a.. How Extensive Is the Problem of Specific Adverse Drug Reactions?

b.. Specific Examples of Patients with Drug-Induced Diseases

c.. Summary of Adverse Reactions and the Drugs that Cause Them

How Extensive Is the Problem of Specific Adverse Drug Reactions?

Each year, more than 9.6 million adverse drug reactions occur in older Americans. One study found that 37 percent of adverse reactions in the elderly were not reported to the doctor, presumably because patients did not realize the reactions were due to the drug. This is not too surprising considering that most doctors admitted they did not explain possible adverse effects to their patients.1

We based the following national estimates on well-conducted studies, mainly in the United States:

a.. Each year, in hospitals alone, there are 28,000 cases of life-threatening heart toxicity from adverse reactions to digoxin, the most commonly used form of digitalis (drugs that regulate the speed and strength of heart beats) in older adults.2 Since as many as 40% or more of these people are using this drug unnecessarily (see discussion on digoxin), many of these injuries are preventable.

b.. Each year 41,000 older adults are hospitalized—and 3,300 of these die—from ulcers caused by NSAIDs (nonsteroidal anti-inflammatory drugs, usually for treatment of arthritis).3 Thousands of younger adults are hospitalized. (See list of drugs that can cause gastrointestinal bleeding.)

c.. At least 16,000 injuries from auto crashes each year involving older drivers are attributable to the use of psychoactive drugs, specifically benzodiazepines and tricyclic antidepressants.4 Psychoactive drugs are those that affect the mind or behavior. (See list of drugs that can cause automobile accidents.)

d.. Each year 32,000 older adults suffer from hip fractures attributable to drug-induced falls, resulting in more than 1,500 deaths.5, 6 In one study, the main categories of drugs responsible for the falls leading to hip fractures were sleeping pills and minor tranquilizers (30%), antipsychotic drugs (52%), and antidepressants (17%). All of these categories of drugs are often prescribed unnecessarily, especially in older adults. (See section on sleeping pills and tranquilizers, antipsychotic drugs, and antidepressants; see also list of drugs that can cause hip fractures because of drug-induced falls.)

e.. Approximately 163,000 older Americans suffer from serious mental impairment (memory loss, dementia) either caused or worsened by drugs.7, 8 In a study in the state of Washington, in 46% of the patients with drug-induced mental impairment, the problem was caused by minor tranquilizers or sleeping pills; in 14%, by high blood pressure drugs; and in 11%, by antipsychotic drugs. (See list of drugs that can cause or worsen dementia.)

f.. Two million older Americans are addicted or at risk of addiction to minor tranquilizers or sleeping pills because they have used them daily for at least one year, even though there is no acceptable evidence that the tranquilizers are effective for more than four months, and the sleeping pills for more than 30 days.9

g.. Drug-induced tardive dyskinesia has developed in 73,000 older adults; this condition is the most serious and common adverse reaction to antipsychotic drugs, and it is often irreversible. Tardive dyskinesia is characterized by involuntary movements of the face, arms and legs. About 80% of older adults receiving antipsychotic drugs do not have schizophrenia or other conditions that justify the use of such powerful drugs, so many of these patients have serious side effects from drugs that were prescribed inappropriately.10 (See list of drugs that can cause tardive dyskinesia or other movement disorders.)

h.. Drug-induced parkinsonism has developed in 61,000 older adults also due to the use of antipsychotic drugs such as haloperidol (HALDOL), chlorpromazine (THORAZINE), thioridazine (MELLARIL), trifluoperazine (STELAZINE), and fluphenazine (PROLIXIN). There are other parkinsonism-inducing drugs as well, such as metoclopramide (REGLAN), prochlorperazine (COMPAZINE), and promethazine (PHENERGAN), prescribed for gastrointestinal problems.11 (See list of drugs that can cause parkinsonism.)

