Introduction

Providing safe, effective drug therapy is one of the greatest challenges in

geriatrics. The elderly use more drugs than any other age group and have many
chronic disorders that affect drug response. Acute or chronic disorders can
further deplete the already diminished physiologic reserves of the elderly,
increasing their risk of adverse drug effects. Aging also alters pharmacodynamics
and pharmacokinetics and thus affects the choice, dose, and frequency of use of
many drugs. For the elderly, drug therapy is further complicated because they
may be unable to obtain or afford drugs or adhere to complex drug regimens.

Prevalence of prescription drug use among ambulatory adults increases

substantially with aging. Among people ≥ 65, > 90% use ≥ 1 drug/week, > 40%
use ≥ 5 different drugs/week, and 12% use ≥ 10 different drugs/week. Women
take more drugs, particularly psychoactive and arthritis drugs. Drug use is
greatest among the frail elderly, hospitalized patients, and nursing home
residents; typically, a nursing home resident is given 7 to 8 different drugs on a
regular basis.

When prescribed and used appropriately, most drugs can benefit the elderly.
Drugs are critical for prevention and treatment of acute and chronic disorders.
Many directly modulate disease; others control symptoms that reduce quality of
life. However, the elderly are at substantial risk of having adverse drug effects
(see Adverse Drug Reactions; see Drug Therapy in the Elderly: Adverse Drug
Effects in the Elderly). Among ambulatory people ≥ 65, adverse drug events
occur at a rate of about 50 events/1000 person-years; nearly 30% of these events
result from drug errors, predominantly in drug prescribing and monitoring, as
well as lack of patient adherence. For optimal drug therapy in the elderly,
benefits must be maximized while risks are minimized.

Polypharmacy (concurrent use of many drugs) alone does not accurately gauge
appropriateness of therapy because the elderly often have many disorders
requiring treatment; however, the elderly often use unnecessary drugs, prescribed
for minor symptoms that are best treated nonpharmacologically. Use of
unnecessary drugs (eg, analgesics, antibiotics, H2 blockers, hypnotics, laxatives)
increases cost and may lead to avoidable toxicity.
 Some drugs are underused in the elderly. Examples are drugs to treat depression,
pain, heart failure, incontinence and to prevent glaucoma, influenza, and
pneumococcal infections.

Adverse Drug Effects in the Elderly

The elderly are at increased risk of adverse effects with certain drugs (see Table
3). Increased risk may result from age-related changes in pharmacokinetics or
pharmacodynamics. Risk of an adverse effect increases exponentially with the
number of drugs used, partly because multiple drug therapy reflects the presence
of many diseases and increases risk of drug-disease and drug-drug interactions.

Drug-disease interactions (exacerbation of a disease by a drug given for another

reason) can occur in any age group but are especially important in the elderly,
who are more likely to have multiple disorders. Distinguishing often subtle
adverse drug effects from the effects of disease is difficult (see Table 4).
Anticholinergic drugs are a common cause of such interactions.

Drug-drug interactions are myriad, but there appear to be few differences in

drug-drug interactions in the elderly. However, induction of drug metabolism by
dichloralphenazone, glutethimide, and rifampin SOME TRADE NAMES
RIFADIN
RIMACTANE
Click for Drug Monograph
may be decreased in the elderly. Concurrent use of more than one drug with
similar toxicity can increase the risk or severity of adverse effects

Considerations for Effective Drug Therapy in the Elderly

 The prescribing cascade begins when an adverse drug effect is misinterpreted as
a new disorder. In response, another drug is prescribed, and patients may develop
additional adverse effects related to the second, unnecessary drug. Additional
adverse effects may also be misinterpreted as a new disorder and treated
unnecessarily, and so on. In elderly patients, prescribers should always consider
the possibility that a new symptom or sign is due to drug therapy.

Doses must often be reduced, although dose requirements vary considerably

from person to person. In general, starting doses of about 1⁄3 to 1⁄2 the usual adult
dose are indicated for drugs with a low therapeutic index and when a condition
may be exacerbated by a drug. However, titrating the dose upward as tolerated is
essential to providing maximal therapeutic benefit for the elderly.

Adherence (compliance) is affected by many factors but not by age per se.
However, about 40% of elderly patients do not take drugs as directed, usually
taking less than prescribed (underadherence). Causes are the same as for younger
adults (see Concepts in Pharmacotherapy: Adherence to a Drug Regimen). In
addition, financial and physical constraints may make purchasing drugs difficult,
dementia may make taking drugs difficult, and lack of information may lead to
errors. Taking drugs can be facilitated by easy-access containers, containers
equipped with reminder alarms, containers filled by daily drug needs, or
reminder phone calls.

