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In the United States, 25 percent of prescription drug use is accounted for by people who are older than 65--that is, 12.6 percent of the population. This fact, along with a greater understanding of how older people are more likely to experience adverse drug reactions, has prompted increased interest in how aging affects the ways our bodies handle drugs. Government recommendations now require that older people be included in the testing of medications before they are released to the public. Despite these recommendations, there is still a surprising lack of information concerning the principles and practices of drug treatment in older people.
In this chapter we will review how aging affects the ways our bodies respond to, process, and eliminate drugs. We will learn about the adverse effects of drugs and how to reduce our chances of experiencing an adverse drug reaction.
The word pharmacokinetics (from the Greek, meaning "drug" and "movement") refers to the ways a drug travels to its destination. This includes the processes of drug absorption, distribution throughout the body, and elimination from the body. Information about the age-related changes in the body affecting pharmacokinetics is helpful for determining the appropriate dosage of medications. (See Table 4 for factors that alter pharmacokinetics with aging.) The absorption of medications generally changes very little as we age. However, some drugs that we take by mouth are rapidly filtered out of circulation by the liver, which metabolizes drugs toward elimination from the body. The liver performs a number of important functions including altering chemicals and nutrients absorbed into the blood, regulating blood sugar, and manufacturing and storing proteins and vitamins. Any reduction in the liver's ability to extract a drug can result in an increased amount of the drug remaining for longer times in the general circulation. Medications that have been shown to circulate for longer times include labetalol, propranolol, and lidocaine. However, there is no uniform effect of age on the initial extraction of drugs from the circulation by the liver. In other words, no general guidelines are available for assessing age-related liver function.
Table 4. Factors That Alter Drug Disposition in Old Age
The distribution of drugs is also affected by changes in our bodies including the relative increase in body fat and decrease in body water and lean muscle mass. Drugs are either fat or water soluble; drugs that dissolve in fat are distributed more widely than those that dissolve in water. However, increased distribution of fatsoluble drugs can delay their elimination from our body, and this may prolong the effect of a single dose. This is particularly important for drugs that are given in single doses on an intermittent basis such as some pain relievers and sleeping medications. For example, it may take up to 90 hours for an older person's body to eliminate the drug diazepam whereas it may only take 24 hours for younger people.
While distribution may increase for fat-soluble drugs, it may decrease for water-soluble drugs. For example, the volume of distribution of digoxin, a water-soluble digitalis compound, is decreased with age. When the body contains less water, as is the case with older persons, the dosage required to obtain a specific concentration of a drug in the blood is less than it would be in a younger person's body, where water volume is higher. Thus, the initial amount of digoxin needed to produce a given blood level in people with heart disease is 30 percent lower in older people than in younger people. For similar reasons, older people may be at an increased risk of intoxication from alcohol because there is less water in the body to dilute the alcohol.
Some drugs bind very strongly to proteins in the blood, limiting their full effectiveness of circulation throughout the body. Thus the amount of the drug that is free (unbound) is more relevant than the total amount in the body. Aging can affect the quantity of binding proteins and thereby change the amount of the drug that circulates unbound. Examples of drugs showing this effect include phenytoin, warfarin, and many nonsteroidal anti-inflammatory drugs (NSAID).
Most drugs are absorbed, metabolized, and prepared for elimination from the body by the liver. For some drugs, the rate of blood flowing to the liver is what determines this absorption and elimination. For other medications, however, this depends upon the rate of the liver's ability to chemically metabolize them. Some drugs fall in between so that their absorption and elimination depend upon both the rate of the liver's metabolism and the rate of blood flow to the liver. Because of this, age-associated reductions in liver metabolizing ability and liver blood flow can change drug processing.
As we age, the kidney's ability to eliminate drugs is reduced. The filtering rate and the function of the kidney tubules generally decline. The effect of age on drug metabolism varies widely as aging is only one of many factors that affect our metabolism of drugs. For example, cigarette smoking, alcohol intake, dietary modification, other medications, viral infections, the amount of caffeine taken in, and other unknown factors also seem to affect the rate of drug metabolism. In addition, there is remarkable variation (up to sixfold) among individuals in the rate of drug metabolism that is thought to be genetic in origin. Therefore, unless an effect of age is very large and consistent, it may be hidden by these other factors.
In addition to the factors that determine the drug concentration at the site of action, the effects of a given drug also depend upon the sensitivity of the target organ. This target organ sensitivity is called pharmacodynamics (from the Greek, meaning "drug," "power"). The influence of aging on the biochemical and physiologic effects of drugs and how they work is largely unknown. In part, this is because it is very difficult to determine drug effects accurately using the noninvasive techniques usually required in clinical studies.
