Excretion

In older adults, changes in aging kidneys include a decrease in renal mass by 20% to

30%, decrease in renal blood flow, and decrease in tubular secretion.

18

Increases in

sclerotic glomeruli and decreases in functioning glomeruli may contribute to a

decline in glomerular filtration rate (GFR).

18 After age 30, GFR is estimated to

decline 8 mL/minute every 10 years, although not all older adults have decreased

renal function.

12

The plasma half-life is prolonged for a number of renally excreted drugs in

“healthy” older adults, and the highest-risk drugs are those that depend entirely on the

kidney for elimination. Examples of these are listed in Table 107-2.

GFR is the most prevalent measurement that is used to evaluate overall renal

function and to diagnose kidney disease, using markers that are renally excreted such

as creatinine.

19 These markers are measured by collecting urine over a 6- to 24-hour

period and drawing blood before or after. Because timed urine and serum collections

may not always be possible or accurate in older adults due to inconvenience, or

incomplete collection in those with incontinence, several equations are used to

estimate creatinine clearance.

20 Whereas GFR is used to diagnose and stage kidney

disease, equations that estimate creatinine clearance are used to guide practitioners

in drug dosing. The Cockcroft–Gault equation is commonly used for most drug

dosing; however, controversies exist with regard to using actual or ideal weight, and

using correction factors in the calculation. The use of lean body weight in the

equation may reflect serum creatinine (SCr) production more accurately because

creatinine is produced in muscle mass, which is decreased in older patients. The

Cockcroft–Gault equation depends on SCr concentration and tubular secretion of

creatinine, which may result in an overestimation of renal function in obese patients.

CASE 107-1, QUESTION 4: For renally cleared drugs that require dosage adjustment for M.G., is the

Cockroft–Gault equation an appropriate tool to estimate renal function?

Cockroft and Gault

M.G. is 75 years old, weighs 120 lbs or 54.43 kg, and her serum creatinine is 1.9

mg/dL. Using the Cockcroft–Gault equation, her estimated CrCl is 22 mL/minute. The

equation was derived from a predominantly male veteran population who had a

single measured 24-hour creatinine clearance, and a correction factor of 0.85 is used

in female patients.

21

Table 107-2

Drugs Highly Dependent on Renal Function for Elimination

18,20,a

Acetazolamide Duloxetine Nizatidine

Acyclovir Edoxaban Penicillins (most)

Allopurinol Enalapril Phenazopyridine

Amantadine Enoxaparin Pregabalin

Amiloride Famotidine Probenecid

Aminoglycosides Fluconazole Procainamide

Amphotericin B Fluroquinolones (most) Pyridostigmine

Apixaban Fondaparinux Ranitidine

Atenolol Furosemide Rivaroxaban

Aztreonam Gabapentin Spironolactone

Captopril Imipenem Sulfamethoxazole

Cephalosporins (most) Levetiracetam Thiazides

Clonidine Lisinopril Tramadol

Cimetidine Lithium Trimethoprim

Colchicine Methotrexate Triamterene

Dabigatran Metoclopramide Vancomycin

Digoxin Nadolol

aThis list does not include all drugs highly dependent on renal function for elimination.

Adapted from American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication

Use in Older Adults. J Am Geriatr Soc. 2015;63:2227–2246 and Arnoff GR et al., eds. Drug Prescribing in Renal

Failure: Dosing Guidelines for Adults. 5th ed. Philadelphia, PA: American College of Physicians; 2007.

M.G. is not underweight or obese, so the Cockroft-Gault equation is an

appropriate tool to estimate creatinine clearance for drug dosing and remains the

most common method to determine dosing of renally cleared drugs. Other

assessments of renal function, including urine output, should be considered when

assessing drug dosage adjustments in older individuals such as M.G., along with

close monitoring for adverse drug reactions.

Table 107-3 provides a composite picture of the age-related physiologic changes,

disease states, and pharmacologic factors that affect pharmacokinetic processes in

older adults.

PHARMACODYNAMIC CHANGES

Pharmacodynamics refers to the effect of a medication at its receptor site, or site of

action, and is largely determined by drug concentration and its ability to bind at the

receptor site.

22 Aging can affect the number of receptors available and their affinity to

medications. Together, comorbidities, pharmacokinetic changes, and

pharmacodynamic changes make an individual drug response in an older adult largely

unpredictable. Because older persons can be sensitive to the effects of medication,

care should be taken to avoid unwanted adverse effects when starting or stopping

medications.

The ability to preserve homeostasis decreases with aging, which results in a

decrease in functional reserve and a decreased ability to respond in times of

physiologic stress.

23 Cardiovascular changes during aging along with an impaired

baroreceptor response increase the prevalence of orthostatic hypotension in the

elderly population.

23,24 Prevalence ranges from 6% in middle age to 30% or greater

in patients 70 years of age or older.

25 Orthostatic hypotension is often aggravated by

drugs with sympatholytic activity (e.g., α-adrenergic blocking agents, phenothiazines,

tricyclic antidepressants [TCAs]), volume-depleting drugs (e.g., diuretics), and

vasodilating agents (e.g., nitrates, alcohol).

24,26

In a study of 100 geriatric psychiatric

outpatients, almost 40% complained of dizziness and falling, which were attributed

to psychotropic medications.

27 Patients with impaired cardiac output and taking

concurrent diuretic therapy are especially vulnerable.

24 Changes in gait and balance

are common in the older adult population.

