Polymedicine in the Elderly Tracy Gutman Geriatrician Objective: - - PDF document

9/18/2015 1

Polymedicine in the Elderly

Tracy Gutman Geriatrician

Objective: Explain basic principles of aging and pharmacology

• Explain pharmacodynamic changes
• Explain pharmacokinetic changes including

absorption, distribution, hepatic metabolism and renal clearance / excretion

Objective: Define polymedicine / polypharmacy

• Define polymedicine / polypharmacy and list

some of the problems with inappropriate medication use

• Discuss risks and benefits of polymedicine
• List risk factors for polymedicine
• Discuss problems associated with

polymedicine

9/18/2015 2

Objective: Review adverse drug effects in the elderly; highlight and understand problem drugs in the elderly and drugs to avoid / closely monitor

• List risk factors for adverse drug reactions
• Describe age related changes that increase susceptibility to adverse

drug effects in the elderly

• Define potentially inappropriate medications in the elderly using

Beers and STOPP lists

• List the side effects of anticholinergic medications
• Give examples of medications with anticholinergic properties
• Give examples of specific problem drugs in the elderly, their

negative side effects, and alternative options

• Define drug interactions and describe the impact of drug

interactions in elderly patients

• Explain geriatric syndromes that can be caused by drugs

Objective: Discuss best practices for prescribing in older adults

• Define and give examples of the polymedicine or

prescribing cascade to avoid

• Explain the utility of the BEERS list and STOPP and

START lists

• Discuss medication adherence problems in the

elderly and what can be done to improve adherence

• Explain best opportunities and practices for

assessing medication use and reviewing medications in elderly patients

Objective: Define and discuss deprescribing

• List some of the barriers to deprescribing and avoiding

polypharmacy

• Discuss overall principles of deprescribing and methods to

attempt this practice

• Prioritize questions to ask when deciding on deprescribing.
• Provide reasons to stop a medication or reduce the dose of

a medication

• List some medications commonly associated with

discontinuation syndromes requiring slow tapering

• Discuss a framework of determining drug utility
• Review principles for appropriate prescribing in end‐of‐life

patients

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Age‐related changes that increase susceptibility to adverse drug effects

Pharmacodynamic changes (what the drug does to the body); altered sensitivity to medications; what factors affect whether medication will have a greater or lesser affect with same serum concentrations Pharmacodynamic changes – physiologic and biochemical effects of drugs on the body

• Increased sensitivity to cardiovascular medications, anticoagulants,
• pioid analgesics, antipsychotics, benzodiazepines
• Altered concentration of neurotransmitters and receptors, altered

receptor binding properties and responsiveness == results in exaggerated drug effects

• functional reserves decline with age affecting cardiovascular,

musculoskeletal, and CNS – exaggerated drug effects

• impaired homeostatic mechanisms – more pronounced side effects;
• rthostatic hypotension with antihypertensives; lack of

compensatory responses – impaired reflex tachycardia, impaired regulation of temperatures and electrolytes

• side effects may develop over time because of these changes even

in patients on stable doses of medications; side effects may be mistaken for new diseases with new medications added to treat

Pharmacokinetic changes (what the body does to the drug): alterations in factors that affect drug concentration at the target receptor or organ

• Absorption – minimal clinical relevance (little change due to aging alone)

– generally if drug is swallowed, it will be absorbed but decreased active transport decreases bioavailability of some drugs [Calcium with achlorhydria]; reduced first pass metabolism (reduced liver mass and blood flow) increases bioavailability of some drugs [metoprolol, propranolol, nortriptyline, calcium channel blockers, and tricyclic antidepressants); can be affected by medications and conditions common in older people

• Distribution – significant clinical relevance but not readily predictable

1. increased fat mass increases volume distribution and half life of lipophilic medications; increased body fat prolongs half life of fat soluble drugs (diazepam, amitriptyline) 2. decreased total body water results in decreased volume of distribution and increased concentration of water‐soluble drugs [digoxin, ethanol, levodopa, morphine] 3. decreased fat‐free mass/plasma protein leads to higher percentage of unbound (active) drug

9/18/2015 4 Age‐related decreases in metabolism and clearance of drugs

Hepatic Metabolism

• Decreased first‐pass metabolism leads to

increased concentration of drugs that typically have high levels of first‐pass metabolism; i.e., hepatic clearance before reaching system circulation

• Hepatic disease or reduced hepatic volume and

blood flow results in reduced oxidative metabolism (reduced metabolism through CYP450) and higher steady‐state concentrations

• f some drugs [diazepam, metoprolol, phenytoin,

theophylline, alprazolam]

Excretion and Renal Clearance – significant impact

• Excretion – decreased cardiac output (e.g. heart failure) results in

less perfusion of kidneys and liver which reduces elimination [imipramine, morphine, propranolol]

• increased concentration of renally cleared drugs
• serum creatinine alone does not provide adequate information to

guide dosing

• use Cockcroft‐Gault to estimate glomerular filtration rate; more

conservative than other calculators, e.g. MDRD, less likely to

• verestimate eGFR especially in frail older patients; drug company

renal dose recommendations are based on CG

• reduced kidney function reduces elimination of renally excreted

drugs or metabolites [digoxin, cephalexin, morphine, meperidine, gabapentin, sotalol, Lisinopril, Ramipril, diuretics, metformin]

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Kidneys!

• Decrease in renal drug clearance corresponds to

decline in creatinine clearance

• May be difficult to distinguish age related

changes from disease related changes – diabetes, hypertension, CAD may also account for diminished kidney function in the elderly

• Even if a dosage is decreased appropriately based
• n age‐related pharmacokinetic changes,

physiologic changes and decreased homeostasis can cause greater sensitivity to drug interactions

Polymedicine or Polypharmacy

• Defined as taking 5 or more medications a day
• Use of more medications than are clinically indicated
• Use of unnecessary medications
• Use of inappropriate medications that have greater potential risk for

harm than benefit, are less effective or more costly than available alternatives, or do not agree with accepted medical standards

• Can be considered an age‐related geriatric syndrome and is a predictor of

malnutrition, hospitalization, nursing home placement

• Can be conceptually perceived as a disease with possibly more serious

consequences than the diseases the different drugs are prescribed for

• Leads to increase in mobility impairment, risk of falls, adverse drug events,

and to morbidity and death

Polymedicine or Polypharmacy

Limitations to this terminology:

