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Introduction

Reports in the popular press about the increasing longevity of Americans and the aging of the baby boom generation are constant reminders that the American population is becoming older. Consequently, an issue of growing medical, health policy, and social concern is the appropriate and rational use of medications by the elderly.

Although becoming older does not necessarily correlate with increasing illness, aging is associated with anatomical and physiological changes that affect how medications are metabolized by the body. Furthermore, aging is often related to an increased frequency of chronic illness (often combined with multiple health problems) and an increased use of medications. Thus, a better understanding of the absorption, distribution, metabolism, and excretion of drugs;1 of the physiologic responses to those medications; as well as of the interactions among multiple medications is crucial for improving the health of older people.

In 1996, the National Institute on Aging and the National Institutes of Health (NIH) Office of Research on Minority Health requested that the Institute of Medicine (IOM) conduct a workshop study to examine research opportunities and barriers to research on pharmacokinetics, pharmacodynamics, and drug interactions in the elderly with attention to elderly African-American populations. In addition, the workshop was intended to update a 1990 report by the IOM Forum on Drug Development, Drug Development for the Geriatric Population. In response to this request, the IOM formed a Committee on Pharmacokinetics and Drug Interactions in the Elderly and selected members with expertise in the relevant disciplines including basic science and clinical pharmacology, geriat-

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Note: The terms drug and medication are used interchangeably throughout this report.



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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary 1 Introduction Reports in the popular press about the increasing longevity of Americans and the aging of the baby boom generation are constant reminders that the American population is becoming older. Consequently, an issue of growing medical, health policy, and social concern is the appropriate and rational use of medications by the elderly. Although becoming older does not necessarily correlate with increasing illness, aging is associated with anatomical and physiological changes that affect how medications are metabolized by the body. Furthermore, aging is often related to an increased frequency of chronic illness (often combined with multiple health problems) and an increased use of medications. Thus, a better understanding of the absorption, distribution, metabolism, and excretion of drugs;1 of the physiologic responses to those medications; as well as of the interactions among multiple medications is crucial for improving the health of older people. In 1996, the National Institute on Aging and the National Institutes of Health (NIH) Office of Research on Minority Health requested that the Institute of Medicine (IOM) conduct a workshop study to examine research opportunities and barriers to research on pharmacokinetics, pharmacodynamics, and drug interactions in the elderly with attention to elderly African-American populations. In addition, the workshop was intended to update a 1990 report by the IOM Forum on Drug Development, Drug Development for the Geriatric Population. In response to this request, the IOM formed a Committee on Pharmacokinetics and Drug Interactions in the Elderly and selected members with expertise in the relevant disciplines including basic science and clinical pharmacology, geriat- 1   Note: The terms drug and medication are used interchangeably throughout this report.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary rics, drug development, and drug use policy. The committee met twice during the course of the 10-month study and held a scientific workshop at Xavier University of Louisiana College of Pharmacy in April 1997. This report highlights the workshop presentations and summarizes the committee's conclusions regarding future research directions. DEFINITIONS A starting point in most discussions on aging populations is the definition of the terms aging and elderly. In cellular and animal models, aging is measured by replicative senescence or chronology (e.g., 40–50 replications of fibroblasts; 24–28 months of age in rats; 3–4 years in rabbits; and 8–10 years in dogs). Although gerontologists view human aging as a continuous process, no two individuals age in exactly the same manner; consequently there is considerable heterogeneity2 in the elderly population, with wide variance in physical health and cognitive function. However, for societal, demographic, and measurement purposes, there is a need to define the term elderly based on chronological age. Geriatricians and gerontologists often use the following construct to subdivide the population: 20–39 years adult, 40–59 years middle age, 60–74 years young old, 75–85 years old old, and >85 years very old or oldest old. Diverse levels of physical health and overall well-being make it difficult to categorize what constitutes “normal aging.” Within each of the subgroups of people over 60 years of age, individual biological responses to aging are affected by a range of physiological, genetic, socioeconomic, and environmental factors including nutrition, access to medical care, smoking, and weight. Further, the over-60 subgroups vary widely in physical, emotional, and mental health, social function, activity levels, and overall vitality. Definitional issues also surround the terms race and ethnicity. Although this report discusses aging issues related to race and ethnicity, particularly in elderly African-American populations, the committee acknowledges the complexities and limitations of racial categories. Individuals may be categorized into a particular group for purposes of identifying a study population; however, there may 2   The elderly population encompasses a range of people including those who have aged successfully, those with few health conditions and risk factors, and those with health conditions and disability (Wenger, 1993).