28

p. 2219

p. 2220

Table 107-3

Changes Affecting Pharmacokinetic Parameters

Parameter Physiologic Changes Disease States Pharmacologic Factors

Absorption (bioavailability,

first-pass metabolism)

Gastric pH

Absorptive surface

Splanchnic blood flow

GI motility

Gastric emptying rate

Achlorhydria, diarrhea,

gastrectomy,

malabsorptive syndromes,

pancreatitis

Drug interactions,

antacids, anticholinergics,

cholestyramine, food

Distribution Cardiac output

TBW

Lean body mass

Serum albumin

α1

-Acid glycoprotein

Body fat

Altered relative tissue

perfusion

HF, dehydration, edema,

ascites, hepatic, failure,

malnutrition, renal failure

Drug interactions, proteinbinding displacement

Metabolism Hepatic mass

Enzyme activity

Hepatic blood flow

HF, fever, hepatic failure,

malignancy, malnutrition,

thyroid disease, viral,

infection or immunization

Dietary makeup, drug

interactions, insecticides,

alcohol, smoking, induction

of metabolism, inhibition of

metabolism

Excretion Renal blood flow

GFR

Tubular secretion

Renal mass

Hypovolemia, renal

insufficiency

Drug interactions

GFR, glomerular filtration rate; GI, gastrointestinal; HF, heart failure; TBW, total body water.

Table 107-4

Adverse Drug Reactions That May Affect Mobility of the Older Patient

Medication Class Adverse Drug Reaction

Tricyclic antidepressants (TCAs) Orthostatic hypotension, tremor, cardiac arrhythmias,

sedation

Benzodiazepines and sedative hypnotics Sedation, weakness, coordination, confusion

Opiate analgesics Sedation, coordination, confusion

Antipsychotics Orthostatic hypotension, sedation, extrapyramidal effects

Antihypertensives Orthostatic hypotension

β-Adrenergic blockers Ability to respond to workload (dose needed may increase

risk)

Certain medications or classes of medications, such as antiarrhythmics, diuretics,

digoxin, narcotics, anticonvulsants, psychotropics, and antidepressants, can lead to

gait disturbances and contribute to drug-induced falls in older adults. Table 107-4

reviews the therapeutic agents commonly associated with adverse drug reactions that

may affect the mobility of older patients.

Blood–Brain Barrier

The function and integrity of the interface between the brain and the body, the blood–

brain barrier, may decline as a result of aging, disease, or ischemic injury.

29 An

exaggerated response and increased sensitivity to some drugs that effect the central

nervous system (CNS) may be seen as a result of changes in permeability of the

blood–brain barrier and changes in receptor sensitivity in older adults.

30 Normal

aging involves a reduction in cerebral blood flow and oxygen consumption, and

increased cerebrovascular resistance. Drugs with anticholinergic properties are

associated with memory loss, confusion, cognitive impairments, and functional

decline in older patients.

31 Several examples of therapeutic classes with

anticholinergic properties are listed in Table 107-5.

Both central responsiveness and peripheral responsiveness of adrenergic

receptors decline with aging.

32 Monoamine-oxidase activity increases with normal

aging, and this is reflected by a decline in norepinephrine and dopamine levels in

aging brains.

33 The decline in CNS dopamine synthesis is associated with increased

sensitivity to dopamine blocking agents (e.g., antipsychotics). However, β-receptor

sensitivity to both β-agonists and β-antagonists decreases, even if the number of βreceptors does not decrease in older patients.

34,35 Because these neurologic and

biochemical reserves are reduced as a normal consequence of aging, iatrogenic

behavioral disorders are relatively common in older adults, and drugs are one of the

most common causes of sudden, unexplained mental impairment in the older adult.

PROBLEMS ASSOCIATED WITH DRUG USE IN

OLDER ADULTS

Polypharmacy

Over half of all older adults carry three or more chronic diseases. This

multimorbidity is associated with increased morbidity, mortality, functional decline,

health resource use, and multiple medication use.

36

p. 2220

p. 2221

Table 107-5

Categories of Anticholinergic Drugs That May Induce Confusion in Older

Patients

5,19

Therapeutic Class Example

Antimuscarinics Darifenacin

Fesoterodine

Flavoxate

Oxybutynin

Solifenacin

Tolterodine

Trospium

Antispasmodic Atropine

a

Clidinium-chlordiazepoxide

Dicyclomine

Homatropine

a

Propantheline

Scopolamine

a

Antiparkinson Benztropine

Trihexyphenidyl

Antihistamine Brompheniramine

Chlorpheniramine

Clemastine

Dimenhydrinate

Diphenhydramine

Doxylamine

Hydroxyzine HCL

Meclizine

Antidepressant Amitriptyline

Clomipramine

Desipramine

Doxepin (>6 mg)

Imipramine

Nortriptyline

Paroxetine

Trimipramine

Antiarrhythmic Disopyramide

Quinidine

Antipsychotic Clozapine

Olanzapine

Quetiapine

Hypnotic Hydroxyzine Pamoate

Skeletal Muscle Relaxant Cyclobenzaprine

Orphenadrine

This chart does not include all anticholinergic drugs that may cause confusion in older adults.

aDoes not include ophthalmic.

Adapted from American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication

Use in Older Adults. J Am Geriatr Soc. 2015;63:2227–2246.

Multiple medication use is associated with increased healthcare costs and

increased drug-related adverse events in the older population.

37 Polypharmacy exists

due to multiple chronic diseases, which often need to be treated with multiple

medications. For these reasons, monitoring drug therapy in these patients is not only

challenging but imperative. Duplicative prescribing within the same drug class may

occur, and unrecognized drug side effects may be treated with additional drugs.

Careful medication regimen review is essential to identify potentially unnecessary or

inappropriate medications and to systematically taper and discontinue these agents,

with attentive monitoring to older adults.

38

Adverse Drug Events

An adverse drug event includes preventable and nonpreventable events and accounts

for errors related to prescribing and administration. The combining of several

medications can also increase the risk of clinically significant drug–drug interactions

and subsequent adverse drug events in the elderly. Nearly one in 25 communitydwelling older adults is potentially at risk for a major drug–drug interaction.

39

Adverse drug events in general are expected to increase due to the increase in

medication use for prevention, medication use for chronic conditions, aging and

better access to prescription coverage.