• I use polymedicine: Homage to the clinical pharmacist I

worked with running a polymedicine clinic

• Problems with the word Polypharmacy:

‐‐‐‐Poly – many; many pharmacies ‐‐‐‐Connotation of negative, inappropriate use of medications; unnecessary; medication does not meet diagnosis ‐‐‐Vague – e.g. excessive medication use could mean: frequency, dosage, unintentional overuse, intentional misuse

• r abuse, use of drug when non drug therapy is more

appropriate ‐‐‐Does not include qualitative differences between different drug classes and inappropriate drug use

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Polymedicine – critical, systematic, thoughtful review of medications can sometimes involve need for multiple medications

‐‐Medication reviews and appropriate prescribing involve prescribing appropriate combinations sometimes of multiple medications – e.g., polymedicine can be appropriate (START guidelines) ‐‐Elderly have many chronic conditions that increase with age – stroke, cardiovascular diseases, musculoskeletal disorders and dementia: more medications needed ‐‐Don’t forget the guidelines (even though they don’t always apply and are problematic – see next slide): guidelines for secondary prevention and targeting goals for blood pressure, diabetes, lipids, osteoporosis: more medications ‐‐Polymedicine – multiple medications that are appropriate / clinically indicated

Difficulties in prescribing for older adults: Lack of Evidence

• Lack of data to guide use of medications in older adults

because they are rarely included in RCTs

• Elderly are underrepresented in drug trials even though

they are the greatest users of medications

• Most evidence based clinical guidelines are extrapolated

from younger populations

• Even when older adults are included, healthy elderly

subjects do not represent frail older patients typically using these medications

• Guidelines do not always make sense for frail elders and

very old; following guidelines in these patients adds medications without considering life expectancy, goals of care, time to potential benefit

Polymedicine

• More than 50% of female Medicare beneficiaries

took 5 or more medications daily

• 20‐65% of older adults take potentially

inappropriate medications

(Wallace J, & Paauw DS. (2015). Appropriate prescribing and important drug interactions in older adults. Medical Clinics of North America, 99(2), 295‐310.)

• More than 50% of older adults in institutions and

27% of older adults in the community are taking more than five prescribed medications daily; proportion increases with age

(Frank, C. (2014). Deprescribing: A new word to guide medication review. CMAJ Canadian Medical Association Journal, 186(6), 407‐408.)

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• One national survey of US nursing home

resident – 40% received 9 or more medications

Ravona‐Springer R, & Davidson M. (2014). Considerations in psychotropic treatments in dementia – can polypharmacy be avoided? International Journal of Neuropsychopharmacology, 17(7), 1107‐1117.

• The US Center for Medicare and Medicaid

Services estimates that polymedicine costs more than $50 billion dollars annually

Bushardt, R, Massey, EB, Simpson, TW, Ariail, JC, & Simpson, KN. (2008). Polypharmacy: Misleading, but manageable. Clinical Interventions in Aging. 3(2), 383‐389.

In the US

• 60% of older patients receive 5 or more drugs
• 20% receive 10 or more drugs
• About 1 in 3 older patients living in the community and

taking at least 5 drugs will experience an adverse drug reaction

• Up to 20% of older patients living in the community

receive at least 1 inappropriate medication as do 1/3 of hospitalized patients and as many as 50% of those living in residential care facilities

Scott, IA, Gray, LC, Martin, JH, & Mitchel, CA. (2012). Minimizing Inappropriate Medications in Older Populations: A 10‐step Conceptual Framework. The American Journal of Medicine. 125, 529‐537.

Risk factors for polymedicine

• 1. Demographic: advancing age, female gender,

low education level

• 2. Health status markers: recent hospitalization,

multiple comorbidities, depression; involvement

• f multiple prescribers; greater health care

utilization; difficulties with IADLs; frailty

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Why is this a problem?

• Evidence indicates that using more medications is

associated with increased medication side effects and adverse health events

• Polymedicine is associated with increased risk of

adverse drug reactions and interactions, inappropriate prescribing, inappropriate drug use, nonadherence, impaired balance and falls, hospitalization, increased risk of cognitive impairment, institutionalization, mortality

Problems associated with Polymedicine

• adverse drug reactions
• drug‐drug interactions
• drug‐disease interactions
• higher risk of using potentially inappropriate medications
• decreased adherence
• increased risk of medication errors
• increased cost
• increased morbidity and mortality
• Risk factor for dementia; risk of dementia increases with

number of drugs used

• Elderly people can develop cognitive and functional

impairment as a result of their medications

Drug Interactions / Adverse Drug Reactions

• increased vulnerability to drug interactions

due to underlying comorbid conditions

• Use of multiple medications increases the risk
• f adverse drug reactions: 13% among

patients taking five medications v. 6% among those taking one or two

(Frank, C. (2014). Deprescribing: A new word to guide medication review. CMAJ Canadian Medical Association Journal, 186(6), 407‐408.)

9/18/2015 9 Those at highest risk of adverse drug reactions:

• patients prescribed 8 or more medications
• previous adverse drug reaction
• 4 or more medical co‐morbidities
• liver disease
• heart failure
• renal disease
• receiving high risk drugs: anticoagulants, insulin or oral

hypoglycemic drugs, psychotropic medications, sedatives / hypnotics, cardiovascular drugs (digoxin, nitrates, vasodilators), NSAIDs

• cognitive impairment
• living alone
• history of nonadherence
• known psychological disorders or substance abuse

Drug Interaction

• A clinically meaningful alteration in the effect
• f one drug as a result of coadministration of

another drug; interactions can be beneficial but may also increase effects of a drug causing toxicity or inhibit the effects of a drug leading to diminished benefit

Examples of Drug Interactions / Effects in the Elderly

• Warfarin interactions: many elderly take warfarin to

reduce stroke risk from atrial fibrillation or to decrease risk of recurrent thromboembolic disease or thrombotic risk due to mechanical heart valves

• Proton Pump Inhibitors – increased risk of MI?, reduce

absorption of medications and supplements including thyroid hormone, calcium, magnesium; increased fracture risk in PPI users; reduce vitamin B12 absorption; increased risk of B12 deficiency; associated with diarrhea (C diff) and pneumonia

9/18/2015 10 Examples of drug side effects in elderly

• SSRIs – more likely to develop hyponatremia;

SNRIs as well; increased risk of GI bleed

• quinolones – CNS side effects (anxiety,

restlessness, insomnia, hallucinations, psychosis, seizures); higher risk for tendonitis and tendon rupture; implicated as a cause of peripheral neuropathy