Drug Categories of Concern in the Elderly

Some drug categories (eg, analgesics, anticoagulants, antihypertensives,

antiparkinsonian drugs, diuretics, hypoglycemic drugs, psychoactive drugs) pose
special risks for elderly patients.
Analgesics: NSAIDs are widely used; several are available without prescription.
Serious adverse effects include peptic ulceration and upper GI bleeding; risk is
increased when an NSAID is begun and when dose is increased. Risk of upper
GI bleeding increases when NSAIDs are given with warfarin or aspirin. NSAIDs
may increase risk of cardiovascular events and can cause fluid retention.
Selective COX-2 inhibitors (coxibs) cause less GI irritation and platelet
inhibition than other NSAIDs. Nonetheless, coxibs have a risk of GI bleeding,
especially in patients taking warfarin (even at low dose) and in those who have
had GI events. Coxibs, as a class, appear to increase risk of cardiovascular
events, but that risk may vary by drug; their use should be approached
cautiously. Coxibs have renal effects comparable to those of other NSAIDs.
Monitoring serum creatinine is necessary, especially in patients with other risk
factors (eg, heart failure, renal impairment, cirrhosis with ascites, volume
depletion, diuretic use).

Anticoagulants: Aging does not alter the pharmacokinetics of warfarin but may
increase sensitivity to its anticoagulant effect. Careful dosing and scrupulous
monitoring can largely overcome the increased risk of bleeding in elderly
patients taking warfarin
.

Antihypertensives: In many elderly patients, lower starting doses of

antihypertensives may be necessary to reduce risk of adverse effects; however,
for most elderly patients with hypertension, achieving BP goals requires standard
doses and multidrug therapy. Initially, a thiazide-type diuretic is usually given
alone or with one of the other classes (ACE inhibitors, angiotensin II receptor
blockers, β-blockers, Ca channel blockers) shown to be beneficial. Short-acting
dihydropyridines (eg, nifedipine ) may increase mortality risk and should not be
used.

Antiparkinsonian drugs: Levodopa clearance is reduced in elderly patients, who

are also more susceptible to orthostatic hypotension and confusion. Therefore,
elderly patients should be given a lower starting dose of levodopa and carefully
monitored for adverse effects (see Movement and Cerebellar Disorders:
Treatment). Patients who become confused while taking levodopa may also not
tolerate newer dopamine agonists (eg, bromocriptine, pergolide
, pramipexole , ropinirole ). Because elderly patients with parkinsonism may be
cognitively impaired, anticholinergic drugs should be avoided.
Digoxin: Digoxin clearance decreases an average of 50% in elderly patients with
normal serum creatinine levels. Therefore, maintenance doses should be started
low (0.125 mg/day) and adjusted according to response and serum digoxin
levels. Digoxin must be used with caution in patients with heart failure. In men
with heart failure and a left ventricular ejection fraction of ≤ 45%, serum digoxin
levels > 0.8 ng/mL are associated with increased mortality risk. Among women
with heart failure and depressed left ventricular function, digoxin, regardless of
serum level, is associated with increased mortality risk.

Diuretics: Lower doses of thiazide diuretics (eg, hydrochlorothiazide or

chlorthalidone 12.5 to 25 mg) can effectively control hypertension in many
elderly patients and have less risk of hypokalemia and hyperglycemia (see also
Arterial Hypertension: Diuretics). Thus, K supplements may be required less
often. K-sparing diuretics should be used with caution in the elderly; the K level
must be carefully monitored, particularly when these diuretics are given with
ACE inhibitors.

Antihyperglycemics: Doses of antihyperglycemics should be titrated carefully in

patients with diabetes mellitus. Risk of hypoglycemia due to sulfonylureas may
increase with aging. Chlorpropamide is not recommended because elderly
patients are at increased risk of hyponatremia due to syndrome of inappropriate
antidiuretic hormone secretion (SIADH) and because the drug's long duration of
action is dangerous if adverse effects or hypoglycemia occurs. Risk of
hypoglycemia is greater with glyburide than with other oral antihyperglycemics.

Metformin , a biguanide excreted by the kidneys, increases peripheral tissue

sensitivity to insulin and can be effective given alone or with sulfonylureas. Risk
of lactic acidosis, a rare but serious complication, increases with degree of renal
impairment and with patient age. Heart failure is a contraindication.