40

The use of high-risk medications such as anticholinergics, antipsychotics, opiate

analgesics, and hypnotics, along with polypharmacy, increases the risk of adverse

drug events.

38

Up to 31% of hospitalizations of older persons involve adverse drug events.

41

Adverse drug events may be underreported and be difficult to detect in older patients

because they often present atypically and with nonspecific symptoms, such as

lethargy, confusion, lightheadedness, or falls. Nevertheless, most adverse reactions

represent extensions of a drug’s pharmacologic effect, have identifiable predictors,

and are potentially preventable.

42

ADVERSE DRUG REACTIONS IN OLDER PATIENTS

CASE 107-2

QUESTION 1: S.E. is an 85-year-old woman and resident of a long-term care facility (LTCF). She is 5

′2

″ and

102 pounds, with a serum creatinine of 1.6 mg/dL. She is admitted to the hospital for chest pain and shortness

of breath, and to rule out myocardial infarction (MI). Her physician is concerned about oversedation with

narcotics and prescribes ketorolac 30 mg IV every 6 hours. She has a history of severe HF and angina for

which she takes lisinopril 10 mg daily, furosemide 40 mg daily, aspirin 81 mg daily, and isosorbide mononitrate

30 mg daily. The lisinopril dosage is increased to 20 mg daily, and the furosemide dosage is increased to 40 mg

twice daily. Her blood pressure (BP) is 110/66 mm Hg, and her urine output has been from 20 to 30 mL/hour

for 4 hours since ketorolac was initiated. What risk factors are present in S.E. for drug-induced renal problems?

S.E. has a number of risk factors for the development of drug-induced acute renal

failure. Angiotensin-converting enzyme (ACE) inhibitors are indicated for HF

management and improve renal function by increasing cardiac output. However, they

can diminish efferent arteriole glomerular capillary filtration pressure and precipitate

acute renal failure in predisposed patients. The use of ketorolac is another risk

factor. A 13% incidence of azotemia has been reported in LTCF residents started on

a short course of NSAID treatment.

43 A low serum sodium concentration, high-dose

diuretics, diabetes, severe HF (i.e., New York Heart Association [NYHA] class IV),

use of a long-acting ACE inhibitor, and concurrent NSAID use are all risk factors for

drug-induced acute renal failure (see Chapter 28, Acute Kidney Injury). Elderly

patients may be particular susceptible, owing to the renal changes of aging described

earlier. Patients with these risk factors should be monitored closely when an ACE

inhibitor is initiated and when the dosage of an ACE inhibitor is increased (see

Chapter 14, Heart Failure). Renal prostaglandins (PGE2

, PGI2

) increase or help

maintain renal blood flow when renal function is compromised by intrinsic renal

disease, HF, liver disease with ascites, or hypertension; therefore, the use of a

prostaglandin inhibitor such as ketorolac places S.E. at an increased risk for acute

renal failure.

p. 2221

p. 2222

The ketorolac dose is excessive for S.E. based on the maximum recommended

dose of 60 mg/day for elderly patients.

44

APPROACH TO APPROPRIATE PRESCRIBING

As a result of high rates of multimorbidity and polypharmacy in older adults, in 2012,

the American Geriatrics Society convened an Expert Panel on the Care of Older

Adults with Multimorbidity to design a set of Guiding Principles for the Care of

Older Adults with Multimorbidity.

36 The five steps include the following: eliciting

and incorporating patient preferences and goals of care, recognizing the applicability

and limitations of available evidence, framing clinical decisions in terms of

prognosis, considering treatment complexity and feasibility, and continually

optimizing treatment plans. Effective implementation of these principles is likely to

require the input of interprofessional team members and high-quality-care

coordination. Pharmacists have an integral role in applying these guiding principles.

DISEASE-SPECIFIC GERIATRIC DRUG THERAPY

Cardiovascular Disease in the Ambulatory Older

Patient

CASE 107-3

QUESTION 1: T.M. is a 73-year-old woman who comes to a “brown bag” session at the local senior center.

She reports recently feeling “sluggish” and dizzy. She lives at home alone on a modest, fixed retirement income.

T.M.’s chronic medical problems include coronary artery disease (CAD), HF, hypertension, diabetes, and

hyperlipidemia. She states that different specialists prescribe her “a lot of medications,” but she does not know

their names. She admits to skipping her medications periodically when she does not feel well. T.M. usually

maintains an active social life, visiting her friends and attending the local seniors’ luncheons. She is interested in

natural medicines, and self-medicates with nonprescription medications and herbal remedies that her friends

also take. Because of the recent weakness, however, she has not gone out as much. Review of her brown bag

reveals the following items: glyburide 2.5 mg twice daily, hydrochlorothiazide 25 mg daily, atenolol 50 mg daily,

niacin 500 mg 3 times a day, ASA 325 mg as needed, digoxin 0.25 mg daily, isosorbide dinitrate (ISDN) 20 mg

4 times a day, nitroglycerin (NTG) 0.4 mg sublingual (SL) as needed, captopril 25 mg 3 times a day, furosemide

40 mg twice daily, acetaminophen 500 mg as needed, verapamil 60 mg 4 times a day, multivitamins with

minerals, calcium carbonate 500 mg 3 times a day, ibuprofen 200 mg as needed, and pioglitazone 30 mg daily.

She also drinks a glass of red wine with dinner. What initial steps are necessary for safe and effective

management of T.M.’s drug therapy?

Like many ambulatory older patients who are being treated for multiple chronic

medical conditions, T.M. is at high risk for drug-induced problems secondary to

nonadherence, medication errors, prescribing from multiple providers, selfmedicating, and polypharmacy. She is representative of more than nine million older

adults who live at home alone. The isolated community-dwelling older patient is

typically female 75 years of age or older, has multiple medical issues, and takes

multiple medications.

1 With rising life expectancy, the increased complexity of

managing multiple medical conditions has put nonhospitalized elderly individuals at

higher risk of experiencing adverse drug reactions and for adverse drug-related

admissions.