A serious problem exists because both doctors and patients do not realize that practically any symptom in older adults and in many younger adults can be caused or worsened by drugs.12 Some doctors and patients assume that what are actually adverse drug reactions are simply signs of aging. As a result, many serious adverse reactions are entirely overlooked or not recognized until they have caused significant harm.

The drugs responsible for the most serious adverse reactions in older adults are tranquilizers, sleeping pills, and other mind-affecting drugs; cardiovascular drugs such as high blood pressure drugs, digoxin, and drugs for abnormal heart rhythms;13 and drugs for treating intestinal problems.

Mental Adverse Drug Reactions: depression, hallucinations, confusion, delirium, memory loss, impaired thinking

Nervous System Adverse Drug Reactions: parkinsonism, involuntary movements of the face, arms, legs (tardive dyskinesia), sexual dysfunction

Gastrointestinal Adverse Drug Reactions: loss of appetite, constipation

Urinary Problems: difficulty urinating, leaking of urine

Dizziness on Standing

Falls Sometimes Resulting in Hip Fractures

Automobile Accidents Resulting in Injury

Specific Examples of Patients with Drug-Induced Diseases Woman homebound due to a misprescribed heart drug

Liz, a 54-year old woman, was prescribed the heart drug amiodarone (CORDARONE) to treat a common heart condition. She was not told that the drug was not approved by the FDA for her condition. The pharmacy leaflet mentioned nausea and dizziness as side effects, but not lung toxicity. She is now dependent on an oxygen tank to breathe and does not have the strength to clean her house.

Man develops parkinsonism from antipsychotics prescribed for “irritable bowel syndrome”

Larry was an otherwise healthy 58-year-old man with diarrhea believed to be due to “irritable bowel syndrome.” He was given trifluoperazine (STELAZINE), a powerful antipsychotic, to “calm down” his intestinal tract. STELAZINE is not even approved for treating such medical problems. Six months after starting STELAZINE, Larry developed severe parkinsonism, a neurological condition characterized by tremor, limited movements, rigidity and postural instability. To correct this, Larry was started on L-dopa (also known as levodopa), a drug to treat Parkinson’s disease. Presumably, the doctor did not realize the parkinsonism was drug-induced, and the STELAZINE was continued. For seven years, Larry took both drugs until seeing a Parkinson’s specialist. The specialist recognized the real cause of his problem, stopped the STELAZINE, and slowly withdrew the L-dopa over a six-month period. Larry’s severe, disabling parkinsonism cleared completely.

The same Parkinson’s specialist who “cured” Larry of his drug-induced parkinsonism saw, in just three years, 38 other patients with drug-induced parkinsonism and 28 with drug-induced tardive dyskinesia, a syndrome of involuntary movements.

None of these patients were psychotic, the one condition for which antipsychotic medications are approved. Rather, the most common reasons for using the parkinsonism-inducing drugs were chronic anxiety and gastrointestinal complaints. The most frequent culprit (in 19 of these 39 patients) was REGLAN, usually prescribed for heartburn or for nausea and vomiting. Doctors often prescribe REGLAN before trying other more conservative and safer methods. Other drugs that brought on parkinsonism included prochlorperazine (COMPAZINE), haloperidol (HALDOL) and chlorpromazine (THORAZINE).14

Did You Know? Drug-Induced Parkinsonism

Each year, 61,000 older adults develop drug-induced parkinsonism. At least 80 percent of them, like Larry, should never have been put on the drugs causing the parkinsonism in the first place. Also, as in Larry’s situation, a large proportion of these people have doctors who think that their patients’ parkinsonism developed spontaneously.

The problem is two-fold. Doctors fail to suspect that the condition is caused by a drug such as STELAZINE or other drugs such as metoclopramide (REGLAN), prochlorperazine (COMPAZINE) or promethazine (PHENERGAN). Then they add a second drug to treat the disease that has actually been caused by the first drug.

