DRUGS AND AGING

Medication use by older people continues to receive attention in the lay media and in medical literature. People age sixty-five and over make up approximately 13 percent of the total population, yet they consume about 40 percent of all medications (Jones-Grizzle et al.). This rate of medication use among seniors coincides with the rate of many chronic diseases, which rise sharply with age. For example, arthritis, high blood pressure, and angina are reported by 47 percent, 43 percent, and 31 percent, respectively, by people age sixty-five years or older.

Patterns of medication use by seniors living at home or in nursing homes have previously been described (Avorn et al.; Chrischilles et al; and Cooper). In general, seniors living at home consume three to eight medications, with an increase in use with increasing age, for females, and for those with poor self-reported health (Chrischilles and Cooper). In the nursing home the number of ordered medications ranges from four to nine (Beers 1992).

The most commonly used classes of medications generally reflect the types of diseases that seniors have (Table 1). For example, the most commonly used medication classes are drugs for high blood pressure, arthritis, and stomach or intestinal diseases, and blood thinners and drugs such as antidepressants or tranquilizers (Chrischilles et al.).

Adverse drug reactions

Unfortunately, medication use carries an inherent level of risk, particularly when people are taking multiple medications concomitantly. One risk is the occurrence of adverse drug reactions. An adverse drug reaction is defined as a response to a drug that is harmful or unintended, which occurs at doses used in humans for the prevention, diagnosis, or treatment of disease. They can range from minor symptoms such as stomach upset, to conditions requiring hospitalization, such as gastrointestinal bleeding, or in some cases to death (Hanlon et al., 1995).

It has been estimated that 10 to 25 percent of community-dwelling seniors and 54 to 67 percent of seniors living in nursing homes suffer from an adverse drug reaction (Gurwitz and Avorn; Cooper). Among community dwellers, heart/blood pressure medications and analgesics (pain killers) are the most commonly implicated medications. In the nursing home, heart/blood pressure drugs and psychiatric drugs are usually responsible.

The risk of adverse drug reactions is related to many factors, some of which are modifiable. Important predictors of adverse drug reactions include the number of medications that a patient consumes and the number of diseases that a patient has. Although some researchers have suggested that seniors and females are at higher risk, this remains controversial (Gurwitz and Avorn; Hanlon et al.).

Adverse drug reactions and health care utilization

Approximately 10–16 percent of hospital admissions result from adverse drug reactions from which approximately two-thirds of patients recover (Colt and Shapiro; Col). Inappropriate prescribing is a leading cause of adverse drug reactions. Fifty percent of adverse drug reactions detected on admission to hospital in one study were from absolutely contraindicated or unnecessary medications (Lindley et al.). Furthermore, there were 0.34 adverse drug reactions for each unnecessary medication and only 0.08 per necessary medications. In a study of nursing home patients, 61 percent of adverse drug reactions were felt to have resulted from inappropriate prescribing (Cooper).

Adverse drug reactions have an important impact on health care use. Of seniors who report experiencing adverse drug reactions, 63 to 75 percent need to contact their physician, 50 percent have laboratory tests ordered, 10 percent visit the emergency room, and 7 to 11 percent are hospitalized (Chrischilles et al., "Selfreported Adverse Drug Reactions"; Hanlon, 1997). When projected to the entire communitydwelling older population, this translates into two million annual physician visits, one million laboratory tests, and 146,000 hospitalizations from adverse drug reactions (Chrischilles et al., "Self-reported Adverse Drug Reactions").

Increases in health care utilization can also be measured in the length of hospital stay or in dollar costs. For patients admitted to hospital who suffered an adverse drug reaction, this occurrence was associated with an increased length of stay of two days and a cost increase of $2,263 (Classen). Results from another study highlights this point: for every dollar spent on medications in nursing facilities, $1.33 is spent in the treatment of medication-induced problems that can be prevented (Bootman et al.).

Medication use in the older population

It is not clear why medication use in the older population is so challenging, however, multiple interacting factors complicate medication use in seniors. Important issues include: increased disease burden; changes in physiology, pharmacokinetics, and pharmacodynamics with aging; patient and family expectations; poor patient-physician communication; over-the-counter medication use; using other people's medications; and the use of multiple physicians, to name a few. Lastly, seniors are often excluded from clinical trials that are conducted when drugs are being studied. Therefore when these drugs are marketed, they have not been extensively studied in older people, even though these are generally the patients most likely to receive them.

