continuing education

The Skinny on By Keturah R. Robinson, PharmD, BCPS

pon successful completion of this risk of becoming obese is article, the pharmacist should be approximately 25 percent, Useful Web Sites able to: and the rise continues to be ■ 1. Identify and utilize assessment a health concern for adults, www.obesity.org The Obesity Society is a leading scientific techniques to properly recognize children, and adolescents. society dedicated to the study of obesity. obesity and initiate appropriate Results from the 2005-2006 U Since 1982, the Obesity Society has been therapy. National Health and Nutri- committed to encouraging research on 2. Calculate body-mass index (BMI), determine tion Examination Survey the causes and treatment of obesity, and weight status, and recognize cardiovascular (NHANES), using mea- to keeping the medical community and risk factors associated with obesity. sured heights and weights, public informed of new advances. 3. Identify preventive and maintenance strate- indicate that an estimated ■ www.cdc.gov/nccdphp/dnpa/obesity/ gies, and nonpharmacological and phar- 34.3 percent of U.S. adults The Centers for Disease Control and macological treatment options for patients 20 years and older are Prevention Web site provides accurate, diagnosed with obesity. obese and 5.9 percent are up-to-date information on obesity. Re- 4. Identify medications to avoid and use in extremely obese. sources to state-based programs, tools, obese patients with concomitant disease During the past 20 years and guidance are provided. ■ states or health conditions. there has been a dramatic www.who.int/topics/obesity/en/ The World Health Organization is 5. Choose an appropriate treatment strategy increase in obesity in the responsible for providing leadership on based on patient findings. United States. In 2007, only global health matters, shaping the health one state (Colorado) had research agenda, setting norms and stan- obesity is the excessive accumulation of fat, a prevalence of obesity dards, articulating evidence-based policy and is associated with serious health complica- less than 20 percent. Thirty options, providing technical support to tions such as , , states had a prevalence countries, and monitoring and assessing musculoskeletal disorders, psychosocial dis- equal to or greater than 25 health trends. orders, and cancers. It occurs over time when percent, and three of these there is an imbalance between the calories states (Alabama, Missis- consumed and the calories expended. Obesity sippi and Tennessee) had a prevalence of obesity equal may be due to a global shift in high in fats to or greater than 30 percent. Among diverse populations and sugars and a decrease in physical activ- within the United States, obesity is higher among women ity. However, factors such as genetics and the of racial and ethnic minority populations than in non-His- environment may also contribute to obesity. panic Caucasian women. In men, Mexican-Americans obesity’s prevalence is increasing world- have a higher prevalence of obesity than Caucasians and wide among adults, adolescents, and children, African-Americans. Furthermore, women of lower socio- and is now considered to be a global epidemic. economic status are approximately 50 percent more likely According to the World Health Organization to be obese than those of higher socioeconomic status. (WHO), at least 400 million adults were obese in Overall, health care expenditures are significantly higher 2005, and more than 700 million people will be for obese individuals, and the economic cost of obesity in obese by 2015. In the United States, the lifetime the United States in 2000 was estimated to be $117 billion

www.americaspharmacist.net June 2009 | america’s Pharmacist  and growing, resulting in disabilities and diseases which with the amount of body fat, it does not directly create huge burdens for families and health systems. measure body fat and the correlation varies by the rise in obesity rates continues to be a growing sex, race, age, and athleticism. For example, at concern because of the implications for the health of the same BMI, women tend to have more body Americans. Studies support that there is a direct cor- fat than men. Older people, on average, tend to relation with obesity and the risk of developing many have more body fat than younger people; and diseases and health conditions, including coronary heart highly trained athletes may have a high BMI disease; mellitus; endometrial, breast, because of increased muscularity instead of and colon cancer; ; dyslipidemia; stroke, increased body fat. As for race, percent body liver and gallbladder disease; and respirato- fat is reached at a much lower BMI in Asians, ry problems; ; and gynecological problems. and in African-Americans, percent body fat is reached at a much higher BMI in comparison Diagnosing Obesity to Caucasians. Thus, taking this into account, The clinician diagnosing the obese patient should evalu- BMI should not be the sole determination of ate both clinical and laboratory findings in an effort to diagnosing obesity, and it does not provide an determine the severity of obesity, potential health risks, accurate measurement for certain individuals and to provide a basis for selecting appropriate lifestyle such as body builders, elderly, and children. interventions, pharmacotherapy, and possible surgery. The National Heart, Lung, and Blood Institute guidelines Waist Circumference recommend looking at three predictors related to risk for There is a high correlation between abdominal disease and health conditions. The three predictors that obesity, which is also known as central adi- should be evaluated are body-mass index (BMI), waist posity, visceral, android, or male-type obesity, circumference, and other medical risks which include type and health consequences when compared to 2 diabetes mellitus, hypertension, and CVD. Screening for peripheral fat distribution. Therefore, abdominal obesity should occur at the periodic health examination. obesity is a major concern. As increasing cen- tral adiposity is associated with an increased Defining Obesity risk of morbidity and mortality, waist circumfer- According to WHO and the National Institutes of Health ence should be measured to provide additional (NIH), obesity is defined as a BMI of 30 kg/m2 and documentation for a diagnosis of obesity. above. The calculation of BMI takes into account a Waist circumference measures abdominal fat person’s weight in kilograms (kg) divided by their height by measuring the distance around the abdo- in meters squared (m2). Another way of calculating the men. It is one of the most practical tools to BMI is by multiplying the weight in pounds by 703, then assess abdominal fat for chronic disease risks dividing it by the square of the height in inches (in). The and treatment progress and/or BMI is easy to measure, reliable, and highly correlates failure. Women with a waist circumference of with percentage of body fat and body fat mass. (See more than 35 inches, and men with a waist Table 1 and Table 2, pages 37–38.) As an alternative to circumference of more than 40 inches, are at calculating the BMI, many practitioners utilized universal increased risk for developing chronic diseases tables to identify their patients BMI. BMI such as hypertension, type 2 diabetes mellitus, tables are utilized often and they are quick, and easy to and dyslipidemia. use. (See Table 3, page 39.) As with BMI, waist circumference values for currently, the WHO and the NIH guidelines for BMI different ethnic groups should be taken into ac- are applied to Caucasians, Hispanics, and African-Ameri- count. Asian women with a waist circumference cans. As BMI accounts for height and weight, it correlates of more than 31 inches, and Asian men with a strongly with the total fat content in adults. However, it waist circumference of more than 35 inches are is important to remember that although BMI correlates at risk for developing the previously mentioned

