Prescribing in the Elderly

Karen Birmingham, PharmD, BCPSSpecialty Clinical Pharmacy Services

Group Health

“Quote”worthy Definitions

Aging

“Progressive accumulation

of random changes”

“Time-related loss of

functional units”

“Better than the alternative”

Elderly

“Age nearing or surpassing

the average life span”

“Age 65 years and older”

“Always 15 years older than me”

A Global “Gray Tsunami”

• By the year 2006: – almost 500 million people worldwide had reached or

exceeded age 65

• By the year 2030:– Total world population estimated to reach over 9 billion– Elderly population in developing countries projected to

increase 140%– World population of people ≥ 65 years old expected to

reach 1 billion

• By the year 2050:– 20% of all elderly patients will be ≥ 80 years old

U.S. Elderly

• Constitute 13% of the population• Consume 34% of all prescription medications• Use 40% of all over-the-counter drugs• Up to 50% of elderly take multiple medications• Medicare population analysis in 1999 (n=1.2 million)

– 82% had at least one chronic condition– 24% had at least four chronic conditions

Prescription Drug Use by Elderly

www.cdc.gov

%

Prescription $ Per Chronic Condition

www.cdc.gov

$

Drugs Most Used by Elderly Patients

Clinical Pharmacology and Therapeutics 2007

ADE, ADR and ME

Annals of Internal Medicine 2004

Adverse Drug Events

• Occur in 20% of elderly patients

• Account for 5-10% of hospitalizations– Nearly 20% ranked as severe– Fatal outcomes in 6% of cases– Repeat hospitalizations in 30% of ADEs

• Prevalence of 5-37% in hospitalized patients– Interventions required in ~30% of patients

• Affect ~ 350,000 long-term care patients annually

Adverse Drug Events and Death

“If medication-related problems were ranked as a disease by cause of death,it would be the 5th leading cause of death in the United States.”

Archives of Internal Medicine 2003

Risk Factors For Adverse Drug Events

• Inappropriate prescribing• Polypharmacy• Misuse of OTC products• Lack of appropriate drug monitoring• Complicated dosing instructions• Language or educational barriers• Nonadherence

How a Drug Does What It Does

The Pharmacologic Basis of Therapeutics, 11th ed.

Changes Due to Aging

Adapted from Journal of the American College of Cardiology 2010

↓ glomerular filtration rate↓ renal circulation↓ renal clearance

↓ hepatic circulation↓ hepatic mass↓ first-pass metabolism↓ activation of prodrug↑ bioavailability

↑ gastric pH↓ absorption surface↓ GI mobilityAltered drug absorption

↑ body fat↑ volume of distribution of lipophilic drugs↑ half-life↑ time to steady-state concentration

↓ lean body mass↓ total body water↓ volume of distributionof water-soluble drugs

cognitive changes↑ sensitivity to anticholinergicsAltered HPA axis

Cytochrome P450 Enzyme System

• Fifty human CYP450 genes• Estimated 8-10 isoforms responsible

for drug metabolism• Large range of activity in healthy

humans (6-fold difference in rates)• Weight-adjusted CYP3A clearance

more rapid in women• Currently no predictive data for

effects of age on CYP2C• Faster clearance of CYP2D6 in men;

decrease doses of drugs ~10-20% for women, decrease ~20% more in elderly women

• Renal impairment may affect CYP P450 due to decreased gene expression

Adapted from The Pharmacological Basis of Therapeutics 1996

CYP3A

CYP2E9CYP1A2

CYP2C

CYP2D6

Drug Metabolism: Older vs. Younger

Adapted from Bressler and Bahl, Mayo Clinic Proceedings 2003

P-Glycoprotein and Drug Disposition

• Efflux transporter• Found in hepatocytes, intestinal mucosal cells,

and blood-brain barrier• Conflicting results from small studies:

– Animal studies suggest differences between male and female, not yet observed in humans

– One study showed no significant difference in leukocyte P-glycoprotein in comparisons of young healthy adults vs. elderly healthy and frail adults

– Another study suggested decreased blood-brain barrier P-glycoprotein activity, possibly exposing brain to higher levels of drugs

Age Effects on Hemostasis

Coagulation Proteins

Fibrinolytic Proteins

Anticoagulant Proteins

↑ Factor V↑ Factor VII↑ Factor VIII↑ Factor IX↑ Factor XIII↑ Fibrinogen↑ kininogen↑ prekallikrein

