geriatrics - pharmacotherapy · geriatrics emily r. haj jar, shelly l. gray, patricia w. slattum,...

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e|CHAPTER 8 Geriatrics Emily R. Hajjar, Shelly L. Gray, Patricia W. Slattum, Catherine I. Starner, Robert L. Maher Jr, Lauren R. Hersh, and Joseph T. Hanlon

KEY CONCEPTS

The population of persons age 65 years and older is increasing.

Age-related changes in physiology can aff ect the pharmacokinetics and pharmacodynamics of numerous drugs.

Improving and maintaining functional status is a cornerstone of care for older adults.

Drug-related problems in older adults are common and cause considerable morbidity.

Pharmacists can play a major role in optimizing drug therapy and preventing drug-related problems in older adults.

Pharmacotherapy for older adults can cure or palliate disease as well as enhance health-related quality of life (HRQOL). HRQOL con-siderations for older adults include focusing on improvements in physical functioning (e.g., activities of daily living), psychological functioning (e.g., cognition, depression), social functioning (e.g., social activities, support systems), and overall health (e.g., general health perception). 1

Despite the benefi ts of pharmacotherapy, HRQOL can be compromised by drug-related problems. Prevention of drug-related adverse consequences in older adults requires that health profes-sionals become knowledgeable about a number of age-specifi c issues. To address these knowledge needs, this chapter discusses the epidemiology of aging; physiologic changes associated with aging, with emphasis on changes that can affect the pharmacokinetics and pharmacodynamics of drugs; clinical conditions commonly seen in older adult patients; epidemiology of drug-related problems in older adults; and an approach to reducing drug-related problems through the provision of comprehensive geriatric assessment.

EPIDEMIOLOGY OF AGING 1 The older American population is highly diverse and heteroge-

neous with respect to health status. The demographics and health characteristics of persons age 65 to 74 years differ from those of persons 85 years of age and older, as do those of persons who are institutionalized compared with those living in the community. Teas-ing apart the various threads of wellness and illness, independence and dependence, and function and dysfunction makes the available demographic and health status data relevant for clinical practice. Understanding the diversity and growth of older populations will allow society to plan for the training, research, and resources needed for future clinical practice and adequate healthcare.

The proportion of the population age 65 and older is increasing. In 2008, persons age 65 and older accounted for 13.0% (39 million)

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of the total U.S. population, up from 12.4% in 2006. Among those older than 65 years, women accounted for 58% of this segment of the population. The gender gap widens with increasing age, with women accounting for 67% of the cohort age 85 years. 2 In 2011, the fi rst baby boomers turned 65 years old; this marked the beginning of a rapid increase in the older population. By 2030, this older popula-tion is projected to almost double in size; one in fi ve Americans will be older than 65 years. This 20% projection will remain relatively stable through 2050. However, the proportion of the “oldest old” (>85 years) will continue to grow; by 2050, one in four older adults will be 85 years or older.

The increase in the number of older persons is caused not only by the higher post–World War II birth rate but also by the declin-ing mortality rate and overall improved health status among older adults. 3 The decline in early death and the better health of older adults arises from a variety of reasons: (a) public health measures affect-ing all age groups (e.g., immunizations, prenatal care), (b) advances in medical technology, (c) promotion of a healthy lifestyle, and (d) improvements in living conditions. 4 More relevant to health profes-sionals providing care to older Americans is the steadily increas-ing life expectancy at 65 years of age. In 2006, women 65 years of age could expect an average additional 19.70 years of life, and men could expect to live 17.0 additional years. Life expectancies are lower for black men and women. 2 Upon reaching 85 years of life, women may expect to live another 6.8 years and men another 5.7 years. 2 Given this increase in life expectancy, the 5.8% increase in the number of centenarians ( n = 53,364) from 2000 to 2010 was not unexpected. 5

Along with changes in the life expectancy of future older adults, the older population will become more diverse in racial and ethnic composition. In 2008, an estimated 80% of persons age 65 years and older were non-Hispanic white, 9% were black, 7% were Hispanic, and 3% were Asian. By 2050, the older Hispanic group is projected to grow the fastest and will account for 20% of the older adult population. The percent of non-Hispanic white older adults is projected to decline to 59%, whereas increases are projected for blacks (12%) and Asians (9%). 2 Most older persons are self-suffi cient and live in the community. However, as they age in the community, the likelihood of living alone increases, more so for women than men. In 2010, only 3.1% of older persons resided in skilled-nursing facilities, representing a decrease since 1990 (5.1%). This decline may result from the improved health status of older adults or the use of alternative residential services (e.g., assisted-living facilities, in-home healthcare). The propor-tion of older adults residing in skilled nursing facilities increases with age, rising sharply after age 85 years. Of those 65 to 74 years old, only 0.9% resided in a nursing home compared with 10.4% and 24.7% of the population 85 to 94 years and 95 years or older, respectively. 5

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eFIGURE 8-1 Leading causes of death in 2010 in those age 65 years and older. (Data from Centers for Disease Control and Prevention’s National Center

for Health Statistics.8)

Accidents (unintentional injuries)Kidney related

Influenza and pneumoniaDiabetes mellitus

Alzheimer’s diseaseCerebrovascular diseases

Chronic lower respiratory diseasesMalignant neoplasmsDiseases of the heart

Rates per 100,000

0 200 400 600 800 1000 1200 1400

As Americans live longer, there is a growing emphasis on healthy aging and improving the quality of remaining years of life. One important factor for healthy aging is regular physical activity, which has many positive health benefits, including disease reduction (e.g., cardiovascular disease), weight maintenance, and reduction in physical disability. Only 22% of older adults engage in regular leisure-time physical activity, and this percentage decreases with increasing age.2 Obesity in older adults increased from 22% (1988–1994) to 31% (1999–2000) and has leveled off since then. The prevalence of obesity is lower in those older than 75 years (27%) compared with those 65 to 74 years (37%).2

An important goal in the care of older adults is to maintain independence and avoid the need for institutionalization for as long as possible. Functional loss or disability often is a common precipi-tant for final institutionalization in older persons, especially among those older than 75 years. The most commonly referenced indicators of functioning in older adults include basic activities of daily liv-ing (ADLs; e.g., dressing, bathing, transferring, feeding, toileting), instrumental activities of daily living (IADLs; e.g., use of telephone, housework, meal preparation, shopping or managing money), and aspects of physical function (e.g., ability to lift 10 pounds, write, grasp small objects, walk two to three blocks, or reach overhead). Usual definitions of disability include limitations of ADLs, IADLs, or significant mobility problems.

