KEEPING MEDICATIONS IN MIND: Tonja M. Woods, PharmD, CGP Wyoming Geriatric Education Center March 26, 2013 Potential Risks vs. Benefits

Introduction Dementia - General term for cognitive impairment Characterized by impairment of memory and at least one other cognitive domain Aphasia Difficulty remembering words → unable to speak, read, or write Apraxia Unable to do task when asked when willing Agnosia Unable to recognize things prior to there being significant ‘memory loss’ Executive function Loss of ability to plan, problem solve, memorize things

Dementia Alzheimer’s disease (AD) is the most common form Other major types: Vascular dementia Mixed Lewy body dementia Parkinson’s dementia Frontotemporal dementia Reversible dementias

Disorders Causing Dementia Symptoms CNS Disorders Adjustment disorder Amnestic syndrome Delirium Depression/mental illness Drugs & toxins Alcohol Antihypertensives Anxiolytics/sedatives CNS depressants Anticholinergics Hypoglycemics Heavy metals Intracranial causes Systemic Illness Cardiovascular disease Deficiency states Vitamin B12, folate Infection Metabolic disorders Hypothyroidism Hypoglycemia Tumors Subdural Hematoma

Mild Cognitive Impairment (MCI) Cognitive complaints insufficient to warrant a diagnosis of dementia Gateway between normal cognition, normal cognitive aging, and dementia Includes… cognitive complaint objectively impaired neuropsychological test performance, and… essentially intact ADLs Carries a 10-15% chance per year of progressing to AD diagnosis

Dementia Screening Tests CBC with sed rateAnemic anoxia, infection, neoplasm Serum electrolytesHyper/hyponatremia, renal function BUN, SCrRenal function BilirubinHepatic dysfunction Thyroid functionHyper/hypothyroidism Iron, B12, folateDeficiency states, anemia Stool occult bloodBlood loss, anemia Syphilis serologyNeurosyphilis UAInfection, proteinuria Chest x-rayNeoplasm, infection, airway disease ECGCardiac disease Brain scanCerebral tumors, cerebrovascular disease Depression screenDepression, pseudodementia Mental status examGeneral cognitive screen

Pathophysiology: Major Brain Changes “Amyloid cascade hypothesis” Deposition of amyloid-β peptide in the brain Neuritic plaques Patches found in the brain; amyloid protein within the center of plaque Neurofibrillary tangles Twisted pieces of protein called ‘tau’; disrupts normal cell function Neurotransmitter abnormalities ↓ Acetylcholine (ACh) synthesis ↑ Glutamate

Clinical Presentation Cognitive Changes Memory loss Aphasia Apraxia Agnosia Disorientation Impaired executive function Functional Changes Inability to care for self (ADLs) Non-cognitive Changes Depression, psychotic symptoms Behavioral disturbances Wandering Agitation/aggression Motor hyperactivity Uncooperativeness Combativeness Repetitive mannerisms and activities

Activities of Daily Living (ADLs) ADLs Bathing Dressing Transferring from bed or chair Walking Eating Toilet use Grooming Complex ADLs Telephone use Shopping Cleaning Using TV/Radio

Assessment Scales Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) Most common tools used Developed for rapid screening to identify cognitive dysfunction Can be performed during office visit Clinician’s Interview-Based Impression of Change (CIBIC) Clinician’s assessment of a patient based on a comprehensive interview (may involve caregiver) Global Deterioration Scale (GDS) Assesses cognitive functional decline in stages

Staging Alzheimer’s Disease Stage of Decline No cognitive decline Very mild cognitive decline Mild cognitive decline Moderate cognitive decline Features Normal cognitive state Forgetfulness, subjective complaints only; no objective decline Objective decline through psych testing; work/social impairment; mild anxiety and denial Concentration, complex skills decline; flat affect and withdrawal

Staging Alzheimer’s Disease Stage of Decline Moderately severe cognitive decline Severe cognitive decline Very severe cognitive decline Features Early dementia; difficulty in interactions; unable to recall or recognize people or places Requires assistance with bathing, toileting; behavioral symptoms present (agitation, delusions, aggressive behavior) Loss of psychomotor skills and verbal abilities; incontinence; total dependence

Goals of Therapy …No known cure Treat cognitive difficulties Maintain patient’s function as long as possible Minimize adverse effects of medications Treat behavioral and psychiatric complications appropriately Agitation Depression Reduce caregiver burden

Nonpharmacologic Therapy Consider vision, hearing, and other sensory impairments Keep requests, demands and tasks simple Avoid confrontation Redirect activities to divert patient from problematic situations Remain calm, firm, and supportive Keep environment consistent and safe Use lighting to reduce confusion at night