42,45 Another group of older individuals at higher risk of having adverse

drug reactions is those who are recently discharged from the hospital. The

postdischarge period is often a time of confusion, and elderly patients may have

difficulty coping and sorting out new versus replacement or duplicate drugs. A

summary of the various factors contributing to nonadherence in the older patient is

presented in Table 107-6.

46

Table 107-6

Factors Influencing the Inability to Adhere to a Medication Regimen

Low health literacy (understanding of medication instructions and importance)

Medication cost

Significant cognitive or physical impairment (e.g., memory, hearing, vision)

Inconsistent filling or refilling of prescriptions

Adverse effects

Lack of clinical evidence of effectiveness

Adapted From Bosworth HB et al. Medication adherence: a call for action. Am Heart J. 2011;162(3):412–424.

doi:10.1016/j.ahj.2011.06.007.

CASE 107-3, QUESTION 2: T.M. presents to the multidisciplinary geriatric care team on the advice of

pharmacists at the brown bag session. During the intake interview, she admits to selective adherence with many

medications based on how they make her feel and their costs. Her wine intake with dinner is 8 to 12 ounces

most days of the week. She also has not taken her furosemide and potassium supplement because she feels that

they are contributing to her sluggishness and dizziness. T.M.’s medical history and physical examination are as

follows: 73-year-old white woman, 5

′6

″

, 189 pounds; vital signs are as follows: BP, 168/82 mm Hg; heart rate

(HR), 54 beats/minute; temperature, 98.7°F; and respiratory rate, 18 breaths/minute. Pertinent laboratory values

are as follows:

Serum creatinine, 1.5 mg/dL

Blood urea nitrogen, 35 mg/dL

Sodium, 153 mEq/L

Potassium, 3.1 mEq/L

Magnesium, 1.5 mEq/L

Glucose, 250 mg/dL

Glycosylated hemoglobin (Hgb A1c

), 9.5%

Total cholesterol, 259 mg/dL

Low-density lipoprotein, 140 mg/dL

High-density lipoprotein, 40 mg/dL

Triglycerides, 200 mg/dL

Urine dipstick 2+ protein

Digoxin level, 1.5 ng/mL

Electrocardiogram showed sinus bradycardia with an old anterior MI. Echocardiogram showed an ejection

fraction (EF) of 25%. Her problem list includes new-onset sluggishness and fainting, chest pain and shortness of

breath (SOB) on exertion, 3(+) pitting edema bilaterally, NYHA class II–III HF, hypertension, type 2 diabetes,

obesity, excessive alcohol intake, CAD, and hyperlipidemia. What factors may be contributing to T.M.’s feeling

of sluggishness and dizziness?

T.M. needs a primary-care provider to coordinate her medical care and to

evaluate the new-onset sluggishness and dizziness. She should also be advised to

establish a client–patient relationship at a specific pharmacy for all her medications

to be on one profile for continuous assessment. Furthermore, T.M. should be

counseled to discontinue alcohol, which can interact with several of her current

medications and worsen her conditions. Finally, assessment of the risk for

medication-related problems (MRPs) is highly recommended.

47

T.M.’s sluggishness and dizziness are most likely caused by her low heart rate,

somewhat dehydrated state, and multiple

p. 2222

p. 2223

medications that have the potential for producing weakness. Specifically, digoxin

0.25 mg daily is considered a high dose; patients over age 70 should be limited to

0.125 mg daily as initial therapy to limit the development of toxicities from reduced

renal clearance. A level of 1.5 ng/mL is excessive because the therapeutic range is

from 0.5 to 0.9 ng/mLfor HF; therefore, the digoxin dose should be lowered to 0.125

mg daily.

48

If HF is controlled, one can try discontinuing digoxin to evaluate the continued

necessity of this agent. Finally, atenolol and verapamil can both lower the heart rate

and contribute further to the sluggishness. Switching atenolol to an extended-release

β-blocker indicated for heart failure may help. Verapamil can be discontinued

because it may not have benefits for T.M. other than for hypertension and may

contribute to a worsening of her HF.

HEART FAILURE

CASE 107-3, QUESTION 3: What is appropriate management for T.M.’s stage of HF?

On the basis of T.M.’s history of an old MI evidencing structural heart disease, her

low EF, and the presence of fluid-retention symptoms, T.M. is in stage C HF based

upon the American College of Cardiology/American Heart Association classification

scheme (see Chapter 14, Heart Failure). Heart failure is a common cause of

morbidity and mortality in older patients. The standard therapy for HF with reduced

ejection fraction typically consists of ACE inhibitors or ARBs, and β-blockers. In

symptomatic patients, diuretics may be used for symptomatic relief, and an

aldosterone antagonist for its morbidity and mortality benefits. In selected patients,

digoxin or hydralazine/isosorbide may also be appropriate to reduce morbidity and

mortality, as well as to prevent hospitalizations. The recommended therapy for T.M.

includes an ACE inhibitor, or ARB, a β-blocker, aldosterone antagonist, and diuretic

for symptomatic relief. Routine use of multiple medications in the treatment of HF

with coexisting medical conditions makes close monitoring of drug therapy essential.

Concurrent behavior modification with weight loss and salt restriction will also

allow better control of HF.

49

DIURETICS

CASE 107-3, QUESTION 4: Is the combination of furosemide and hydrochlorothiazide the most appropriate

diuretic regimen for T.M.?

Loop diuretics are generally more effective than thiazides in providing

symptomatic relief; furosemide is also preferred in T.M. because

hydrochlorothiazide is less effective in moderate-to-severe renal compromise

(creatinine clearance <30 mL/minute).