In 2007, 24.5% of community-dwelling older adults reported difficulty with one or more ADLs, and 13.8% reported difficulty with one or more IADLs.2 Limitations in physical function are also common, with 23.4% of women and 14.3% of men reporting an inability to walk 2 to 3 blocks. Disability and limitations in physical function increase with age and are higher in institutionalized older persons. Segments of the population that are especially vulnerable to disability include women, minorities, and those in lower socio-economic classes.

Disability rates have declined since the 1980s, with significant declines over the 1990s. Trends in ADL and IADL disability have remained stable from 1998 to 2008 despite an increase in the prev-alence of chronic disease.6 Multiple factors are likely responsible for the decline in disability prevalence, including increased screen-ing, improved medical treatment, changes in health behaviors (e.g., reduced smoking), and widespread use of assistive devices.

Chronic diseases or impairments, such as heart disease, stroke, and diabetes, are major causes of disability in older adults. A total of 92% of older adults report at least one chronic health condition. Since 1998, those reporting four or more chronic conditions has increased from 11.6% to 17.4%.6 Many chronic conditions can be prevented or improved with behavioral modification, such as diet and physical activity. The prevalence of select common conditions in 2007 to 2008 included hypertension (56%), arthritis (50%), heart disease (32%), any cancer (23%), diabetes (19%), asthma (10%), chronic obstructive pulmonary disease (9%), and stroke (9%).2

Sensory impairments are common in older adults and pose challenges for maintaining functional independence and interac-tions with healthcare providers. Furthermore, 35% of older adults reported some trouble hearing, and 18% reported difficulties with vision.7 Moderate or severe memory impairment was reported in 13% of older adults, which is a major risk factor for nursing home admission. The prevalence of memory impairment increases dra-matically (to 32%) for the oldest old.7

Chronic diseases are the primary cause of death in older adults. The leading causes of death among older adults have changed little over the past 25 years. eFigure 8-1 illustrates the leading causes of death in 2010.8 Some important trends have emerged over the past quarter century. First, the death rates for heart disease and stroke have decreased by 50%. This trend is a consequence of the gains made in the prevention and treatment of these diseases. Second, death rates associated with diabetes, chronic lower respiratory dis-eases, and Alzheimer’s disease have increased significantly over this period.8

Older adults use more healthcare resources than any other group, including prescription medications. With older persons accounting for 13% of the population, they account for 38% of all hospital stays and 43% of all days of care in hospitals.9 The Medi-care Modernization Act (MMA) began offering a voluntary outpa-tient prescription drug benefit for beneficiaries in January 2006. As of September 2011, 10% of Medicare beneficiaries still did not have coverage under Medicare Part D or other sources of credit-able coverage.10 Furthermore, 2.0 million beneficiaries eligible for low-income subsidy were not receiving the subsidy. Part D spending for prescription drugs was expected to reach $53 billion in 2012.10 Although Medicare Part D benefit has improved prescription drug coverage for older adults, a concerning feature is the so-called “doughnut hole”—the gap in coverage lying between the initial cov-erage limit and the catastrophic coverage threshold. After surpass-ing the initial coverage of prescription drug plans, beneficiaries are financially responsible for the cost of prescription drugs until they qualify for the catastrophic coverage threshold. Studies reveal that older adults reduce prescription medication use when they enter the gap.11 The Affordable Care Act (ACA) passed in 2010 is incremen-tally reducing the coverage gap for prescription drugs, with elimina-tion slated for 2020.

HUMAN AGING AND CHANGES IN DRUG PHARMACOKINETICS AND PHARMACODYNAMICS

2 Many theories have been proposed to explain the human aging process. Clinical manifestations of normal aging include changes in the biochemical makeup of tissues, reduced capacity of body

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systems, reduced ability to adapt to physiologic stress, and increased vulnerability to disease.12 Interindividual variability in physiology increases with age13 because individuals experience aging at differ-ent rates along with the development of disease processes. eTable 8-1 reviews some common physiologic changes associated with aging, with an emphasis on changes that can affect pharmacotherapy. For more detailed information, readers are referred to excellent reviews.12,14

Age-associated physiologic changes may result in reduced func-tional reserve capacity (i.e., ability to respond to physiologic chal-lenges or stresses) and reduced ability to maintain homeostasis, thus making older adults susceptible to decompensation in stressful situ-ations.12,14,15 Examples of homeostatic mechanisms that may become impaired include postural or gait stability, orthostatic blood pressure responses, thermoregulation, cognitive reserve, and bowel and blad-der function. An event resulting in functional impairment may involve an insult for which the body cannot compensate, and relatively small stresses may result in major morbidity and mortality.12,14,15

The clinical response to a medication in an older adult is the net result of the interaction of a number of complex processes, includ-ing pharmacokinetics and pharmacodynamics. Age-related changes in physiology can affect drug pharmacokinetics and pharmacody-namics (see eTable 8-1). Concurrent medications, comorbidities, and frailty also play roles. When applying general knowledge of phar-macokinetic and pharmacodynamic alterations in an older adult in the clinical setting, it is necessary to consider the patient’s overall condition, age, diseases, and concurrent medications.

Altered PharmacokineticseTable 8-2 and the following discussion summarize what is known about the effect of aging on each of the four major facets of phar-macokinetics.13,16,17 Of interest, when multivariate population pharmacokinetic analyses are conducted, age by itself seldom is a significant predictor of individual pharmacokinetic parameters (e.g., clearance). Age-associated changes in drug absorption, distribu-tion, metabolism, and elimination are more important predictors of altered pharmacokinetics than is age per se.

AbsorptionMost drugs are taken orally; age-related changes in gastrointestinal physiology could affect the absorption of medications. Drug–food interactions, concurrent medication use, and comorbidities affecting gastrointestinal function must also be considered.