↑ D-dimer↑ PAI-1↓ plasmin

Antithrombin III ♂ ↓ ♀ ↓Protein C ♂ ↔ ♀ ↑Protein S ♂ ↔ ♀ ↑TFPI ♂ ↓ ♀ ↑

Adapted from Journal of the American College of Cardiology 2010

Pharmacodynamics in the Elderly

Drug Name Drug Action Drug Effect

diltiazemantihypertensivePR interval prolongation

furosemide diuretic

scopolamine cognitive function

morphine analgesia

diazepam sedation

verapamil antihypertensive

warfarin anticoagulant

Adapted from British Journal of Pharmacology 2004

Effect of Illness on Drug Actions

absorptiongastrointestinal pHgastrointestinal motilitygastric contents

distributionserum albuminchanges in binding sitesincreased endogenous inhibitors

metabolismrenal impairmenthepatic impairmentdrug interactions

excretionrenal impairmentgastrointestinal motility

receptor interaction

changes in numberchanges in sensitivity altered target site

Drug Response1) Altered: -metabolism -cell environment -concentrations2) Tolerance3) Resistance4) Interactions

=

Congestive Heart Failure Effects

Parameter Alteration

bioavailability

bowel edema reduces drug absorption of oral drugsfirst pass metabolism altered by hepatic congestion

peripheral edema decreases absorption of topical/subcutaneous/intramuscular agents

distributionunpredictable due to changes in total body water and tissue perfusion

metabolism reduced liver perfusion alters drug metabolism

excretion impaired renal function may inhibit drug elimination

pharmacodynamicincreased risk of radiocontrast nephropathyincreased sensitivity to antiarrhythmic medication

Adapted from Clinics in Chest Medicine 2003

High Risk Drugs Assessment Tools

Year Country Tool

19911997200020072008

200820092010

USACanadaCanadaFranceIreland

JapanNorwayItaly

Beers (updated in 1997 and 2003)Canadian CriteriaIPET - Improving Prescribing in Elderly Tool French Consensus Panel ListSTOPP – Screening Tool of Older Persons’ Prescriptions START – Screening Tool to Alert to Right Treatment Japanese Beers CriteriaNORGEP – Norwegian General practiceUnnamed

Adapted from Annals of Pharmacotherapy 2010

Medication Appropriateness Index

Criterion Standard Weight Modified WeightDrug-drug interactions? 2 2Drug-disease interactions? 2 2Is the drug indicated? 3 1Is the drug effective? 3 1Unnecessary drug duplication? 1 1Appropriate therapy duration? 1 1Correct dosage? 2 0Correct directions? 2 0Practical directions? 1 0Cost effective compared with other drugs of equal efficacy? 1 0

Adapted from Annals of Pharmacotherapy 2010

Anticholinergic Risk Scale3 points 2 points 1 point

amitriptyline amantadine carbidopa-levodopa

atropine baclofen entacapone

carisoprodol cetirizine haloperidol

chlorpheniramine cimetidine methocarbamol

chlorpromazine clozapine metoclopramide

cyproheptadine cyclobenzaprine mirtazapine

dicyclomine desipramine paroxetine

diphenhydramine loperamide pramipexole

hydroxyzine loratadine quetiapine

imipramine nortriptyline ranitidine

promethazine olanzapine risperidone

meclizine prochlorperazine selegiline

promethazine tolterodine trazodone

Adapted from Archives of Internal Medicine 2008

Drug Burden Index (DBI)

Total drug burden = BAC + BS

E

= __D__ + D

↑ DBI = ↓ physical performance and cognition

DBI:

Equations from Archives of Internal Medicine 2007

The Big Issues

• Cognition, sedation, falls• GI toxicity• Cardiopulmonary effects• Bleeding/clotting• Renal impairment• Liver toxicity

High Risk For Falls

Anticholinergicsscopolamine pentobarbital hyoscyamineatropine phenobarbital secobarbital belladonna propantheline dicyclomine

MuscleRelaxants

carisoprodol methocarbamol cyclobenzaprine chlorzoxazone meprobamate metaxalone

TricyclicAntidepressants

amoxapine doxepin protriptylineamitriptyline imipramine clomipramine

Antihistamines diphenhydramine, hydroxyzine, cyproheptadine

Antiemetics promethazine, trimethobenzamide

Benzodiazepines

diazepam, flurazepam, triazolam, chlordiazepoxide

Narcotics meperidine, propoxyphene

Recommendations for Screening

Perform fall risk screening on all elderly patients, including:– History of falls or problems with gait/balance– Complete medication review, including

prescriptions, over-the-counter drugs, herbal products, nutritional supplements, etc.

– Chronic condition risk factors, e.g. osteoporosis, cardiovascular disease, visual impairment, etc.