50 Furthermore, the combination of furosemide

and hydrochlorothiazide (HCTZ) is duplicative in diuretic action and may be

excessive. Discontinuing the HCTZ will likely help with T.M.’s hypokalemia and

slightly dehydrated state. Regular monitoring of serum creatinine, urea nitrogen,

sodium, and potassium is essential while on diuretics. The need for potassium

supplementation will depend on the resultant level after T.M. adheres to furosemide

while being maintained on an ACE inhibitor. Elderly patients often dislike taking

diuretics because of the frequent need to urinate. T.M. may be advised to take

furosemide later during the day after she returns from her social engagements.

ACE INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS

CASE 107-3, QUESTION 5: T.M. has been taking captopril 25 mg 3 times a day. Is this an appropriate

choice of ACE inhibitor for T.M.?

Blockade of the renin–angiotensin–aldosterone system is essential in the

management of HF. However, 3 times daily dosing of captopril is inconvenient and

may contribute to poor adherence. Although captopril, enalapril, and lisinopril have

all proven efficacious for HF in clinical trials, lisinopril is the only agent of these

that may be dosed daily. Alternatively, fosinopril may also be desirable based on its

50% hepatic and 50% renal elimination profile.

51 An ARB may also be appropriate

if therapy with an ACEI is not tolerated. Although previous studies have supported

the addition of an ARB to ACE inhibitor therapy based on a lower mortality and

hospitalization rate compared with an ACE inhibitor alone,

52 more recent data

present concerns about the use of combination therapy, particularly in the elderly,

owing to higher risk of hyperkalemia and worsening renal function.

53

β-BLOCKERS

CASE 107-3, QUESTION 6: T.M. is being treated with atenolol 50 mg daily. Is this an appropriate choice of

β-blocker for T.M.?

The β-blockers carvedilol, metoprolol, and bisoprolol have been proven to reduce

morbidity and mortality in patients with HF.

54–56

In T.M.’s case, atenolol is not

clinically indicated for HF and should be discontinued. Additionally, it is renally

cleared and may contribute to excessive sluggishness in an elderly patient with

compromised kidney function. Although any of the proven agents would be

appropriate, extended-release versions of carvedilol or metoprolol may reduce

T.M.’s medication burden.

CARDIOVASCULAR DISEASE AND HYPERLIPIDEMIA

CASE 107-3, QUESTION 7: T.M. does not take her niacin because she experienced unbearable facial

flushing. Despite her history of MI, she does not believe that cholesterol and “heart disease” are major health

concerns for a woman. Are women older than age 65 at different risk of death owing to coronary heart disease

(CHD) compared with their male counterparts, and is it important to manage cholesterol in an elderly woman

with CHD?

More than 60% of cardiovascular disease (CVD) deaths occur in people aged 75

or older. Approximately 70% of older adults aged 60 to 79 have CVD.

57 For those

over age 80, 83.0% of men and 87.1% of women have CVD.

57 Although male sex is

an independent risk factor for CVD, more women than men die from heart attacks

because these events occur in women at an older age. The significantly higher rate of

hypercholesterolemia in women seems also to predict a higher CVD risk than for men

later in life. Therefore, it is important to treat dyslipidemia in most patients with

clinical ASCVD, in those aged 40 to 75 with diabetes who have LDL-C levels of 70

to 189 mg/dL, and in those without diabetes and an estimated 10-year ASCVD risk

>/=7.5%.

58

CASE 107-3, QUESTION 8: What is an optimal therapeutic plan for management of T.M.’s hyperlipidemia?

T.M. is a 73-year-old female with history of diabetes, elevated cholesterol and

blood pressure conferring a 10-year ASCVD risk greater than 7.5%.

58 T.M.’s

treatment plan should begin with lifestyle and dietary modifications. Based on her

high ASCVD risk level and concomitant diabetes, a high intensity statin should be

started to lower LDL by at least 50%. However, the relative benefits of statin therapy

should be weighed against the potential risk of adverse reactions. Liver

transaminases should be monitored on a regular basis. Although rare, elderly

patients, particularly the frail elderly with low body mass, may be at increased risk

for muscle-related side effects. The hydrophilic statins pravastatin,

p. 2223

p. 2224

rosuvastatin, and pitavastatin are not metabolized significantly by the cytochrome

P-450 system and may present fewer side effects and lower potential of drug

interactions.

59 Both atorvastatin and rosuvastatin may be given at any time of day,

owing to their longer half-lives. Additionally, atorvastatin is less effected by renal

impairment and may be preferred in T.M.

60

Clinical guidance for the care of adults over age 74 with hyperlipidemia is limited

by lack of clinical trial data. Current guidelines recommend for the continuation of

currently tolerated statins as patients age.

58

If new statin initiation is required after

age 74, a careful assessment of risk versus benefit is warranted, and guidelines

recommend for consideration of moderate-intensity statins in patients who would

otherwise be candidates for high-intensity therapy. Medical conditions, such as

presence of high cardiovascular risk or vascular dementia, functional status, and

overall prognosis, may be helpful determinants in these cases.

At this time, there are insufficient data for guidelines to support combination

therapy. If combination therapy is indicated, ezetimibe can be added to further reduce

the levels of LDL and reduce cardiovascular outcomes without escalating the dose

and potential side effects of a statin as shown in the IMPROVE-IT trial.

61

Combination of a statin with niacin is less preferred. Results from the AIM-HIGH

trial found no added clinical benefit despite improvements in lipid profile and a

possible increase in stroke risk and adverse drug events.

62 Additionally, intolerable

side effects of flushing and risk for myopathy and hyperglycemia may limit use. The

addition of fibrates to statins has become controversial in patients with diabetes, as

shown recently in the ACCORD lipid trial. The addition of fenofibrate to simvastatin

in patients with diabetes did not reduce the rate of fatal CHD events, nonfatal MI, or

nonfatal stroke compared with those who received only simvastatin.

63 Finally,

because alcohol can increase triglycerides as much as 50%, abstinence is strongly

recommended.

64

CASE 107-3, QUESTION 9: What other interventions should be implemented to optimize management of

T.M.’s CAD?