• Bactrim – at risk for the development of

hyperkalemia especially if taking Ace inhibitor or ARB and with renal insufficiency

Be careful even with common drugs

• Elderly patients who take ace inhibitors are 20

fold more likely to be hospitalized for hyperkalemia if they receive a potassium sparing diuretic in the prior week

• Elderly patients who take an ace inhibitor or

ARB are nearly 7 fold more likely to be hospitalized with hyperkalemia if they have recently received SMX/TMP

Geriatric syndromes that can be caused by drugs

• 1. Falls: sedatives, hypnotics, anticholinergics,

antihypertensives, antidepressants, antidiabetics

• 2. Cognitive impairment: anticholinergics,

benzodiazepines, antihistamines, tricyclic antidepressants

• 3. Incontinence: alpha‐blockers, sedatives (benzos),

diuretics

• 4. Constipation: anticholinergics, opioids, tricyclic

antidepressants, calcium channel blockers, calcium supplements

• 5. Delirium: antidepressants, antipsychotics, antiepileptics
• 6. Diarrhea: antibiotics, proton pump inhibitors,

allopurinol, SSRIs, ARBs, anxiolytics, antipsychotics

• 7. GI bleeding: NSAIDs, oral anticoagulants

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Medication Adherence Issues

• high number of drugs and regimen complexity – limit number of

medications; try to simplify regimen to daily dosing when possible

• inadequate patient understanding – include drug indication on

prescription; explain rationale for every new drug started and anticipated duration of therapy

• prescription not congruent to patient goals, cost barriers – what are

patient goals

• memory problems, poor organization – medication organizers,

medisets, blister packs, electronic dispensing devices, cues / calling, monitoring, drug administration

• difficulty taking (vision or dexterity problems or dysphagia) – order

easy to remove bottle caps, larger font labeling, magnifying glass, spacer for inhalers or nebs; consider smaller tablets, solutabs, liquid versions

What do we do about it?

• Carefully evaluate risk benefit of each

medication given lack of guidelines / evidence based medicine that includes frail, older adults

• Medication regimens should fit patient

preferences and goals of care

• Reduce the number of inappropriate drugs

prescribed

What do we do about it? Think carefully

• Given the large risks of adverse drug reactions

in the elderly, think about the drugs you are prescribing

• The drugs should be absolutely necessary to

achieve well defined goals and given at the lowest effective doses

• Discontinue drugs that do not achieve desired

end points and that are no longer needed

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Problem Drugs

• Two‐thirds of adverse drug effects that result in

ER visits and hospitalizations for older adults are due to 4 medications: warfarin and antiplatelet medications (bleeding); insulin and sulfonylurea agents (hypoglycemia)

• Consider stopping aspirin in patients with stable

coronary artery disease on warfarin; continuing both aspirin and warfarin doubles the risk of bleeding without conferring additional cardioprotection

Problem Drugs

• Muscle relaxants (e.g., cyclobenzaprine,

methocarbamol) – sedation, anticholinergic, increased fall and fracture risk, uncertain efficacy

• Iron more than once daily – increased GI side effects

(nausea, constipation), usually outweigh small marginal gains in iron absorbed when daily dose increased to twice a day

• Chronic daily NSAIDs – GI bleed, renal insufficiency,

fluid retention, blood pressure elevation; short term use may be appropriate

Problem Drugs

• First generation antihistamines (e.g. Benadryl) –

sedating, anticholinergic effects: confusion, dry mouth, dry eyes, constipation, urinary retention

• Glyburide – higher risk of hypoglycemia

(including episodes requiring hospitalizations and causing death)

• Benzodiazepines – confusion, memory loss,

dizziness, daytime sleepiness, falls and fractures, depressed mood, functional impairment, dependency / withdrawal

9/18/2015 13 Problem Drugs: Anticholinergic Meds

• increased blood‐brain barrier permeability

and age related declines in cholinergic transmission are contributing factors

• Patients with dementia are more susceptible

to the effects of anticholinergic medications and are more likely to receive them

Problem Drugs: Anticholinergic Meds

• Falls
• Sedation
• Confusion, delirium
• Urinary Retention
• Constipation
• Dry mouth
• Glaucoma, dry eyes, blurred vision
• Memory impairment / cognitive dysfunction
• Dizziness
• Impulsive behavior
• Loss of independence

Medications with Definite Anticholinergic Effects

• Amantadine
• Amitriptyline
• Amoxapine
• Atropine
• Benztropine
• Brompheniramine
• Carbamazepine
• Chlorpheniramine
• Chlorpromazine
• Clozapine
• Cyclobenzaprine
• Desipramine
• Dicyclomine
• Diphenhydramine
• Doxepin
• Hydroxyzine
• Hyoscyamine
• Imipramine
• Meclizine
• Meperidine
• Methocarbamol
• Nortriptyline
• Olanzapine
• Oxcarbazepine
• Oxybutynin
• Paroxetine
• Perphenazine
• Promethazine
• Quetiapine
• Scopolamine
• Thioridazine
• Tolterodine
• Trifluoperazine

9/18/2015 14

Anticholinergic, don’t forget

Second generation antihistamines such as cetirizine and loratidine; H2 blockers like ranitidine; avoid if possible but better than first generation

Examples of problem drugs and their alternatives

Antihistamines: First Generation: Side effects

First Generations Antihistamines

• Brompheniramine
• Carbinoxamine
• Chlorpheniramine
• Clemastine
• Diphenydramine
• Dimenhydrinate
• Hydroxyzine

Alternatives: Allergies or Itching – Use Loratidine or Cetrizine Insomnia

• Sleep hygiene
• Melatonin
• Mirtazapine
• Trazodone

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Antidepressants

• Amitriptyline
• Amoxapine
• Clomipramine
• Desipramine
• Doxepin
• Imipramine
• Nortriptyline
• Paroxetine
• Trimipramine
• SSRIs: sertraline,

citalopram (max 20 mg), lexapro

• SNRIs: venlafaxine,

duloxetine

• Other: mirtazapine,

bupropion

Pain

NO NSAIDS!!!!!!!!!!!!!