ii america’s Pharmacist | June 2009 www.americaspharmacist.net Prevention Table 1: Formulas and Calculations for Body-Mass Index (BMI) The first step towards prevention is Measurement Units Formula and Calculations understanding obesity’s etiology. Most Kilograms (kg) and meters (m) Formula: weight (kg) / [height (m)]2 cases of obesity are related to non- Take the weight in kilograms medical disorders such as a sedentary divided by height in meters squared. lifestyle and increased caloric intake. Example: Weight = 68 kg, Height A thorough history, including onset = 64.96 in (1.65 m) Calculation: 68 ÷ (1.65)2 = 24.98 of , previous weight loss attempts, change in dietary patterns, Pounds (lbs) and inches (in) Formula: weight (lb) / [height (in)]2 x 703 history of , current and past Divide the weight in pounds (lbs) medications, and history of smok- by height in inches (in) squared and multiply by a conversion ing cessation should all be taken into factor of 703. account. Medication histories are Example: Weight = 150 lbs, particularly important because there Height = 5’5” (65”) Calculation: [150 ÷ (65)2] x 703 are several common medications that = 24.96 cause weight gain and obesity, such as insulin, sulfonylureas, and antipsychot- Reproduced from: “Clinical G Clinical Guidelines on the Identification, Evaluation, and Treatment of and Obesity in Adults-The Evidence Report.” ics. Medication options to avoid weight National Institutes of Health. Obes Res 1998; 6:515. gain in certain disease states will be discussed later. chronic diseases. Parameters for this particular Along with obtaining a detailed patient history, dietary ethnic group are slightly lower compared to lifestyle patterns should be evaluated. There should be others. As an alternative to measuring waist a balance between diet and exercise, and a diet high in circumference, ultrasound, computed tomog- fats and sugars should be avoided. An increase in the raphy, and magnetic resonance imaging (MRI) consumption of fruits and vegetables, as well as legumes, are more accurate than waist circumference for whole grains, and nuts, should be part of a healthy diet. assessing the distribution of body fat and body Furthermore, regular, moderate-intensity activity for 30 min- fat distribution. However, these tests are too ex- utes for most days of the week will help to control weight. pensive to be used for the diagnosis of obesity A healthy diet with the addition of regular exercise can help alone. Waist-to-hip ratio provides no additional prevent and treat obesity, which in turn, can prevent chronic benefit over waist circumference. disease and reduce economic cost associated with obesity.

Risk Status Assessment Nonpharmacological Treatments Along with an increased BMI and waist circum- Lifestyle modifications which include caloric reduc- ference, the presence of cardiovascular risk tion and regular exercise in combination with behavior factors or comorbidities should be assessed. modifications or treatments are essential to maintaining a A detailed medical history, routine blood healthy weight and/or losing weight. Although 29 percent pressures, lipid profiles, and fasting glucose of men in the United States and 44 percent of the women measurements should be taken into account. describe themselves as trying to lose weight, only about Cardiovascular risk factors to be identified 20 percent report restricting caloric intake and increasing include hypertension, dyslipidemia (low HDL or physical activity simultaneously, despite recommenda- high LDL), impaired fasting glucose, prema- tions indicating that this combination is effective. ture family history of CHD, at risk age (greater Many studies support that obese individuals can lose than or equal to 45 for men, greater than or approximately one-half pound per week simply by reducing equal to 55 for women), cigarette smoking, their caloric intake by 500 to 1,000 kcal below their required and physical inactivity. for the maintenance of their current weight. Although add-