Nonpharmacologic Therapy Provide frequent reminders and cues Predictable routine Adjust expectations as patient declines Notify healthcare provider in event of changes Exercise as a treatment modality Been shown to improve physical health, depression, and quality of life in patients with AD Traditional interventions require communication abilities that may be compromised in the patient with AD Animal studies show decrease in amyloid plaques

Nonpharmacologic Therapy Mental stimulation A lot of evidence suggests that exercising the mind reduces the chances of developing AD and other forms of dementia related to old age Chess, cards, crossword puzzles, musical instruments, etc. Provide NEW mental challenges as well May be hard to implement in the elderly

Pharmacologic Therapy Ideally would have… Resolution of symptomatic effects Reverses symptoms by enhancing cognitive function Disease-modifying effects Halt neurodegenerative-relevant molecular processes Minimal adverse effects and drug-drug/drug- disease interactions

Pharmacologic Therapy Cholinesterase Inhibitors Donepezil - Aricept® Rivastigmine - Exelon® Galantamine - Razadyne® NMDA Receptor Antagonist Memantine - Namenda®

Pharmacologic Therapy Mild-moderate AD Donepezil - Aricept® Rivastigmine - Exelon® Galantamine - Razadyne® Moderate-severe AD Donepezil - Aricept® Memantine - Namenda®

Cholinesterase Inhibitors Mechanism Of Action (MOA): Blocks the breakdown of a chemical in the brain called acetylcholine ACh is involved in remembering things and thinking clearly 1 in 12 patients improve No way to predict beneficial time frame Most frequent adverse effects are mild to moderate gastrointestinal symptoms Nausea, Vomiting, Diarrhea Increase dose slowly

Donepezil - Aricept® Dose: 5 – 10 mg daily, 23mg daily MOA: blocks breakdown of acetylcholine, therefore, increasing levels of ACh in brain Adverse effects: N/V, diarrhea, anorexia, dizziness, weight loss Drug Interactions: Minimal 1 st line therapy Best tolerated *Approved for severe AD dementia

Rivastigmine - Exelon® Dose: Oral: 1.5 mg twice daily, ↑ to 3-6 mg twice daily Take with food Transdermal Patch: 4.6, 9.5, 13.3 mg/day MOA: inhibits acetyl- and butyrylcholinesterase Adverse Effects: N/V, anorexia, fatigue, dizziness Drug Interactions: Few No adjustments necessary for kidney or liver impairment Indicated for Parkinson’s dementia

Galantamine - Razadyne® Dose: 4 mg twice daily, ↑ to 12 mg twice daily (ER – once daily) Take with food MOA: selective, competitive, reversible ACh inhibitor, enhances action of acetylcholine on nicotinic receptors Adverse Effects: N/V, diarrhea, anorexia, weight loss DI: Few Caution in severe kidney & liver impairment Formerly named “Reminyl”

Cholinesterase Inhibitor Perles As dose ↑, acetylcholinesterase inhibition ↑ Increase dose in 4 week intervals as tolerated to minimize gastrointestinal adverse effects Switching between agents is not recommended unless patient is not tolerating initial agent Avoid interruptions, especially longer than 3 weeks 4-point improvement on ADAS-cog considered clinically significant change Considered a reversal of progression of disease symptoms by 6 months Change in MMSE has more clinical usefulness

Memantine - Namenda® Dose: 5 mg/day, ↑ weekly to 20 mg/day in 2 divided doses MOA: blocks a brain receptor that is thought to add to the cellular harm associated with AD (glutamate) ? neuroprotection Adverse Effects: similar to placebo GI complaints, confusion, dizziness, headache, hallucinations DI: Clearance ↓ by 80% when urinary pH >8; caution with carbonic anhydrase inhibitors, sodium bicarbonate “improves additional benefit on cognitive/behavioral symptoms” -

OTHER TREATMENT APPROACHES

Other Treatment Approaches Estrogen Not recommended due to possible cardiovascular risk Anti-inflammatory agents NSAIDs, prednisone – not recommended, adverse effect potential COX-2 inhibitors – not recommended Statins Lower prevalence associated with pravastatin and lovastatin Atorvastatin currently being studied Association with cognitive impairment as an adverse effect? Simvastatin and lovastatin Homotaurine Derived from red algae Proposed to decrease amyloid plaque in the brain Continued studies

Other Treatment Approaches Vitamin E Role in treatment only, not proven in prevention Do not use doses > 400 IU/day Gingko biloba mg/day of standard leaf extract twice daily may be used early on when decrease in cognitive function is noted 2 year study (published Sept 2012 – Lancet), NO decreased risk in progression Current practice guidelines do not recommend use in AD Huperzine A Alkaloid isolated from Chinese club moss Similar to gingko, issues arise with long-term use and standardization

Other Treatment Approaches Vitamin D Latest studies show that patients with AD had lower levels vs. those without AD “Neurosteroid” Treatment or Prevention? VITAL study (NIH) 5 years, 20,000 people Vitamin D & Omega fatty acids – do they affect various aspects of health, including cognition? Standardize testing?