Psychoactive drugs: In nonpsychotic, agitated patients, antipsychotics control

symptoms only marginally better than do placebos. Antipsychotics can reduce
paranoia but may worsen confusion (see also Schizophrenia and Related
Disorders: Conventional antipsychotics). Elderly patients, especially women, are
at increased risk of tardive dyskinesia, which is often irreversible. The FDA has
issued a warning regarding the use of atypical antipsychotics in the treatment of
behavioral disorders in elderly patients with dementia. A review of placebo-
controlled studies has shown a higher death rate associated with their use.
Sedation, orthostatic hypotension, anticholinergic effects, and akathisia
(subjective motor restlessness) can occur in up to 20% of elderly patients taking
an antipsychotic, and drug-induced parkinsonism can persist for up to 6 to 9 mo
after stopping the drug. Antipsychotic drugs should be reserved for psychosis.
When an antipsychotic is used, the starting dose should be about ¼ the usual
starting adult dose and should be increased gradually. Extrapyramidal
dysfunction can develop when atypical antipsychotics (eg, olanzapine,
quetiapine, risperidone) are used, especially at higher doses. Clinical trial data
relating to dosing, efficacy, and safety of these drugs in the elderly are limited;
thus, dose reduction is prudent.

Use of anxiolytics and hypnotics can be problematic. Treatable causes of

insomnia should be sought and managed before using hypnotics (see also Sleep
and Wakefulness Disorders: Hypnotics). Nonbenzodiazepine hypnotics (eg, the
imidazopyridines, alpidem and zolpidem) are options for treating insomnia in the
elderly if nonpharmacologic measures (eg, avoiding caffeinated beverages,
limiting daytime napping, modifying bedtime) are ineffective. These drugs bind
mainly to a benzodiazepine receptor subtype. Imidazopyridines disturb the sleep
pattern less than benzodiazepines and have a more rapid onset, fewer rebound
effects, and less potential for dependence. Longer-acting benzodiazepines (eg,
clonazepam
, diazepam, flurazepam) should be avoided because they are likely to accumulate
and have adverse effects (eg, drowsiness, impaired memory, impaired balance
leading to falls and fractures). Duration of anxiolytic or hypnotic therapy should
be limited if possible because tolerance and dependence may develop;
withdrawal may lead to rebound anxiety and insomnia. Short- or intermediate-
acting benzodiazepines with half-lives < 24 h (eg, alprazolam, lorazepam,
oxazepam, temazepam) may be preferable to long-acting benzodiazepines, but
these drugs may also have adverse effects, including those that lead to falls and
fractures. Antihistamines (eg, diphenhydramine, hydroxyzine) are not
recommended as anxiolytics or hypnotics because they have anticholinergic
effects.

Buspirone , a partial serotonin agonist, can be effective for general anxiety

disorder; elderly patients tolerate doses up to 30 mg/day well. The slow onset of
anxiolytic action (up to 2 to 3 wk) can be a disadvantage in urgent cases.

Of antidepressants, SSRIs and mixed serotonin/ dopamine reuptake inhibitors are

generally preferred. These drugs appear to be as effective as tricyclic
antidepressants and cause less toxicity. A possible disadvantage of fluoxetine is
 the long elimination half-life, especially of its active metabolite. Paroxetine is
more sedating than other SSRIs, has anticholinergic effects, and, like some other
SSRIs, can inhibit hepatic cytochrome P-450 2D6 enzyme activity, possibly
impairing the metabolism of several drugs, including some antipsychotics,
antiarrhythmics, and tricyclic antidepressants. Sertraline is more activating;
diarrhea is a common adverse effect. Doses of these drugs should be reduced by
up to 50%. Many SSRIs are available, but data on their use in the elderly are
sparse. Tricyclic antidepressants are effective but should rarely be used in the
elderly because safer alternatives exist.

Pharmacodynamics in the Elderly

Pharmacodynamics is defined as what the drug does to the body or the response
of the body to the drug; it is affected by receptor binding, postreceptor effects,
and chemical interactions (see Pharmacodynamics: Drug-Receptor Interactions).
The effects of similar drug concentrations at the site of action (sensitivity) may
be greater or smaller than those in younger people (see Table 2). Differences
may be due to changes in drug-receptor interaction, in postreceptor events, or in
adaptive homeostatic responses and, among frail patients, are often due to organ
pathology.

