ADVERSE DRUG REACTIONS

How Serious Is the Problem and How Often and Why Does It Occur?

Although some adverse drug reactions (ADR) are not very serious, others cause the death, hospitalization, or serious injury of more than 2 million people in the United States each year, including more than 100,000 fatalities. In fact, adverse drug reactions are one of the leading causes of death in the United States.[1] Most of the time, these dangerous events could and should have been avoided. Even the less drastic reactions, such as change in mood, loss of appetite, and nausea, may seriously diminish the quality of life.

Despite the fact that more adverse reactions occur in patients 60 or older, the odds of suffering an adverse drug reaction really begin to increase even before age 50. Almost half (49.5%) of Food and Drug Administration (FDA) reports of deaths from adverse drug reactions and 61% of hospitalizations from adverse drug reactions were in people younger than 60.[2] Many physical changes that affect the way the body can handle drugs actually begin in people in their thirties, but the increased prescribing of drugs does not begin for most people until they enter their fifties. By then, the amount of prescription drug use starts increasing significantly, and therefore the odds of having an adverse drug reaction also increase. The risk of an adverse drug reaction is about 33% higher in people aged 50 to 59 than it is in people aged 40 to 49.[3],[4]

Adverse Reactions to Drugs Cause Hospitalization of 1.5 Million Americans Each Year

An analysis of numerous studies in which the cause of hospitalization was determined found that approximately 1.5 million hospitalizations a year were caused by adverse drug reactions.[1] This means that every day more than 4,000 patients have adverse drug reactions so serious that they need to be admitted to American hospitals.

A review of patients admitted to medical wards of a hospital found that although for 3.8% of hospital admissions, adverse drug reactions led directly to hospitalization, 57% of these adverse drug reactions were not recognized by the attending physician at the time of admission. As in numerous other studies, many of these admissions should have been prevented. In fact, 18.6% of all drugs prescribed prior to admission were contraindicated.[5]

Another review of studies of the percentage of hospital admissions related to adverse drug reactions found that up to 88% of ADR-related hospitalizations in the elderly are preventable. In addition, elderly people were four times more likely to be hospitalized by ADR-related problems than nonelderly.[6]

Although the rate of drug-induced hospitalization is higher in older adults (an average of about 10% of all hospitalizations for older adults are caused by adverse drug reactions) because they use more drugs, a significant proportion of hospitalizations for children are also caused by adverse drug reactions.

A recent review of all studies concerning the reasons for pediatric hospitalization (children under the age of 19) found that 2.09% of all pediatric hospitalizations were caused by adverse drug reactions and that 39% of these were life-threatening.[7] Using the most recent published data on pediatric hospitalizations,[8] there were 3.8 million children under the age of 19 hospitalized in the United States in 1997. This means that in one year, there are 79,000 children (2.09% x 3.8 million children) admitted to the hospital because of adverse drug reactions, 31,000 of these children having life-threatening adverse reactions.

Adverse Reactions as a Major Cause of Emergency Room Visits

A recent review of studies concerning the causes of people going to hospital emergency rooms found that as many as 28% of all emergency department visits were drug-related, including a large proportion due to adverse drug reactions and inappropriate prescriptions. Of all of the drug-related visits, the authors found that 70% were preventable.[9]

Adverse Reactions Occur During Hospitalization to 770,000 People a Year

In addition to the 1.5 million people a year who are admitted to the hospital because of adverse drug reactions, an additional three-quarters of a million people a year develop an adverse reaction after they are hospitalized. According to national projections based on a study involving adverse drug reactions developing in patients in the hospital, 770,000 additional patients a year—more than 2,000 patients a day—suffer an adverse event caused by drugs once they are admitted. Many of the reactions in the patients studied were serious, even life-threatening, and included cardiac arrhythmias, kidney failure, bleeding, and dangerously low blood pressure. People with these adverse reactions had an almost twofold higher risk of death compared to other otherwise comparable hospitalized patients who did not have a drug reaction. Most important, according to the researchers, almost 50% of these adverse reactions were preventable. Among the kinds of preventable problems were adverse interactions between drugs that should not have been prescribed together (hundreds of these are listed in the Drug-Induced Diseases section of this web site), known allergies to drugs that had not been asked about before the patients got a prescription, and excessively high doses of drugs prescribed without considering the patient’s weight and kidney function.[10]

Thus, adding the number of people with adverse drug reactions so serious that they require hospitalization to those in which the adverse reaction was “caused” by the hospitalization, more than 2.2 million people a year, or 6,000 patients a day, suffer these adverse reactions. In both situations, many of these drug-induced problems should have been prevented.