www.americaspharmacist.net June 2009 | america’s Pharmacist iii that suppress appetite, orlistat is the Table 2: Standard Weight Status Categories Associated With only medication approved for weight BMI Ranges for Adults loss by mechanism of reducing nutrient BMI Weight Status absorption. Serotonergic agents such < 18.5 kg/m2 Underweight as fenfluramine (Pondimin) and dexfen- > or = 18.5 to 24.9 kg/m2 Normal weight fluramine (Redux) are no longer available > or = 25.0 to 29.9 kg/m2 Overweight in the United States due to abuse and > or = 30.0 to 34.9 kg/m2 Class I Obesity potential and life-threatening side effect > or = 35.0 to 39.9 kg/m2 Class II Obesity profiles. All prescription medications discussed have been approved by the >40.0 kg/m2 Class III Obesity (Severe, Extreme, Morbid Food and Drug Administration (FDA) Obesity) for use of short-term (12 weeks or less) treatment of obesity. Each medication is Reproduced from: “Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults-The Evidence Report.” National unique in its own way, and agents should Institutes of Health. Obes Res 1998; 6:515. be chosen in the best interest of patient needs per the approved indication. ing exercise to caloric restriction minimally increases weight loss during the acute phase of weight loss, it appears to be Noradrenergic Agents the component of treatment that is most likely to promote Diethylpropion (Tenuate) long-term maintenance of a reduced weight. Behavioral Diethylpropion (brand name Tenuate) is a sympa- treatments help obese persons to develop adaptive think- thomimetic amine that is used as an anorexiant ing, eating, and exercise habits that enable them to de- agent. It is structurally and chemically related to crease their weight and avoid regaining the weight. Persons the amphetamines and it is classified as a con- who combine caloric restriction and exercise with behav- trolled substance (C-IV). Diethylpropion is indicat- ioral treatment may expect to lose about 5 to 10 percent ed as adjunct therapy for short-term management of pre-intervention body weight over a period of four to six of exogenous obesity in patients with a BMI equal months. Bariatric surgical treatments, such as gastric by- to or greater than 30 kg/m2 in conjunction with a pass, can induce long-term weight loss, but are appropriate regimen of routine exercise, behavioral modifica- only for selected patients with a body-mass index of at least tion, and caloric reduction. Diethylpropion stimu- 40 kg/m2 or a body-mass index of at least 35 kg/m2, along lates the release of norepinephrine and dopamine with obesity-related medical conditions. from the nerve terminal and inhibits their reuptake. Diethylpropion is available in a 25 mg im- Prescription Pharmacological mediate release tablet or a 75 mg controlled Treatments release tablet. The usual dose for adult is a 25 Most medications used directly for weight loss are ap- mg immediate release tablet three times daily petite suppressants which work primarily by increasing before meals, or a 75 mg controlled release the availability of anorexigenic neurotransmitters such as tablet daily at mid-morning. Weight loss is norepiniphrine, serotonin, dopamine, or a combination greatest during the first week of therapy and de- of these three in the central nervous center. The appetite creases in succeeding weeks. It should be con- suppressants currently on the market can be placed in tinued only if the patient has satisfactory weight two main categories-noradrenergic agents and mixed loss (at least four pounds) during the first four noradrenergic-serotonergic agents. Noradrenergic agents weeks of therapy. If the rate of weight loss slows include diethylpropion, phentermine, benzphetamine, down, stops, or if tolerance develops, the dose and phendimetrazine. The mixed noradrenergic-seroto- of diethylpropion should not be increased but nergic class contains one medication currently on the instead be discontinued. Prolonged use of market, known as sibutramine. Along with the agents diethylpropion may induce dependence with

iv america’s Pharmacist | June 2009 www.americaspharmacist.net Table 3. Body-Mass Index Table

Height (in) BMI 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76

Wgt 4’10” 4’11” 5’0” 5’1” 5’2” 5’3” 5’4” 5’5” 5’6” 5’7” 5’8” 5’9” 5’10” 5’11” 6’0” 6’1” 6’2” 6’3” 6’4” (lbs)

