The U.S. population is aging. Patients 65 years and older represent approximately 13 percent of the population, but they consume about 30 percent of all prescription medications.¹ Older American consumers spend an average total of $3 billion annually on prescription medications.² Sixty-one percent of older people seeing a physician are taking at least one prescription medication,³ and most older Americans take an average of three to five medications.^4,5 These data do not include the use of over-the-counter medications or herbal therapies. An estimated 40 percent of older Americans have used some form of dietary supplement within the past year⁶ (Table 1).⁷

The physician who cares for aging patients with numerous chronic medical conditions must make daily decisions about appropriate drug therapy. More than 60 percent of all physician visits include a prescription for med-ication.⁸ The multiple medications and complex drug schedules may be justified for older persons with complex medical problems. However, the use of too many medications can pose problems of serious adverse drug events and drug-drug interactions, and often can contribute to nonadherence (Table 2).⁹

Adherence and Adverse Drug Events

Many factors influence the efficacy, safety, and success of drug therapy with older patients. These factors include not only the effects of aging on the pharmacokinetics and pharmacodynamics of medications but also patient characteristics (Table 3)¹⁰ and other issues, including atypical presentation of illness, the use of multiple health care professionals, and adherence to drug regimens (Table 4).^11,12

Adherence or compliance with drug therapy is essential to successful medical management. Noncompliance or nonadherence with drug therapy in older patient populations ranges from 21 to 55 percent.^13,14 The reasons for nonadherence include more medication use (total number of pills taken per day), forgetting or confusion about dosage schedule, intentional nonadherence because of medication side effects, and increased sensitivity to drugs leading to toxicity and adverse events.¹² Older patients may intentionally take too much of a medication, thinking it will help speed their recovery, while others, who cannot afford the medications, may undermedicate or simply not take any of the medication. Simple interventions by the health care team, such as reinforcing the importance of taking the prescribed dose and encouraging use of pill calendar boxes, can improve adherence and overall compliance with drug therapy (Table 5).¹¹

One study¹⁵ revealed that adverse drug events in older patients led to hospitalizations in 25 percent of patients 80 years and older. Adverse drug reactions are a common cause of iatrogenic illness in this age group, with psycho-tropic and cardiovascular drugs accounting for many of these.¹¹ Many drugs can cause distressing and potentially disabling or life-threatening reactions (Table 6).¹¹ A basic understanding of how drugs affect the aging body is needed to appreciate the risk inherent in prescribing to older adults.

How Do Drugs Interact with the Aging Body?

Pharmacokinetics includes absorption, distribution, metabolism, and excretion. Of the four, absorption is least affected by aging.¹⁶ In older persons, absorption is generally complete, just slower. In addition to age-related changes, common medical conditions such as heart failure may reduce the rate and extent of absorption. Distribution of most medications is related to body weight and composition changes that occur with aging (decreased lean muscle mass, increased fat mass, and decreased total body water). Drug dosage recommendations may have to be modified based on estimates of lean body mass. Loading doses of drugs may be lowered because of decreased total body water. Fat-soluble drugs may have to be administered in lower dosages because of the potential for accumulation in fatty tissues and a longer duration of action.¹⁶

How a drug is cleared, through hepatic metabolism or renal clearance, dramatically changes with aging. Hepatic metabolism is variable and depends on age, genotype, lifestyle, hepatic blood flow, hepatic diseases, and interactions with other medications.¹⁶ Hepatic metabolism occurs through one of two biotransformation systems. Phase I reactions (oxidation, reduction, demethylation, or hydrolysis) via the cytochrome P450 system (CYP450) can produce biologically active metabolites. Phase I reactions tend to occur more slowly in older adults, which often leads to less than optimal drug metabolism. In contrast, phase II metabolism, including acetylation, sulfonation, conjugation, and glucuronidation, is little changed with aging (Table 7).¹⁶ Cigarette smoking, alcohol use, and caffeine use may also affect hepatic metabolism of medications.¹⁶

Renal excretion of drugs is affected by aging, although there is great interindividual variation. Drug elimination is correlated with creatinine clearance, which declines by 50 percent between 25 and 85 years of age.¹⁶ Because lean body mass decreases with aging, the serum creatinine level is a poor indicator of (and tends to overestimate) the creatinine clearance in older adults. The Cockroft-Gault formula¹⁷ should be used to estimate creatinine clearance in older adults:

For example, a 25-year-old man and an 85-year-old man, each weighing 72 kg (158.4 lb) and having a serum creatinine value of 1 mg per dL (76 μmol per L), would have different estimated creatinine clearance even though their serum creatinine value is the same. The younger man would have an estimated creatinine clearance of 115 mL per minute (1.92 mL per second), while the older man's would be 55 mL per minute (0.92 mL per second). This difference is especially important with drugs that have a low therapeutic index and appreciable renal excretion (aminoglycosides, lithium, digoxin, procainamide [Pronestyl], vancomycin [Vancocin]).²