Confusion and hallucinations caused by ulcer drugs

Leticia wrote to Public Citizen about her 80-year-old father, saying that she had to repeatedly ask his doctor about the possible role of her dad’s ulcer drugs in causing confusion and hallucinations before the doctor listened. Her father had tried three different drugs – cimetidine (TAGAMET), ranitidine (ZANTAC) and famotidine (PEPCID) – for his ulcers, and each had caused these side effects. When the doctor finally switched Leticia’s father to an antacid – aluminum hydroxide and magnesium hydroxide (MAALOX) – his mind completely cleared and he was his old self, no longer confused or hallucinating

Woman develops reversible mental impairment from tranquilizer

The first time 79-year-old Sally saw her physician son-in-law after several months, he noted that she had suffered severe impairment of her otherwise sharp mind. She was acting confused and, for the first time in her life, was unable to balance her checkbook. When he questioned her, she was able to remember that her problem had started around the time she was put on the tranquilizer lorazepam (ATIVAN). After this link was discovered, the drug was slowly discontinued and the mental impairment disappeared.

Man has auto accident after one dose of tranquilizer

Ben, a 64-year-old, was scheduled to have a biopsy done at a local hospital one morning. The doctor gave him a free sample of a tranquilizer, alprazolam (XANAX), to take an hour or so before the procedure so that he would be relaxed for the biopsy. Ben was not told that he should not use the drug if he was going to drive. While driving to the hospital for the biopsy, he blacked out. The car went over a fence and sustained $6,000 worth of damage, but fortunately Ben was unhurt. (See drugs that can cause automobile accidents.)

Dangerously slow heart rate with propranolol use in the elderly

Shara, a 60-year-old assistant at a senior citizens’ center, was started on propranolol (INDERAL, INDERAL LA) to treat her high blood pressure. Unfortunately, her doctor did not realize that the dose of this sometimes useful drug must be reduced in older adults, and the dose she was prescribed was too high for her. Two days after she started taking the drug, she began feeling very weak. The side effect was so bad that by the third day on the drug, she went to a hospital emergency room, where her pulse rate was found to be 36 beats per minute. This dangerously low rate fully explained her weakness. The drug was stopped, and Shara’s heart rate returned to normal. Later a low dose of a different drug was prescribed and produced no side effects.

Child dies from drug prescribed for attention deficit hyperactivity disorder

Jamal, a bright 7-year-old boy, was prescribed an antidepressant, imipramine (TOFRANIL), to treat attention deficit hyperactivity disorder. His parents were not provided with complete, accurate information about the drug. As a result, they were unaware that the drug can cause life-threatening heartbeat irregularities (called arrhythmias), that the dose prescribed to Jamal was too high and that the tremor and convulsions that Jamal began to have were actually side effects from the TOFRANIL. Treatment with the drug was continued, and one day, while at school, he collapsed and died of an arrhythmia. If his parents had been adequately warned about this drug, Jamal might still be alive today.

Poor prescribing is often the cause of symptoms The World Health Organization, in discussing the problem of side effects in the elderly, has stated some principles applicable to people of all ages:

Quite often, the history and clinical examination of patients with side effects reveal that no valid indication [purpose] for the offending drug has been present ... Adverse reactions can to a large extent be avoided in the elderly by choosing safe and effective drugs and applying sound therapeutic principles in prescribing, such as starting with a small dose, observing the patient frequently, and avoiding excessive polypharmacy [the use of multiple drugs at the same time].15

In other words, patients who suffer adverse drug reactions are very often victims of drugs that they should not have been taking that way in the first place.

