Consultant Pharmacist: December 1998

The Consultant Pharmacist is published by the
American Society of Consultant Pharmacists.

How to Manage Drug-Induced Weight Changes in Residents of Long-Term Care Facilities

Many medications commonly used in long-term care populations can cause or contribute to unwanted, potentially debilitating weight gain or weight loss.

Here we explore the pharmacodynamics of drug-induced weight change, biological and behavioral influences, and strategies for helping elderly patients attain and maintain optimal body weight.

Jeannette Y. Wick

Weight change is a frequent topic of conversation across the United States. Americans are very concerned about weight, especially weight gain. Despite a plethora of low-fat and sugar-free foods, obesity continues to be a problem. We spend over $68 million annually on health care directly related to obesity-induced problems. Obesity also affects quality of life in ways that cannot be measured in dollars; it has been called, "the last uncontrolled social prejudice."⁵ We search for causes and cures for obesity like Ponce de Leon searched for the fountain of youth. And residents of long-term care facilities are no exception.

Weight loss is less of a problem in general, but presents a treatment dilemma in the long-term care population. With age, many people begin to lose body weight. As they do, their proportion of muscle decreases, and adipose tissue increases. Loss of body weight is a symptom of many diseases, and a serious problem for many people, particularly when it is related to HIV infection, depression, or a malignancy. Weight gain in these people frequently represents an improvement in their health status.

The health care professional's goal is to help every resident find and achieve a healthy and desirable ideal weight. Sometimes, drug therapy can interfere with that goal. This article presents an overview of body weight theory, and identifies drugs that affect residents' ability to reach their proposed ideal weight.

People Concerns

Weight changes cause concern for everyone involved in the health care system. For the resident, changes in weight can be distressing for several reasons. Appearance remains important for most people throughout life, and changes in appearance serve as constant reminders of the aging process. Changes in weight can also affect exercise tolerance and endurance, causing residents to feel tired or sluggish. In addition, if mobility is impaired, residents may lose their independence. Relinquishing the activities of daily living can be frightening and depressing.

For caregivers, weight changes present challenges. With the impaired or immobile resident, weight gain can make transfer activities (e.g., from bed to chair) more difficult and may increase the risk of injury to staff or resident. Weight loss, on the other hand, increases the risk of pressure ulcers and falls and fractures. The level of care required can be increased significantly by both weight gain and weight loss.

Health care providers in general are concerned because obesity (as measured by a body mass index greater than 27 kg/m²) represents an independent risk factor for Type 2 diabetes, cardiovascular disease, stroke, and gall bladder disease. It is second only to smoking as a cause of death, being implicated in approximately 300,000 deaths every year.

Calculating Body Mass Index (BMI)
1
Multiply the resident's weight by 703.
2
Square the resident's height in inches.
3
Divide #1 by #2
[weight X 703/height²]

BMI < 19 = underweight
BMI 19 - 26 = normal weight
BMI > 27 = overweight

Obesity in general is treatment-resistant. The best approach is prevention. Our search for appetite suppressants to treat obesity has been fraught with misadventure. Weight loss, or wasting, is an equally serious problem and can be treatment-resistant also. We know less about drug-induced weight loss.

Weight Regulation

Weight is maintained only when there is a balance of caloric intake and energy expended. Part of the reason that Americans grapple with weight relates to our status as an industrialized nation. In industrialized nations in general, energy expenditure decreases as less physical activity or sustained exercise is required to accomplish work. Caloric intake decreases in these nations over time, but usually it doesn't decrease enough to match the decreased activity or exercise. In the United States, the gap between the number of calories we now expend and consume, compared with the number of calories we expended and consumed 50 years ago, is about +300 calories per day.

Obesity
in general is treatment-resistant. The best approach is prevention. Our search for appetite suppressants to treat obesity has been fraught with misadventure.
Simply put, weight is governed by total caloric intake, daily fat intake, resting metabolic rate, thermic response to food, level of habitual physical activity, and nutrient partitioning. These factors usually vary day to day and over the years in every person. The elderly resident's energy balance profile will most certainly be different than it was decades ago.