• Kidney damage
• GI bleeding
• Hypertension
• Edema
• MI

Avoid anticholinergic muscle relaxants:

• Cyclobenzaprine
• Methocarbamol

First Line: Acetaminophen scheduled ‐‐Neuropathic pain – gabapentin; pregabalin ‐‐Consider duloxetine (watch renal function and don’t use with liver issues) ‐‐Topicals ‐‐Physical therapy ‐‐Alternatives: chiropractic, acupuncture, Tai Chi

Problem Drugs for Older Adults

AGS BEERS CRITERIA

FOR POTENTIALLY INAPPROPRIATE MEDICATION USE IN OLDER ADULTS http://www.americangeriatrics.org/files/docum ents/beers/PrintableBeersPocketCard.pdf

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Dealing with Problem Drugs: Reducing Polypharmacy and Appropriately Prescribing

• STOPP: prevent overprescribing
• START: prevent underprescribing –to avoid not

giving an elderly patient a medication that is clearly indicated

STOPP and START criteria – for detecting potentially inappropriate prescribing in old age; 2003 STOPP –screening tool of

• lder persons (potentially

inappropriate) prescriptions = potential errors of prescribing commission START – screening tool to alert to right treatment = potential error of prescribing omission

STOPP –screening tool of older persons (potentially inappropriate) prescriptions = potential errors of prescribing commission

https://www.ascp.com/articles/potentially‐inappropriate‐medications‐elderly

• A. Cardiovascular System
• 1. Digoxin at a long‐term dose > 125µg/day with impaired renal function (increased risk of toxicity).
• 2. Loop diuretic for dependent ankle oedema only i.e. no clinical signs of heart failure (no evidence of efficacy, compression

hosiery usually more appropriate).

• 3. Loop diuretic as first‐line monotherapy for hypertension (safer, more effective alternatives available).
• 4. Thiazide diuretic with a history of gout (may exacerbate gout).
• 5. Non‐cardioselective beta‐blocker with Chronic Obstructive Pulmonary Disease (COPD) (risk of bronchospasm).
• 6. Beta‐blocker in combination with verapamil (risk of symptomatic heart block).
• 7. Use of diltiazem or verapamil with NYHA Class III or IV heart failure (may worsen heart failure).
• 8. Calcium channel blockers with chronic constipation (may exacerbate constipation).
• 9. Use of aspirin and warfarin in combination without histamine H2 receptor antagonist (except cimetidine because of

interaction with warfarin) or proton pump inhibitor (high risk of gastrointestinal bleeding).

• 10. Dipyridamole as monotherapy for cardiovascular secondary prevention (no evidence for efficacy).
• 11. Aspirin with a past history of peptic ulcer disease without histamine H2 receptor antagonist or Proton Pump Inhibitor

(risk of bleeding).

• 12. Aspirin at dose > 150mg day (increased bleeding risk, no evidence for increased efficacy).
• 13. Aspirin with no history of coronary, cerebral or peripheral vascular symptoms or occlusive arterial event (not indicated).
• 14. Aspirin to treat dizziness not clearly attributable to cerebrovascular disease (not indicated).
• 15. Warfarin for first, uncomplicated deep venous thrombosis for longer than 6 months duration (no proven added benefit).
• 16. Warfarin for first uncomplicated pulmonary embolus for longer than 12 months duration (no proven benefit).
• 17. Aspirin, clopidogrel, dipyridamole or warfarin with concurrent bleeding disorder (high risk of bleeding).

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• B. Central Nervous System and Psychotropic Drugs.
• 1. Tricyclic antidepressants (TCA’s) with dementia (risk of worsening cognitive impairment).
• 2. TCA’s with glaucoma (likely to exacerbate glaucoma).
• 3. TCA’s with cardiac conductive abnormalities (pro‐arrhythmic effects).
• 4. TCA’s with constipation (likely to worsen constipation).
• 5. TCA’s with an opiate or calcium channel blocker (risk of severe constipation).
• 6. TCA’s with prostatism or prior history of urinary retention (risk of urinary retention).
• 7. Long‐term (i.e. > 1 month), long‐acting benzodiazepines e.g. chlordiazepoxide, fluazepam, nitrazepam, chlorazepate and

benzodiazepines with long‐acting metabolites e.g. diazepam (risk of prolonged sedation, confusion, impaired balance, falls).

• 8. Long‐term (i.e. > 1 month) neuroleptics as long‐term hypnotics (risk of confusion, hypotension, extra‐pyramidal side

effects, falls).

• 9. Long‐term neuroleptics ( > 1 month) in those with parkinsonism (likely to worsen extra‐pyramidal symptoms)
• 10. Phenothiazines in patients with epilepsy (may lower seizure threshold).
• 11. Anticholinergics to treat extra‐pyramidal side‐effects of neuroleptic medications (risk of anticholinergic toxicity).
• 12. Selective serotonin re‐uptake inhibitors (SSRI’s) with a history of clinically significant hyponatraemia (non‐iatrogenic

hyponatraemia <130mmol/l within the previous 2 months).

• 13. Prolonged use (> 1 week) of first generation antihistamines i.e. diphenydramine, chlorpheniramine, cyclizine,

promethazine (risk of sedation and anti‐cholinergic side effects).

• C. Gastrointestinal System
• 1. Diphenoxylate, loperamide or codeine phosphate for treatment of diarrhoea of unknown cause (risk of delayed diagnosis,

may exacerbate constipation with overflow diarrhoea, may precipitate toxic megacolon in inflammatory bowel disease, may delay recovery in unrecognised gastroenteritis).

• 2. Diphenoxylate, loperamide or codeine phosphate for treatment of severe infective gastroenteritis i.e. bloody diarrhoea,

high fever or severe systemic toxicity (risk of exacerbation or protraction of infection)

• 3. Prochlorperazine (Stemetil) or metoclopramide with Parkinsonism (risk of exacerbating Parkinsonism).
• 4. PPI for peptic ulcer disease at full therapeutic dosage for > 8 weeks (earlier discontinuation or dose reduction for

maintenance/prophylactic treatment of peptic ulcer disease, oesophagitis or GORD indicated).

• 5. Anticholinergic antispasmodic drugs with chronic constipation (risk of exacerbation of constipation).
• D. Respiratory System.
• 1. Theophylline as monotherapy for COPD. (safer, more effective alternative; risk of adverse effects due to narrow

therapeutic index)

• 2. Systemic corticosteroids instead of inhaled corticosteroids for maintenance therapy in moderate‐severe COPD

(unnecessary exposure to long‐term side‐effects of systemic steroids).