Dangerous Prescribing Outside the Hospital for 6.6 Million Older Adults a Year

Based on the Do Not Use principle we have advocated concerning certain drugs for more than 16 years in our Worst Pills, Best Pills books, web site, and monthly newsletter, several published studies have examined the extent to which people are prescribed drugs that are contraindicated because there are safer alternatives. One study, whose authors stated that “Worst Pills, Best Pills stimulated this research,” found that almost one out of four older adults living at home—6.6 million people a year—were prescribed a “potentially inappropriate” drug or drugs, placing them at risk of such adverse drug effects as mental impairment and sedation, even though the study only examined the use of a relatively short list of needlessly dangerous drugs (fewer than the number listed as Do Not Use drugs on this site).[11]

Other researchers looked not only at people for whom a contraindicated drug was prescribed, but also at prescriptions for older people involving two other categories: questionable combinations of drugs and excessive treatment duration. The authors categorized all of this as “high-risk prescribing” and limited their analysis to just the three classes of drugs most commonly causing drug-related illness: cardiovascular drugs, psychotropic drugs (ones that act on the mind) such as tranquilizers and antidepressants, and anti-inflammatory drugs. They found that 52.6% of all people 65 or older were given one or more prescriptions for a high-risk drug.[12] Thus, more than twice as many older adults were the victims of high-risk prescribing when these two additional categories were added.

Nine Reasons Why Older Adults Are More Likely Than Younger Adults to Have Adverse Drug Reactions

Many of the studies and much of the information concerning the epidemic of drug-induced disease focuses on people 60 and over. As we have mentioned previously, some of the changes that eventually lead to great numbers of adverse reactions in older adults (in combination with increased drug use) really begin to occur in the mid-thirties. In connection with the idea that drug-induced disease begins to get more common before age 60, it is interesting to note that in a number of studies comparing the way “older” people clear drugs out of the body with the way younger people do, the definition of older is above 50, and younger is below 50.[3]

1. Smaller Bodies and Different Body Composition: Older adults generally weigh less and have a smaller amount of water and a larger proportion of fat than younger adults. Body weight increases from age 40 to 60, mainly due to increased fat, then decreases from age 60 to 70, with even sharper declines from 70 on. Therefore, the amount of a drug per pound of body weight or per pound of body water will often be much higher in an older adult than it would be if the same amount of the drug were given to a younger person. In addition, drugs that concentrate in fat tissue may stay in the body longer because there is more fat for them to accumulate in.
2. Decreased Ability of the Liver to Process Drugs: Because the liver does not work as well in older adults, they are less able than younger people to process certain drugs so that they can be excreted from the body. This has important consequences for a large proportion of the drugs used to treat heart conditions and high blood pressure, as well as many other drugs processed by the liver. The ability of the body to rid itself of drugs such as Valium, Librium, and many others is affected by this decrease in liver function.
3. Decreased Ability of the Kidneys to Clear Drugs Out of the Body: The ability of the kidneys to clear many drugs out of the body decreases steadily from age 35 to 40 on. By age 65, the filtering ability of the kidneys has already decreased by 30%. Other aspects of kidney function also decline progressively as people age. This has an effect on the safety of a large number of drugs.

4. Increased Sensitivity to Many Drugs: The problems of decreased body size, altered body composition (more fat, less water), and decreased liver and kidney function cause many drugs to accumulate in older people’s bodies at dangerously higher levels and for longer times than in younger people. These age-related problems are further worsened by the fact that even at “normal” blood levels of many drugs, older adults have an increased sensitivity to their effects, often resulting in harm. This is seen most clearly with drugs that act on the central nervous system, such as many sleeping pills, alcohol, tranquilizers, strong painkillers such as morphine or pentazocine (TALWIN), and most drugs that have anticholinergic effects (see Anticholinergic in the Glossary). This latter group includes antidepressants, antipsychotic drugs, antihistamines, drugs used to calm the intestinal tract (for treating ulcers or some kinds of colitis) such as Donnatal, atropine, and Librax, antiparkinsonian drugs, and other drugs such as Norpace.
   
   For all of the drugs in the above-mentioned groups that are listed on this web site, we include an “anticholinergic” warning as follows:

    

   Anticholinergic Effects

    Anticholinergic Effects

   WARNING: SPECIAL MENTAL AND PHYSICAL ADVERSE EFFECTS

   Older adults are especially sensitive to the harmful anticholinergic, effects of this drug. Drugs in this family should not be used unless absolutely necessary.

   Mental Effects: confusion, delirium, short-term memory problems, disorientation, and impaired attention

   Physical Effects: dry mouth, constipation, difficulty urinating (especially for a man with an enlarged prostate), blurred vision, decreased sweating with increased body temperature, sexual dysfunction, and worsening of glaucoma.