In general, drugs function by binding with a receptor and by modulating the activities of individual cells. Age-related changes on this cellular level can occur at many different steps, including binding to the receptor and translating either the receptor's response into some biochemical reaction or the cellular response to a biochemical event. In some tissues, the receptors will respond, but the desired chain of results may not be fully realized. Therefore, as we age, defects in receptor responsiveness may occur at more than one location in the cell.
Most drug effects in older people are either similar to or greater than those in younger people. In other words, we become more sensitive to drugs. Moreover, these effects may be magnified if we have a disease that alters the drug's elimination from the body or the body response to the drug.
We are at increased risk for adverse drug reactions from certain classes of drugs as we grow older. Following is a review of some of these adverse reactions to illustrate a few of the mechanisms of increased drug toxicity with aging. (See also Medication Problems in Chapter 26.)
Cardiovascular drugs are a common group of medications that sometimes cause adverse reactions. Decreased dosages of digitalis compounds are generally needed for older people who have heart disease. This is because of the age-related reductions in our body's water and muscle mass and reductions in the clearance rate of the drug, as discussed above. Excessive dosing probably accounts for much of the adverse effects caused by digitalis including nausea, loss of appetite, and changes in mood. Fortunately, digitalis can be safely withdrawn in those of us who have had it prescribed for either mild heart failure or swelling of the legs that has no clear origin. Therefore, if you are taking digitalis, you should review the condition for which it was originally prescribed, and discuss with your physician whether it could be stopped.
Diuretics rank high among the classes of drugs that can cause side effects. These "fluid pills" can cause dehydration and low potassium, sodium, and magnesium in the blood, making one feel weak, tired, and run down. Such adverse effects are poorly tolerated because of the changes in our body's organs and regulating systems that occur with advancing age. You can help to compensate for this by drinking plenty of fluids (at least eight to ten eightounce glasses a day) and asking your doctor about having your blood checked at regular intervals.
The drugs that are sometimes prescribed to prevent irregular heartbeats can also cause problems. Because these antiarrhythmics have a very narrow range between their useful and toxic effects, careful dosing and judicious monitoring of blood levels are required. The side effects that these medications can produce in people of any age--drowsiness, slurred speech, confusion, and numbness and tingling in the arms and legs--are increased as we age. Not all of the antiarrhythmic drugs cause these problems, but the likelihood of side effects is high enough that you should always check with your doctor if you feel there is a complication.
Medication for depression and anxiety is particularly likely to cause adverse effects as we age. The initial doses of these medicines should be very small, as they increase your risk of a drop in blood pressure as well as your level of sedation; therefore, low doses of high-potency drugs such as haloperidol are often favored. However, drug-induced Parkinsonism occurs more commonly with the use of high-potency compounds. You should also be aware that the incidence of abnormal body motions called tardive dyskinesias is due to antipsychotic medication. The frequency of other movement side effects also increases with age.
We also become more vulnerable to adverse effects of antidepressants as we age, such as a fall in blood pressure, the inability to void, disturbances of the heart rhythm, confusion, and sedation.
Benzodiazepines are sometimes prescribed for anxiety; certain drugs in this class take longer to be removed from your body (examples include chlordiazepoxide, diazepam, flurazepam, and alprazolam). However, lorazepam, oxazepam, and temazepam are metabolized more readily. Any of these drugs, however, can greatly increase sedation and your risk of falls. Some experts suggest that they should not be used at all in elderly people because of their tendency to cause memory problems and falls.
Older people use pain-relieving agents more frequently than any other age group. Although the liver's ability to metabolize acetaminophen for elimination from the body may decline slightly, dosage adjustments are not usually necessary.
Our ability to metabolize some nonsteroidal anti-inflammatory drugs (NSAIDs) is decreased, but it is not clear that these differences alone increase the risk of toxicity. Bleeding in the gastrointestinal tract is related to the use of NSAIDs for all age groups and increases in significance as we get older. Recent or current users of these medications are more likely than nonusers to suffer significant gastrointestinal bleeding.
The drug metabolism of the anticoagulant warfarin does not appear to change as we age. The clinical benefit of this drug remains the same for a number of conditions. Therefore, unless you have a significant risk for bleeding, such as from falls, unsteady gait, poor compliance with medicines, or a tendency to bleed, you should not avoid using this medicine just because of your age. Another blood thinner called heparin must be injected and is generally used for hospitalized people with certain conditions that predispose them to blood clotting. The anticoagulant effect of this drug remains unchanged with age.