A 1992 study published in Medical Care examined prescriptions given to people being discharged from a community hospital. It focused on those who were prescribed three or more drugs to treat chronic illnesses.1

The results of this study are quite disturbing, both in what they say about the doctors’ prescribing practices and as evidence of the potential damage that these prescribing practices can do to older adults. Of the 236 people intensively studied:

a.. 81 percent had one or more prescribing problems with the prescriptions they were given, including inappropriate drugs, doses or schedule;

b.. 60 percent had been given one or more prescriptions for a drug that was an inappropriate choice of therapy because it was either “less than optimal medication given the patient’s diagnosis” or there was no established indication for it;

c.. 50 percent were given either too high or too low a dose of the drug;

d.. 44 percent of the patients were given a combination of drugs that can result in harmful drug interactions;

e.. 20 percent were given drugs that unnecessarily duplicated the therapeutic effect of another drug they were taking. Fortunately, a consultant pharmacist involved in the care of more than half of the people was able to reduce the risks to the patients by making recommendations to the prescribing physicians.

Available on the web site are lists of the most common drug-induced adverse effects along with the drugs that can cause them. In the box below are some of the symptoms that, although they are frequently caused by drugs, are the kinds of problems that you or many doctors might first attribute simply to “growing old” or “getting nervous” instead of to a drug.

Which Adverse Effects Can Be Caused by Which Drugs?

The drug-induced disease lists on this web site are to be used by patients who have any of a variety of medical problems (or by doctors) to find out which drugs, especially ones they are using or are considering using, can cause specific adverse reactions. The lists are compiled from a variety of sources.17, 18, 19, 20, 21, 22, 23

Although some of these adverse effects occur most commonly in older adults, all of them have also been documented in younger people, although sometimes not as often.

Summary of Adverse Reactions and the Drugs That Cause Them Only the most easily detectable problems are considered, and only the most common drugs causing each problem are listed. Adverse Drug Reaction Number of Drugs Examples of Brand Names

Depression 166 Accutane, Advil, Catapres, Cipro, Dalmane, Factive, Inderal, Naprosyn, Norpace, Pepcid, Reglan, Tagamet, Talwin, Ultracet, Valium, Xanax, Zantac

Psychoses/ hallucinations 156 Aldomet, Benadryl, Catapres, Celebrex, Cipro, Dexatrim, Elavil, Halcion, Inderal, Lanoxin, Procanbid, Sonata, Tagamet, Ultracet, Valium, Vioxx

Confusion/ delirium 147 Amaryl, Ambien, Benadryl, Catapres, Cipro, Compazine, Diabeta, Diabinese, Dymelor, Elavil, Mellaril, Sinemet, Tagamet, Valium, Xanax, Zantac

Dementia 76 Aldomet, Inderal, Maxzide, Mellaril, Regroton, Restoril, Ser-Ap-Es, Tagamet, Valium, Xanax,Zantac Insomnia 35 Avelox, Floxin, Inderal, Lasix, Mevacor, Nicorette, Sudafed, Synthroid, Theo-24

Parkinsonism 40 Abilify, Aldomet, Asendin, Cardizem, Compazine, Elavil, Geodon, Haldol, Mellaril, Prozac, Reglan, Regroton, Risperdal, Thorazine

Tardive dyskinesia 19 Abilify, Asendin, Buspar, Compazine, Geodon, Haldol, Mellaril, Risperdal, Thorazine, Wellbutrin, Zyban, Zyprexa Dizziness on standing 154 Abilify, Calan SR, Cardizem CD, Cardura, Catapres, Compazine, Elavil, Geodon, Haldol, Hytrin, Inderal, Isordil, Lasix, Minipress, Nitro-Bid, Prinivil, Procardia, Sonata, Tenormin, Valium, Xanax

Falls/hip fracture 59 Ambien, Celexa, Compazine, Dalmane, Elavil, Haldol, Isordil, Lexapro, Navane, Nembutal, Prozac, Restoril, Sinequan, Valium, Xanax

Automobile accidents 28 Ambien, Asendin, Ativan, Celexa, Elavil, Lexapro, Norpramin, Pamelor, Paxil, Prozac, Sinequan, Tofranil, Valium, Xanax, Zoloft

