American Society on Aging
71 Stevenson St., Suite 1450
San Francisco, CA 94105-2938
www.asaging.org
info@asaging.org
By Mark H. Beers
People over age 65 are especially vulnerable to medication-related problems because of the number of medications they take and the biological changes of aging and disease. Older people are the greatest consumers of prescription and over-the-counter medications, and they are more likely to be taking multiple medications at the same time for various health problems. What is more, changes in physiology place older people at greater risk of adverse reactions when taking some medications. Older people are more likely to suffer hospitalization or psychiatric problems as a result of adverse medication reactions and are at greater risk of memory loss, hip fracture, and automobile-related injuries, for example, as a result of adverse medication effects. Among older people, visual or cognitive impairment can combine with psychological, social, and caregiving needs to interfere with the proper use of medications.
Experts agree that the same medication often affects older and younger people differently because age-related changes in the human body cause differences in the way that the body responds to medications. For example, older patients often lack the ability to eliminate medications from their systems as efficiently as younger patients do because of decreased liver and kidney function, and elders are also more sensitive to the effects of medications. For all these reasons, the elderly are often not able to tolerate usual adult dosages (General Accounting Office, 1996). Further, there are pronounced differences even among age groups within the older population.
In discussing age as a risk factor for medication-related problems, it is of course important to remember that older people are not all alike. In fact, the older we get, the more different we become. There will be people at both ends of the spectrum: the athletic older person with fabulous kidney and liver function to whom many of these cautions do not apply, and the 50-year-old who is out of shape and has poor kidney and liver function, to whom this does apply.
Age as a Risk Factor
Is age itself a risk factor for adverse medication effects? The answer is, yes and no. Some studies of the incidence of medication side effects by age alone have shown that once a person gets over the age of about 50, the chance of having a medication side effect increases; over the age of 70, the incidence of side effects goes up a great deal.
And yet other published studies indicate that age alone is not the determining factor. The number and nature of the medical conditions, the specific medications taken, the individual's social situation, and the person's ability to pay for, comply with, and understand the treatment regimen all contribute to medication-related problems in the older population. The bottom line is, the older people get, the more likely they are to be affected by these factors, and, thus, the more likely they are to develop medication-related problems. A 1997 study identified potential risk factors for medication-related problems in the older population from a review of the literature. The risk factors are related to classes of medications, individual characteristics, and specific medications (see below) (Fouts et al., 1997).
To understand age-related changes as a risk factor for medication-related problems, it is important to appreciate the physiological changes that may affect medications--specifically related to pharmacokinetics and pharmacodynamics--what the body does to a medication and what the drug does to the body.
Pharmacokinetic Changes
Simply put, pharmacokinetics is what the body does to a medication. Pharmacokinetics has three components: absorption, how the medication gets into the body; distribution, where and how the medication goes once it gets into the body; and clearance, how the medication is ultimately cleared from the body.
Absorption. There is little change in absorption with age, regardless of how you take a medication. There are some minor changes in absorption of topical preparations, but oral dosage forms are absorbed much the same way regardless of age.
Distribution. Most medications are distributed to either body fat or body water. With aging, there is an increase in the percentage of body fat. The typical older person has about 25 to 30 percent more fat than the typical younger person; the percentage is higher for older women. With the increase in percentage of body fat, there is a corresponding decrease in the percentage of the body consisting of water.
In older people, blood levels of water-soluble medications will be higher than would be expected in younger people because there is less body water to distribute into. Fat-soluble medications stay in the body much longer because there is more fat in which to be stored. This situation results in increasingly complicated effects of medications in the elderly. Minor changes occur in protein binding, but these changes rarely cause problems except in older people who are malnourished or acutely ill.
Clearance. The most dramatic change with age is seen in clearance, or elimination. Medications are either cleared (eliminated) through the kidneys or metabolized in the liver.
There is about a 50 percent decline in the renal (kidney) clearance of medications by the time people reach age 75 to 80. That is a dramatic decrease. However, because the traditional measure of clearance--elimination of serum creatinine--is unchanged with aging, this measure alone is an inadequate measure of kidney function in older people. There are equations to calculate creatinine clearance given the age and weight of a person.
Hepatic (liver) changes are also dramatic with age. Hepatic blood flow decreases to about half, which has a substantial effect on certain medications. More important, the major enzymatic system by which the liver metabolizes medications--the p450 system--is rapidly saturated in old age, so many medications are not metabolized nearly as well.
For example, if a young person takes a dose of the antianxiety drug diazepam, the liver rapidly metabolizes the medication, and its level in the body falls off. However, in the process of metabolizing, the liver produces a substance that is also a sedating agent, which is then excreted by the kidneys. Just as rapidly as the diazepam level falls, the sedating agent increases until it is eliminated by the kidneys.