Fortunately, most drugs are absorbed via passive diffusion, and age-related physiologic changes appear to have little influence on drug bioavailability.17 Nutrients absorbed by active transport, such as vitamin B

12, iron, calcium, magnesium, and leucine, may

have impaired absorption in older adults.16 There is evidence for a decreased first-pass effect on hepatic or gut wall metabolism that results in increased bioavailability and higher plasma concentrations of drugs such as propranolol and labetalol and reduced bioavailabil-ity of some prodrugs such as enalapril and codeine.13,16

Drugs requiring an acidic environment for absorption may have reduced extent of absorption in a relatively small proportion of older adults with increased gastric pH caused by atrophic gastritis or in those taking medications that increase gastric pH.13 The effects of aging on the absorption of modified-release orally administered dosage forms are not known, although changes in gastrointestinal motility or pH might affect absorption from some dosage forms in some patients.13

DistributionThe distribution of medications in the body depends on factors such as blood flow, plasma protein binding, and body composition, each of which may be altered with age. For example, the volume of

eTABLE 8-1 Physiologic Changes with AgingOrgan System Manifestation

Balance and gait

↓ Stride length and slower gait↓ Arm swing↑ Body sway when standing

Body composition

↓ Total body water↓ Lean body mass↑ Body fat↔ or ↓ Serum albumin↑ α

1-Acid glycoprotein (↔ or ↑ by several disease

states)

Cardiovascular ↓ Cardiovascular response to stress↓ Baroreceptor activity leading to ↑ orthostatic

hypotension↓ Cardiac output↑ Systemic vascular resistance with loss of arterial

elasticity and dysfunction of systems maintaining vascular tone

↓ Resting and maximal heart rate

Central nervous system

↓ Size of the hippocampus and frontal and temporal lobes

↓ Number of receptors of all types and ↑ sensitivity of remaining receptors

↓ Short-term memory, coding and retrieval, and executive function

Altered sleep patterns

Endocrine ↓ Estrogen, testosterone, TSH, and DHEA-S levelsAltered insulin signaling

Gastrointestinal ↓ Motility of the large intestine↓ Vitamin absorption by active transport mechanisms↓ Splanchnic blood flow↓ Bowel surface area

Genitourinary Atrophy of the vagina with decreased estrogenProstatic hypertrophy with androgenic hormonal

changesDetrusor hyperactivity may predispose

to incontinence

Hepatic ↓ Hepatic size↓ Hepatic blood flow↓ Phase I (oxidation, reduction, hydrolysis) metabolism

Immune ↓ Antibody production in response to antigen↑ Autoimmunity

Oral Altered dentition↓ Ability to taste salt, bitter, sweet, and sour

Pulmonary ↓ Respiratory muscle strength↓ Chest wall compliance↓ Arterial oxygenation and impaired carbon dioxide

elimination↓ Vital capacity↓ Maximal breathing capacity↑ Residual volume

Renal ↓ GFR↓ Renal blood flow↓ Filtration fraction↓ Tubular secretory function↓ Renal mass

Sensory Presbyopia (diminished ability to focus on near objects)↓ Night visionPresbycusis (high-pitch, high-frequency hearing loss)↓ Sensation of smell and taste

Skeletal ↓ Skeletal bone mass (osteopenia)Joint stiffening caused by reduced water content

in tendons, ligaments, and cartilage

Skin/hair Thinning of stratum corneum↓ Langerhans cells, melanocytes, and mast cells↓ Depth and extent of the subcutaneous fat layerThinning and graying of hair caused by more hairs

in the resting phase and shortening of the growth phase as well as changes in follicular melanocytes

DHEA-S, dehydroepiandrosterone-S; GFR, glomerular filtration rate; TSH, thyroid-stimulating hormone.

From Cefalu12 and Colloca et al.15

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to 50%, and hepatic clearance of propranolol and amitriptyline may be reduced by 40% or more in older adults.17 Other high-extraction-ratio drugs that have been shown to have reduced hepatic clearance in older adults include diltiazem, lidocaine, metoprolol, morphine, and verapamil.20 Interpreting the effect of age on the metabolism of drugs that undergo capacity-limited metabolism is more complex. Hepatic clearance of capacity-limited drugs depends on the frac-tion unbound in blood and the intrinsic hepatic clearance. Most, but not all, studies have reported reduced liver size and enzyme con-tent in older adults.20 Total hepatic clearance of capacity-limited drugs, however, may be reduced (lorazepam, piroxicam, warfarin), increased (ibuprofen, naproxen, phenytoin) or unchanged (diaze-pam, temazepam, and valproic acid) with aging.20 Hepatic clearance of the unbound drug, rather than the total hepatic clearance, which includes bound and unbound drug, may be more relevant in under-standing the effect of age on hepatic clearance.21

Serum albumin concentrations decline with age. For capacity-limited drugs with extensive protein binding, older adults with reduced serum albumin concentrations may experience a significant increase in fraction unbound, leading to increased total hepatic clearance even though unbound clearance is significantly reduced. Naproxen, for example, has capacity-limited metabolism and is highly bound to albumin. Older adults experience reduced unbound clearance and increased total clearance compared with younger adults.20

Most research on hepatic drug metabolism and aging has focused on age differences in phase I drug metabolism pathways. Generally, phase II metabolic pathways are preserved in healthy older people.20 Frail older adults, however, experience reduced phase II metabolism. Frailty is a risk factor for declining health sta-tus and disability. Although frailty has proven difficult to define, it is characterized by reduced lean body mass, muscle loss, malnourish-ment, reduced function, and reduced endurance.20 Frailty is associ-ated with inflammation, which may downregulate drug metabolism and transport.22

EliminationRenal excretion is the primary route of elimination for many drugs and metabolites. Age-related reductions in glomerular filtration rate (GFR) are well documented. However, as many as one third of “normal” older adult subjects may have no reduction as mea-sured by creatinine clearance, and older adults maintaining a high protein diet have a GFR similar to younger adults.23 Additionally, declines in kidney function may be more closely implicated to dis-ease processes such as hypertension and heart disease than aging itself. Therefore, age alone may not have as great impact on renal excretion of drugs than previously thought.16

The estimation of creatinine clearance, although not entirely accurate in individual patients, can serve as a useful screening approximation for the purpose of dosage adjustments. Cockcroft and Gault24 created one of the most commonly used equations for adults with stable renal function whose actual weight is within 30% of ideal body weight:

Creatinine clearance =(140 − Age) (Actual body weight)

72 (Serum creatinine concentration)

where age is given in years, actual body weight in kilograms, and serum creatinine concentration in milligrams per deciliter. The resulting creatinine clearance is in units of mL/min. For women, multiply this result by 0.85.