    

   Yet another example of the marked increase in the sensitivity of older adults to drugs has to do with stimulant drugs that are in the same family as amphetamines, or “speed.” Despite the dangers of these drugs for anyone, especially older adults, they are widely promoted and prescribed, including Ornade, Tavist-D, Entex LA, and Actifed. All of these contain amphetamine-like drugs such as pseudoephedrine. For any of these drugs discussed on this web site, most of which are listed as Do Not Use drugs, the following warning is given: 

    

   WARNING

   [Name of drug] can cause or worsen high blood pressure. It is especially dangerous for people who have high blood pressure, heart disease, diabetes, or thyroid disease. People over 60 are more likely than younger people to experience effects on the heart and blood pressure, restlessness, nervousness, and confusion.

    

5. Decreased Blood-Pressure-Maintaining Ability: Because older adults are less able to compensate for some of the effects of drugs, there is yet another reason why they are more vulnerable to adverse effects of drugs and more sensitive to the intended effects. The most widespread example of older adults’ decreased ability to compensate is seen when they get out of bed and/or suddenly rise from a seated position. As you rise, your blood pressure normally falls, decreasing the blood flow to your head and resulting in less blood flow to the brain. Younger people’s bodies can compensate for this: receptors in the neck, sensing that the blood pressure is falling as the person rises, tighten up the blood vessels in other parts of the body, thus keeping the overall blood pressure high enough. In older adults, these receptors do not work as well. Often, upon standing, older adults feel giddy, lightheaded, and dizzy. They may even faint because the blood pressure in the head falls too rapidly.
   
   The ability to maintain a proper blood pressure is further weakened when you use any of a very long list of drugs, the most common examples being high blood pressure drugs. Other categories of drugs that cause an exaggerated blood pressure drop include sleeping pills, tranquilizers, antidepressants, antipsychotic drugs, antihistamines, drugs for heart pain (angina), and antiarrhythmics. (See full list of drugs that can cause dizziness on standing.)
   
   This problem of so-called postural hypotension—the sudden fall in blood pressure on standing, brought about by a combination of aging and drugs—can be catastrophic. The falls that often result can end in hip fractures, a leading cause of death in older adults, or other serious injuries.
6. Decreased Temperature Compensation: Younger adults are more easily able than older people to withstand very high or very low temperatures. They sweat and dilate (widen) blood vessels to get rid of excess heat when it is hot, and constrict (narrow) blood vessels to conserve heat when it is cold. Older adults’ bodies are less able to do this. As in the case of blood pressure compensation, this “normal” temperature-regulating problem of older adults can be significantly worsened by any of a large number of prescription and over-the-counter drugs, resulting in fatal or life-threatening changes in body temperature. Many older adults’ deaths during heat waves or prolonged cold spells can be attributed to drugs that interfere with temperature regulation. Most of these people did not know they were at increased risk. All drugs on this site that contain a warning about anticholinergic effects can have this harmful effect on withstanding heat waves.
7. More Diseases That Affect the Response to Drugs: Older adults are much more likely than younger adults to have at least one disease–such as liver or kidney damage (not just the decreased function of older age), poor circulation, and other chronic conditions—that alters their response to drugs. Little is known about the influence of multiple diseases on drug effects in the elderly.
   
   One well-understood example, however, is the effect of heart failure on the way people can handle drugs. When the heart is not able to pump as much blood as it used to, the change that occurs in heart failure, there is also a decrease in the flow of blood to the kidneys. For the same reasons discussed in reason number 3, the reduced flow of blood to the kidneys decreases the kidneys’ ability to rid drugs from the blood and excrete them in the urine.
8. More Drugs and, Therefore, More Adverse Drug Reactions and Interactions: Since older adults use significantly more prescription drugs than younger people, they have greatly increased odds of having a drug reaction caused by the dangerous interaction between two drugs. Often, older adults take one or more over-the-counter drugs in addition to their prescription drugs. This further increases the likelihood of adverse drug interactions. One of the more common kinds of adverse drug interactions is the ability of some drug to cause a second drug to accumulate to dangerous levels in the body. At the end of the discussion of each drug on this site, except for the Do Not Use drugs, there is a list of other drugs that can cause serious adverse interactions.
9. Inadequate Testing of Drugs in Older Adults Before Approval: Although older adults use a disproportionate share of prescription drugs, few of these drugs are adequately tested in older adults before being approved by the FDA.
   
   Dr. Peter Lamy of the University of Maryland School of Pharmacy has stated, “We test drugs in young people for three months; we give them to old people for 15 years.” The FDA is slowly remedying this serious problem by requiring that the people on whom a drug is tested be representative of those who will use the drug if it is approved. Nonetheless, most drugs on the market today, which are heavily used by older adults, were not adequately tested in this age group.

In summary, there are significant differences between younger and older patients, often not realized by doctors or patients. Increasing awareness of these differences will result in the prescription of far fewer drugs to older adults, and those that are prescribed will be given at lower doses in most instances.

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