Sexual dysfunction 127 Abilify, Calan SR, Geodon, Lopid, Lopressor, Norpace, Pepcid, Proscar, Prozac, Sarafem, Tagamet, Tegretol, Transderm-Scop, Zantac

Loss of appetite, nausea, vomiting 63 Advil, Avelox, Daypro, Demerol, EES, Feldene, Feosol, K-Lor, Lanoxin, Levaquin, Relafen, Sumycin, Theo-24, Ultracet, Ultram

Abdominal pain, ulcers, GI bleeding 48 Advil, Anaprox, Celebrex, Cortone, Daypro, Decadron, Feldene, Indocin, Motrin, Relafen, Somophyllin, Theo-24, Ultracet, Vioxx, Zithromax

Constipation 107 Amphojel, Benadryl, Caltrate, Cogentin, Inderal, Lotronex, Maalox, Talwin, Tylenol No. 3, Tylox, Ultram, Urised

Diarrhea 56 Aciphex, Aldomet, Avelox, Cipro, Dulcolax, Maalox, Phillips’ Milk of Magnesia, Nexium, Peri-Colace, Precose, Prilosec, Sporanox, Sumycin, Zelnorm

Lung toxicity 59 Cordarone, Feldene, Inderal, Prinivil, Tegretol, Vasotec, Visken

Blocked urination 56 Antivert, Artane, Benadryl, Bentyl, Compazine, Duragesic, Elavil, Felbatol, Haldol, Sinequan, Tavist, Ultram, Zyban

Urine leakage 84 Aricept, Celexa, Esidrix, Hytrin, Inderal, Lasix, Lexapro, Lithobid, Minipress, Neurontin, Paxil, Restoril, Tenormin, Valium, Xanax, Zaroxolyn, Ziac, Zoloft

---------------------------------------------------------- 1 Of the 42.34 million Americans 60 and older (Statistical Abstracts of the United States 1992, 1991 population data) approximately 90% are taking one or more medications for a total of 37.83 million older people. According to a study of verified adverse drug reactions (German PS, Klein LE. Adverse drug experience among the elderly. Pharmaceuticals for the Elderly. Pharmaceutical Manufacturers Association, November 1986), 25.4% of the elderly patients 60 and older had at least one adverse drug reaction during the six-month interval that the study encompassed. Twenty-five and four-tenths percent of 37.83 million people is 9.61 million adverse reactions for the six-month period. The number of adverse reactions in a year would certainly be higher. The actual number of adverse reactions is also much higher since this calculation assumes all patients were being seen outside of the hospital or nursing home. Because the use of drugs in nursing homes and hospitals is much higher than in clinics, the number of adverse reactions is also higher.

2 Using the basis for estimating the number of admissions to medical wards of hospitals of 6.05 million in 1990 (see reference 1 in the previous chapter for the basis of this estimate), and the estimate that in 22.4% of medical admissions the patients are using digoxin and that 2.06% of these suffer life threatening heart toxicity from digoxin (both are from Miller RR, Greenblatt DJ. Drug Effects in Hospitalized Patients. New York: John Wiley and Sons, 1976), this amounts to 6.05 million times 22.4% times 2.06% or 27,917 older adults in hospitals who suffer from life-threatening heart toxicity from digoxin. This estimate understates the magnitude of the problem because the proportion of patients in the Miller/Greenblatt book using digoxin and experiencing life-threatening heart toxicity is based on all patients of all ages, whereas the rate of digoxin use and therefore the rate of life-threatening reactions is higher in older adults. The estimate is also lower because it does not include cases of digoxin toxicity that occur in surgical patients.

3 Ray WA, Griffin MR, Shorr RI. Adverse drug reactions and the elderly. Health Affairs 1990; 9: 114 - 122.

4 Ray WA, Fought RL, Decker MD. Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. American Journal of Epidemiology Oct 1, 1992; 136: 873 - 883.