• 3. Nebulised ipratropium with glaucoma (may exacerbate glaucoma).
• E. Musculoskeletal System
• 1. Non‐steroidal anti‐inflammatory drug (NSAID) with history of peptic ulcer disease or gastrointestinal bleeding,

unless with concurrent histamine H2 receptor antagonist, PPI or misoprostol (risk of peptic ulcer relapse).

• 2. NSAID with moderate‐severe hypertension (moderate: 160/100mmHg – 179/109mmHg; severe:

≥180/110mmHg) (risk of exacerbation of hypertension).

• 3. NSAID with heart failure (risk of exacerbation of heart failure).
• 4. Long‐term use of NSAID (>3 months) for relief of mild joint pain in osteoarthtitis (simple analgesics preferable

and usually as effective for pain relief)

• 5. Warfarin and NSAID together (risk of gastrointestinal bleeding).
• 6. NSAID with chronic renal failure (risk of deterioration in renal function).
• 7. Long‐term corticosteroids (>3 months) as monotherapy for rheumatoid arthrtitis or osteoarthritis (risk of major

systemic corticosteroid side‐effects).

• 8. Long‐term NSAID or colchicine for chronic treatment of gout where there is no contraindication to allopurinol

(allopurinol first choice prophylactic drug in gout)

• F. Urogenital System
• 1. Bladder antimuscarinic drugs with dementia (risk of increased confusion, agitation).
• 2. Bladder antimuscarinic drugs with chronic glaucoma (risk of acute exacerbation of glaucoma).
• 3. Bladder antimuscarinic drugs with chronic constipation (risk of exacerbation of constipation).
• 4. Bladder antimuscarinic drugs with chronic prostatism (risk of urinary retention).
• 5. Alpha‐blockers in males with frequent incontinence i.e. one or more episodes of incontinence daily (risk of

urinary frequency and worsening of incontinence).

• 6. Alpha‐blockers with long‐term urinary catheter in situ i.e. more than 2 months (drug not indicated).
• G. Endocrine System
• 1. Glibenclamide or chlorpropamide with type 2 diabetes mellitus (risk of prolonged hypoglycaemia).
• 2. Beta‐blockers in those with diabetes mellitus and frequent hypoglycaemic episodes i.e.  1 episode per month

(risk of masking hypoglycaemic symptoms).

• 3. Oestrogens with a history of breast cancer or venous thromboembolism (increased risk of recurrence)
• 4. Oestrogens without progestogen in patients with intact uterus (risk of endometrial cancer)
• .
• H. Drugs that adversely affect those prone to falls (≥ 1 fall in past three months)
• 1. Benzodiazepines (sedative, may cause reduced sensorium, impair balance).
• 2. Neuroleptic drugs (may cause gait dyspraxia, Parkinsonism).
• 3. First generation antihistamines (sedative, may impair sensorium).
• 4. Vasodilator drugs known to cause hypotension in those with persistent postural hypotension i.e. recurrent >

20mmHg drop in systolic blood pressure (risk of syncope, falls).

• 5. Long‐term opiates in those with recurrent falls (risk of drowsiness, postural hypotension, vertigo).
• I. Analgesic Drugs
• 1. Use of long‐term powerful opiates e.g. morphine or fentanyl as first line therapy for mild‐moderate pain (WHO

analgesic ladder not observed).

• 2. Regular opiates for more than 2 weeks in those with chronic constipation without concurrent use of laxatives

(risk of severe constipation).

• 3. Long‐term opiates in those with dementia unless indicted for palliative care or management of

moderate/severe chronic pain syndrome (risk of exacerbation of cognitive impairment).

• J. Duplicate Drug Classes
• Any duplicate drug class prescription e.g. two concurrent opiates, NSAID’s, SSRI’s, loop diuretics, ACE inhibitors

(optimisation of monotherapy within a single drug class should be observed prior to considering a new class of drug). Excluding duplicate prescribing of inhaled beta2 agonists (long and short acting) for asthma or COPD

9/18/2015 18

Examples:

• Loop diuretic for edema
• Loop diuretic as first line therapy for

hypertension

• Aspirin greater than 150 mg per day: increased

bleeding risk, no increased efficacy

• TCAs
• Long term benzodiazepines
• Prolonged use of first generation antihistamines
• Long term NSAID use

START – screening tool to alert to right treatment = potential error of prescribing omission

• Warfarin for atrial fibrillation
• Aspirin for ASCVD
• Statin for ASCVD where the patient’s functional

status remains independent for ADLs and life expectancy is greater than 5 years

• Ace inhibitor for CHF and after MI
• Calcium and vitamin D for osteoporosis
• Metformin

Polymedicine Cascade

• Consider any new symptom as a possible

drug side‐effect; any new symptoms in an elderly patient should be considered a drug effect unless proven otherwise; treating a new symptom that may be drug related with another medication can lead to polymedicine where patient is taking excessive and unnecessary medications

9/18/2015 19

Avoid the Prescribing Cascade

• An adverse effect of one drug is misinterpreted as a

new medical condition that leads to prescription of another drug, a new medication is added to manage side effects of current medications

• It is easy to overlook medication adverse side effects

when patients are having so many symptoms that could be attributed to their complex chronic diseases

• Before starting a medication, ask, is this medication

possibly being prescribed to treat the side effects of an existing medication

• Thorough history; timing of new symptoms in

relation to medication starts or changes

Prescribing cascades – treating side effects

• f medications with other medications
• E.g. Furosemide  urinary frequency 
• xybutynin
• Ibuprofen  hypertension 

antihypertensive

• Metoclopramide  parkinsonism 

levodopa/carbidopa

• Risperidone  parkinsonism  benztropine
• Amlodipine  edema  furosemide
• Gabapentin  edema  furosemide
• Ciprofloxacin  delirium  antipsychotic
• Lithium  tremor  propranolol
• Bupropion  insomnia  mirtazapine
• Donepezil  urinary incontinence  oxybutynin
• Meperidine  delirium  antipsychotic
• Beta blocker  depression  antidepressant
• Amitriptyline  decreased cognition  donepezil
• NSAID  heartburn  H2 blocker or PPI; increased salt retention and

renal effects – increased blood pressure – blood pressure medication

• Omeprazole  low B12  B12 replacement
• Sudafed  urinary retention  alpha blocker
• Antipsychotic  akathisia, activation, agitation  more psychoactive

medications

9/18/2015 20

Prescribing for the older adult

• Consider nonpharmacologic approaches – try to avoid

unnecessary drugs

• Consider the risk versus the benefit before prescribing any

drug

• Set specific goals and timelines for assessing drug therapy
• utcomes
• Discontinue unnecessary or ineffective therapy
• Think carefully about medications that carry a substantially

higher risk of adverse effects; Use safer alternatives instead

• f high risk drugs
• When initiating new agents, start with lower doses, titrate

slowly, increase as indicated

• Include pharmacists on the interdisciplinary team

Prescribing for the older adult

Match each medical condition with medications being taken to identify

• overuse (no indication or medications with no clear

evidence‐based indications) – Stop

• underuse (clear indication but no suitable drug being
• ffered)
• misuse (administration of a different drug may be more

effective with less side effects) Currently prescribed medications could be discontinued if