Pharmacodynamics relates to how sensitive tissues are to drugs. Sensitivity to drugs may increase or decrease with aging, and these full effects are poorly understood as a component of the aging process.¹⁶ Pharmacodynamic changes may be related to changes in receptor binding, decreased receptor number, or altered translation of a receptor-initiated cellular response. For older adults, complete elimination of a drug from body tissues, including the brain, can take weeks because of a combination of pharmacokinetic and pharmacodynamic effects.

How Many Drugs Are Too Many?

Polypharmacy is simply the use of many medications at the same time. Other definitions include prescribing more medication than is clinically indicated, a medical regimen that includes at least one unnecessary medication, or the empiric use of five or more medications.¹⁸ Polypharmacy is particularly harmful when the patient receives too many medications for too long and in too high a dosage. The major concern about polypharmacy is the potential for adverse drug reactions and interactions. It has been estimated that for every dollar spent on pharmaceuticals in nursing homes, another dollar is spent treating the iatrogenic illnesses attributed to the medications.¹⁹ Drug-induced adverse events can mimic other geriatric syndromes or precipitate confusion, falls, and incontinence (Table 6),¹¹ possibly causing the physician to prescribe yet another drug. This prescribing cascade^20,21 is a preventable problem that requires the physician to be certain that all medications being taken by the patient are appropriately indicated, safe, and effective.

To prevent an iatrogenic illness caused by overprescribing, it is important to consider any new signs and symptoms in an older patient to be a possible consequence of current drug therapy.²⁰ A 10-step approach to help reduce polypharmacy has been described (Table 8).²² Another way to avoid adverse drug events is to use lower dosages for older patients. Many popular drugs do not have effective lower-dosage recommendations from the manufacturers. Physicians should remember to start low and go slow. Starting with one third to one half of the recommended dosage may help eliminate potential harmful effects.²²

What Medications Could Potentially Cause Trouble?

Drug-related problems including therapeutic failure, adverse drug reactions, and adverse drug withdrawal events are common in older patients.²³ To address this problem, a list of drugs that may be inappropriate to prescribe to older persons, especially the frail elderly, was developed through a consensus of experts in geriatric medicine and pharmacology.^24,25 This list, known as the Beers criteria, was originally targeted at nursing homes but has been expanded for community-dwelling seniors.²⁶

A recent review²⁷ of the Beers criteria applied to various health care settings, from community-dwelling seniors to frail nursing home patients, found that between one in four and one in seven older patients received at least one inappropriate medication. The problematic drugs most often prescribed were long-acting benzodiazepines, dipyridamole (Persantine), propoxyphene (Darvon), and amitriptyline (Elavil).²⁷ When applying these criteria to a patient, it is important to remember that if a drug has been used for a long time without a serious adverse effect, it may not need to be discontinued. The physician should continually monitor a patient's drug list and carefully ascertain if any medication is causing harm. Physicians can address this issue by keeping a list of drugs that can cause serious adverse events when prescribed to older adults (Table 9).^24,25 [References ²⁴ and ²⁵, Evidence level C: expert opinion/consensus]

What Medications Can Benefit Older Patients?

To avoid adverse drug events and polypharmacy, drugs that are beneficial in the treatment or prevention of serious diseases may not be prescribed to older adults.^27,28 For example, clinical evidence is now available showing that older adults benefit from beta-blocker therapy after myocardial infarction, adequate control of hypertension, and adequate treatment of hyperlipidemia. Other medications that have shown benefit in older adults, but are sometimes not prescribed, include angiotensin-converting enzyme inhibitors for heart failure and anticoagulants for nonvalvular atrial fibrillation (Table 10).^29–39

Prescribing medications for older adults requires maintaining a balance between using too few and too little, and too many and too much.⁴⁰ Frequent follow-up visits, especially if a new drug has been introduced, allow the physician to assess for adverse drug events and possible drug-disease and drug-drug interactions. One recommended strategy is to verify at each patient visit if there is an indication for each drug, if it is effective in this case, if there is any unnecessary duplication with other drugs, and if this is the least expensive drug available compared with others of equal benefit. Before deciding that a medication is a therapeutic failure, the physician should make sure that an adequate dosage has been administered for an appropriate length of time.⁴¹ The goals in using drug therapy are to treat disease, alleviate pain and suffering, and prevent the life-threatening complications of many chronic diseases. Being successful with these goals requires a balance between benefit and risk to optimize prescribing for the aging population.