When serum creatinine is expressed in μmol/L, creatinine clearance in units of mL/min can be calculated by the following equation:

Creatinine clearance =(140 − Age) (Actual body weight)

0.814 (Serum creatinine concentration)

distribution of water-soluble drugs is decreased, whereas lipophilic drugs exhibit an increased volume of distribution.13,17 Changes in the volume of distribution can have a direct impact on the amount of medication that must be given as a loading dose. Older adults may also exhibit differences in the distribution of drugs to their sites of action. Tissue perfusion may decrease with aging, slowing the distribution to less highly perfused tissues such as muscle and fat.13 Small changes in protein binding (decreased albumin and increased α

1-acid glycoprotein) have been documented with aging, but these

changes do not generally have a significant effect on drug distribu-tion except for drugs that are highly extracted by the liver, exten-sively protein bound, and administered IV.13,17

Blood–brain barrier permeability may also be altered in older adults, thereby affecting distribution of medications into the central nervous system (CNS). Cerebrovascular P-glycoprotein influences the transport of drugs across the blood–brain barrier. Studies using verapamil labeled with carbon-11 (a positron emitter) and positron emission tomography have demonstrated decreased P-glycoprotein activity in the blood–brain barrier with aging. As a result, the brain of elderly individuals may be exposed to higher than normal levels of drugs and toxins.18

MetabolismThe liver is the major organ responsible for drug metabolism, including phase I (oxidative) and phase II (conjugative) reactions. Variations in drug metabolism and consequently drug clearance are a major source of variability in the response to medications in older adults.19 Hepatic metabolism of drugs depends on liver perfusion, capacity and activity of drug metabolizing enzymes, and protein binding, all of which may altered by the aging process.17 For drugs that have high intrinsic clearance (high hepatic extraction ratio) and undergo rapid hepatic metabolism, drug clearance is dependent on hepatic blood flow (flow-limited metabolism). For drugs that have low intrinsic clearance (low hepatic extraction ratio) and are slowly metabolized by the liver, drug clearance is dependent on hepatic enzyme activity (capacity-limited metabolism).

Age-related decreases in hepatic blood flow can decrease sig-nificantly the metabolism of high extraction ratio drugs that undergo flow-limited metabolism. Hepatic blood flow may decline by 20%

eTABLE 8-2 Age-Related Changes in Drug Pharmacokinetics

Pharmacokinetic Phase Pharmacokinetic Parameters

Gastrointestinal absorption

Unchanged passive diffusion and no change in bioavailability for most drugs

↓ Active transport and ↓ bioavailability for some drugs

↓ First-pass metabolism, ↑ bioavailability for some drugs, and ↓ bioavailability for some prodrugs

Distribution ↓ Volume of distribution and ↑ plasma concentration of water-soluble drugs

↑ Volume of distribution and ↑ terminal disposition half-life (t

1/2) for lipid-soluble

drugs

Hepatic metabolism ↓ Clearance and ↑ t1/2

for some drugs with poor hepatic extraction (capacity-limited metabolism); phase I metabolism may be affected more than phase II

↓ Clearance and ↑ t1/2

for drugs with high hepatic extraction ratios (flow-limited metabolism)

Renal excretion ↓ Clearance and ↑ t1/2

for renally eliminated drugs and active metabolites

From Hilmer,13 Shi and Klotz,16 and Corsonello et al.17

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number of dopaminergic neurons, and decreased density of several types of dopamine receptors. These changes are consistent with the increased sensitivity of older adults to the adverse drug effects of antipsychotics.33 Increased sensitivity to the CNS effects of medica-tions in older adults has been demonstrated for benzodiazepines, anesthetic agents, opioid analgesics, antipsychotics, lithium, and anticholinergic medications.32,33

Aging is associated with numerous changes in the structure and function of the cardiovascular system that may predispose older adults to altered pharmacodynamic response to drugs acting on the cardiovascular system. Older adults are more likely to experience orthostatic hypotension as an adverse drug event.33 Age-related changes in pharmacodynamics have been reported for calcium channel blockers (increased hypotensive and bradycardic effects), β-blockers (reduced blood pressure response), diuretics (reduced effectiveness), and warfarin (increased risk of bleeding).32,33

CLINICAL GERIATRICS3 Maintenance of independence and prevention of disability are

primary goals in the clinical care of persons 65 years of age and older. To achieve these goals, it is necessary that all healthcare pro-fessionals understand the concept of functional status. Functional status is a proxy measure of a patient’s ability to live independently and can be determined, in part, by inquiring about an older person’s ability to perform specific tasks. Two types of functional measure-ments are basic ADLs and the more complex instrumental ADLs.1 To fully assess functional status, the patient’s psychological state, financial resources, physical function, and social circumstances also must be considered.1,34

One of the challenges of maintaining and improving func-tional status in geriatric individuals is recognizing and managing conditions frequently seen in older adults. Problems found more commonly in older persons sometimes are referred to as the “Is of geriatrics” (eTable 8-3).35 These problems are often the result of underlying disease processes that may or may not be diagnosed. Examples of diseases and syndromes that can present as common problems in older adults include Parkinson’s disease, falls, hip fractures, benign prostatic hypertrophy, dementia, glaucoma, and postherpetic neuralgia.