100 21 20 20 19 18 18 17 17 16 16 15 15 14 14 14 13 13 13 12 105 22 21 21 20 19 19 18 18 17 16 16 16 15 15 14 14 14 13 13 110 23 22 22 21 20 20 19 18 18 17 17 16 16 15 15 15 14 14 13 115 24 23 23 22 21 20 20 19 19 18 18 17 17 16 16 15 15 14 14 120 25 24 23 23 22 21 21 20 19 19 18 18 17 17 16 16 15 15 15 125 26 25 24 24 23 22 22 21 20 20 19 18 18 17 17 17 16 16 15 130 27 26 25 25 24 23 22 22 21 20 20 19 19 18 18 17 17 16 16 135 28 27 26 26 25 24 23 23 22 21 21 20 19 19 18 18 17 17 16 140 29 28 27 27 26 25 24 23 23 22 21 21 20 20 19 19 18 18 17 145 30 29 28 27 27 26 25 24 23 23 22 21 21 20 20 19 19 18 18 150 31 30 29 28 27 27 26 25 24 24 23 22 22 21 20 20 19 19 18 155 32 31 30 29 28 28 27 26 25 24 24 23 22 22 21 20 20 19 19 160 34 32 31 30 29 28 28 27 26 25 24 24 23 22 22 21 21 20 20 165 35 33 32 31 30 29 28 28 27 26 25 24 24 23 22 22 21 21 20 170 36 34 33 32 31 30 29 28 27 27 26 25 24 24 23 22 22 21 21 175 37 35 34 33 32 31 30 29 28 27 27 26 25 24 24 23 23 22 21 180 38 36 35 34 33 32 31 30 29 28 27 27 26 25 24 24 23 23 22 185 39 37 36 35 34 33 32 31 30 29 28 27 27 26 25 24 24 23 23 190 40 38 37 36 35 34 33 32 31 30 29 28 27 27 26 25 24 24 23 195 41 39 38 37 36 35 34 33 32 31 30 29 28 27 27 26 25 24 24 200 42 40 39 38 337 36 34 33 32 31 30 30 29 28 27 26 26 25 24 205 43 41 40 39 38 36 35 34 33 32 31 30 29 29 28 27 26 26 25 210 44 43 41 40 39 37 36 35 34 33 32 31 30 29 29 28 27 26 26 215 45 44 42 41 39 38 37 36 35 34 33 32 31 30 29 28 28 27 26 220 46 45 43 42 40 39 38 37 36 35 34 33 32 31 30 29 28 28 27 225 47 46 44 43 41 40 39 38 36 35 34 33 32 31 31 30 29 28 27 230 48 47 45 44 42 41 40 38 37 36 35 34 33 32 31 30 30 29 28 235 49 48 46 44 43 42 40 39 38 37 36 35 34 33 32 31 30 29 29 withdrawal syndrome on cessation of therapy. mimetics with diethylpropion should be avoided due to risk Diethylpropion is contraindicated in patients of hypertensive crisis. When using diethylpropion, patients with pulmonary hypertension, arteriosclerosis, may experience blurred vision, diarrhea, insomnia, head- hyperthyroidism, glaucoma, severe hyperten- ache, and unpleasant taste. Abrupt cessation following sion, and history of drug abuse. Concurrent use prolonged high dosage administration can result in extreme of drugs such as serotonin-reuptake inhibitors fatigue and mental depression. Symptoms of chronic intoxi- (SSRIs), monoamine oxidase inhibitors (MAOIs), cation of diethylpropion include marked insomnia, person- psychostimulants, sibutramine, and sympatho- ality changes, and psychosis in severe cases.

www.americaspharmacist.net June 2009 | america’s Pharmacist  Table 3. Body-Mass Index Table — continued

Height (in) BMI 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76

Wgt 4’10” 4’11” 5’0” 5’1” 5’2” 5’3” 5’4” 5’5” 5’6” 5’7” 5’8” 5’9” 5’10” 5’11” 6’0” 6’1” 6’2” 6’3” 6’4” (lbs)

240 50 49 47 45 44 43 41 40 39 38 37 36 35 34 33 32 31 30 29 245 51 50 48 46 45 43 42 41 40 38 37 36 35 34 33 32 32 31 30 250 52 51 49 47 46 44 43 42 40 39 38 37 36 35 34 33 32 31 30 255 53 52 50 48 47 45 44 43 41 40 39 38 37 36 35 34 33 32 32 260 54 53 51 49 48 46 45 43 42 41 40 38 37 36 35 34 33 33 32 265 56 54 52 50 49 47 46 44 43 42 40 39 38 37 36 35 34 33 32 270 57 55 53 51 49 48 46 45 44 42 41 40 39 38 37 36 35 34 33 275 58 56 54 52 50 49

Reproduced from: “Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report.” National Institutes of Health. Obes Res 1998; 6:515.

Phentermine (Adipex-P) ally develops within a few weeks of starting Phentermine (brand name Adipex-P) is an oral sympa- therapy. When tolerance develops, it is recom- thomimetic amine used as an adjunct for short-term mended that phentermine be discontinued as treatment of exogenous obesity. It is indicated for opposed to increasing the dose. weight reduction in combination with exercise, behav- Phentermine is contraindicated in patients ioral modification, and caloric reduction for obese pa- with advanced arteriosclerosis, symptomatic tients with BMI equal or greater than 30 kg/m2, or equal cardiovascular disease, moderate to severe or greater than 27 kg/m2 in the presence of risk fac- hypertension, pulmonary hypertension, hyper- tors such as diabetes and hypertension. Phentermine thyroidism, glaucoma, and valvular disease. stimulates the release of norepinephrine and dopamine Patients with history of drug abuse or use of from the nerve terminal, and inhibits their reuptake. MAOIs during or within two weeks of initiation Phentermine is structurally and chemically related to the should not use phentermine. Concurrent use amphetamines, but is generally associated with a lower with duloxetine, psychostimulants, SSRIs, sym- incidence and severity of CNS side effects. Phenter- pathomimetics, venlafaxine, and sibutramine mine is classified as a controlled substance (C-IV), and should be avoided due to potential for additive as amphetamines and related stimulants have been adverse events, such as hypertensive crisis or extensively abused, the possibility of abuse with similar cardiac arrhythmias. Common side effects in- agents cannot be ruled out. clude tachycardia, elevation of blood pressure, Phentermine is available in a 37.5 mg tablet. The dizziness, insomnia, and dry mouth. Shortness usual dose for adults is 37.5 mg daily before breakfast of breath during normal activities requires im- or 10 to 14 hours before retiring. Phentermine should mediate medical attention. not be taken in the late evening due to the possibility of insomnia. The pharmacokinetics of phentermine for pa- Benzphetamine (Didrex) and tients with hepatic and renal impairments are not known; Phendimetrazine(Bontril) therefore, caution with use and dose adjustment may be Benzphetamine (brand name Didrex) and Phen- necessary in certain populations, including the elderly. dimetrazine (brand name Bontril) are both sym- Tolerance to the anorexiant effects of phentermine usu- pathomimetic amines for the short-term use of