When you give diazepam to a 68-year-old man, the p450 enzyme system is rapidly saturated. After an initial decrease in diazepam level, there is a very, very slow continuous fall-off, unlike the rapid fall-off seen in a younger person. As the sedating agent is produced during metabolism by the liver, the kidneys are slow to excrete it, which results in a prolonged half-life (the time required for half of a substance to be eliminated from the system) and thus sedating effect of the drug in older people--ninety-six hours. Medications continue to accumulate for six half-lives; therefore diazepam, if taken daily, will continue to accumulate for almost three weeks.
This is the scenario that we see: The medication is started in the hospital, where the average length of stay is about five to six days. If the patient is discharged from the hospital while still taking the medication, two weeks later we find the person dazed, confused, and unable to get out of bed; two to three weeks later the person is delirious and readmitted to the hospital. Careful monitoring for the first few days of therapy is not sufficient to avoid medication-related problems in this case; it requires an understanding of the pharmacokinetics of the medication.
(Fortunately, the other mechanism of liver metabolism--glucoronal transferase--is not dramatically affected by aging and so provides pharmaceutical manufacturers an alternative basis for developing more appropriate medications for older people.)
Pharmacodynamic Changes
The second area of clinical change with aging is pharmacodynamics, or what the drug does to the body. Age-related changes in pharmacodynamics compound the pharmacokinetic issues described above.
As we get older, we are more sensitive, rather than less sensitive, to most drugs. This is especially true for medications that affect the central nervous system. For example, a single 30 mg dose of the sedative flurazepam will cause measurable side effects in nearly half of people over age 60, whereas in younger people, only 5 to 10 percent experience side effects. Even at a lower dose, 10 percent of older people experience side effects.
Many changes that occur in the brain with aging affect sensitivity to medications. Changes in the blood-brain barrier allow more drugs to enter the central nervous system at higher levels. The older brain is far more sensitive to all drugs that cross the blood-brain barrier. Jerry Avorn, a prominent pharmacologist, said it best: "In the elderly, every drug can be psychoactive." The list of medications that cause confusion or changes to the central nervous system in older people is very long.
A younger person who stops taking a medication generally experiences complete reversal of the side effects within a day or two; in the older person, symptoms can take weeks to resolve because of pharmacokinetic and pharmacodynamic changes as well as the older brain's reduced ability to recover.
Polypharmacy
Polypharmacy--which basically means taking a lot of medications at the same time--is also frequently associated with adverse medication effects. However, polypharmacy is not always inappropriate; the person with seven medical conditions, not uncommon in the older population, will need a lot of medications.
Still, the more drugs that are taken, the more likely there will be a medication-related problem. People over the age of 65 in the United States take an average of four and one-half prescription medications at any one time, plus another two over-the-counter (nonprescription) medications. The average nursing home resident takes eight to ten medications, putting such a person at even greater risk for medication-related problems.
The following lines are from Love in the Time of Cholera, the novel by Gabriel Garcia Marquez (1988): "He arose at the crack of dawn when he began to take his secret medicines, bromide to raise the spirits, salicylates for the aches in his bones when it rained, ergosterol drops for vertigo, belladonna for sound sleep. But in his pocket he always carried a little pad of camphor that he inhaled deeply when no one was watching, to calm his fear of so many medicines mixed together."
This scenario describes what is commonly seen in geriatric practice: Older people take a lot of medicines; we know they are fearful of them. Medicines sometimes cause side effects that then require another medicine. We give a patient a diuretic that causes a decrease in potassium levels. We give a potassium supplement that causes indigestion. We give a medication for the indigestion caused by the potassium supplement. The question is, are all those medications really needed? Are they the right medication to treat the condition? Are the doses correct? Is there a drug-drug interaction? Is a medication that is good for one problem contraindicated by another? Do we cause an enormous cascade of problems rather than stepping back and thinking, was that first medication needed in the first place? Is there something that we can do to combat the side effects without increasing the number of medications?
Pharmaceutical care provides a framework to address the complexity of identifying, resolving, and preventing medication-related problems (see below). The first responsibility is to ensure that all of a patient's medication therapy is appropriately indicated, the most effective available, the safest possible, and that it can be taken as intended. These are the issues that must be considered every time we either prescribe, give, or take a medication.
Conclusion
Can we identify the medications that are most problematic in the older population? The answer is yes. We now know enough about pharmacology, pharmacokinetics, and pharmacodynamics, and we have data from outcomes research to identify the most egregious prescribing problems in the elderly.
Two consensus papers have been published that define, as a starting point, the most problematic medications in the older population (see this issue, pages 0000, and Beers et al., 1991, and Beers, 1997). The Health Care Financing Administration has recently incorporated these guidelines in the federal regulations governing nursing home care. The guidelines are already in widespread use by senior care pharmacists and are being used in outpatient drug utilization review programs as a way to create first-level alerts for practitioners.
The guidelines are not the be-all and end-all of prescribing review, but they do provide an important starting point to guide interventions to improve prescribing. The guidelines can be used as the basis for educating physicians, pharmacists, nurses, and other healthcare and aging professionals, can be provided to patients and caregivers, and can be incorporated into computerized medication dispensing systems.