Another factor contributing to the challenge of clinical geri-atrics is the unreliability of the classic medical models used to establish diagnoses given that approximately half of older patients present with atypical symptoms or complaints. For example, cardiac ischemia in an older person may present as syncope or weakness rather than the typical presentation of chest pain. Confusion may be the presenting symptom of an acute abdominal process rather than severe pain, rigid abdominal muscles, and leukocytosis. Seri-ous adverse consequences may result if a diagnosis is delayed or missed because of these atypical presentations. Such unusual pre-sentations may be caused by age-related physiologic changes, the presence of multiple comorbid illnesses or compromised function, and the presence of psychological stressors.36 eTable 8-4 lists other

The Modified Diet in Renal Disease equation and the Chronic Kidney Disease Epidemiology Collaboration equation have become more widely used for estimation of GFR.25,26 The validity of each of these equations for use in estimating GFR in older adults has been advocated and challenged.27–29 However, dosing guidelines for medications that primarily are renally cleared are still based on estimated creatinine clearance determined using the Cockcroft and Gault equation, and current consensus is to continue to use of this equation for renal drug dosing in older adults. New methods based on serum creatinine and cystatin C continue to be developed, so this recommendation may change in the future.30

Consensus guidelines for oral dosing of primarily renally cleared drugs in older adults have been developed. Medications to avoid in older adults with creatinine clearance below 30 mL/min (0.5 mL/s) include chlorpropamide, colchicine, cotrimoxazole, gly-buride, meperidine, nitrofurantoin, probenecid, spironolactone, and triamterene. Oral medications with recommended dosage adjust-ments for reduce renal function in older adults include acyclovir, amantadine, ciprofloxacin, gabapentin, memantine, ranitidine, rimantadine, and valacyclovir.31 Some hepatically metabolized medications can yield active, primarily renally excreted metabo-lites, such as N-acetylprocainamide, normeperidine, and morphine-6-glucuronide, which can accumulate with advancing age because of reduced renal function.

Clinical Controversy. . .When using the Cockcroft and Gault equation to estimate creatinine clearance in older adults, some clinicians round the value up to 1 if the patient’s serum creatinine concentration is less than 1 mg/dL (88 μmol/L). Rounding the serum creatinine concentration may provide an underestimation of creatinine clearance and result in improper dose adjustment of renally eliminated medications. It is important to realize that the equation is merely an estimate, and attempts should be made to determine creatinine clearance accurately when contemplating the use of certain medications (e.g., gabapentin).

Altered PharmacodynamicsAge-related changes in pharmacokinetics are well characterized compared with changes in pharmacodynamics. Understanding the effects of age on pharmacodynamics has proven to be complex.

There is a general trend of altered drug response or increased “sensitivity” in older adults. Possible mechanisms that have been proposed include (a) changes in concentrations of the drug at the receptor, (b) changes in receptor numbers, (c) changes in receptor affinity, (d) postreceptor alterations, and (e) age-related impairment of homeostatic mechanisms.32,33 Differences in pharmacodynamics with age may be due to altered sensitivity (greater change in effect for a given change in drug concentration) but may also be due to dif-ferences in baseline performance or different concentrations of drug at the site of action between young and older adults.17 Most studies of pharmacodynamic differences with age have focused on drugs acting on the CNS and cardiovascular system.

Older adults are particularly sensitive to the CNS effects of drugs. Changes in brain size and weight as well as changes in neu-rotransmitter systems have been reported with advancing age. In addition, drugs may penetrate the CNS more easily.32 For example, there are multiple changes to the dopaminergic system with age, including decreased levels of the dopamine transporter, decreased

eTABLE 8-3 The Is of Geriatrics: Common Problems in Older Adults

Immobility InstabilityIsolation Intellectual impairmentIncontinence ImpotenceInfection ImmunodeficiencyInanition (malnutrition) InsomniaImpaction IatrogenesisImpaired senses

From Kane et al.35

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eTABLE 8-4 Atypical Disease Presentation in Older Adults

Disease Presentation

Acute myocardial infarction

Only ~50% present with chest pain. In general, older adults present with weakness, confusion, syncope, and abdominal pain; however, electrocardiographic findings are similar to those in younger patients.

Congestive heart failure

Instead of dyspnea, older patients may present with hypoxic symptoms, lethargy, restlessness, and confusion.

Gastrointestinal bleed

Although the mortality rate is ~10%, presenting symptoms are nonspecific, ranging from altered mental status to syncope with hemodynamic collapse. Abdominal pain often is absent.

Upper respiratory infection

Older patients typically present with lethargy, confusion, anorexia, and decompensation of a preexisting medical condition. Fever, chills, and a productive cough may or may not be present.

Urinary tract infection

Dysuria, fever, and flank pain may be absent. More commonly, older adults present with incontinence, confusion, abdominal pain, nausea or vomiting, and azotemia.

From Fried et al.36 and Jarrett et al.37

examples of medical illnesses that often present atypically in older adults.36,37 For very frail older adults, delirium, falls, and nonspecific functional decline (e.g., failure to thrive) frequently are presenting problems that may mask an underlying disease process.36,37

Multiple coexisting chronic illnesses are another common threat to independence that distinguishes older adults from younger patients. Older patients usually have multiple comorbidities, such as osteoarthritis, heart disease, and diabetes. Although multiple comorbidities can have a substantial impact on a patient’s functional status, the mere existence of multiple diseases alone does not deter-mine functional impairment.

DRUG-RELATED PROBLEMS IN OLDER ADULTS

4 Although medications used by older adults can lead to improve-ment in HRQOL, negative outcomes caused by drug-related problems are considerable.38,39 Three important and potentially pre-ventable negative outcomes caused by drug-related problems are (a) adverse drug withdrawal events (ADWEs), which are clinically sig-nificant sets of symptoms or signs caused by the removal of a drug; (b) therapeutic failure (inadequate or inappropriate drug therapy and not related to the natural progression of disease); and (c) adverse drug reactions (ADRs), defined as reactions that are noxious and unintended and occur at dosages normally used in humans for pro-phylaxis, diagnosis, or therapy.38,39

Data on the prevalence of ADWEs and therapeutic failures in older adults are limited. Graves et al. reported ADWEs in 38 of 124 male outpatients who had discontinued taking 238 medications.40 Kaiser et al. reported that 11% of hospital admissions in a group of older frail men were related to therapeutic failure.41 ADRs occur commonly in community-dwelling older adults. In a large study of more than 30,000 Medicare outpatients, Gurwitz et al. reported that 5% experienced an ADR in a 1-year period, with more serious reac-tions more likely to be preventable.42 Highlighting the vulnerability of frail older populations, Hanlon et al. reported that 33% of frail

male outpatients experienced at least one ADRs in a 1-year period.43 A review suggests that ADRs are the most common type of medica-tion-related problem in elderly nursing home patients.38