• riginal diagnosis / condition does not still exist or the

medications are having little or no therapeutic effect

Prescribing for the older adult

Where life expectancy is less than 12 months, medications that usually take longer than this to have benefit may be inappropriate

• bisphosphonate therapy to prevent
• steoporotic fractures or statins to prevent

cardiovascular events Identify and try to discontinue medications that are of little or no benefit or potentially harmful

9/18/2015 21

Prescribing for the Older Adult

• Be less aggressive in reaching rigid target goals

(blood sugar, blood pressure, lipids)

• Focus on quality of life and patient / family

preferences

• Start slow and go slow but go
• Stop most and reduce dose
• Sometimes a problem drug (potentially

inappropriate medication) is appropriate if benefit outweighs risk to patient

Look at the big picture

• Many older adults experience increasing numbers
• f incurable comorbidities, disability, and

suffering for increasingly prolonged periods before death

• The model of one disease – one therapy /

guideline does not work for these patients

• Almost half of people older than 65 years have 3

chronic conditions, with 21% having 5 or more

• Single disease approach leads to polypharmacy

Garfinkel, D & Mangin, D. (2010). Less Is More. Feasibility Study of a Systematic Approach for Discontinuation of Multiple Medications in Older Adults. Addressing

• Polypharmacy. Archives of Internal Medicine, 170(18), 1648‐1654.

Medication Review

• brown bag review – both prescription and
• ver the counter medications
• contacting pharmacies; utilizing home health

nurses

• medication review appointments – consider

each medication and whether it is effective, tolerated and appropriate for the patient

9/18/2015 22

Medication Review

• Any patient interaction can be an opportunity

for critical medication review

• Transitions of care between care settings
• Changes in overall health of patient that affect

life expectancy, diagnosis of terminal condition or progression of dementia or clinical frailty; eliminate medications that are unlikely to provide meaningful benefit to the patient in their remaining time

What are your goals of care?

• Disease centered approach – often leads to

polymedicine

• Consider patient’s current condition and longer

term goals of care; consider prognosis, time to benefit, potential adverse effects – more important with advancing age

• Multiple medications may be needed – improve

function, control symptoms, limit disease progression, extend life

• Assess function, health, goals of care – ongoing

review of medications is needed

Questions to Ask:

• Is the drug clearly indicated and effective?
• What are the therapeutic end points?
• What are the potential benefits – what is the

clinical indication, what is the appropriateness of the medication; what do the guidelines say?

• What are the potential harms – adverse drug

reactions / adverse events

• Do the benefits outweigh the risks?
• Is the drug being used to treat side effects of

another drug?

9/18/2015 23

Questions to Ask

• Could it interact with underlying diseases or other

drugs in the regimen?

• Consider adherence and cost; Drug utilization –

duration of use? Adherence? If poor, then stop if patient remains stable off

• Does the patient / caregiver know indication for drug,

how to take it, and adverse effects?

• What are possible ADWEs – adverse drug withdrawal

events – clinically significant symptoms / signs caused by stopping a medication; cardiovascular and central nervous system drug classes are most common medications associated with ADWEs

Discontinuing Medications

• But be aware of recurrent or new symptoms; educate patients to

report

• 74% of medication discontinuations are well tolerated; reducing

medications has been shown to decrease hospitalization and mortality rates ; no significant adverse events of deaths have been attributed to discontinuation

• Studies have shown that discontinuing medications can be done

safely with no significant adverse events and there are reports of subjective clinical, functional, mood, and cognitive improvement

• 88% of patients reported global improvement in health
• Slow tapers; e.g. beta blockers, SSRIs, opioids, benzodiazepines
• Communicate medication discontinuation to the pharmacy; it is not

uncommon for patients to refill and take medications that have been discontinued

• Discontinuing anticholinergics and

benzodiazepines has been shown to decrease risk

• f cognitive decline
• Stopping some medications in older patients does

not necessarily worsen clinical outcomes, is not usually associated with withdrawal syndromes, and can improve some outcomes including falls, behavioral issues, and cognitive status

• Consider stopping unnecessary medications and

medications that cause side effects

9/18/2015 24 Consider trying to reduce pill burden

• Reduce pill burden – pill burden is the total

number of pills or doses a patient must swallow during the day

• complex regimens and poor timing or

unnecessary separation of multiple medications can lead to error in medication administration and affect quality of life

• Consider using combination products or

switching from multiple times daily to once daily formulations

Deprescribing : active review process; determine risks and benefits and stop meds

Deprescribing

• positive, patient‐centered, inherently

ambiguous

• requires shared decision making; informed

consent

• close monitoring of effects
• address the cumulative risk from multiple

drugs

• benefits: reduction in falls and improvement

in cognitive and psychomotor function

9/18/2015 25

How to Deprescribe

• Prioritization – reconsider which medications are really

needed; consider adverse drug reactions, patient nonadherence, no clear indication, lack of benefit, use

• f medication to treat adverse reaction to another

medication that can be changed, severity of condition being treated, risk of withdrawal symptoms

• Discontinuation – medications that can be stopped; get

rid of duplicative drugs; consider changing drugs to prn if not really needed routinely (e.g. prn pain meds for arthritis, prn PPI for GERD, prn allergy meds)

Alexander GC, Sayla, MA, Holmes, HM, & Sachs, GA. (2006). Prioritizing and stopping prescription

• medicines. CMAJ Canadian Medical Association Journal, 174(8), 1083‐1084.
• Goals of care – end of life / palliative versus curative;

What are the patient’s values and preferences; emphasis on shared decision making

• Simplification of medication regimen improves

adherence

• The only way to determine if a medication is needed

may be stop it

• Guideline recommended drugs may not make sense in
• lder adults with multiple comorbidities at end of life

Alexander GC, Sayla, MA, Holmes, HM, & Sachs, GA. (2006). Prioritizing and stopping prescription medicines. CMAJ Canadian Medical Association Journal, 174(8), 1083‐1084.

