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 TestsCBC with sed rate Anemic anoxia, infection, neoplasm

Serum electrolytes Hyper/hyponatremia, renal function

BUN, SCr Renal function

Bilirubin Hepatic dysfunction

Thyroid function Hyper/hypothyroidism

Iron, B12, folate Deficiency states, anemia

Stool occult blood Blood loss, anemia

Syphilis serology Neurosyphilis

UA Infection, proteinuria

Chest x-ray Neoplasm, infection, airway disease

ECG Cardiac disease

Brain scan Cerebral tumors, cerebrovascular disease

Depression screen Depression, pseudodementia

Mental status exam General 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 PresentationCognitive 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 ScalesMini-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

• 1st 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• 120-240 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

• www.alz.org (general information)• www.alz.org/Care/overview.asp (for caregivers)

• American Health Assistance Foundation• www.ahaf.org/alzdis/about/adcare.htm

• Alzheimer’s Foundation of America• http://www.alzfdn.org/

• Mayo Clinic – AD information• http://www.mayoclinic.com/health/alzheimers/AZ99999

• Clinical Trials about Alzheimers• http://clinicaltrials.gov/ (Search: Alzheimers)

Questions?