Three other influences are important in setting the stage for weight change: regulated or internal biological factors; integrated biological and behavioral factors, and naturally occurring or imposed biological factors.

Regulated or internal biological factors are the factors that are inherent. They include a genetic predisposition to obesity as mediated by endocrine function. Genetics is not the sole determinant for obesity, although obesity does occur with greater frequency in some families and is probably genetic in part. Endocrine functions that influence weight include insulin regulation, hormonal changes, and adrenal gland functions. Changes in any of these contribute to development of undesired or unhealthy weight changes.

Integrated biological and behavioral factors include individual psychology as it relates to food, eating patterns, and weight goals. They differ vastly from person to person, and can affect weight tremendously. Lifestyle, environment, and cultural conditions also influence weight. It would follow that families are exposed to similar sets of these factors and would suggest that familial patterns of obesity go beyond genetic explanations.

Naturally occurring or imposed biological factors influence weight as well. Although they are not the main determinants of weight, they can cause changes that are sometimes significant. These include diet, exercise, surgery, and drugs.

Drugs and Weight Change

Drugs affect weight in three ways. They can increase or decrease appetite. They can cause thirst. They can also affect the way things taste, causing either anorexia or increased food intake.

Research has not clearly explained the mechanisms involved in drugs' effects on appetite, although recent developments, especially those related to the psychoactive drugs, have brought us greater understanding. Generally, weight is regulated when afferent signals from adipose tissues are sent to the hypothalamic nucleus in the brain. The brain, in turn, sends efferent signals to the body, affecting energy intake and expenditure. Most drugs that affect weight influence efferent signals. In particular, the serotonin system is implicated in weight control, but other systems are also important.

Neurotransmittors and Hormones Involved in Weight Regulation

Neurotransmitter or Hormone	Proposed Effect on Weight	Drugs That May Affect or Interfere with System
Serotonin	Increased serotonin availability reduces food intake and decreases carbohydrate cravings	Selective serotonin re-uptake inhibitors Antipsychotics Antidepressants Cyproheptadine Lithium
Norepinephrine	Increased availability elicits a hardy eating response
a-adrenergic stimulation	Increases eating	Clonidine
ß-adrenergic stimulation	Suppresses feeding
y-aminobutyric acid (GABA)	Reduces energy expenditure and induces carbohydrate intake	Valproic acid
a- and ß-adrenergic blockade	Decreases thermogenesis and basal metabolic rate	Beta blockers
Hormones (thyroxine, ACTH, growth hormone, insulin, etc.)	Affect thermogenesis and basal metabolic rate	Thyroid supplements Lithium Corticosteroids Antidiabetes agents

Some drugs cause thirst, which prompts intake of fluids or causes fluid retention. Residents who prefer high-calorie beverages to water or sugar-free beverages may gain weight. Categories of drug that cause thirst include lithium and any drug with anticholinergic side effects.

Antibotics and Their Effects on Appetite

Antibiotic	Effect
Cephalosporins	Anorexia, loss of appetite
Erythromycins	Destruction of gut flora
Griseofulvin	Altered taste
Metronidazole	Altered taste, loss of appetite
Penicillins	Taste disturbances
Tetracyclines	Weight loss or gain of unknown cause

Many drugs cause changes in taste or complete loss of taste or smell. Most residents will report a metallic, bitter, or sour taste after taking certain drugs. Some will experience decreased appetite if their ability to taste or smell is impaired. Other residents may eat or drink more in an effort to mask the taste of a drug. If taste or smell is lost completely, the joy of eating is also lost and anorexia may follow.

Specific Agents

Many drugs have the potential to affect a resident's weight. Drug-induced weight change presents the smallest problem when the drug is used only for a short course of therapy. It presents a serious health management issue when weight change is clearly drug-induced, and the drug must be prescribed long-term. In the latter case, adherence to the drug regimen often becomes a problem.