Drugs can place stress on a number of the body's systems that may have changed with aging, thereby producing adverse effects, and interfering with the way the body regulates itself. For example, a common side effect of some medications is a fall in blood pressure when a person stands up. Drugs can also affect heart function or the regulation of body fluids to further accentuate this fall of blood pressure with change in position.
As we age we are also susceptible to medications such as barbiturates and benzodiazepines that can increase the risk of a very low body temperature (hypothermia). Medications given to people with psychiatric illness can also produce these effects. (Alcohol use can also cause a drop in your body temperature.) People who are known to have a low body temperature or who have had a previous episode of very low body temperature may be at risk for significant druginduced hypothermia. (See page 440 for more on hypothermia.)
A low level of sodium in the blood (hyponatremia) is a common complication of diuretics, usually within the first week of therapy. The symptoms you might experience depend upon how low your sodium is and how fast it declined, but mild reductions may not produce symptoms. Common symptoms are fatigue, lethargy, muscle cramps, loss of appetite, confusion, and nausea. Symptoms of severe declines in sodium are coma and seizures. For thiazide diuretics a low sodium occurs in part because of age-related impairments in kidney function. A low sodium in the blood is a complication of other drugs such as chlorpropamide, nonsteroidal anti-inflammatory drugs, and high-dose narcotics. A low potassium in the blood caused by diuretic therapy occurs with increased frequency as we age. An elevated potassium in the blood also occurs as a side effect of drugs or because of such conditions as diabetes mellitus, kidney failure, and other kidney diseases.
Nonsteroidal anti-inflammatory drugs need to be used with caution as we get older, because of the risk of gastrointestinal bleeding and kidney impairment. Aging puts us at risk for kidney problems due to the changes in kidney blood flow caused by these drugs. This adverse effect is most likely to occur if we have congestive heart failure, liver disease, or certain types of kidney disease.
A cardinal principle of treatment is to avoid drugs that might adversely affect preexisting medical conditions. Table 5 lists some of the disorders that are associated with the risk of an adverse drug effect. Because the conditions that are listed in this table commonly occur as we age, a cautious approach to drug treatment is warranted. If you are taking medication, you should ask and be informed about the potential adverse side effects and promptly seek medical advice if any of these effects appear.
An episode of sudden confusion, called delirium, is often due to medications. (Delirium is discussed in detail in Chapter 13.) The drugs that are known to cause delirium are divided into two groups, depending upon whether they affect specific receptors within the brain, called muscarinic receptors (named for the substance muscarine, which was first isolated from the poisonous mushroom Amanita muscaria).
Antimuscarinic toxicity caused by drugs can be difficult to recognize. Many of the essential features--warm, dry skin; dilated pupils; or a fast heart rate--may be less evident in older people than they are in younger people. Medications such as narcotics, antidepressants, antipsychotic agents, drugs used to relieve spasms in the bowel, and many other nonprescription medications, such as antihistamines, have appreciable antimuscarinic effects. These drugs frequently cause confusion, and individuals with Alzheimer's dementia are especially susceptible.
These drugs may also cause more subtle changes than obvious episodes of delirium. For example, and paradoxically, antimuscarinic drugs may relieve agitation and paranoia in people who have Alzheimer's disease. But they may also reduce a person's self-care activities, presumably because of further declines in the cognitive function caused by the drug. Therefore, if you notice any decline in function, such drug side effects should be considered as a possible cause.
Table 5. Some Important Drug/Disease Interactions in Older Persons
Drugs without significant antimuscarinic effects can also cause confusion and delirium. Drugs used in the management of Parkinson's disease are common offenders and can cause confusion when used together or alone. Others include corticosteroids, cardiovascular drugs, NSAIDs, and some antibiotics. These medications are given just as examples; any drug should be suspected when an episode of acute confusion occurs.
In summary, medications can have beneficial and adverse effects. Aging tends to increase our vulnerability to side effects. As we age we lose body water and muscle and increase our proportion of body fat. This change in body composition means that a given dose of a water-soluble drug gives a higher concentration since it is dissolved in a smaller amount of water. Drugs that are fat soluble have more prolonged effects. Changes in the liver and kidneys tend to reduce the metabolism and elimination of drugs. Any sudden change in our function should raise our suspicion of an adverse drug reaction, although side effects can also appear gradually and undramatically. We should always consider an adverse drug reaction for any new or unexplained symptom. (For more information, see pages 447 to 453.)