Elderly patients are particularly sensitive to anticholinergic drug effects. Many

drugs (eg, tricyclic antidepressants, most nonselective antihistamines, some
antipsychotic drugs, many OTC hypnotics and cold preparations) are
anticholinergic. The elderly, most notably those with dementia, are particularly
prone to CNS adverse effects of such drugs and may develop confusion and
somnolence. Anticholinergic drugs also commonly cause constipation, urinary
retention (especially in elderly men with benign prostatic hyperplasia), blurred
vision, orthostatic hypotension, and dry mouth.

Pharmacokinetics in the Elderly

Pharmacokinetics (see Pharmacokinetics) is best defined as what the body does
to the drug; it includes absorption, distribution across body compartments,
metabolism, and excretion. With aging, the metabolism and excretion of many
drugs decrease, and the physiologic changes of aging require dose adjustment for
some drugs. Toxicity may accumulate slowly because levels of chronically used
drugs tend to increase for about 6 half-lives. For example, certain
benzodiazepines ( diazepam , flurazepam , chlordiazepoxide ) have half-lives of
up to 96 h in many elderly patients; signs of toxicity may not appear until days or
weeks after therapy is started.

Absorption: Despite an age-related decrease in small-bowel surface area and an

increase in gastric pH, changes in drug absorption tend to be trivial and clinically
inconsequential.

Distribution: With aging, the body's fat compartment increases, and the water
compartment decreases. Increased fat increases the volume of distribution for
highly lipophilic drugs (eg, diazepam) and may increase their elimination half-
lives.

Serum albumin decreases and α1-acid glycoprotein increases with aging, but the
clinical effect of these changes on serum drug binding is unclear. In patients with
an acute disorder or undernutrition, rapid reductions in serum albumin may
enhance drug effects because serum levels of unbound drug may increase.

Hepatic metabolism: Overall hepatic metabolism of many drugs through the

cytochrome P-450 enzyme system decreases with aging. For drugs with
decreased hepatic metabolism (see Table 1), clearance typically decreases 30 to
40%. Theoretically, maintenance drug doses should be decreased by this
percentage; however, rate of drug metabolism varies greatly from person to
person, and individual titration is required.

Table 1
Effect of Aging on Drug Metabolism* and Elimination

Class or Category Decreased Hepatic Decreased Renal

Metabolism Elimination
Analgesics and Dextropropoxyphene —
anti-inflammatory Ibuprofen
drugs
Meperidine
Morphine
Naproxen

Antibiotics — Amikacin

Ciprofloxacin
Gentamicin
Nitrofurantoin
Streptomycin
Tobramycin

Cardiovascular Amlodipine N-Acetylprocainamide

drugs Diltiazem Captopril
Lidocaine Digoxin
Nifedipine Enalapril
Propranolol Lisinopril
Quinidine Procainamide
Theophylline Quinapril
Verapamil

Diuretics — Amiloride
Furosemide
Hydrochlorothiazide
Triamterene

Psychoactive Alprazolam Risperidone

drugs
 Chlordiazepoxide
Desipramine
Diazepam
Imipramine
Nortriptyline
Trazodone
Triazolam

Others Levodopa Amantadine

Chlorpropamide
Cimetidine
Lithium
Ranitidine

*When aging's effect on hepatic metabolism of a drug is controversial, effects

reported in the majority of studies are listed.
The effect occurs in men but not in women.

Hepatic clearance of drugs with multistage metabolism (nonsynthetic and

synthetic reactions) is more likely to be prolonged in the elderly (see
Pharmacokinetics: Metabolism). Usually, age does not greatly affect clearance of
drugs that are metabolized by conjugation, typically with glucuronic acid.

Renal elimination: After age 30, creatinine clearance decreases an average of 8

mL/min/1.73 m2/decade; however, interindividual variation in the decline with
aging is substantial. Serum creatinine levels often remain within normal limits
despite a decrease in GFR because the elderly have less muscle mass and thus
produce less creatinine. Decreases in tubular function parallel those in
glomerular function.

These changes decrease renal elimination of some drugs (see Table 1). Clinical
implications depend on the extent that renal elimination contributes to total
systemic elimination and on the drug's therapeutic index (ratio of maximum
tolerated dose to minimum effective dose). Creatinine clearance (measured or
estimated using computer programs or a formula—see Approach to the
Genitourinary Patient: Estimating creatinine clearance) is used to guide drug
dose. Because renal function is dynamic, maintenance doses of drugs should be
adjusted when patients become ill, dehydrated, or have recently recovered from
dehydration.