vi america’s Pharmacist | June 2009 www.americaspharmacist.net exogenous obesity in combination with regular unpleasant taste, nausea, diarrhea, other gastrointestinal exercise, behavioral modification, and reduce disturbances, urticaria, other allergic reactions involving caloric intake. Both agents should be used for the skin, and changes in libido. Psychological disturbanc- a short time duration (three to 12 weeks) to help es have been reported in patients and caution should be establish new eating habits at the beginning of used in patients with even mild hypertension. the process. They are both structurally and chemically related to the amphetamines Mixed Noradrenergic-Serotonergic and are classified as controlled substances Agents (C-III). Abuse potential tends to be higher than Sibutramine (Meridia) both diethylpropion and phentermine. Sibutramine (brand name Meridia) is indicated for the Benzphethamine initial doses should range , including weight loss and main- from 25 mg to 50 mg once daily in the mid- tenance of weight loss and should be used in conjunction morning or mid-afternoon. Doses can slowly be with, at minimum, a reduced-calorie diet. Sibutramine is titrated to a maintenance dose ranging from 25 recommended for obese patients with a body-mass index mg to 50 mg one to three times daily. Phen- (BMI) of equal to or greater than 30 kg/m2, or equal to or dimetrazine initial doses should range from 35 greater than 27 kg/m2 in the presence of risk factors such mg twice or three times daily one hour before as diabetes, dyslipidemia, or hypertension. Obesity due meals. In some cases, a 1/2 tab equivalent to untreated hypothyroidism should be ruled out. Sibutra- to 17.5 mg twice or three times daily may be mine is classified as a controlled substance (C-IV) due adequate for some patients. However, dosage to its history of abuse and misuse. Sibutramine works by should not exceed more than two tablets three inhibiting the neuronal uptake of norepinephrine, sero- times daily. For both drugs, dosages should tonin, and to a lesser extent, dopamine. By blocking the be individualized according to the response of reuptake of these neurotransmitters, sibutramine indirect- the patient. If tolerance develops, the recom- ly causes weight loss. The initial dose of sibutramine is 10 mended dose should not be exceeded in an mg to 15 mg daily, and may be given in 5 mg daily doses attempt to increase the effect, instead the drug for patients who can not tolerate the 10 mg daily dose. should be discontinued. Insulin requirements over a six-month period, patients who followed a re- in diabetes mellitus may be altered and dietary duced-calorie diet and received sibutramine typically lost restrictions may be needed. 5–8 percent of their preintervention body weight, as com- Due to limited use of these medications, pared with 1–4 percent among patients who received their use should be weighed against the risk. placebo. Data from three long-term (> six months) obe- Benzphetamine and phendimetrazine are con- sity trials have shown that patients on sibutramine, who traindicated in patients with advanced arterio- lose at least four pounds in the first four weeks of therapy, sclerosis, symptomatic cardiovascular disease, are more likely to achieve significant long-term weight moderate to severe hypertension, hyperthyroid- loss. Blood pressure and pulse should be measured prior ism, and glaucoma. Patients are at risk for hy- to therapy and monitored regularly thereafter. Some of the pertensive crisis if these medications are used common side effects of sibutramine include dry mouth, concomitantly or within 14 days following use of anorexia, insomnia, constipation, and headache. MAOIs and should not be used concomitantly Sibutramine is contraindicated in patients receiving with other CNS stimulants. Adverse reactions MAOIs during or within two weeks of beginning therapy, to benzphetamine and phendimetrazine may and sibutramine should not be used with other centrally- include palpitations, tachycardia, elevation of acting appetite suppressants. Moreover, sibutramine blood pressure, over stimulation, restlessness, should be avoided in patients with a history of coronary dizziness, insomnia, tremor, sweating, head- artery disease, congestive heart failure, arrhythmias, or ache, psychotic episodes, depression following stroke. Patients with untreated hypothyroidism, severe withdrawal of the drug, dryness of the mouth, renal impairment, and severe hepatic impairment should