Other Treatment Approaches Aspirin October 2012: observational study of 489 women (70-92 yo) showed those on ASA were less likely to show decline on MMSE Citicoline Supplement marketed to “help memory in patients with vascular mild cognitive impairment and may hinder cognitive deterioration” Originally developed in Japan for stroke Increases phosphatidylcholine in the brain

Axona™ High concentration of medium chain triglycerides Alternative source of fuel for the brain Marketed for mild to moderate AD No clinical testing $85/month 120cal & 12g sat fat/packet Coconut Oil Blend of short and medium chain TG Caprylic Acid Found in Axona

NEW TREATMENT POSSIBILITIES

New Treatment Possibilities Solanezumab Monoclonal Antibody Lab-produced molecule that mimics the antibodies in one’s body, designed to produce as if part of one’s normal cellular make-up and can help block amyloid formation Phase 3 trial data shows promise in slowing progression of cognitive decline but not functional decline Bexarotene - Targretin® Currently on the market for the treatment of skin cancer Effective in animal study at removing large amounts of amyloid from the brain Further investigation needed in humans ~$2500/month if approved

New Treatment Possibilities Angiotensin Receptor Blockers (ARBs) 890 patients, reduced amyloid deposition in the brain Improve cognitive function Study-design needs improvement

When to START therapy? Decision must be individualized – often a family decision Assess the following: Quality of Life Treatment Goals Potential Benefit Adverse Effect Potential

When to START therapy? PROS 1 in 12 benefits Sets the ‘cognition clock’ back by ~6 months Patient feels empowered Family is encouraged / feels “peace of mind” CONS 1 in 12 benefits 1 in 12 experiences AE Does not slow rate of disease progression Not proven to reduce need for nursing home placement Cost vs. Benefit

When to STOP therapy? Quality of life is poor Adverse effects are intolerable Gastrointestinal side effects Cardiac side effects Bradycardia If improvement is not observed within 3-6 months or with dose titration When slowing disease progression is no longer a goal i.e. Severe impairment, Rapid decline As disease progresses, nonpharmacologic interventions become more important

PHARMACOTHERAPY FOR NON-COGNITIVE SYMPTOMS Behavioral and psychological symptoms of dementia (BPSD)

BPSD Psychotic symptoms Psychosis Delusions Hallucinations Depression Disruptive behavior Agitation Aggression Hyperactivity Hypervocalization Disinhibition

Management of BPSD AChI and Namenda® have been shown to have small to modest benefit Small beneficial effect on caregiver burden and active time use among caregivers of patients with AD Nonpharmacologic modalities should be tried first before using other treatments

Management of BPSD Atypical Antipsychotics May be useful for particular neuropsychiatric symptoms, but no indication for management of behavioral symptoms in AD Seroquel, Risperdal, Zyprexa, Abilify, Saphris, Geodon, Fanapt, Invega, Latuda, Clozaril Adverse effects can be significant and common Somnolence, extrapyramidal symptoms, abnormal gait, worsening cognition, cerebrovascular events, and increased risk of death 2-fold higher mortality rate vs. placebo in elderly Cardiovascular causes Infectious causes

Management of BPSD Others Benzodiazepines Xanax, Ativan, Valium, Halcion Anticonvulsants Carbamazepine Valproic Acid Lamotrigine Buspirone Selegiline

Depression Occurs in about 50% of patients with AD, but could be more because of difficulty with diagnosis SSRIs most commonly recommended Prozac, Zoloft, Celexa, Lexapro, Paxil SNRIs an alternative Effexor, Pristiq, Cymbalta, Savella Avoid agents with anticholinergic activity

Other Considerations Approximately 60% of patients with AD have 3+ comorbidities Increased risk for poly-pharmacy and drug-drug interactions Prevent Medication Related Problems!!! Need for interdisciplinary care team! Patient-Centered Medical Home

Don’t Forget the Caregiver! Caregiver burden is a huge component of AD management 75% of care is provided by family and friends Greatest financial cost of AD is institutionalized care Understand the resources that are available for your patients…and their caregivers!

Resources Alzheimer’s Association (general information) (for caregivers) American Health Assistance Foundation Alzheimer’s Foundation of America Mayo Clinic – AD information Clinical Trials about Alzheimers (Search: Alzheimers)

Questions?