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary not be important biological significance to the categorization. There is a great deal of genetic heterogeneity within broad racial categories (IOM, In press), even though they are used as discrete variables in many surveys including the U.S. Census. It is important to remember that immigration and the rapid rise in the number of interracial marriages are resulting in a U.S. population that is increasingly multiracial, comprising individuals of mixed heritages from a number of racial and ethnic groups. In addition, racial categories that are currently in use may include people from widely different geographical locations and sociocultural backgrounds that have great genetic diversity (e.g., the term Hispanic may be used to include people of Caribbean, Mexican, and Central and South American descent). Thus, grouping people along racial and ethnic lines to study functional differences in their drug-metabolizing capacity or to interpret results of research and clinical trials relating to various drugs has proven to be complex and challenging. These definitional issues extend far beyond the committee's charge and are noted here to acknowledge the complexities involved in the study of diverse aging populations. The task of this committee primarily relates to pharmacokinetics (defined in its simplest form [Benet, 1996] as “what the body does to a drug”) and the age- and ethnicity-related changes in drug disposition. Pharmacodynamics (in its simplest form “what the drug does to the body” or the consequences of drug dosing) must also be considered. However, little work has previously been undertaken in this area, and changes in pharmacodynamics that cannot be explained based on age-related pharmacokinetic changes are less well known. The identification of purely age-related pharmacodynamic changes will not easily be understood until the areas of future research summarized in Chapter 3 of this report have been substantially addressed. DEMOGRAPHICS Declining fertility and mortality rates, lengthened average life spans, and the aging of the baby boom generation are all factors in the changing demography of the U.S. population. In 1994, the 33.2 million Americans aged 65 or over constituted 12.5 percent of the population; the U.S. Bureau of the Census (1995) estimates that by the year 2050, the number of elderly persons will more than double to about 80 million, or approximately 20 percent of the total U.S. population (Table 1.1). The portion of the population aged 85 and over (the “oldest old”) is the most rapidly growing elderly age group, and this group typically has the highest incidence of chronic disabling diseases and the highest health care expenditures. It is expected that this age group, which numbered 3 million in 1994 (making up 9 percent of elderly Americans and over 1 percent of the U.S. population), will increase to 19 million in 2050 (making up 24 percent of elderly Americans and 5 percent of the U.S. population).

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary TABLE 1.1 Projected Demographic Statistics   1994 Projected for 2050 Number of Americans age 65 or older 33.2 million 80 million Percentage of the U.S. population age 65 or older 12.5 20 Number of Americans age 85 or older 3 million 19 million Percentage of the U.S. population age 85 or older >1 5 SOURCE: U.S. Bureau of the Census, 1995. The elderly American population will also be more ethnically and racially diverse in the future. In 1994, 1 in 10 Americans was identified as being of a race other than Caucasian; demographers project that this ratio will change to 2 in 10 by the year 2050. By that time, the number of elderly African Americans will more than triple (to constitute over 10 percent of the elderly population) and the elderly Hispanic population will increase from less than 4 percent of the elderly population to nearly 16 percent. COMORBIDITY AND POLYPHARMACY Despite the great heterogeneity in health status and functional levels within the elderly population, aging generally increases an individual 's risk of illness and, subsequently increases use of medications. Community-dwelling elderly persons over age 64 take an average of two to three prescription medications, whereas older elderly persons (>80 years), elderly hospitalized patients, and elderly patients in long-term care facilities on average take significantly more medications (LeSage, 1991; Chutka et al., 1995). Cardiovascular drugs, antihypertensive medications, analgesics, anti-inflammatory drugs, sedatives, and gastrointestinal medications are the medications most commonly used by elderly Americans (Hale et al., 1987). Although persons over age 65 represent nearly 13 percent of the total U.S. population, it has been estimated that they consume nearly one third of all medications in the United States (Avorn, 1995). Of the $36 billion spent on prescription medications in the U.S. in 1991, it is estimated that the elderly population spent between $12.7 billion and $14.3 billion (Long, 1994). The frequent presence of coexisting illnesses and the use of multiple medications by the elderly increases the potential for drug interactions. Thus, enhanced understanding of the issues involved in research on pharmacokinetics,