Antipsychotics

Since the 1960s, there have been reports in the literature about weight gain in patients who take antipsychotic medication. Starting with the oldest of these agents, chlorpromazine and thioridazine, researchers noticed that patients had a tendency to gain weight. The mechanism was never clear, but interference with the serotonin system was suspected. Of all of the traditional neuroleptics, molindone was the least likely to cause weight gain or increased appetite. Its structural similarity to serotonin was noted, and a possible link postulated. Weight gain secondary to use of these drugs was (and remains) clinically important, but received little clinical attention for several reasons. Primarily, in the risk-benefit equation, weight gain seemed an unimportant risk when control of psychoses was a needed benefit.

For several decades, there were few drugs available to treat schizophrenia and schizo-affective disorders. All the drugs offered equal effectiveness; only their side effect profiles differed. Psychiatrists juggled side effects for most patients. If sedation and anticholinergic side effects were a problem when chlorpromazine or thioridazine were used, haloperidol or thiothixene could be tried. For those patients who complained of weight gain, molindone could be tried. Haloperidol appeared to cause less weight gain than other traditional agents, but it was still a concern.

With traditional antipsychotics, certain tendencies are clear. Most weight gain occurs early in treatment, and is centrally distributed. Waist-to-hip ratio increases, and weight generally reaches a plateau after six months to a year. This type of weight gain is generally reversible when the drug is discontinued, and the weight gain may be preventable if steps are taken in advance to stabilize food intake or increase exercise. The exact amount of weight gained varies by patient, but it is not unusual for patients to gain 10-15 pounds over the first six months to one year of treatment. Mobility can be impaired, and self-esteem issues often arise. Patients with mental illnesses have concerns about weight that mirror those of the general population. This type of weight gain is also the most undesirable in terms of overall health, since centrally distributed weight gain is closely associated with cardiac disease and other morbidity.

Ever since the introduction of the atypical antipsychotics beginning with clozapine, psychiatrists and other prescribers have had new options to address the neurologic side effects. These drugs offer significant improvement over the traditional agents. However, weight gain remains a problem. Some researchers believe that it is associated with serotonin receptor blockade; drugs that enhance serotonin transmission decrease appetite, and the reverse is also true.

All the atypical agents (clozapine, risperidone, olanzapine, and quetiapine) can contribute to significant weight gain. Many residents will gain up to eight pounds over the first six to eight weeks of treatment, and continue to gain over the first year. With these agents, weight gain is often described as moderate to marked, with increases of 7% over baseline weight common. With risperidone, there is some evidence that the weight gain is dose-dependent. Again, weight gain is usually centrally distributed, accumulates early in treatment, reaches a plateau after a year or two, and can exacerbate co-morbid conditions.^7-10

People who take these agents long-term generally complain about weight gain, and it can be serious enough to affect compliance. At a recent conference, one psychiatrist listening to a lecture about the medical side effects of atypical antipsychotics said, "It looks like obesity is going to be the tardive dyskinesia of the future for the mentally ill." While this is arguably an overstatement, with both the traditional and the atypical agents, good counseling is imperative in order to help ensure compliance.

Antidepressants

The antidepressants have been associated with weight gain for decades, too. Starting with the tricyclic antidepressants (TCAs), researchers noted that patients had a tendency to gain weight. Weight gain could not be correlated with gender or with prior weight loss or gain. Because weight changes are often associated with depression itself, there was some initial confusion about whether the weight gain was a sign that the patient's depression was responding to the drug or that the patient was gaining weight independent of response. Even today it can be difficult to differentiate. We do know a little more, however.

TCAs clearly stimulate appetite and cause carbohydrate cravings. People who take TCAs report an increased desire for both complex carbohydrates and sweet food. Amitriptyline appears to cause the greatest appetite stimulation, with the others causing cravings in varying degrees. The degree of weight gained is related to the dose and duration of use of the drug. It is also reversible. TCAs may decrease basal metabolic rate 17%-24%. Part of the weight gain may be related to the drugs' strong anticholinergic effect, which increases thirst.

The selective serotonin re-uptake inhibitors (SSRIs) do not cause weight gain. In fact, they cause slight weight loss in some people; this is probably related to their ability to enhance serotonin availability. Decreased appetite and decreased carbohydrate craving are often reported. Further, they have few anticholinergic effects, so increased thirst does not contribute to weight gain.

