Transcript KEEPING MEDICATIONS IN MIND: Potential Risks vs. Benefits Tonja M. Woods, PharmD, CGP

KEEPING MEDICATIONS
IN MIND:
Potential Risks vs. Benefits
Tonja M. Woods, PharmD, CGP
Wyoming Geriatric Education Center
March 26, 2013
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
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Adjustment disorder
Amnestic syndrome
Delirium
Depression/mental illness
Drugs & toxins
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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 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 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
• Features
• No cognitive decline
• Normal cognitive state
• Very mild cognitive
• Forgetfulness, subjective complaints
decline
only; no objective decline
• Mild cognitive decline
• Objective decline through psych testing;
• Moderate cognitive
work/social impairment; mild anxiety and
denial
• Concentration, complex skills decline; flat
affect and withdrawal
decline
Staging Alzheimer’s Disease
• Stage of Decline
• Features
• Moderately severe
• Early dementia; difficulty in interactions;
cognitive decline
unable to recall or recognize people or
places
• Severe cognitive
decline
• Very severe cognitive
decline
• 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
CONS
• 1 in 12 benefits
• 1 in 12 benefits
• Sets the ‘cognition clock’
• 1 in 12 experiences AE
back by ~6 months
• Patient feels empowered
• Family is encouraged /
feels “peace of mind”
• 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?