• Assess frequency and magnitude of benefit, time to

attain benefit versus burdens – frequency and magnitude of adverse effects, adherence burden, costs

• Try a behavioral intervention – e.g. for insomnia;

bladder behavior therapies / timed voiding

• Benefit unlikely to be realized in patient’s lifetime –

e.g., bisphosphonate, statins for primary prevention (statin in patient with limited life expectancy less than 5 years; bisphosphonate in patient with limited life expectancy less than 2 years)

Alexander GC, Sayla, MA, Holmes, HM, & Sachs, GA. (2006). Prioritizing and stopping prescription medicines. CMAJ Canadian Medical Association Journal, 174(8), 1083‐1084.

9/18/2015 26 Determine which medications are still providing benefit

• Ask about the symptoms for which each

symptom based drug is being used

• Look at signs – for example blood pressures

and blood glucose to help determine whether medications used to treat hypertension and diabetes are needed; watch out for hypoglycemia and hypotension – avoid these – use more conservative targets for blood pressure and blood sugar Questions to ask when trying to determine drug utility: What is the strength of the indications?

1. Provides immediate relief of distressing symptoms (e.g. analgesics, antiemetics) 2. Effectively modifies an acute condition that is life threatening or will soon result in distressing symptoms if not treated (e.g., antibiotics for sepsis, diuretics for CHF, bronchodilators for asthma) 3. Effectively modifies a chronic condition that might progress to become life threatening or cause distressing symptoms if not treated; e.g. methotrexate for RA, ace inhibitors for CHF Disease and/or symptom control drugs – those that control active disease and symptoms and maintain quality of life (e.g. analgesics, antianginals, anti‐heart failure drugs, levothyroxine); if treatment with drugs ceased, patients may become symptomatic or lose function from worsening disease; but drugs could be stopped if they are ineffective or reduced in dose or used prn if disease is mild and symptoms intermittent

• 4. Has the potential to prevent serious diseases or

adverse events in the future without immediate effect / preventive drugs; e.g. antiplatelet agents to prevent CVD, bisphosphonate to prevent osteoporotic fracture, antihypertensive to prevent stroke; prevent future morbid events; consider risks, benefits, life expectancy, time to benefit, goals of care

• 5. Is unlikely to be useful in either the short or long

term; e.g. vitamin supplement

• 6. Is prescribed where a non‐drug therapy (e.g. PT

instead of NSAID) is more beneficial

9/18/2015 27 What is the likelihood of misuse, toxicity, non adherence?

1. Is associated with little benefit and high risk of toxicity in most older patients – e.g. Beers, STOPP 2. Is a duplicate in drug therapy (second drug from same class) 3. Is prescribed for an adverse drug reaction 4. Is a potentially beneficial drug but is prescribed at a dose likely to cause toxicity 5. Has the potential for significant drug‐drug or drug‐disease interactions 6. Is taken more often than once daily 7. Can be safely administered as a combination medicine 8. Is causing significant problems with adherence

Use care if you and your patient / family decide to stop a medication

• Balance clinical impact (reduction in side effects)

with the risk of adverse drug withdrawal events – clinically significant signs of symptoms caused by stopping a drug – e.g. physiologic withdrawal reactions (e.g. tachycardia with beta blocker discontinuation); appearance of new symptoms (e.g. sweating with antidepressant withdrawal); exacerbation of an underlying condition (e.g. worsening angina after stopping nitrates)

• ADWE more likely with long duration of use,

higher dose, and short half life

Stop / discontinuing / deprescribing usually means tapering

• Taper medications to reduce risk and severity of

ADWEs; do gradual tapers

• Consider tapering bp meds, e.g. CCBs, beta

blockers; anticonvulsants; antidepressants; antipsychotics; corticosteroids; digoxin; diuretics; gabapentin; hypnotics; narcotics; PPIs; these meds have higher risk of ADWE

• Monitor for withdrawal effects; may need several

attempts at withdrawal; regular follow up

9/18/2015 28

Develop a weaning strategy

• Identify adverse effects from discontinuation
• f medication
• Identify recurrence of original symptoms
• If need to restart, consider best drug in class

for older people

• Do brown bags reviews to assess what drugs

are being taken and how

Medications commonly associated with discontinuation syndromes requiring tapering

• Alpha blockers – agitation, headache, hypertension, palpitations
• ACE‐inhibitors ‐‐ Heart failure and hypertension
• Antianginal agents ‐‐ Angina
• Anticonvulsants ‐‐ Anxiety, depression and seizures
• Antidepressants ‐‐ Akathisia, anxiety, chills, coryza, gastrointestinal distress, headache,
• insomnia, irritability, malaise, myalgia and depression
• Antiparkinsonian agents ‐‐ Hypotension, psychosis, rigidity and tremor
• Antipsychotic ‐‐ Dyskinesias, insomnia, nausea and restlessness
• Anticholinergics ‐‐‐ Anxiety, nausea, vomiting, headache and dizziness
• Baclofen ‐‐ Agitation, anxiety, confusion, depression, hallucinations, hypertonia,
• insomnia, mania, nightmares, paranoia and seizures
• Benzodiazepines ‐‐ Agitation, anxiety, confusion, delirium, insomnia and seizures
• β‐Blockers ‐‐ Angina, anxiety, hypertension, acute coronary syndrome and tachycardia
• Corticosteroid ‐‐ Anorexia, hypotension, nausea, weakness, hypothalamic–pituitary–
• adrenal axis suppression and inflammatory states
• Digoxin‐‐ Heart failure and palpitations
• Diuretic ‐‐ Heart failure and hypertension
• Narcotic analgesia ‐‐ Abdominal cramping, anger, anxiety, chills, diaphoresis, diarrhea,
• insomnia and restlessness
• NSAIDs ‐‐ Recurrence of gout and arthritis

Clinical pharmacist colleagues are crucial!