ADRs and other drug-related problems (e.g., ADWEs, thera-peutic failure) are major threats to the HRQOL of outpatient elders and account for billions of healthcare dollars per year.44 In the nurs-ing home setting alone, a cost-of-illness study estimated that drug-related problems (including ADRs and therapeutic failure) cost $4 billion per year.45

Risk FactorsOverusePolypharmacy can be defined as either the concomitant use of mul-tiple drugs or the administration of more medications than are indi-cated clinically.46 Polypharmacy is common and increasing among older adults.47 Community-based surveys reveal that older adults take an average of 2 to 10 prescription and nonprescription medica-tions each day.46,48 Increased use of dietary supplements, such as herbal products, vitamins, and minerals, may add to the increase in polypharmacy. In a nationwide survey, Qato et al. found that 49% used at least 1 dietary supplement.49 Outside of the community setting, a nursing facility survey found that institutionalized older persons took an average of 6.69 routine medications and 27.1% took 9 or more medications on a regular basis.50 Drug-use stud-ies that defined polypharmacy as use of one or more unnecessary medications showed that polypharmacy occurs in 55% to 59% of older outpatients.46 A study of frail veterans at hospital discharge reported that 44% of patients were taking one or more unneces-sary medications, with 25% of patients starting the medication(s) during hospitalization.51 Polypharmacy has been strongly associated with ADRs, risk of geriatric syndromes (e.g., falls, cognitive impair-ment), nonadherence, diminished functional status, and increased healthcare costs.46

Inappropriate PrescribingInappropriate prescribing can be defined as prescribing medications outside the bounds of accepted medical standards.52 Studies using explicit drug-use review criteria have found that between 15% and 24% of community-dwelling older adults take one or more medi-cations that have a dose, duration, duplication, or drug-interaction problem.53–55 This phenomenon occurs commonly in older inpa-tients, as exemplified by one study in which 92% of patients were taking at least one medication with one or more inappropriate rat-ings based on clinical review applying explicit criteria.56

Alternatively, inappropriate prescribing can be defined as pre-scribing drugs whose use should be avoided because their risk out-weighs their potential benefit.57 An Irish study found that 21% of older primary-care patients used at least one inappropriate medicine as defined by explicit criteria.58 Studies of inappropriate drug use in U.S. long-term care facilities found that 25% to 42% of residents took one or more inappropriate medications as defined by explicit criteria.59,60

UnderuseAn important problem in older adults is underuse of medications, defined as the omission of drug therapy that is indicated for treat-ment or prevention of a disease.52 The Assessing the Care of Vul-nerable Elders (ACOVE) criteria includes measures for underuse involving bisphosphonates, anticoagulant or antiplatelet therapy, ACE inhibitors, and β-blockers.61Another tool, called START (Screening Tool to Alert Doctors to the Right Treatment), is focused on risks associated with underuse of appropriate medications for diseases involving cardiovascular, respiratory and endocrine sys-tems in older adults.62

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reporting of vague or nonspecific symptoms (altered presentation), (d) coexistence of multiple diseases or use of multiple medications, (e) reliance on a caregiver for the history, and (f) lack of medical records to confirm findings. Despite these potential difficulties, health professionals should find value in collecting this vital medi-cation history information. The importance of inquiring about use of nonprescription medications and dietary supplements in older adults cannot be overstressed.

Asking older adults and their caregivers about methods they use to keep track of medicines is also important because one recent study documented that more than three-fourths of community elders have a system to manage their medications. The most common med-ication management strategies in ranking order include (1) using a pill box; (2) laying out whole days’ medications in the morning or at meal times; (3) putting medications in place to remind them; and (4) creating and maintaining a checklist or calendar.76 Having a better understanding of past and current medication management strategies facilitates the design of patient-specific solutions to any problems detected and prevents implementation of previously used, ineffective methods.

Patients and caregivers should be asked about risk factors for prescribing problems (e.g., using multiple physicians and pharma-cies) and both nonintentional and intentional adherence problems (e.g., impaired hearing, vision, or cognition; inability to open safety caps, pay for medicines, or swallow medications; recogni-tion of adverse effects; and perception of health risk).67,77–80 Several approaches to formally assess medication adherence in older adults have been reported in the literature. Because of the high frequency of medication-related problems, the drug history should conclude with an inquiry about any past allergies and intolerances and whether the patient currently or in the recent past experienced any adverse effects, unwanted reactions, or other problems with his or her medications.79 In addition, it is worthwhile to screen for geriatric syndromes (e.g., falls, urinary incontinence, cognitive impairment) because of their association with medication use.

Assessing and Monitoring Drug TherapyThe first step in assessing medication appropriateness is to match the medical problem list with the drug list. This simple approach can identify two thirds of prescribing problems (i.e., overuse and under-use).71 If a drug does not have a match with the problem list, the drug is not effective, the risks outweigh the benefits, or there is evidence of therapeutic duplication (i.e., two drugs from the same class), the drug may not be needed.51 Three items from the Medication Appro-priateness Index (MAI) (described in further detail in the follow-ing paragraph) along with explicit criteria from 2012 AGS Beers criteria for drugs to avoid can aid in the assessment of unnecessary drug use.57,81 The second step is to determine whether the patient has a chronic condition and is not taking an evidence-based medica-tion that has been shown to improve the management of a particular condition. Two separate expert panels from the United States and Ireland have developed explicit criteria for evidence-based drugs for specific conditions from which older adults would benefit.55,57 Next, laboratory test results and vital signs that can be used to monitor the efficacy and toxicity of each medication should be examined.82 eTable 8-5 lists laboratory monitoring recommendations for medica-tions used in long-term care facilities and recommended monitoring parameters.87,90

A similar list for laboratory tests to monitor in ambulatory care has been published for use regardless of age along with Health-care Effectiveness Data and Information Set (HEDIS) criteria for monitoring specific drugs.83 Finally, the appropriateness of the

Although criteria and tools highlight the need for improve-ment of underuse, it still remains a problem that can impact health outcomes, including functional disability, health services use, and death.52,63 A prospective cohort study evaluated the impact of potential underuse of antiplatelet, anticoagulant, antihypertensive, or statin therapy on cardiovascular outcomes. Among the older men studied, 56.7% were found to have potential underutiliza-tion and had a significantly higher risk of myocardial infarction or stroke.63