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary pharmacodynamics, and drug interactions in the elderly has the potential to benefit a substantial portion of the aging population. REPORT OUTLINE This report provides a summary of the presentations and discussions of the IOM Workshop on Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations (Chapter 2) and presents the committee's conclusions on future directions for research on pharmacokinetics and drug interactions in the elderly (Chapter 3). Many of the issues presented in this document have been the subject of recent IOM reports. These issues include gender-specific issues for elderly women (IOM, 1994e, 1996b); careers in clinical research (IOM, 1994b) and specifically in geriatrics (IOM, 1993, 1994d); recruiting minorities into the health professions (IOM, 1994a); and confidentiality of patient information (IOM, 1994c); as well as recent reports on health care for the aging population (IOM, 1990b, 1991, 1996a). ACKNOWLEDGMENTS The committee appreciates the assistance provided by Stanley Slater of the National Institute on Aging and John Ruffin of the NIH Office of Research on Minority Health. In addition, the committee extends its appreciation and thanks to Marcellus Grace, Burde Kamath, and many other individuals on the staff of Xavier University of Louisiana who helped plan the IOM workshop and who graciously welcomed the committee, the workshop participants, and the workshop attendees (see Appendix). The workshop speakers shared their extensive expertise with the committee, and the committee appreciates the informative presentations. This report is presented to stimulate discussions on this important topic and to provide useful directions for future research on pharmacokinetics and drug interactions in the elderly. The report highlights and summarizes only the topics presented by the speakers and discusses the committee 's conclusions based on the workshop presentations. REFERENCES Avorn J. 1995. Medication use and the elderly: Current status and opportunities. Health Affairs Spring:276–286. Benet LZ. 1996. General principles: Introduction. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th edition. New York: McGraw-Hill.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary Chutka DS, Evans JM, Fleming KC, Mikkelson KG. 1995. Drug prescribing for elderly patients. Mayo Clinic Proceedings 70:685–693. Hale WE, May FE, Marks RG, Stewart RB. 1987. Drug use in an ambulatory elderly population: A five-year update. Drug Intelligence and Clinical Pharmacy 21:530– 535. Institute of Medicine (IOM). 1990a. Drug Development for the Geriatric Population. Washington, DC: National Academy Press. Institute of Medicine (IOM). 1990b. The Second Fifty Years: Promoting Health and Preventing Disability. Washington, DC: National Academy Press. Institute of Medicine (IOM). 1991. Extending Life, Enhancing Life: A National Research Agenda on Aging. Washington, DC: National Academy Press. Institute of Medicine (IOM). 1993. Strengthening Training in Geriatrics for Physicians. Washington, DC: National Academy Press. Institute of Medicine (IOM). 1994a. Balancing the Scales of Opportunity: Ensuring Racial and Ethnic Diversity in the Health Professions. Washington, DC: National Academy Press. Institute of Medicine (IOM). 1994b. Careers in Clinical Research: Obstacles and Opportunities. Washington, DC: National Academy Press. Institute of Medicine (IOM). 1994c. Health Data in the Information Age: Use, Disclosure, and Privacy. Washington, DC: National Academy Press. Institute of Medicine (IOM). 1994d. Training Physicians to Care for Older Americans: Progress, Obstacles, and Future Directions. Washington, DC: National Academy Press. Institute of Medicine (IOM). 1994e. Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies. Washington, DC: National Academy Press. Institute of Medicine (IOM). 1996a. Health Outcomes for Older People: Questions for the Coming Decades. Washington, DC: National Academy Press. Institute of Medicine (IOM). 1996b. In Her Own Right: The Institute of Medicine's Guide to Women's Health Issues. Washington, DC: National Academy Press. Institute of Medicine (IOM). In press. Genetics, Health, and Behavior: Science in Perspective. Washington, DC: National Academy Press. LeSage J. 1991. Polypharmacy in geriatric patients. Nursing Clinics of North America 26(2):273–289. Long SH. 1994. Prescription drugs and the elderly: Issues and options. Health Affairs 13(2):157–174. U.S. Bureau of the Census. 1995. Sixty-Five Plus in the United States. Statistical Brief 95-8. Washington, DC: U.S. Bureau of the Census. Wenger NK, ed. 1993. Inclusion of Elderly Individuals in Clinical Trials: Cardiovascular Disease and Cardiovascular Therapy as a Model. Kansas City, MO: Marion Merrell Dow, Inc.