www.americaspharmacist.net June 2009 | america’s Pharmacist vii also not use sibutramine. Sibutramine is a major substrate too low in a meal, the dose can be omitted. The of cytochrome P450 3A4 enzyme, and CYP3A4 inhibitors most common side effects are gastrointestinal such as azole antifungals, clarithromycin, diclofenac, and symptoms such as oily spotting, abdominal protease inhibitors may increase the levels of sibutramine. pain, flatus with discharge, fatty stool, fecal By the same token, CYP3A4 inducers such as phenytoin, urgency, or increased defecation. carbamazepine, phenobarbital, and rifampin may reduce sibutramine serum concentrations. Also, patients using Dietary Supplements and Herbals sibutramine in combination with selective serotonin reup- Unlike prescription and over the counter medica- take inhibitors may develop serotonin syndrome. Vitamins tions, dietary supplements are not prospectively and herbal supplements should also be taken into con- reviewed for safety or efficacy by the FDA, which sideration before prescribing sibutramine to avoid risk of takes action only if a dietary supplement is serious or life-threatening adverse effects. shown to present “a significant or unreasonable” harm. There have been several herbal and di- Nutrient Inhibitor etary supplements that claim to promote weight Orlistat (Xenical) loss. However, with the exception of ephedra Orlistat (also known as Xenical) is a lipase inhibitor used alkaloids (Ma Huang) and caffeine, most reports in the management of obesity including weight loss and are based on poorly designed trials. when used in conjunction with a reduced calorie diet. It can reduce the risk of weight Ephedra (Ma Huang) and regain after prior weight loss, but is only indicated for Ephedrine Alkaloids obese patients with an initial body mass index equal to Ephedra, also known as Ma Huang, is a stimu- or greater than 30 kg/m2, or greater than or equal to 27 lant containing the herbal form of ephedrine. kg/m2, with the presence of other risk factors, such as The botanical is found in the desert regions, type 2 diabetes, hypertension, and dyslipidemias. When and its main active ingredients are the ephed- given at adequate doses, the absorption of dietary fats is rine alkaloids and pseudoephedrine. It is widely inhibited by 30 percent. used for weight loss, as an energy booster, and orlistat (also available OTC in 60 mg capsules as Alli) to enhance athletic performance. Of the herbal is one treatment for obesity that does not act as an appe- products, ephedra alkaloids and caffeine are tite suppressant, but works by interfering with the action the only types for which there are data from ran- of gastrointestinal lipase in the GI tract. In the lumen of domized, double blind, placebo-controlled trials the stomach and the small intestine, a covalent bond indicating efficacy in promoting weight loss. is formed with the active site of gastric and pancreatic Ephedrine alkaloids are amphetamine-like com- lipase. The inactivated enzyme is unable to form triglyc- pounds used in OTC and prescription drugs. erides into free fatty acids and monoglycerides, resulting Of the ephedra alkaloids, ephedrine is the most in triglycerides passing through the body intact creating potent thermogenic, meaning that the chemical a caloric deficit. In obese people or people on weight has the ability to raise the rate at which calories control diets, the adequate amount of fat-soluble vitamins are burned. The effects of these chemicals can already may be low, and orlistat can reduce this even have serious effects on the central nervous more. Therefore, a multivitamin containing the fat-soluble system and the heart. vitamins A, D, E, and K should be administered once a Although ephedra or ephedrine alkaloids day at least two hours before or after orlistat to ensure do not have FDA-approved indications for their adequate . use, the FDA, due to widespread usage, has the recommended dose is one 120 mg capsule three set up guidelines for dosing. According to the times daily, one hour before or with each meal contain- FDA, the recommended dose of any dietary ing fat. The daily intake of fat should be distributed over supplement containing ephedra should not ex- three meals, and if a meal is missed or the fat content is ceed 8 mg as a single dose, 24 mg in 24-hour

viii america’s Pharmacist | June 2009 www.americaspharmacist.net period, or be given longer than seven days. currently being used in practice today. The following three Exceeding the recommended dose increases medications listed are not inclusive of all medications used the risk of potentially fatal side effects such as in obese patients for chronic disease states. stroke, heart attacks, hypertension, palpita- Bupropion (brand names Wellbutrin and Zyban) is tions, neuropathy, seizures, or severe mental an atypical antidepressant and smoking cessation aid disorders. Other less severe side effects include that is chemically unrelated to tricyclic agents or selective headaches, irritability, dizziness, and stomach serotonin-reuptake inhibitors. It is a relatively weak inhibi- upset. Patients who are on MAOIs, pregnant or tor of the neuronal uptake of serotonin, norepinephrine, breast feeding, or have pheochromocytoma, and dopamine, and has structural similarities to diethyl- should not take ephedra or ephedrine alkaloids. propion. After it was noted in studies concerning depres- Ephedra is not recommended for use in the sion that bupropion was associated with small weight elderly and children. Additionally, some drugs losses, trials evaluating the use of sustained-release such as beta-blockers, diuretics, ACEIs, or bupropion in the treatment of obesity were initiated. supplements containing potassium or sodium the metabolite inhibits the reuptake of norepi- citrate, sodium acetate, sodium bicarbonate, or nephrine, and though not fully understood, the primary sodium lactate may interact with ephedra and mechanism of action is thought to be dopaminergic ephedrine alkaloids. and/or noradrenergic. It is FDA approved in the treat- An evidenced-based review was conducted ment of major depressive disorder, including seasonal assessing the clinical efficacy and safety of affective disorder, and adjunct therapy in smoking products containing ephedra or synthesized cessation. Unlabeled or investigation use may include ephedrine alkaloids used for weight loss and attention-deficit/hyperactivity disorder, or depression athletic performance. Fifty-two controlled associated with bipolar disorder, and the medication is clinical trials and numerous case reports were only approved in adults. Bupropion is contraindicated in reviewed. The review concluded that the use patients with seizures, bulimia and anorexia, and bupro- of ephedrine, ephedrine plus caffeine, and pion has a low incidence of causing sexual dysfunction. dietary supplements containing ephedra and The most common side effects include headaches, botanicals with caffeine is associated with a insomnia, dizziness, xerostomia, weight loss, nausea, modest increase in weight loss over a relatively and tachycardia. short time (six months or less). There were no Metformin (Glucophage) is an antidiabetic agent studies that included treatment for more than that inhibits hepatic glucose production and improves six months, or any follow up reports after the sensitivity to insulin. Glucophage is the first line treatment product was stopped. Thus, long-term effects in the management of type 2 diabetes mellitus as mono- of ephedra are not known. therapy when hyperglycemia cannot be managed on diet alone, particularly in overweight, obese, and those with Fighting Obesity and normal kidney function. Some evidence suggests it might Concomitant Disease States be the best choice in people with heart failure. It is the or Health Conditions only anti-diabetes agent that has been proven to protect Several medications with different mechanisms against the cardiovascular complications of diabetes. of action are currently used in patients that are di- Glucophage doesn’t cause weight gain but may cause agnosed with obesity, in addition to other chronic weight loss, and also reduces the LDL and triglyceride disease states and health conditions. Several levels. Studies are in progress with metformin in over- medications used for depression, smoking ces- weight, non-diabetes adults and children to determine sation, diabetes mellitus, and seizure disorders its effects on body weight, insulin resistance, and related are associated with weight gain. The following medical conditions. medications have been studied in clinical trials glucophage is associated with adverse events such for safety and efficacy in obese patients and are as lactic acidosis, which is rare, but potentially a severe