Lithium

Lithium can cause weight gain in several ways. Weight gain of 20-25 pounds over two to six years of treatment occurs in approximately 20% of lithium patients.^4-5 The weight gain may be caused in part by increased thirst leading to increased fluid intake. Lithium also has a complex effect on serotonin, decreasing serotonin receptor site sensitivity. In addition, lithium changes thyroid function, with more than 15% of people receiving it developing hypothyroidism during the first few years of treatment. People who are overweight or gain weight easily before lithium therapy is started are more likely to gain weight after therapy begins.

Weight gain related to lithium use may be reversible, but the mechanism is complex and there are no assurances that this will be the case. Further, this issue must be addressed with lithium candidates before therapy is started and periodically thereafter. Spontaneous or unsupervised dieting can cause toxicity in lithium patients; therapeutic effect is a fine balance and can be affected by changes in sodium or fluid balance.

Anticonvulsants

Two common anticonvulsants can cause weight changes: valproic acid and carbamazepine. Although the exact mechanism of valproic acid's effect on weight is unknown and probably complex, researchers think that it enhances neurotransmission mediated by gamma-aminobutyric acid. This leads to increased carbohydrate cravings and intake and decreased energy expenditure. Residents also may eat more in response to gastrointestinal discomfort that is fairly common with this drug. Weight gain can be significant.

Carbamazepine tends to cause less weight gain than valproic acid, but it can still be a problem. With this drug, water retention may be a contributing factor, and edema is not uncommon.

Diuretics And Cardiac Drugs

Fluid balance is an important consideration for patients who have cardiac problems or hypertension. Diuretics can cause mild-to-serious alterations in taste and appetite. Acetazolamide has been reported to cause loss of appetite leading to weight loss. The thiazide diuretics can cause taste alterations; most residents who experience this adverse effect report a bitter taste. Depending on the severity of the problem and the resident's response in terms of eating patterns, weight gain or loss may result.

Digoxin causes gastrointestinal side effects in approximately 25% of residents, and can cause loss of appetite. When residents report or demonstrate loss of appetite and they are taking digoxin, immediate assessment is needed. Loss of appetite is one of the first signs of digoxin toxicity. Fluid balance is also important in maintaining therapeutic serum levels.

The beta blockers can cause mild-to-modest, sustained weight gain over months and years of treatment. The proposed mechanism involves their effect on beta-adrenergic receptors, specifically ß₃ receptors. There is clear evidence that propranolol, atenolol, and labetolol can contribute to weight gain. Others in this class probably do as well.

Drugs That are Highly Anticholinergic
Tricyclic antidepressants
Some antipsychotics
Many antihistamines
All antiparkinsonian agents
Many antispasmodics
Atropine
Dicyclomine
Clonidine may also cause weight gain. It is an a-adrenergic stimulant, which may increase appetite. Taste changes have been reported with use of this drug.

Diltiazem and nifedipine can alter taste, causing changes in food and fluid intake. Nifedipine may also cause water retention or edema.

Many angiotensin-converting agents impair taste perception. Captopril and enalapril have been associated with weight loss. Captopril may bind zinc, causing loss of taste.

Antidiabetic Agents

Initiation of insulin therapy can cause weight gain averaging 15 pounds in three months. It appears that adipose mass increases as insulin reverses catabolic defects in carbohydrate metabolism, corrects fat and protein metabolism, and decreases basal metabolic rate. Weight loss is a symptom of type I diabetes, and this weight gain is not always a problem. For some residents, weight gain may be welcome.

With the sufonylurea-type agents, weight gain has also been reported. Generally, the gain is modest, leveling off at about 10 pounds over 3-12 months. The gain is mainly adipose tissue. Not all patients gain weight after starting on sulfonylureas, mainly because dietary control is an integral part of patient education.

Chlorpropamide may cause weight gain as a result of water retention. Tolbutamide may cause taste alterations.

