1. Alzheimer Disease Ibrahim Sales, Pharm.D. Assistant Professor of Clinical Pharmacy King Saud University isales@ksu.edu.sa

2. Overview The most common form of dementia Progressive memory loss and cognitive decline β-amyloid plaque accumulation, neurofibrillary tau tangles, and depletion of acetylcholine No pharmacologic agents can reverse the progression

3. Typical Characteristics Known – Elderly > 60 y/o – Blood relatives – Genetic mutations Suspected – Females – History of head trauma – CVD/risk factors

4. Mortality of AD 6 th leading cause of death in the US 5 th leading cause of death among 65+ Most patients > 65 survive 4-8 years after diagnosis 40% of time is spent in the most severe stage

5. Diagnosis Official diagnosis after death Health and behavioral changes (memory, language) Changes began years before effects on daily living become manifest

6. Stages of AD Preclinical – Measurable brain/CSF changes – No symptoms 20 years before symptoms Mild Cognitive Impairment – Measurable changes in thinking – No effect on everyday activities – 10-20% of those > 65 y/o Dementia – Memory, thinking, and behavioral changes – Impaired daily living

7. Symptoms 1.Memory loss that affects daily living 2.Challenges in planning or problem solving 3.Difficulty completing familiar tasks 4.Confusion with time or place 5.Difficulty with visual images or spatial relationships 6.Problem with words, speaking, writing 7.Misplacing items, inability to retrace steps 8.Decreased or poor judgment 9.Withdrawal from work or social activities 10.Changes in mood or personality

8. Progression of AD Mild AD – Change in sleep patterns – Behavioral changes – Forgetting life history or who you are – Difficulty speaking, talking in confusing sentences Severe AD – Can no longer: Speak Recognize friends or family Eat, dress, bathe, toilet – Swallowing difficulties

9. Medications Studies have usually assessed effectiveness using several scales: – Alzheimer’s Disease Assessment Scale for Cognition (ADAS-cog; 70-point scale) – Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL; 54-point scale) – Severe Impairment Battery (SIB; 100-point scale) Clinically significant improvement (noticeable improvement by the patient or caregiver) should be at least a 10% increase on the scale length

10. Acetylcholinesterase Inhibitors Reversibly bind and inactivate the enzyme which degrades acetylcholine (memory) First-line agents for mild to moderate Alzheimer disease – Donepezil is the only acetylcholinesterase inhibitor approved for use in all stages of the disease No notable differences in effectiveness – A Cochrane review of treatment for 6 months to 1 year resulted in an improvement in cognitive function by an average of -2.7 points on the ADAS-cog.

11. Acetylcholinesterase Inhibitors Most common adverse effects are nausea, vomiting, and diarrhea (dose related) Additional trials are needed – Determine the benefits of long-term therapy – Effectiveness in moderate to severe disease Discontinue treatment if no improvement within 6 to 8 weeks May restart if symptoms worsen after discontinuing

12. Donepezil DrugDosing Schedule Donepezil5mg at bedtime Donepezil ODT (5 or 10mg)10mg at bedtime (after 4-6 weeks at 5mg) Donepezil23mg at bedtime (after 3 months at 10mg) 5-10mg is used for mild-moderate AD 10-23mg is used from moderate-severe AD

13. Rivastigmine DrugDosing Schedule RivastigmineStart at 1.5mg BID, may increase to 3mg BID after 2 weeks, if tolerated Increase to 4.5mg BID and 6mg BID after 2 weeks on previous dose Rivastigmine Patch4.6mg/24 hours for at least 4 weeks Increase to 9.5mg/24 hours, may increase to 13.3mg/24 hours after a minimum of 4 weeks on previous dose Indicated for mild to moderate dementia of the Alzheimer’s type and dementia associated with Parkinson’s disease Patients on a total daily dose of <6 mg of oral rivastigmine can be switched to the 4.6 mg/24 hours patch Patients on a total daily dose of 6 mg to 12 mg of oral rivastigmine can be switched to the 9.5 mg/24 patch

14. Galantamine DrugDosing Schedule Galantamine4mg BID, increased to 8mg BID after a minimum of 4 weeks May increase to 12mg BID after a minimum of 4 weeks on the previous dose Administer with morning and evening meals Galantamine ERStart at 8mg/day, increase to 16mg/day after a minimum of 4 weeks May increase to 24mg/day after 4 weeks on the previous dose Administer once daily, in the AM, with food

15. Acetylcholinesterase Inhibitors Most common side effects – Nausea, vomiting, diarrhea – Anorexia, weight loss Precautions – Urinary – Pulmonary – Cardiovascular – Neurological – Gastrointestinal – Renal* – Hepatic* *Galantamine

16. Acetylcholinesterase Inhibitors 23 mg per day

17. Memantine N-methyl-D-aspartate receptor (NMDA) antagonist Overstimulation of NMDA receptors by glutamate is thought to contribute to AD symptoms Blocks NMDA receptors in the brain No evidence that it stops or slows neuron death in AD Approved for moderate to severe disease Cochrane review – 20mg daily over 6 months improved cognition (3 points on SIB); ability to do activities of daily living (1.3 points on the ADCS-ADL) in moderate to severe disease

18. Memantine DrugDosing Schedule MemantineStart at 5mg/day, increase at one week intervals to 5mg BID, 5mg & 10mg as separate doses, then 10mg BID May be taken with or without food Memantine XRStart at 7mg daily, increase at one week in 7mg intervals to a target of 28mg daily Target = 14mg daily with severe renal impairment

19. Memantine Common side effects – Headache, dizziness – Diarrhea, vomiting – Hypertension, hypotension, syncope – Seizures Precautions – Urinary Increased urinary pH (decrease elimination) – Severe hepatic impairment – Severe renal impairment CrCl = 5-29mL/min (5mg BID; 14mg for XR)

20. Memantine MedicationCommon dosagePharmacological actions Adverse effects and expected incidence (overall %) Memantine (Namenda) 10mg twice per dayLow to moderate affinity NMDA receptor antagonist that binds to NMDA receptor-operated cation channels; prevents glutamatergic overstimulation at NMDA receptor Adverse effects and dropout rates not statistically different from placebo Dizziness (5 to 7) Confusion (6) Headache (6) Diarrhea (2 to 5) Vomiting (2 to 3) Memantine Extended Release 28mg daily

21. Antipsychotics Not approved for treatment – Commonly used for behavioral symptoms Some atypical agents may reduce aggression and/or psychosis Drug interactions with Acetylcholinesterase Inhibitors: Increased effects; therefore use lower doses Galantamine and CYP2D6 Inhibitors: amitriptyline, fluoxetine, paroxetine – 40% increase in bioavailability – Citalopram, escitalopram are recommended

22. Key Recommendations for Practice Clinical RecommendationEvidence rating Acetylcholinesterase inhibitors are modestly effective in patients with mild to moderate Alzheimer’s; limited by adverse effects A Combination therapy with an acetylcholinesterase inhibitor and memantine should be considered in moderate to severe Alzheimer’s B Atypical antipsychotic agents can improve some behavioral manifestations, but are associated with increased mortality in older patients B NSAIDs, Vitamin E, testosterone, estrogen, statins, and insulin sensitizers are not recommended for the treatment of Alzheimer’s B Physicians should consider discontinuing treatment for Alzheimer’s in patients who continue to decline despite maximal therapy C A – Consistent, good-quality patient-oriented evidence; B – Inconsistent or limited- quality patient-oriented evidence; C – Consensus, disease-oriented evidence, usual practice, expert opinion, or case series.

23. Treatment Strategies