5 The estimate of 32,000 hip fractures in older adults is based on projecting the findings of this study of drug-induced hip fractures in older Michigan Medicaid patients to the entire country.

6 Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ. Psychotropic drug use and the risk of hip fracture. New England Journal of Medicine Feb 12, 1987; 316: 363 - 369.

7 This estimate is based on projecting the findings of the Larson study on the 1.43 million Americans 65 and older who have dementia. See discussion on sleeping pills and tranquilizers (p. xxx) for more details about this serious problem.

8 Larson EB, Kukull WA, Buchner D, Reifler BV. Adverse drug reactions associated with global cognitive impairment in elderly persons. Annals of Internal Medicine Aug 1987; 107: 169 - 173.

9 See discussion on sleeping pills and tranquilizers (p.xxx) for more details on this estimate.

10 See discussion on antipsychotic drugs (p. xxx) for more details about drug-induced tardive dyskinesia and misprescribing of antipsychotic drugs.

11 The estimate of 61,000 older adults suffering from drug-induced parkinsonism is derived as follows: As described in detail in the chapter on antipsychotic drugs (see p. xxx), there are an estimated 750,000 people 65 and older in nursing homes or living in the community who are regularly (for three or four months or longer) being prescribed antipsychotic drugs. According to a survey in 1981 of 5,000 patients being treated with antipsychotic drugs, 13.2% had parkinsonism (see reference 15 below and p. xxx in the Mind Drugs section for further discussion of this problem). Another study by the same researchers found that 62% became better (no longer had parkinsonism) within 30 days of discontinuing the drug. Thus, at least 62% of the 13.2% of patients getting antipsychotic drugs or 7.92% of all patients getting these drugs suffer from drug-induced parkinsonism. Calculating 7.92% of 750,000 patients getting these drugs for at least several months yields 61,380 patients with drug-induced parkinsonism. This is a very conservative estimate because it does not include either those patients using antipsychotic drugs for less than three to four months (an additional 1.16 million people) who are also at risk for drug-induced parkinsonism (because 90% of the cases occur within 72 days after beginning the drug) or those who get drug-induced parkinsonism from the related drugs metoclopramide/REGLAN, prochlorperazine/COMPAZINE and promethazine/PHENERGAN usually prescribed for nausea.

12 Vestal RE;, ed. Drug Treatment in the Elderly. Sydney, Australia: ADIS Health Science Press, 1984.

13 Ouslander JG. Drug therapy in the elderly. Annals of Internal Medicine Dec 1981; 95: 711 - 722.

14 Grimes JD. Drug-induced parkinsonism and tardive dyskinesia in nonpsychiatric patients. Canadian Medical Association Journal Mar 1, 1982; 126: 468.

15 Drugs for the Elderly. 2nd edition. Copenhagen, Denmark: World Health Organization, 1997: 28.

16 Lipton HL, Bero LA, Bird JA, McPhee SJ. The impact of clinical pharmacists' consultations on physicians' geriatric drug prescribing: A randomized controlled trial. Medical Care Jul 1992; 30: 646 - 658.

17 Davies DM;, ed. Textbook of Adverse Drug Reactions. New York: Oxford University Press, 1977.

18 Aronson JK;Van Boxtel C;, ed. Side Effects of Drugs Annual 18. Amsterdam: Elsevier, 1995.

19 Drugs for the Elderly. 2nd edition. Copenhagen, Denmark: World Health Organization, 1997: 28.

20 Aronson JK;, ed. Side Effects of Drugs Annual 24. Amsterdam: Elsevier, 2001.

21 Drugs that may cause psychiatric symptoms. Medical Letter on Drugs and Therapeutics Jul 8, 2002; 44: 59 - 62.

22 Aronson JK;, ed. Side Effects of Drugs Annual 25. Amsterdam: Elsevier, 2002.

23 Other sources included the Physicians' Desk Reference and outside consultants.

freedom@harshasanka.org