Corticosteroids

Corticosteroids can, and usually do, cause weight when used for long periods. Most of the weight gain is adipose tissue, with increased truncal fat stores. Appetite is probably increased secondary to hyperinsulinemia, which causes fat deposition. Alternate-day therapy causes less of a problem than daily therapy and should be used whenever possible.

Antihistamines

Researchers consider cyproheptadine a key drug in their understanding of appetite control. This drug stimulates appetite, causing weight gain, and it has been used effectively for people with anorexia nervosa to stimulate eating. It acts as a serotonin blocker.

Other antihistamines have also been associated with increased appetite. Both terfenadine and astemizole have been reported to cause weight gain when used long term, and astemizole may alter taste.

Non-steroidal Anti-inflammatory Drugs (nsaids)

NSAIDs inhibit prostaglandin synthesis. In doing so, they may cause fluid retention or increase or decrease appetite. Fluid retention that results from NSAID use does respond to diuretic therapy.

Sulindac has been reported to alter taste. Penicillamine also alters taste, and this effect can be considerable. Some residents will report total loss of taste or appetite. However, zinc supplementation may restore taste.

Antibiotics

Many antibiotics affect taste or appetite, and this is not usually a problem if the drug is used for a short course of therapy (see above). Several mechanisms may be involved. Some researchers suggest that these drugs kill normal gut flora and that this, in turn, affects appetite. Supplementation with lactobacillus or yogurt may help if this is the case. Some antibiotics alter taste, again causing weight loss or gain, depending on how the resident deals with it.

Thalidomide

Thalidomide was recently approved for use in the United States. It has been used to treat patients who have wasting syndromes secondary to AIDS or cancer. In these patients, circulating tumor necrosis factors appear to be related to weight loss. Use of thalidomide can often help the resident gain or maintain a more appropriate weight.

Miscellaneous Agents

Many other drugs can change appetite, alter taste, or cause thirst. Theophylline, albuterol, and the cholinesterase inhibitors (tacrine and donepezil) have been implicated in loss of appetite. Levodopa may cause weight loss as a result of increased fat breakdown, increased circulating insulin, or altered taste. Benzodiazepines may cause loss of appetite or taste changes. The antineoplastics, and especially tamoxifen, can cause weight gain. Amantadine has been known to cause anorexia and to contribute to weight loss.

Conclusion

We know that many drugs contribute to weight gain and that some cause weight loss. Unfortunately, the simple preventive measures have not been tested in controlled studies, so we do not know how effective they are.

There is increased emphasis on monitoring weight from regulatory, certifying, and accrediting bodies. This stems from an increased understanding of body weight as a risk factor in disease. Several measures can help residents reach or maintain their optimal weight. First, when weight changes pursuant to drug use are expected or normal, we have a duty to warn the resident in advance. Counseling should be redundant, being delivered by nursing, dietetics, medical, and pharmacy professionals. Emphasis on healthy choices is essential.

Second, exercise is an important factor in maintaining weight, mobility, and general health. Exercise improves both physical and mental health.

Third, we must keep accurate and regular weight records. For those patients who are starting therapy with a new drug that may cause weight changes, a baseline weight is essential. Monthly or weekly weights, depending on the magnitude and speed of weight changes, are appropriate.

Weight

changes are noted in any resident, careful assessment of the drug regimen may yield clues and solutions.

Fourth, when possible, an alternative drug should be used if weight becomes a serious issue. As always, the lowest effective dosage of any drug should be used, especially if weight change is clearly dose-related.

Finally, the individual's psychological issues as they relate to food must be examined. Sometimes, behavior management programs and psychotherapy can help a resident change destructive eating or drinking habits.

When weight changes are noted in any resident, careful assessment of the drug regimen may yield clues and solutions.

References

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Casey DE. Side effect profiles of new antipsychotic agents. J Clin Psychiatry 57;(Suppl 11):40-5.
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Jeannette Y. Wick, RPh, MBA, is Chief Pharmacist in the District of Columbia's Department of Human Services, Washington, D.C.

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The Consultant Pharmacist is published by the
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