• Talk to your pharmacist: Medication reviews

by pharmacists conveyed to physicians – evidence that this reduces number and cost of medications

9/18/2015 29

Deprescribing is hard

• Bias toward the status quo; hard to stop a medication that has

already been prescribed

• Patient may see a specialist and start a medication – may have

unclear directions and length of use

• Prescribers are reluctant to change drugs other prescribers start
• There are few data on the safety and best ways to discontinue

medications

• Patients may be psychologically and physically attached to their

medications

• Stopping a medication may be perceived by patient / family as

providing inadequate care

• Beware of prescribing inertia – tendency to automatically renew a

medication even when the original indication is no longer present

End of life care / Palliative Care

• Many frail elders are essentially suffering from non curable

diseases and the goal is to relieve suffering

• Advanced age, multiple medical problems, progressive,

advanced disease with limited prognosis

• Focus of care is on quality of life
• End of life patients are at risk of adverse drug effects due to

polymedicine, declining organ function, multiple co‐ morbidities, malnutrition, changes in body composition

• Lack of evidence to guide care
• The risk of polymedicine may outweigh the combined

benefits of the medications

• Consider changing mantra of start low and go slow to stop

most and reduce dose

Consider getting rid of drugs at end of life

• Avoid / discontinue drugs aimed at prolonging

life or preventing disease especially if time to benefit long and not offering symptomatic benefit

• Focus on medications that have a positive

impact on symptoms and quality of life

9/18/2015 30

End of life prescribing

1. Life‐extending drugs are usually not appropriate (unless helping with symptom control) 2. Drugs for primary or secondary prevention usually not appropriate unless time to benefit is shorter than life expectancy and adverse effects are not significant 3. Prescribing more than 5 regular daily drugs should be avoided 4. Patient or caregiver help define most problematic symptoms in order to focus medications on the most burdensome symptoms first 5. Make changes to drug regimen over time 6. Start or withdraw medications step wise – one by one – to assess adverse reactions and impact on symptoms 7. Use simple dosing schedules; can use liquids, buccal, subcutaneous, to tailor treatment

Cruz‐Jentoft, AJ, Boland, B, & Rexach, L. (2012). Drug Therapy Optimization at the End of Life. Dugs& Aging, 29(6), 511‐521.

• Reduce number of drugs at end of life

‐‐‐lipid lowering drugs ‐‐‐drugs used for osteoporosis ‐‐‐anti‐platelet drugs ‐‐cholinergic drugs; memantine??? (carefully) ‐‐‐iron and vitamin supplements ‐‐‐vaccines ‐‐‐chemotherapeutic drugs

• But if drug is controlling symptoms, then keep as

goals are prevention of suffering

Difficult decisions involving preferences and trade offs

9/18/2015 31

References

• Alexander GC, Sayla, MA, Holmes, HM, & Sachs, GA. (2006). Prioritizing and stopping

prescription medicines. CMAJ Canadian Medical Association Journal, 174(8), 1083‐1084.

• Bushardt, R, Massey, EB, Simpson, TW, Ariail, JC, & Simpson, KN. (2008). Polypharmacy:

Misleading, but manageable. Clinical Interventions in Aging. 3(2), 383‐389.

• Cruz‐Jentoft, AJ, Boland, B, & Rexach, L. (2012). Drug Therapy Optimization at the End of
• Life. Dugs& Aging, 29(6), 511‐521.
• Elmstahl S, & Linder, H. (2013). Polypharmacy and Inappropriate Drug Use among Older

People—a Systematic Review. Healthy Aging & Clinical Care in the Elderly, 5, 1‐8.

• Farrell B, Eisener‐Parsche P, & Dalton D. (2014). Turning over the rocks: Role of

anticholinergics and benzodiazepines in cognitive decline and falls. Canadian Family Physician, 60(4), 345‐350.

• Frank, C. (2014). Deprescribing: A new word to guide medication review. CMAJ Canadian

Medical Association Journal, 186(6), 407‐408.

• Frank, C & Weir, E. (2014). Deprescribing for older patients. CMAJ Canadian Medical

Association Journal, 186(18), 1369‐1376.

References

• Garfinkel, D & Mangin, D. (2010). Less Is More. Feasibility Study of a

Systematic Approach for Discontinuation of Multiple Medications in Older

• Adults. Addressing Polypharmacy. Archives of Internal Medicine, 170(18),

1648‐1654.

• Garfinkel, D, Zur‐Gil, S, & Ben‐Israel, J. (2007). The war against

Polypharmacy: A New Cost‐Effective Geriatric‐Palliative Approach for Improving Drug Therapy in Disabled Elderly People. The Israel Medical Association Journal. 9, 430–434.

• Gnjidic D, Le Couteur, DG, Kouladjian, L, & Hilmer, SN. (2012). Deprescribing

Trials: Methods to Reduce Polypharmacy and the Impact on Prescribing and Clinical Outcomes. Clinics in Geriatric Medicine, 28, 237‐253.

• Hines, LE & Murphy, JE. (2011). Potentially Harmful Drug‐Drug Interactions

in the Elderly: A Review. The American Journal of Geriatric Pharmacotherapy, 9(6), 364‐377.

• Kwan, D. (2013). Polypharmacy: Optimizing Medication Use in Elderly
• Patients. Pharmacy Practice, Apr/May, 20‐25.

References

• Ravona‐Springer R, & Davidson M. (2014). Considerations in psychotropic treatments in

dementia – can polypharmacy be avoided? International Journal of Neuropsychopharmacology, 17(7), 1107‐1117.

• Rudolph, JL, Salow, MJ, Angelini, MC, & McGlinchey, RE. (2008). The Anticholinergic Risk

Scale and Anticholinergic Adverse Effects in Older Persons. Archives of Internal Medicine. 168(5), 508‐513.

• Scott, IA, Gray, LC, Martin, JH, & Mitchel, CA. (2012). Minimizing Inappropriate

Medications in Older Populations: A 10‐step Conceptual Framework. The American Journal

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towards evidence‐based deprescribing of drugs in older populations. Evidence‐Based Medicine, 18(4), 121‐124.

• Scott, IA, Hilmer, SN, Reeve, E, Potter, K, Le Couteur, D, Rigby, D. . . Martin, JH. (2015).

Reducing Inappropriate Polypharmacy, The Process of Deprescribing. JAMA Internal Medicine, E1‐E8. doi:10.1001/jamainternmed.2015.0324

• Wallace J, & Paauw DS. (2015). Appropriate prescribing and important drug interactions in
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• Weng MC, Tsai CF, Sheu KL, Lee YT, Lee HC, Tzeng SL, . . . Chen SC. (2013). The impact of

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