Pharmacokinetics, pharmacodynamics, and aging

These are two areas that are well understood, and can be taken into account by clinicians in every day practice.

Pharmacokinetics. Pharmacokinetics is a biological science concerned with the characterization and mathematical description of the absorption, distribution, metabolism, and excretion of drugs, their by-products, and other substances of biologic interest.

These processes determine the amount and rate of appearance of drugs in the body, distribution throughout the tissues, and elimination of the drug from the body. In other words, pharmacokinetics is the study of how the drugs move into and out of the body.

It is simplest to begin with the first event that occurs when a patient takes a medication: absorption. Most drugs that are commonly used are given by mouth (although some medications can be applied to the skin, eyes, or by other means). Absorption of the medication takes place at the lining of the stomach or small intestine, depending on the drug. Although there are various agerelated changes in the physiology of the gut, as a whole they do not result in any clinically significant age-related changes in drug absorption.

Distribution. After a drug is absorbed, it is distributed into the bloodstream and various tissues and/or fluids (e.g., skin, lungs, brain, urine, etc.) where the drug will exert its therapeutic action (see below, pharmacodynamics). The degree to which a drug distributes into different tissues varies, and depends on physicochemical properties of the drug: the drug's relative solubility in fat as opposed to water, its affinity for various tissues, and the drug's binding to plasma proteins. Directly relevant to distribution are the following age-related changes in body composition: there is an increase in body fat (about 15–30 percent) accompanied by a decrease in total body water (about 10–15 percent). These alterations can result in an altered drug distribution profile, which may affect the response to the drug. For example, if a patient is given a drug that is mainly water-soluble, its concentration, and thus its effect, may be greater. This is explained by the fact that the older person has less body water in which the drug would distribute into, leading to a higher drug concentration. In most cases however, this will not be clinically significant, and can be accounted for by proper drug dosing (see below, general principles of drug therapy).

Metabolism. Cytochrome P450 refers to a group of enzymes located on the membrane of the endoplasmic reticulum. The ancestral genes for the P-450 proteins have been estimated to have existed as far back as 3.5 million years ago, suggesting that drug metabolism is a secondary role. The original role for these enzymes likely is to: (1) metabolize endogenous compounds (e.g., cortisol); and (2) detoxify exogenous compounds (e.g., especially after oral ingestion). Consequently, the highest concentrations of these enzymes are in the liver and small intestine, with very small quantities found elsewhere, and the liver is the major site where drugs are metabolized.

Metabolism of a drug produces substances that are called metabolites. This process is called biotransformation. Biotransformation may occur via two major groups of reactions (or through a combination of the two) called phase I and phase II reactions. Phase I reactions typically convert a drug to a more polar compound. Phase II reactions generally involve coupling of the parent compound with a substance found in the body to produce a drug conjugate. Most conjugates are inactive and very water soluble, allowing for rapid excretion by the kidneys (Matzke and Milikin). Metabolites may be biologically inactive, just as active as the parent drug, or more or less active than the parent drug. A drug may be metabolized to a number of metabolites, each with potentially different properties. Although some drugs are metabolized by phase I, followed by phase II reactions, many are metabolized by only one these types of reactions.

Various age-related liver changes impair drug metabolism. Liver mass decreases, as does liver blood flow. The metabolic capacity of phase I reactions also decrease. This is illustrated by a decreased clearance (i.e., the drug remains in the body for a longer period of time) of various drugs such as triazolam, diazepam, alprazolam, warfarin, and others (Sotaniemi et al., 1997). Unfortunately, there are no markers that help determine how well the liver is metabolizing drugs. Nonetheless, this reduced clearance has important clinical implications (Gordon et al.).

In contrast, phase II reactions are largely unaffected by aging. Thus, one factor considered by clinicians in drug selection is whether a drug's metabolism is affected by aging. If so, an alternative drug is selected. If this is not possible, alternative strategies are used to avoid problems.

Elimination. The kidneys play a major role in eliminating drugs and other substances from the body. The last step in the movement of drugs is elimination, which is accomplished by the kidneys. Elimination occurs via two (or a combination of the two) mechanisms: drugs can be filtered or actively secreted through the glomerulus (functional unit of the kidney). The rate the glomerulus filters drugs is called the glomerular filtration rate. As people age, this rate, and thus the ability to eliminate certain drugs, decreases (meaning that the drug will persist in the body for a longer period of time) starting at about age forty (Mayersohn). The glomerular filtration rate, unlike liver enzyme activity, can be estimated by using mathematical equations. This estimate is used to help select appropriate drug doses for seniors, since many commonly used drugs are largely eliminated by the kidney. By doing so, drug build-up in the body is prevented that may otherwise lead to side effects.