– Assessment of vitamin D deficiency

NSAIDS and GI Risk

MostMeclofenamateIndomethacinFenoprofenPiroxicam

FlurbiprofenNaproxen

AspirinKetoprofenIbuprofenDiclofenacSulindacSalsalateEtodolac

LeastNabumetone

Relative GI Toxicity of Select NSAIDs

Adapted from Carman, EBRx Newsletter 2009

Other Adverse Effects of NSAIDs

Renal GI Coagulation

salt/H20 retention

edemahyperkalemia↓ antihypertensive effects↓ diuretic effects↓ urate excretion

abdominal painanorexiagastric erosionshemorrhageanemiaperforationdiarrhea

inhibit platelet activationhemorrhagebruising

ADEs After Start of Pain Prescriptions

Adapted from Solomon, Archives of Internal Medicine 2010

Acetaminophen

• Present in multiple OTC products and prescription pain medications

• Maximum daily dose often exceeded in community and in hospitals

• Increasing reports of severe hepatotoxicity– Higher risk in patients who abuse alcohol and/or

exceed dose recommendations

• By 2014, all acetaminophen prescription products must have no more than 325 mg acetaminophen per dosage unit – New dose limit set by FDA in January 2011

Risk of Respiratory Depression

+ morphine, hydromorphonemeperidine, hydrocodone

fentanyl

GI Drugspromethazinecimetidine

promethazineaprepitant

antimicrobials

macrolidesazole antifungalsprotease inhibitors

psychotropicsbenzodiazepinestricyclic antidepressantsMAOIs

benzodiazepinestricyclic antidepressantsMAOIs

analgesics skeletal muscle relaxants skeletal muscle relaxants

antihistaminesdiphenhydraminehydroxyzine

diphenhydraminehydroxyzine

High Risk Drugs in IllnessCondition Medications EffectSeizures clozapine, bupropion,

chlorpromazinelowered seizure threshold

Clotting Disorders

aspirin, NSAIDS, ticlopidine,dipyridamole, clopidogrel,

prolonged clotting time, inhibited platelet aggregation

Parkinsonism metoclopramide, antipsychotics

antidopaminergic and cholinergic effects

Arrhythmias tricyclic antidepressants proarrhythmic effects and QT interval changes

Obesity olanzapine weight gain

COPD sedatives/hypnotics respiratory depression

Benign prostatic hypertrophy

anticholinergics, narcotics, muscle relaxants

urinary hesitancy

High Risk For Cardiovascular Disease

High Sodium Drugs

sodium polystyrene sulfatepiperacillin, ticarcillinranitidine

fluid retentionheart failure exacerbation

Stimulants

amphetamines diethylpropionmethylphenidate phentermine

↑ blood pressure

CV Drugsshort-acting nifedipineshort-acting dipyridamoledisopyramide

rapid ↓ in blood pressure, ↑ risk of syncope, stroke↑ risk of heart failure

Oral Estrogens

conjugated estrogenesterified estrogen-methyltestosteroneestropipate

↑ risk of stroke

Drug Interactions

• Drug interactions and polypharmacy– Two drugs = DDI occurrence in ~ 13% of patients– Six drugs = DDI occurrence in ~ 80% of patients

• Hospitalizations within one week of interactions– Glyburide + cotrimoxazole= 35/909 patients– Digoxin + clarithromycin = 27/1051 patients– ACE inhibitors + diuretics = 43/523 patients

• Concomitant alcohol use by 20% of elderly• Many patients report use of nutritional or herbal

supplements.

Watch Out For These Interactions

Watch Out For These Interactions

Drug Interactions With Herbals

gingko ginseng garlic ginger echinaceaSt. John’s

wort

antithrombotic X X X X X

ACEI/ARB X X X X

Ca blockers X X X X X

-blockers X X X

statins X X X X X

amiodarone X X X X

digoxin X X X

warfarin X X X X X X

ADEs: Drug Shortages and Recalls

Shortage of IV sulfamethoxazole/ trimethoprim) led to refractory cases of pneumocystis pneumonia from alternative treatment with clindamycin and primaquine

Chemotherapy treatments delayed in a patient with a high potential for remission while attempting to find a source of the needed drug

Unintended intraoperative awareness occurred when a patient was given too little propofol based on weight in an attempt to conserve supplies

Cancellations of surgeries and procedures

Wrong dose of morphine administered after 4 mg/mL prefilled syringes were replaced with 5 mg/mL vials

Pre-diluted methotrexate was unavailable; a vial of dry powder was reconstituted incorrectly and the patient received less than the prescribed dose

Prevention of ADEsFrequent medication review and reconciliation

Evaluation of indications, benefits, side effects

Review of preprinted orders or prescription pads

Ensure medication literacy

Pharmacologic “debridement”

Utilization of online drug evaluation tools

Routine pharmacist consultation