www.americaspharmacist.net June 2009 | america’s Pharmacist ix Figure 1: Obesity Treatment Algorithm

 america’s Pharmacist | June 2009 www.americaspharmacist.net consequence of therapy, and therefore carries Strategies for Medication Initiation a black box warning. It is contraindicated in dis- Prior to initiating weight loss therapy, it is imperative that orders that may increase the risk of developing patients are fully aware that their diagnosis of obesity is a lactic acidosis. Other side effects may include serious chronic condition, and medication therapy should including nausea, vomiting, diarrhea, cramping, not be viewed as a “quick fix” to a long term condition. and increased flatulence. Pharmacotherapy should be initiated with the expectation Topiramate (Topamax) is an anticonvul- that long term use and permanent lifestyle modifications sant that blocks neuronal voltage-dependent will most likely be needed. The risks of long term medical sodium channels, enhances GABA (A) activity, therapy must be weighed against potential improvements antagonizes AMPA/kainite glutamate receptors, in the patient’s risk of obesity-related disease. The NIH and weakly inhibits carbonic anhydrase. Topi- guidelines recommend that pharmacotherapy be initiated ramate is used as monotherapy or adjunctive only in patients with a body mass index of at least 30 kg/ therapy for partial onset seizures and primary m2 in the absence of obesity-related medical conditions, generalized tonic-clonic seizures, adjunctive or a BMI of at least 27 kg/m2 in the presence of such treatment of seizures associated with Lennox- conditions, regardless of what medications might be initi- Gastaut syndrome, and prophylaxis of migraine ated. Being that actual weight loss appears to be similar headache and narcolepsy in children and among the various prescription weight loss medications, young adults. an empirical choice of a specific medication should be A common side effect demonstrated by based on consideration of underlying medical conditions topiramate has been weight loss. Therefore, or contraindications to particular drugs, concurrent medi- the drug has been investigated for use in the cations, need for monitoring, an approval for long term treatment of obesity, especially to aid in the use cost, and the preference of the patient. reduction of binge eating. In several clinical the NIH guidelines suggest that nonpharmacologic trials studying the safety and efficacy of topi- therapies should be attempted for six months and that ramate for seizure control or affective disor- weight-loss drugs should be considered if weight loss ders, reduced food intake and weight loss is unsatisfactory (e.g., less than 0.45kg per month). In were noted. Trials of the safety and efficacy of addition, behavioral treatment combined with pharmaco- topiramate in obese patients who do not have therapy may result in better outcomes than drug treat- seizures, including patients with binge eating ment alone. An evidence-based algorithm representing disorder or hypothalamic obesity, are ongo- an overall approach to the treatment of obesity is shown ing. Other off-label uses not approved by the in Figure 1 (page 44). FDA may be for bipolar disorder, obsessive compulsive disorder, neuropathic pain, infan- The Pharmacist’s Role tile spasms, alcoholism, cluster headaches, Pharmacists can be an essential resource for obese and smoking cessation. patients attempting to manage their weight. Pharmacists Just as topiramate inhibits carbonic an- should take an active role in monitoring patient medica- hydrase, one potential drug interaction would tion profiles for medications that may have the potential be the concomitant use of other inhibitors for for weight gain, drug and disease state interactions that carbonic anhydrase, which may lead to an could possibly occur with many FDA-approved weight increased risk of renal stones. Side effects most loss medications. Pharmacists can also provide infor- commonly leading to the discontinuation of mation and encouragement about proper weight-loss therapy are memory problems, fatigue, confu- programs. Pharmacists can encourage patients to utilize sion, somnolence, and psychomotor slowing. long-term weight-management goals instead of “quick other potential side effects that may occur are fix” over the counter products, and pharmacists can dizziness, headaches, diarrhea, nausea, pares- stress to their patients that even a moderate amount of thesia, and nervousness. weight loss can be beneficial to their health. Pharmacists