Pharmacodynamics. Pharmacodynamics is defined as the study of the biological effects resulting from the interaction between drugs and biological systems. More simply stated, it is what the drug does to the body. Aging often results in different responses to the same amount of drug.

Aging and the brain: drug effects

The brain has millions of brain cells called neurons (i.e., its working units). Neurons operate using various substances called neurotransmitters, examples of which include acetylcholine and dopamine. For proper brain function there needs to be a balance of these neurotransmitters. Imbalances in or marginal deficits in certain neurotransmitters can lead to symptoms or disorders that could have serious consequences.

In older people, two major changes in neurotransmitters are of importance. There is a decrease in the number of cholinergic and dopaminergic neurons, which leads to a relative state of deficiency of acetylcholine and dopamine (Drachman). This reduces the reserve capacity of the brain and makes the balance between neurotransmitters more delicate. The end result is that medication-related problems are more common, and of serious consequence in seniors. Commonly used medications that can be problematic include antipsychotics (e.g., haloperidol), benzodiazepines (e.g., diazepam), and medications with anticholinergic properties (e.g., diphenhydramine or Benadryl). For example, the incidence of drug-induced Parkinsonism (a condition that mimics Parkinson's disease) is much higher in seniors. This condition can cause significant problems due to problems in moving, walking, performing every day tasks with their hands, and can lead to falls, which can have disastrous consequences. Seniors who take benzodiazepine drugs are also at risk for drug-induced cognitive impairment. This means that they may suffer from memory loss, decreased ability to think, and present with other characteristics that may mimic Alzheimer's disease. Lastly, medications with anticholinergic effects such as diphenhydramine (Benadryl, Tylenol PM), dimenhydrinate (Dramanine), and other commonly used medications present a particular problem in older people. In older people they should be avoided, as they are a common cause of cognitive impairment and delirium.

General principles of drug therapy

Many useful strategies exist that simplify drug use in seniors (Gordon et al.). The two most useful tips are generally (1) Start low, go slow, and (2) Do one thing at once.

The "start low, go slow" principle is how clinicians globally account for the aforementioned changes in the way that the seniors handle drugs. For example, if the normal dose of sertraline (antidepressant) is 50mg daily, 25mg daily commonly would be prescribed. Then, as is common for many drugs, the drug dose is increased to a specific amount. If sertraline is normally increased to 100mg in one week, it would be increased in one and one-half to two weeks by an increment of 25mg. This lessens the chance of severe side effects from using a dose that is too high for an older person that may lead to the patient becoming sick and stop taking the drug or, worse yet, that may lead to hospitalization.

"Do one thing at once" refers to making one medication change at a time. People with more than one medical problem must often take more than one medication. After the patient has been interviewed and examined, the clinician will have ideas as to what the problems are that need to be addressed. This may involve adding, adjusting the dose, or stopping drugs that may be contributing to the problems. Whenever possible, it is essential that only one drug be added or removed (or its dose changed) at a time. Otherwise, if the patient improves or worsens after adjusting more than one drug, the clinician will not be able to determine which drug was of benefit (or detrimental). For example, consider a patient with arthritic knee pain who is prescribed aspirin and ibuprofen together for pain. If the patient's pain improves the question is: which drug helped? Which drug should they continue to take? In order to ascertain which drug was useful, the patient would have to stop one drug, see what happens, and go from there (in other words, if the pain returns, add the second drug, then see if the first drug helped at all). Such an approach is time consuming and complicated. Similarly, if the patient suffers from side effects, they will not know which drug is the offending agent. This is an undesirable scenario that could be avoided by starting with one drug, using it properly, and assessing whether or not the drug worked before adding a second drug. Furthermore, situations like this can result in a patient incorrectly being labeled as "unresponsive" to both drugs, or "allergic" or "intolerant" to both drugs.

Conclusion

The older population is growing rapidly, bringing various challenges to the health care system. One of the major challenges is that of ensuring safe and effective medication use in older people. The unique needs and characteristics of this population must be taken into account by health care professionals involved in the care of older people in order to prevent drug-related problems.

Carlos H. Rojas-Fernandez

See also Alcoholism; Arthritis; Brain; Drug Regulation; Herbal Therapy; Kidney; Aging.