Any strategy to optimize T.M.’s CAD management should take into consideration

the patient’s functional status, comorbidities, and risks versus benefits. T.M. is still

experiencing anginal pain on her current regimen, possibly caused by more advanced

disease or inability to adhere to the 4-times-daily regimen of ISDN. She should be

evaluated for coronary vessel disease and appropriate antiplatelet therapy initiated if

necessary. A once-daily long-acting nitrate preparation (isosorbide mononitrate

[ISMN]) may be better suited for her, with sublingual NTG available as needed.

T.M. should be maintained on first-line CAD therapy of aspirin and β-blockers

because aspirin is indicated for MI prevention and β-blockers may also be beneficial

for HF. To prevent further endothelial injury from the atherosclerosis that leads to

plaque rupture, statins are indicated as described previously. ACE inhibitors have

been shown to reduce mortality and to provide secondary prevention in CAD,

particularly among those 65 years or older. These agents should be part of the

regimen because ACE inhibitors also have benefits for T.M.’s HF and HTN, as well

as diabetic nephropathy.

65 Although calcium-channel blockers are indicated in CAD,

they have not been proven beneficial for HF; therefore, verapamil may be held at this

time whereas the other agents are being optimized.

HYPERTENSION

CASE 107-3, QUESTION 10: T.M. has uncontrolled hypertension. How should this be managed in light of

her advanced age?

Despite her advancing age, T.M.’s blood pressure is well above the goal of less

than 140/90 mm Hg for diabetic patients as set forth by the American Diabetes

Association (ADA) and the 2014 Evidence-Based Guideline for the Management of

High Blood Pressure in Adults: Report From the Panel Members Appointed to the

Eighth Joint National Committee (JNC 8).

65,66

(see Chapter 9, Essential

Hypertension.) Hypertension is present in more than two-thirds of individuals older

than 65 years of age. Despite having the highest prevalence of hypertension, only a

small percentage of this population is controlled or adequately treated for their blood

pressure.

67

In patients greater than 60 years of age without diabetes or CKD, a blood

pressure goal of <150/90 is appropriate. The HYVET study has shown that a mean

reduction of blood pressure from a baseline of 173/91 mm Hg by 15/6 mm Hg in

patients 80 years or older resulted in a 30% reduction in stroke, a 39% reduction in

rate of death from stroke, a 23% reduction in the rate of death from cardiovascular

causes, and a 64% reduction in the rate of heart failure.

68

Although adequate dosing and combination therapy may be essential in achieving

blood pressure control in the elderly population, close monitoring is also necessary

to avoid systolic blood pressure (SBP) less than 120 mm Hg based on the recent

findings from the ACCORD BP trial. Intensive target of SBP less than 120 mm Hg

did not reduce fatal and nonfatal major cardiovascular events but increased the

incidence of adverse effects.

69 Serious side effects of aggressive BP lowering

include hypotension, bradycardia, hypokalemia, and elevated SCr, and these effects

must be diligently monitored. For T.M., it is recommended that adequate doses of

furosemide and an ACE inhibitor or ARB with close monitoring be the main

therapeutic approach for her HTN. Extended- or controlled-release formulations of

metoprolol or carvedilol should be considered as it has for HF management. Though

beneficial for CAD and HTN, verapamil in sustained-release formulation should not

be used based on T.M.’s unstable HF.

49

Diabetes in the Elderly

CASE 107-3, QUESTION 11: T.M. reports that she frequently feels lightheaded and shaky after she takes

the glyburide. She admits to not taking glyburide regularly because it also causes rapid heartbeats. What is an

optimal therapeutic plan for the management of T.M.’s diabetes?

Comprehensive diabetes education needs to be initiated, stressing the importance

of weight loss, self-monitoring of blood glucose, alcohol abstinence, and medication

adherence. A 5% to 10% weight loss will improve T.M.’s glucose control and

cardiovascular status.

66 T.M.’s alcohol consumption and self-reported erratic meal

schedule may be contributing to the hypoglycemia (in addition to the glyburide), as

well as to the worsening of her hypertension and HF. The daily recommended

allowance of alcohol is no more than two drinks (24 ounces of beer, 10 ounces of

wine, or 3 ounces of 80-proof liquor) for men and no more than one drink for

women.

70 Glyburide is also a long-acting sulfonylurea and is associated with severe

hypoglycemia more commonly than other sulfonylureas because of its active

metabolites and highly renal elimination. In general, the elderly are more susceptible,

even at low doses, to hypoglycemia and may have difficulty recognizing the

symptoms of hypoglycemia. Among the second-generation sulfonylureas, glipizide or

glimepiride is preferred in renal impairment. Meglitinides, such as repaglinide or

nateglinide, may be preferred over the sulfonylureas in the elderly population

because they do not require dose adjustment in renal compromise and also allow for

a more flexible meal pattern. These agents, however, require multiple daily dosing

and may still contribute to hypoglycemic risk. Any new diabetes medication should

be initiated in low doses and gradually titrated upward to avoid hypoglycemic

episodes and to achieve glycemic goals in accordance with ADA guidelines.

66

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p. 2225

The current treatment algorithm for diabetes states that metformin with lifestyle

modification is the initial management approach.

71 Per FDA labeling, metformin is

contraindicated in T.M. because of a serum creatinine greater than 1.4 mg/dL;

however, the American Diabetes Association and European Association for the

Study of Diabetes reports that metformin seems safe unless eGFR falls to <30

mL/minute. As such, consideration of dosage reductions when renal function begins

to decline below 45 mL/minute may be appropriate.

