As aging changes patients’ reactions, hospitalists must create the right mix of medication
by Jill Landis, MD
Never before have doctors had such an abundance of therapeutic options. And—not surprisingly—elderly patients are taking more medications than ever.
A national survey from 1998 revealed that more than 40% of elderly American adults take five or more medications a day—and that’s at home. Meantime, drug-related complications have risen steadily.
In 2005, the United States spent $177 billion in the management of drug-related problems—$34 billion more than was spent on the drugs themselves.1 Because up to a third of adverse medication effects warrant a hospital admission, hospitalists are the front line in the diagnosis and treatment of these syndromes.
Additionally, medication-related consequences can complicate hospitalizations required for other reasons. They can be observed as frequently as weekly according to hospitalist Balazs Zsenits, MD, FACP, of Rochester (N.Y.) General Hospital—and they’re often serious. In fact, medication reactions are so frequently fatal they represent the fifth-leading cause of death in the United States.
As one might expect, the elderly are disproportionately affected by the potentially toxic consequences of medication. In fact, a 2005 study published in Pharmacotherapy revealed that more than two-thirds of hospitalized elderly adults had an adverse drug effect over a four-year period.2 Among the more common outcomes were constipation, falls, immobility, confusion, hip fractures, and a decline in functional status requiring nursing home placement. Moreover, the authors noted that drug side effects frequently mimicked other geriatric syndromes, prompting physicians to prescribe additional medication.
While multiple medications may be necessary to prevent the progression of disease in older people, the overuse and misuse of drugs has been linked to serious health problems, including hospitalizations and death.
Patients at greatest risk for a polypharmacy-associated medical complication are those taking five or more concurrent drugs, those with multiple physicians, patients with significant medical comorbidities or impairments in vision or dexterity, and individuals who have recently been hospitalized.4-5 At least 25% of elderly Americans fall into at least one of these categories
But polypharmacy is not the only reason elderly patients experience a disproportionately high rate of adverse medication effects. Age-related altered drug metabolism is also responsible for unexpected drug consequences in this age group.
Aging influences every aspect of physiologic drug processing. While the absorption of oral medications from the GI tract remains relatively constant in the absence of disease states and gastric pH altering medications, bioavailability and clearance dramatically change with aging. These changes become the most pronounced after age 75, when kidney and liver function become limited.
As people age, their total body water decreases, their lean body mass is reduced, and their percentage of body fat increases. This increase in body fat expands the volume of distribution for lipophilic drugs and also decreases the volume of distribution for hydrophilic drugs.6 The result is that water-soluble medications have an elevated active serum concentration, and lipid-soluble agents, while they may have a decreased serum concentration, have a prolonged half-life.
These effects are best exemplified by examining what happens after a geriatric patient takes diazepam. A lipid-soluble drug, diazepam and its metabolites will be stored in an increasingly large body compartment. This will temporarily decrease the serum level of the drug, but will prolong the half-life from an average of 20 hours to greater than 50 hours. Repeated dosing will quickly result in toxic serum levels, at which point the patient is at risk for CNS side effects as well as falls and fractures.
The aging process also affects the role of drug-binding serum proteins. The total serum protein level is usually maintained (while albumin levels may diminish slightly, increasing levels of alpha 1 antitrypsin keeps the total protein level normal). More significantly, the affinity of the serum proteins for protein-bound drugs lessens as patients age. The degree of plasma protein binding has a significant impact on the pharmacologic activity of the drug, because it is the free drug that is physiologically active and exerts the pharmacologic effect.
In treating patients with highly protein-bound drugs, like phenytoin, one should expect toxic reactions at a normal serum level because more of the drug is unbound, and, hence, active. Elderly patients with low albumin levels secondary to malnutrition or liver disease will have an even more pronounced effect.
Many drugs undergo hepatic metabolism to produce more soluble forms for subsequent elimination through renal excretion. Though hepatic metabolism is affected by multiple variables including genotype, lifestyle, hepatic blood flow, hepatic diseases, and interactions with other medications, aging also plays a significant role.7
Of the two biotransformation systems through which hepatic metabolism occurs, it is the cytochrome P450 system (Phase I) most affected by increasing years. For most drugs, this leads to increased serum levels of the unmetabolized entity, leading to a greater potential for toxicity. Disease states that reduce blood flow to the liver, like congestive heart failure and cirrhosis, further inhibit this process. For drugs whose pharmacological activity requires biotransformation from a pro-drug form, inhibition can lead to decreased efficacy.