Medication NonadherenceNonadherence involves patient-related factors, condition-related factors, therapy-related factors, and health system and social fac-tors.64 In addition, nonadherence could be defined more than one way, including not filling the prescription (primary nonadherence), discontinuation of the medication before the entire supply is con-sumed, or taking more or less of the medication than stated by the label. Nevertheless, the prevalence rate of medication nonadher-ence in older adults remains high and ranges from 40% to 86%.65 Some evidence indicates that adherence may be better in older adults for some conditions.66 Older patients may not adhere to their regimens because of possible adverse effects, complex regimens, or a lack of full understanding of information about the prescribed medication.67 Unfortunately, cost and enrollment in Medicare Part D are also cited as reasons why older adults do not fill their prescriptions.64,68

Limited retrospective data suggest that nonadherence is asso-ciated with increased health services use and ADRs. Medication nonadherence has been implicated in approximately 4% to 11% of hospitalizations and 8% of emergency department visits.65 Con-versely, studies highlight the association between increased medi-cation adherence and fewer hospitalizations and decreased costs in patients with certain chronic medical conditions (e.g., diabetes, hypertension).69,70

PROVISION OF COMPREHENSIVE GERIATRIC ASSESSMENT

5 Given that drug-related problems are common, costly, and clinically important, how can they be prevented or managed? A solution may lie in comprehensive geriatric assessment by pharma-cists, regardless of the clinical setting.52,71–74 A number of reviews and book chapters summarize the effectiveness of pharmacists in improving suboptimal prescribing and medication adherence and reducing ADRs in older adults. The following subsections provide an approach that pharmacists in any practice setting (especially those providing medication therapy management services under the Medicare Part D program, conducting medication reconciliation, or performing a medication regimen review in a nursing home facil-ity) can take to optimize medication use through the provision of comprehensive geriatric assessment. Although there is no single data collection form that is applicable to all patients, pharmacists may find the Tool to Improve Medications in the Elderly via Review (TIMER) a helpful modality.75

History TakingA national survey reported that half of community-dwelling older adults take one or more over-the-counter drug products and one or more dietary supplements.49 However, obtaining this information from patients may be challenging because several difficulties may occur while taking medication histories from older adults. They include (a) communication problems (impaired hearing and vision), (b) underreporting (e.g., health beliefs, cognitive impairment), (c)

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therapeutic failure are directions, duration, and cost of medications (eTable 8-7).67

Documenting Problems and Formulating a Therapeutic PlanThe clinician must document the problems that have been detected, develop a therapeutic plan to resolve them, and establish reasonable therapeutic end points. Remember that what may be a reasonable end point for a 40-year-old patient may not be as reasonable for an 80-year-old patient. A conceptual model is helpful in improving rationale prescribing. This model takes into account factors such as remaining life expectancy, time until benefit, treatment target, and goals of care to help determine whether certain medications should be prescribed or continued.90

Consulting the Physician Regarding Problems and ConcernsIn most cases, the pharmacist or other healthcare professional should contact a patient’s physician regarding problems and concerns that have been detected and documented. In discussing the patient in this context, the importance of optimizing the prescribing for the older adult patient before implementing strategies to enhance his or her adherence cannot be overstressed. Otherwise, adherence inter-ventions, if effective, may result in harm in patients who suddenly become adherent to medication regimens that may have inappro-priately been titrated over time. Similarly, in institutional settings, strategies to reduce medication errors may not improve patient out-comes if prescribing is not improved beforehand.

Counseling and Adherence DevicesBefore dispensing medication, consider general factors that may enhance adherence in older adults, such as modifying medication schedules to fit patients’ lifestyles, prescribing generic agents to reduce costs, or selecting agents that are preferred on the patient’s formulary to reduce copay costs when using branded medications. In addition, using easy-to-open bottles, easy-to-swallow dosage forms, and larger type on direction and auxiliary labels may improve medication regimen adherence. The World Health Organization sug-gests clinicians consider five dimensions when assessing medica-tion adherence: social and economic factors (e.g., cultural beliefs), provider–patient and provider–healthcare system factors (e.g., pro-vider–patient relationship), condition-related factors (e.g., chronic conditions), therapy-related factors (e.g., regimen complexity), and patient-related factors (e.g., visual or hearing impairment).91 Finally,

remaining medications should be assessed. A variety of approaches can be used.84

One standardized measure with demonstrated reliability and validity is the MAI.81 The MAI consists of 10 questions that should be asked about each medication (eTable 8-6). Two of the most impor-tant factors strongly associated with ADRs considered by the MAI are drug–drug and drug–disease interactions.88 It is also important to avoid or modify the dosing of medications that are primarily renally cleared in older adults.31,89 Some other MAI factors to consider dur-ing drug regimen review that can influence adherence and potential

eTABLE 8-5 Guidelines for Monitoring Medication Use in Long Term Care Facility Patients

Drug MonitoringMonitoring Interval (in mo)

Acetaminophen (>4 g/d)

Hepatic function tests a

Amiodarone Hepatic function tests, TSH level

6

Antiepileptic agents (carbamazepine, phenobarbital, phenytoin, primidone, valproate)

Drug levels 3–6

Angiotensin-converting enzyme inhibitors or angiotensin I receptor blockers

Potassium levels 6

Antipsychotic agents Extrapyramidal side effects, fasting serum glucose, serum lipid panel

6

Appetite stimulants Weight, appetite a

Digoxin Serum blood urea nitrogen, creatinine, trough drug level

6

Diuretic Serum sodium and potassium levels

3

Erythropoiesis stimulants

Blood pressure, iron and ferritin levels, CBC

1

Fibrates Hepatic function test, CBC

6

Hypoglycemic agents Fasting serum glucose level or glycated hemoglobin level

6

Iron Iron and ferritin levels, CBC

a

Lithium Trough serum drug levels

3

Metformin Serum blood urea nitrogen, creatinine levels

Niacin Blood sugar levels, hepatic function tests

6

Statins Hepatic function tests 6

Theophylline Trough serum drug levels

3

Thyroid replacement TSH level on tests 6

Warfarin Prothrombin time or international normalized ratio

1

CBC, complete blood count; TSH, thyroid-stimulating hormone.aConsensus agreement about interval could not be reached.