Now that we have a sense of the complexity and extent of medication-related problems in older people, we should use our knowledge of pharmacology, pharmacokinetics, and pharmacodynamics, along with medication appropriateness guidelines and any other information available, to fashion interventions to improve prescribing.
Preventing medication-related problems in older people requires an understanding of the following: (1) the differences between younger people and older people, (2) what these differences mean for the way we prescribe medications and monitor medication use, (3) what these differences mean for the way we develop drugs, and (4) what these differences mean for the way we monitor new medications after they are out in the marketplace. All of these are critical if we are going to improve the care of older people.
Mark H. Beers, M.D., is executive director, Geriatrics and Medical Literature, and editor-in-chief of the Merck Manuals, Merck & Co., Inc.; and adjunct associate professor of medicine at mcp-Hahnemann, New York, N.Y.
This manuscript is based on a presentation at the Gerontological Society of America Post-Conference Symposium, Medication-Related Problems and Aging, Philadelphia, Pa., November 24, 1998.
References
General Accounting Office. 1996. Prescription Drugs and the Elderly: Many Still Receive Potentially Harmful Drugs Despite Recent Improvements. Washington, D. C.
Fouts, M., et al. 1997. "Identification of Elderly Nursing Facility Residents at High Risk for Drug-Related Problems." Consultant Pharmacist 12:110311.
Beers, M.H., et al. 1991. "Explicit Criteria for Determining Inappropriate Medication Use in Nursing Home Residents." Archives of Internal Medicine 151: 182532.
Beers, M.H. 1997. "Explicit Criteria for Determining Potentially Inappropriate Medication Use by the Elderly." Archives of Internal Medicine 157: 15316.
Marquez, G. G. 1998. Love in the Time of Cholera. New York. Alfred A. Knopf.
Potential
Risk Factors
for Medication-Related Problems
(Identified via the literature,
investigative team, and expert panel)
Specific Medications
Chlorpropamide
Digoxin
Glyburide
Lithium
Theophylline
Warfarin
Classes of Medication
Antiarrhythmics
Antibiotic, new prescription
Anticholinergics
Anticonvulsants
Antidepressants
Antipsychotics
Benzodiazepine, long-acting
Benzodiazepine, intermediate-acting
Benzodiazepine, short-acting
Diuretics
Histamine-antagonists
Narcotic analgesics
Nonsteroidal antiinflammatory agents
Sedative/hypnotics
Characteristics
Advanced age (85 years-plus)
Number of active chronic medical diagnoses (more than six)
Decreased kidney function
Low body weight or body mass index
Cognitive impairment including dementia
Cancer
Depression
Six or more medications
Nine or more medications
Number of doses of medication per day
(more than 12)Prior adverse drug reaction
Recent discharge from hospital
Adapted with permission from Fouts, M., et al. © 1997 American Society of Consultant Pharmacists, Inc.
Medication-Related Problems
Medication-related problems in older people arise in four basic areas:
appropriateness, effectiveness, safety, and compliance.Medication Appropriateness
* Unnecessary medication therapy. This is a problem that includes medication use without a valid medical indication, medication use when nondrug therapy is more appropriate, multiple medication use for a condition for which one single medication therapy is indicated, and medication use to treat an avoidable adverse medication effect associated with another medication. The problem occurs commonly with the use of antibiotics, with certain gastrointestinal medications, and often with certain sleep medications or medications that affect the central nervous system.
* Need for additional medication therapy. Additional medication required can include medication therapy to treat a previously untreated condition, additional medication therapy to augment the effectiveness of medication to treat a condition optimally, or medication therapy to prevent development of a new medical condition. In the older population, incontinence, heart failure, and depression are grossly undertreated, and vaccines are still dramatically underused, even though we know that immunization saves lives, reduces morbidity, and saves money.
Medication Effectiveness
* Wrong medication. This problem can be defined as a medication that is not effective or is not the most effective for the patient's medical problem, a medication contraindicated in the patient or to which the patient is allergic, or an effective medication for which there is an effective yet less costly or safer alternative.
* Dosage too low. A dose that is too low for the patient is one in which the level of medicine in the blood is below desired therapeutic range or a dosing interval or duration of therapy inadequate to produce the desired response.
Medication Safety
* Adverse medication reaction. Such a reaction can be caused by allergic or idiosyncratic response to medication, altered medication effect due to drug-drug or drug-food interaction, medication interference with a laboratory test result, or risk factors present that make use of medication too dangerous.
* Dose too high. This problem includes a dose too high for the patient, producing blood levels of the drug that are above desired therapeutic range or a dosing interval or duration of therapy inappropriate for the patient.
Compliance
Compliance problems include failure to receive the appropriate medication regimen because of an error in prescribing, dispensing, administering, or monitoring and failure to comply with the directions for use of the medication by the patient because of lack of understanding of the directions, inability to comply, or the high cost of the medication.
American Society on Aging
71 Stevenson St., Suite 1450
San Francisco, CA 94105-2938
www.asaging.org
info@asaging.org