In contrast, Phase II metabolism, including acetylation, sulfonation, conjugation, and glucuronidation, is little influenced by advanced age.
The renal elimination of drugs is altered by aging, although there is significant variation between individuals for any given decade.8 Drug excretion does correlate with creatinine clearance, which declines by 50% by age 75. However, because lean body mass decreases with aging, the serum creatinine level tends to overestimate the creatinine clearance of older adults.
Utilization of the Cockroft-Gault formula (Figure 1, above) allows for an accurate estimation of the creatinine clearance in these patients.9 For example, a 25-year-old man and an 85-year-old man, each weighing 158 pounds and having a serum creatinine value of 1 mg per dL, 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, while the older man’s would be 55 mL per minute.
Approximating creatinine clearance is particularly important when prescribing medications that have a narrow therapeutic index (aminoglycosides, lithium, digoxin, procainamide, vancomycin). Even minimally excessive doses of these drugs will result in a prolonged the half-life, and an increased potential for toxic effects.
Expect and account for these alterations in drug metabolism in elderly patients. Typical changes result in increased active serum concentrations of the drug and extended half-life. Elevated drug concentrations result in more adverse drug events, and these include not only known complications, but also uncommon problems such as blood dyscrasias. If a rare adverse drug reaction does occur, it is most likely to happen in an elderly person.
In light of the physiologic changes associated with aging, as well as the problems posed by taking multiple medications, it is clear that active intervention is required to prevent adverse drug reactions in geriatric patients.
A large cohort study of Medicare enrollees with more than 30,000 patient-years of observation found that 28% of adverse drug reactions were potentially avoidable. Most errors occurred during prescribing and monitoring. A number of strategies have been proposed for reducing these unwanted medication consequences in the hospital setting, including:
Though precise clinical data regarding which medications are harmful to elderly patients in the acute care setting is lacking, multiple expert panels have attempted to delineate which drugs should be generally avoided in this population (Table 1, above).
The most notable of these evaluations is the Beers criteria, a frequently updated set of medications deemed inappropriate for use in geriatric patients. Most recently amended in 2003, this list is formulated by experts in pharmacology and geriatrics, and has been validated in large studies as a useful tool for decreasing medication-related problems in the nursing home setting.10
Though a 2006 study of hospital morbidity found that adverse drug reactions in the acute care setting often occur from drugs not listed in the Beers criteria, avoiding medications like those listed above is still a useful tool in preventing side effects.11-12
To prevent a polypharmacy-induced iatrogenic illness, it is important to consider any new signs and symptoms to be a possible consequence of current drug therapy. Steps for reducing polypharmacy include:
When starting a new drug, start with a low dose and titrate slowly to the desired clinical effect. While the manufacturers of many commonly used medications do not delineate the lower-dosage recommendations necessary for elderly patients, you can bypass this problem by starting with one-third to half the recommended dosage.
After observing that the patient tolerates the new drug, slowly increase the dose until the desired result is obtained. This approach is particularly important in minimizing potential harmful drug effects in patients with severely reduced renal function.14
In its 2001 report “Crossing the Quality Chasm: A New Health System of the 21st Century,” the U.S. Institute of Medicine declared: “The current care systems cannot do the job. Trying harder will not work. If we want safer, higher-quality care, we will need to have redesigned systems of care, including the use of information technology to support clinical and administrative processes.”
While hospitalists are on the front line for preventing adverse drug reactions, they can’t do it by themselves. Here are a few tips for making your job easier:
The elderly portion of the population is expanding more rapidly than the population as a whole, and the recognition and prevention of medication side effects in this group is one of the most critical safety and economic issues facing the healthcare system today. While the magnitude of this problem demands multidisciplinary involvement, hospitalists can be key players in making a difference. TH
Dr. Landis is a rheumatologist and a freelance writer
The Hospitalist newsmagazine reports on issues and trends in hospital medicine. The Hospitalist reaches more than 25,000 hospitalists, physician assistants, nurse practitioners, residents, and medical administrators interested in the practice and business of hospital medicine.