From Handler et al.85,86 and Centers for Medicaid and Medicare Services.87

eTABLE 8-6 Medication Appropriateness IndexQuestions to Ask About Each Individual Medication 1. Is there an indication for the medication? 2. Is the medication effective for the condition? 3. Is the dosage correct? 4. Are the directions correct? 5. Are the directions practical? 6. Are there clinically significant drug–drug interactions? 7. Are there clinically significant drug–disease or drug–condition

interactions? 8. Is there unnecessary duplication with other medication(s)? 9. Is the duration of therapy acceptable?10. Is this medication the least expensive alternative compared with

others of equal utility?

Reprinted and adapted from J Clin Epidemiol, Vol. 45, Hanlon JT, Schmader KE, Samsa GP, et al. A method for assessing drug therapy appropriateness, Pages 1045–1051, Copyright © 1992, with permission from Elsevier.81

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Documenting Interventions and Monitoring Patient ProgressAll interventions must be documented, and the process discusses herein must be repeated over time with older adult patients, espe-cially when patients make care transitions (i.e., moving from one level of care to another). During follow-up contacts, minimum inquiry should include asking patients whether they have ques-tions or concerns regarding medicines and determining whether the therapeutic end points previously established have been achieved.

Targeting High-Risk Older AdultsIn busy practices, the approach outlined may not be feasible for every patient. Therefore, practitioners may consider targeting these activities to patients at high risk for developing drug-related prob-lems. Geriatric experts have identified risk factors for preventable ADRs in older adult nursing home patients, including the follow-ing medication-related factors: (a) polypharmacy (i.e., use of seven or more medications or more than three cardiac medications) and (b) taking specific high-risk drugs (e.g., anticoagulant, antidepres-sant, antiinfective, antipsychotic, anticonvulsant, opioid analgesic, sedative–hypnotic, skeletal muscle relaxant).92 Another study of geriatric experts identified 21 risk factors for ADRs in ambulatory older adults.93 Other unique risk factors include (a) medication-related issues (i.e., use of anticholinergics, benzodiazepines, chlor-propamide, corticosteroids, nonsteroidal antiinflammatory drugs), (b) certain patient characteristics (e.g., multiple comorbidities, mul-tiple prescribers, age ≥85 years, dementia, regular use of alcohol, decreased renal function), (c) use of drugs with narrow therapeutic ranges (e.g., lithium, warfarin), (d) history of an ADR, and (e) recent hospitalization.93 Similarly, O’Connor and colleagues reported risk factors for ADRs during hospitalization for the elderly as the follow-ing: renal failure, increasing number of medications, inappropriate medications, and age 75 years or older.84

CONCLUSIONThe number of people older than 65 years is growing in the United States and around the world, and individuals older than 85 years are the fastest growing segment of the U.S. population. A num-ber of physiologic changes associated with age, especially hepatic metabolism and renal excretion, affect the pharmacokinetics and pharmacodynamics of drugs. Improving and maintaining the patient’s functional status and managing the patient’s comorbidi-ties are hallmarks of clinical geriatrics. Certain medical conditions are restricted to older adults, and drug-related problems represent a major concern for this group. Interprofessional approaches to care are needed to decrease the occurrence of these drug-related problems.

ABBREVIATIONSACOVE Assessing the Care of Vulnerable EldersADL activity of daily livingADR adverse drug reactionADWE adverse drug withdrawal eventCMS Centers for Medicare and Medicaid ServicesHRQOL health-related quality of lifeMAI Medication Appropriateness IndexMMA Medicare Prescription Drug, Improvement and

Modernization Act

when dispensing medications (particularly new medications or pre-viously used medications that have changed in appearance or direc-tions for use), provide both written and oral drug information to the patient and caregiver.67

To improve the likelihood of adherence, the healthcare pro-fessional should recruit active patient and caregiver involve-ment, stress the importance of adherence, and consider the use of adherence-enhancing aids (e.g., special packaging, a medication record, a drug calendar, medication boxes, magnification for insu-lin syringes, dose-measuring devices, and spacers for metered-dose inhalers). In institutional settings, it is prudent to discuss special considerations (e.g., medications that can be crushed and given via feeding tube and gradual dose reductions of psychoactive medi-cations) with healthcare professionals responsible for medication administration.67

eTABLE 8-7 Examples of Clinically Important Drug–Disease Interactions Determined by Expert Panel Consensus

Drug Disease

Acetylcholinesterase inhibitors

Syncope

α-Adrenergic blockers SyncopeStress or mixed urinary incontinence

in womenAnticholinergic agents Benign prostatic hyperplasia

Chronic constipationDementia and cognitive impairmentDelirium

Antipsychotics Dementia and cognitive impairmentHistory of falls or fractureParkinson’s disease

Antispasmodics Chronic constipationAspirin Peptic ulcer diseaseBenzodiazepines Dementia and cognitive impairment

DeliriumHistory of falls or fracture

Bupropion Chronic seizures or epilepsyCalcium channel blockers

(nondihydropyridine)Heart failure (systolic dysfunction)Chronic constipation

Chlorpromazine Chronic seizures or epilepsyDelirium

Cilostazol Heart failureCorticosteroids DeliriumCyclooxygeanse-2

inhibitorsHeart failurePeptic ulcer disease

Decongestants (oral) InsomniaDronedarone Heart failureEstrogen (oral) Urinary incontinence (all types) in womenHistamine-2 receptor

blockersDeliriumDementia and cognitive impairment

Metoclopramide Parkinson’s diseaseNonaspirin nonsteroidal

antiinflammatory drugsChronic kidney disease (stages IV and V)Heart failurePeptic ulcer disease

Olanzapine Chronic seizures or epilepsyRosiglitazone Heart failureSedative/hypnotics Delirium

History of falls or fracturesSelective serotonin

reuptake inhibitorsHistory of falls or fractures

Stimulants InsomniaThioridazine Delirium

Chronic seizures or epilepsySyncope

Tramadol Chronic seizures or epilepsyTricyclic antidepressants

(TCAs)Syncope (tertiary TCAs)DeliriumHistory of falls and fracturesChronic constipation (tertiary TCAs)

Adapted from American Geriatrics Society 2012 Updated Beers Criteria.57

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