72 When metformin is

contraindicated or inadequate, the effective and affordable sulfonylureas or

pioglitazone may be added; caution for risks of side effects such as hypoglycemia

should be exercised. Pioglitazone should be avoided in T.M. owing to her history of

HF. Injections such as GLP-1 analogs are often reserved unless a patient’s Hgb A 1c

remains above 8% while adhering to an appropriately titrated oral combination

regimen. Basal insulin can be added if A1c

is significantly elevated at baseline, or if

patients fail to achieve glycemic goals. More expensive and less effective A1c

-

lowering alternatives may include dipeptidyl peptidase-4 (DPP4) inhibitors and

sodium glucose cotransport 2 (SGLT2) inhibitors. DPP4 inhibitors do not promote

hypoglycemia and may be considered early on during the disease state. Their

dosages, however, need to be adjusted if the creatinine clearance is less than 50

mL/minutes.

73

In general, the priority of diabetes management in the elderly

population should be on reduction of cardiovascular risks with strict control of blood

pressure and lipids in addition to avoidance of hypoglycemic events. Hgb A1c goals

in older adults should generally be 7.5% to 8%. In the presence of few comorbidities

and good functional status, an Hgb A1c goal between 7% and 7.5% may be

appropriate if it can be safely achieved. Higher Hgb A1c

targets may be appropriate

for some elderly patients who are functionally impaired, cognitively impaired, have

complex multimorbidity, end-stage illness, or are prone to hypoglycemia or falls.

66,74

It is recommended that glyburide and pioglitazone be discontinued, and either

glipizide or repaglinide in combination with sitagliptin, or basal insulin such as

glargine, be initiated for T.M.’s diabetes. Finally, comprehensive screening of

diabetic complications should be done routinely to decrease morbidity and

mortality.

66

Depression and the Older Patient

Significant depression is the most common mental illness among adults older than 65

years of age, occurring in about 15%; it is a source of significant morbidity and

mortality in this population.

75 Unfortunately, depression remains under-recognized

and undertreated, even though it is a major risk factor for suicide in the elderly, who

have a suicide death rate that is higher than the national average.

76,77 Older patients

may be at increased risk for depression because of the high prevalence of comorbid

medical conditions (i.e., stroke, cancer, MI, rheumatoid arthritis, dementia,

Parkinson’s disease, DM).

78 Refer to Chapter 86: Depression for further discussion

of risk factors for depression and potential drug-induced causes.

CASE 107-4

QUESTION 1: J.W. is a married, 5

′8

″

, 110-pound, 79-year-old woman who presents for a psychiatric

evaluation. Her husband says she just has not been herself lately. The changes in J.W. began on a family

vacation 6 months earlier when she got lost on the cruise ship. Since that incident, she has become increasingly

anxious and has developed insomnia. Although she does not feelsad or “depressed,” she generally does not feel

well. J.W.’s normally positive attitude toward life has become pessimistic. Her husband confirms that she has

become more forgetful and no longer enjoys eating. In fact, she has lost 18 pounds during the past 2 months.

J.W. no longer does her volunteer work at the local children’s center. She says she wants to die because she is

no longer the person she used to be, but she denies having any specific suicidal thoughts. Her medical history is

significant for diabetes and hypertension, which are both well controlled on glipizide 5 mg every morning and

hydrochlorothiazide 25 mg daily. Her medical evaluation and physical examination are unremarkable.

Laboratory results and head-computed tomography scan are within normal limits. J.W. is diagnosed as having a

major depressive episode. What symptoms of depression are present in J.W.?

J.W.’s presenting symptoms are typical of major depression in an older patient,

which is commonly quite different from that of younger depressed patients. Criteria

set forth in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,

for diagnosing depression were developed using younger subjects and may not be

applicable to the older depressed patient.

79 Older patients are less likely to report

suicidal thoughts, but are more likely to experience weight loss as a symptom of

depression. Anxiety, irritability, somatic complaints, or a withdrawal from normal

activities, as exhibited by J.W., may be more significant features in late-life

depression than depressed mood. Memory problems, such as J.W.’s forgetfulness,

may be attributable to a lack of concentration or effort stemming from her depression.

This is distinct from dementia, which manifests itself predominantly with impairment

in short- and long-term memory (see Chapter 108, Geriatric Neurocognitive

Disorders). Therefore, depressed mood cannot be relied on for determining whether

an older patient has a depressive disorder.

76 Table 107-7 lists atypical depressive

symptoms that may be found in older adults. The presence of any one of these

symptoms should be considered a red flag and should prompt further evaluation for

major depression.

CASE 107-4, QUESTION 2: J.W.’s physician decides to prescribe an antidepressant. Which antidepressants

are preferred for use in older adults?

Selection of an antidepressant drug for elderly patients must take into

consideration age-related changes in pharmacokinetic, pharmacodynamic, and

physiologic parameters that make this population more vulnerable to adverse effects.

Although the available antidepressants are equally effective, selective serotonin

reuptake inhibitors (SSRIs) are better tolerated than older agents, such as the

tricyclic antidepressants. Therefore, low-dose SSRIs should be considered first-line

therapy for older patients. Of course, this does not preclude the use of sound clinical

judgment that incorporates the patient’s history of response, comorbidities, and the

drug’s side effect profile. J.W. should start taking a low-dose SSRI, such as

citalopram 10 mg daily, with gradual dose titration to achieve control of her

depressive symptoms. Doses of citalopram should not exceed 20 mg per day in adults

over age 60 due to risk of QTc prolongation. Table 107-8 lists recommended starting

doses for antidepressants in older patients. Full antidepressant response may take

twice as long in older patients compared with younger patients; it may take 8 to 12

weeks before assessment of J.W.’s full response can be made.

80

Table 107-7

Atypical Depressive Symptoms in the Older Adult

Agitation, anxiety, or worrying

Reduced initiative and problem-solving capacities

Alcohol or substance abuse

Paranoia

Obsessions and compulsions

Irritability

Somatic complaints

Excessive guilt

Marital discord

Social withdrawal

Cognitive impairment

Deterioration in self-care

Source: Sable JA et al. Late-life depression: how to identify its symptoms and provide effective treatment.

Geriatrics. 2002;57:18.

