activity (to avoid muscle wasting) • Soothing music • Sundowning – keep active in day; avoid caffeine • AVOID MAJOR SURGERY & Meds if possible • Reserve drug treatment for situations where non-pharmacological interventions have failed or in situations with dangerous risk,(agitation, hitting).

20. Pharmacological Treatment • 2 classes of pharmacological agents: 1. Primary meds which attempt to slow the progression • Cholinesterase inhibitors • Memantine 2. Symptomatic meds to manage secondary complications (depend on stage of progression) • Antipsychotics • Antidepressants • Benzodiazepines • Hypnotics • Anxiolytics • Mood Stabilizers • Reevaluate all drug therapies q3- 6 mons to see if still indicated

21. Primary: Cholinesterase inhibitors • Donepezil-Aricept™ • Rivastigmine- Exelon™ and Exelon ™Patch • Galantamine-Reminyl ER • Work by increasing amount of Ach in the brain to help messages communicate from cell to cell.

22. Cholinesterase inhibitors • Might slow the decline rate – 3-4% over 6 months • Benefits are small, disease stabilization • No effect on agitation • Trial prescription for ~3months for effect • If don’t respond to one, may help to switch to another • Higher doses have better outcomes • Only work for about 2-3 yrs, then disease progression too much to have benefit • Side-effects • GI issues!, n/v, fatigue, anorexia, decreased heart rate, insomnia, • Expensive ($172-230/month) • EDS coverage • Does not delay institutionalization

23. Primary: Memantine • Works by blocking glutamate, which at high doses is toxic to cells, therefore stopping cell death. • Small to moderately beneficial effect on cognition, ADL and behaviour • Improvements same as cholinesterase inhibitors (modest) • Future: Combining memantine and cholinesterase inhibitors seems to improve outcomes. Expensive! • Memantine is not on SK formulary 

24. Symptomatic Treatment • Treats the behavioural & psychological component • Hyperactivity = irritable, restless, disinhibition • Mood & apathy = anxiety, depressed, no appetite • Psychosis = delusions, hallucinations, anxiety

25. Agitation--antipsychotics • 2nd generation antipsychotics: • risperidone (Risperdal) • olanzapine (Zyprexa) • quetiapine (Seroquel) • aripiprazole (Abilify) • Note: no antipsychotics are approved for dementia • Haloperidol (1st generation antipsychotic) not recommended due to side effects (parkinsonism, rigidity etc) • Start low, go slow, keep dose as low as possible

26. Agitation--Antidepressants May improve aggression, insomnia, depression and psychosis • Start with SSRI (citalopram, sertraline) • Second line venlafaxine • Avoid TCA’s (amitriptyline) due to anticholinergic side effects (confusion, and worsening of Alzheimer’s disease) • Trazodone • Sedating side effect, good for insomnia • Also used to treat sundowning

27. antidepressants • START LOW, GO SLOW, BUT GO! • Reach adequate dose to relieve symptoms of depression • Trial for 6 weeks, longer to take effect in elderly with dementia • Early improvement indicators: improvement in sleep, appetite and energy, before an improvement in mood

28. Anxiety—Benzodiazepines (BZD) • BZD caution! Side effects: over sedation, ataxia, altered sleep, falls motor and cognitive impairment • Indicated for agitations, and anxiety especially when other agents fail • Use low doses of short acting agent without active metabolites (lorazepam, oxazepam, temazepam) • Start low, go slow • Not recommended in elderly—last resort • Anxiolytics—buspirone

29. hypnotics • Sedating antidepressant may be helpful(Trazodone) • Only use hypnotics when absolutely required. • Good alternative is zopiclonevs BZD

30. Other drugs • Mood stabilizers • Used in agitation, aggression, hostility, sleep wake disturbance, mania • Divalproex 125-750mg daily- fewer side effects • Carbamazepine 100-600mg daily • Betablocker—Propranolol 10-80mg/day • possible decrease in aggression

31. Pearls • Always rule out treatable cause • Consider 3 mon trial of cholinesterase inhibitor • Re-evaluate meds often (q3-6mons) • If delusions/hallucinations, only treat if a threat to self/others, or interfere w/ care • AVOID POLYPHARMACY– proven that the more pills, the worse they feel and behave • Stop all unnecessary medications • Focus on TLC!

32. EDS- Cholinesterase inhibitors • Diagnosis of probable Alzheimer’s as per DSM-IV • Mild to moderate stage of disease, with MMSE of 10-26/30, <60 days of application • FAQ <60 days of application • Must discontinue all drugs with anticholinergic activity, at least 14 days before MMSE and FAQ given. • No concurrent anticholinergic therapy. Patients intolerant to one agent may be switched to a different agent. • Current Patients: Require 6 months assessment to continue, must not have both a >2 point reduction in MMSE and a 1 point increase in FAQ. Scores are compared to previous scores. • New Patients: Enter 3 month trial and must exhibit improvement in MMSE and FAQ scoring. RE-evaluate in 6 months as above.

33. EDS continued: • MMSE must stay at or above 10 throughout treatment • The patient is monitored with these 2 scales (MMSE , FAQ) to ensure treatment is still effective. Once the patient is not responding to the medication (scores worsen with set guidelines, MMSE 2 point reduction, FAQ 1 point increase) coverage is stopped. The risk of treatment then outweighs the benefit and treatment is stopped.

34. References • Therapeutic Choices, 5th Edition • Alzheimer’s Society of Canada http://www.alzheimers.ca/english • RX Files • Rhett Carbno, College of Pharmacy Lecture Notes on Dementia. •  Robert J. Webb, MD. Medical Director, Hospice of the Shoals, and Palliative Care Service, ECM Hospital. Florence, AL. Drugs for Dementia Lecture. March 11-12th, 2011. • Dementia Guide http://www.dementiaguide.com/aboutdementia/typesofdementia/alzheimers

35. Questions?