BIBLIOGRAPHY

Avorn, J., and Gurwitz, J. H. "Drug Use in the Nursing Home." Annals of Internal Medicine 123 (1995): 195–204.

Beers, M. H.; Ouslander, J. G.; Fingold, S. F.; Morgenstern, H.; Reuben, D. B.; Rogers, W., et al. "Inappropriate Medication Prescribing in Skilled-Nursing Facilities." Annals of Internal Medicine 117 (1992): 684–689.

Bootman, J. L.; Harrison, D. L.; and COX, E. "The Health Care Cost of Drug Related Morbidity and Mortality in Nursing Facilities." Archives of Internal Medicine 157 (1997): 2089–2096.

Chrischilles, E. A.; Segar, E. T.; and Wallace, R. B. "Self-Reported Adverse Drug Reactions and Related Resource Use. A Study of Community Dwelling Persons 65 Years of Age and Older." Annals of Internal Medicine 117 (1992): 634–640.

Chrischilles, E. A.; Foley, D. J.; Wallace, R. B.; Lemke, J. H.; Semla, T. P.; Hanlon, J. T., et al. "Use of Medications by Persons 65 and Over: Data from the Established Populations for Epidemiologic Studies of the Elderly." Journal of Gerontology 47 (1992): M137–M144.

Classen, D. C.; Pestotnik, S. L.; Evans, R. S.; Lloyd, J. F.; and Burke, J. P. "Adverse Drug Events in Hospitalized Patients. Excess Length of Stay, Extra Costs, and Attributable Mortality." Journal of the American Medical Association 277, no. 4 (1997): 301–306.

Col, N.; Fanale, J. E.; and Kronholm, P. "The Role of Medication Non-compliance and Adverse Drug Reactions in Hospitalization of the Elderly." Archives of Internal Medicine 150 (1990): 841–845.

Colt, H. G., and Shapiro, A. P. "Drug-induced Illness as a Cause for Admission to a Community Hospital." Journal of the American Geriatrics Society 37 (1989): 323–326.

Cooper, J. W. "Probable Adverse Drug Reactions in a Rural Geriatric Nursing Home Population: A Four Year Study." Journal of the American Geriatrics Society 44 (1996): 194–197.

Drachman, D. "Aging and the Brain: A New Frontier." Annals of Neurology 42 (1997): 819–828.

Gordon, J.; Rojas-Fernandez, C.; and Rockwood, K. "Practical Solutions to Polypharmacy Problems in the Elderly." Canadian Journal of Diagnosis 15, no. 4 (1998): 78–90.

Gurwitz, J. H., and Avorn, J. "The Ambiguous Relation Between Aging and Adverse Drug Reactions." Annals of Internal Medicine 114 (1991): 956–966.

Hanlon, J. T.; Schmader, K. E.; and Lewis, I. K. "Adverse Drug Reactions." In Therapeutics in the Elderly. Edited by J. C. Delafuente and R. B. Stewart. Cincinnati: Harvey Whitney Books, 1995. Pages 212–227.

Hanlon, J. T.; Schmader, K. E.; Koronkowski, M. J., et al. "Adverse Drug Events in High Risk Older Outpatients." Journal of American Geriatrics Society 45 (1997): 945–948.

Jones-Grizzle, A. J., and Draugalis, J. R. "Demographics." In Geriatric Pharmacology. Edited by R. Bressler and M. D. Katz. New York: McGraw-Hill, 1993. Pages 1–8.

Lindley, C. M.; Tully, M. P.; Paramsothy, V.; and Tallis, R. C. "Inappropriate Medication is a Major Cause of Adverse Drug Reactions in Elderly Patients." Age and Aging 21 (1992): 294–300.

Matzke, G. R., and Milikin, S. P. "Influence of Renal Function and Dialysis on Drug Disposition." In Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Edited by W. E. Evans, J. J. Schentag, and W. J. Jusko. Vancouver, Wash.: Applied Therapeutics, 1992. Secs. 8.1–8.49.

Mayersohn, M. B. "Special Considerations in the Elderly." In Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Edited by W. E. Evans, J. J. Schentag, and W. J. Jusko. Vancouver, Wash.: Applied Therapeutics, 1992. Secs. 9.1–9.43.

Sotaniemi, E. A.; Arranto, A. J.; Pelkonen, O., et al. "Age and Cytochrome P450-linked Drug Metabolism in Humans: An Analysis of 226 Subjects with Equal Histopathologic Conditions." Clinical Pharmacology and Therapeutics 61 (1997): 331–339.

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