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Table 107-8

Antidepressant Dosing in Older Adults

Initial Dosage Maximum Dosage

Citalopram 10 mg every day 20 mg every day

Escitalopram 5 mg every day 10 mg every day

Fluoxetine 5 mg every day 40 mg every day

Fluvoxamine 25 mg at bedtime 200 mg at bedtime

Paroxetine 10 mg every day 40 mg every day

Sertraline 25 mg every day 150 mg every day

Mirtazapine 7.5 mg at bedtime 45 mg at bedtime

Bupropion 37.5 mg twice a day 75 mg twice a day

Duloxetine 20 mg every day 40 mg every day

Venlafaxine 25 mg twice a day 225 mg every day

Desvenlafaxine 50 mg every day 400 mg every day

Asthma and Chronic Obstructive Pulmonary Disease in

the Elderly

Epidemiologic studies estimate the prevalence of asthma in the elderly to be

approximately 4.5% to 12.7%.

81,82 Although 25% of asthmatics with 65 and older

have a history of childhood asthma diagnosed before the age of 20, 27% are

diagnosed with asthma after the age of 60.

83 Rates of asthma-related hospitalization

and mortality are highest amongst adults over age 65, possibly because of

underdiagnosis and undertreatment of the disease.

83 Symptoms of asthma, including

wheezing, cough, chest tightness, and dyspnea, are similar in both older and younger

patients (see Chapter 18, Asthma). However, because the elderly are more likely to

have coexisting medical conditions (e.g., HF, angina, COPD, gastroesophageal reflux

disease [GERD]) with symptoms that mimic asthma, accurate diagnosis and

assessment of severity is often more difficult.

83

Chronic obstructive pulmonary disease is largely a disease of older patients with a

prevalence of as high as 10% in those 75 and older.

84 This chronic condition is a

major cause of morbidity and mortality in the older population, accounting for

approximately one-fifth of all U.S. hospitalizations in those over age 65.

85

It is often

undiagnosed as it may be mistaken as a “normal” part of the aging process, and may

be confounded by physical deconditioning or comorbidities such as HF.

85 Drug

therapy for COPD in the elderly does not differ significantly from standard

management regimens (see Chapter 19, Chronic Obstructive Pulmonary Disease).

However, older patients with pulmonary disease and coexisting medical problems

may be more sensitive to the adverse effects of pharmacologic agents.

CASE 107-5

QUESTION 1: J.C., a 67-year-old woman, 5

′6

″

, 145 pounds, presents to the ED complaining of shortness of

breath for the past 2 days. She was in her usual state of health until 4 days ago when she exhibited flulike

symptoms consisting of fever, cough, and mild wheezing. J.C. has a history of asthma, diabetes, hypertension,

headache, and GERD. Her current medications include glipizide 5 mg daily, lisinopril 10 mg daily, metoprolol 50

mg twice daily, lansoprazole 30 mg daily, ibuprofen 200 mg every 6 hours as needed for headache, albuterol

metered-dose inhaler (MDI) 2 puffs 4 times a day as needed for SOB, and fluticasone HFA (44 mcg) MDI 2

puffs twice daily. Her drug regimen has been unchanged for the past 2 years, and she reports taking all

medications as prescribed. The only recent change has been the need for albuterol every 3 to 4 hours for

coughing and wheezing during the past few days. What factors (including medications) may have contributed to

her acute asthma exacerbation?

Management of acute asthma exacerbations in previously stable elderly asthmatics

should begin with a review of the medication history for asthma-inducing agents.

Aspirin and other NSAIDs are known to induce acute bronchoconstriction in adult

asthmatics.

86 J.C. should be queried about her previous (especially recent) use of

ibuprofen in relation to her asthma symptoms, and these agents should be avoided if

associated. An alternative agent for pain control is acetaminophen.

87 Nonselective βblockers, including topical ophthalmic formulations, can precipitate acute

bronchoconstriction and should be avoided in patients with reactive airway disease.

Although cardioselective β-blockers are generally considered safe for use in patients

with asthma, it is important to recognize that cardioselectivity may be lost with

higher dosages. Because J.C. has been taking low-dose metoprolol (a cardioselective

agent) for years without problem, this medication is unlikely to be contributing to her

current asthma exacerbation. One of the most important triggers for asthma

exacerbations is respiratory infection (particularly viral). J.C. reports the recent

onset of symptoms consistent with influenza, and this is likely precipitating her

current pulmonary symptoms. As a future prophylactic measure, J.C. should be

counseled to receive the influenza vaccine annually. J.C. does not recall every

receiving the pneumococcal vaccine. In adults aged 65 and older who have never

received the pneumococcal vaccine or who are unsure like J.C., they should receive

a one-time dose of pneumococcal conjugate vaccine (PCV13), and 12 months later

they should receive the pneumococcal polysaccharide vaccine (PPSV23).

88

CASE 107-5, QUESTION 2: Are the medication regimens used to treat asthma in elderly patients different

from those used in children and younger adults? Should J.C.’s maintenance asthma regimen be changed?

Medications used in the management of persistent asthma in the elderly are similar

to those used in younger patients and consist of bronchodilators in combination with

anti-inflammatory agents (see Chapter 23, Asthma). Drug selection and monitoring

may be more complicated in the elderly because of the greater likelihood of

coexisting medical conditions and increased potential for drug–disease and drug–

drug interactions.

Inhaled β2

-agonists are an important class of drugs used to treat asthma in all age

groups. The low incidence of drug interactions and reduced side effect profile make

inhaled β2

-agonists ideal for use in the older asthmatics. However, these agents can

cause dose-dependent systemic side effects, such as tremor, tachycardia,

hypokalemia, and arrhythmias, which are of particular concern in patients with

cardiac conditions.

82

Inhaled corticosteroids are

p. 2226

p. 2227

the preferred treatment for all forms of persistent asthma yet they may be

underused in the elderly. Though generally well tolerated, elderly patients receiving

high-dose therapy are at an increased risk for osteoporosis, cataracts, skin thinning,

and bruising.

89