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CONTINUING EDUCATION QUIZ can direct patients to a number of Web sites that offer ac- Select the correct answer. curate information and peer support. The Web sites (see page ---) are also appropriate for health care providers. 1. Which of the following CV risks factors should be noted during a patient assessment? Summary a. Male gender Obesity is a serious and prevalent disorder whose ef- b. High HDL fective management requires ongoing care. Approved c. Female age 57 prescription medications for weight loss can assist certain d. BP 120/ 80 mm HG patients in this long term health condition. However, serious lifestyle modifications will need to be adopted by 2. Which weight loss medication was removed the patient for overall success. Weight loss medications from the U.S. market due to its life-threatening should be considered as an adjunct only for patients who side effect profile? are at substantial medical risk because of their obesity a. Diethylpropion and in whom nonpharmacologic treatments have not b. Dexfenfluramine resulted in sufficient weight loss to improve health. c. Phentermine d. Sibutramine Keturah R. Robinson, PharmD, BCPS, is a clinical assistant professor of clinical pharmacy at Xavier University of Louisiana College of Phar- 3. What is the Food and Drug Administration’s macy, New Orleans. definition of short-term use in regards to pre- scription weight loss medications? Editor’s Note: To obtain the complete list of references used a. Three weeks or less in the article, contact Chris Linville at NCPA (703-838-2680), or at [email protected]. b. Six weeks or less c. Nine weeks or less d. Twelve weeks or less

4. What is an appropriate initial starting dose of diethylpropion? a. 25 mg sustained release TID b. 75 mg sustained release TID c. 75 mg immediate release TID d. 25 mg immediate release TID

5. What weight status is a patient with a BMI of 37.2 kg/m2? a. Overweight b. Class I obesity c. Class II obesity d. Severe obesity

6. What is the first step toward preventing obesity? a. Increase physical activities b. Initiate weight medication c. Understand the etiology d. Understand the economical cost

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7. Which of the following are healthy lifestyle relayed to the patient in regards to Orlistat by the pharma- modifications for weight loss? cist during counseling? a. Caloric reduction a. Vitamins and herbals should be avoided. b. Decrease regular exercise b. Palpitations and tachycardia c. c. Oily spotting and fatty stool d. Caloric increase c. Blurred vision

8. In comparison to phentermine, which of 14. Psychological disturbances have been reported with the following medications has a higher abuse which of the following medications EXCEPT? potential? a. Benzphetamine a. Ma Huang b. Sibutramine b. Diethylpropion c. Phentermine c. Orlistat d. Diethylpropion d. Phendimetrazine 15. The use of which medications should be most 9. Which of the following medications decreases weighed against the risks before initiating? the amount of fat absorption in the gastrointes- a. Orlistat and Ma Huang tinal tract? b. Sibutramine and Orlistat a. Orlistat c. Benzphetamine and Phendimetrazine b. Benzphetamine d. Diethylpropion and phentermine c. Phentermine d. Phendimetrazine 16. Which medication should be taken at least 10 to 14 hours before bedtime? 10. What maximum number of days should a a. Diethylpropion product containing ephedra be used? b. Phentermine a. Three days c. Ma Huang b. Five days d. Sibutramine c. Seven days d. Ten days 17. Using the Body Mass Index Table, what is the BMI of a 71” male weighing 109 kg? 11. Which medication would cause the least a. 15 kg/m2 weight gain in an obese patient with diabetes b. 23 kg/m2 mellitus? c. 34 kg/m2 a. Insulin d. 37 kg/m2 b. Glyburide c. Glucophage 18. (True/False) A woman with a waist circumference of 37 d. Glimepiride inches is at risk for developing hypertension, Type 2 DM, and dyslipidemia. 12. What is the most appropriate medication to a. True suggest for an obese patient who seeks smok- b. False ing cessation? a. Varenicline b. Nicotine c. Bupropion d. Topiramate

13. Which of the following side effects should be

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19. What is the most appropriate medica- The Skinny on Obesity tion to suggest for an obese patient with a June 1, 2009 (expires June 1, 2012) new diagnosis of partial onset seizures? FREE ONLINE C.E. Pharmacists now have online access to NCPA’s a. Gabapentin C.E. programs through Powered by CECity. By taking this test on- b. Pregabalin line—go to the Continuing Education section of the NCPA Web site (www.ncpanet.org) by clicking on “Professional Development” under c. Topiramate the Education heading you will receive immediate online test results d. Tiagabine and certificates of completion at no charge.

To earn continuing education credit: ACPE Program 207-000-09-006-H01-P 20. Which medication is a major substrate A score of 70 percent is required to successfully complete the C.E. quiz. of cytochrome P450 3A4? If a passing score is not achieved, one free reexamination is permitted. a. Orlistat Statements of credit for mail-in exams will be available online for you b. Sibutramine to print out approximately three weeks after the date of the program (transcript Web site: www.cecerts.ORG). If you do not have access to a c. Ma Huang computer, check this box and we will make other arrangements to send d. Benzphetamine you a statement of credit: q

Record your quiz answers and the following information on this form. q NCPA Member License NCPA Member No. ______State ______no. ______q Nonmember State ______no. ______

All fields below are required. Mail this form and $7 for manual processing to: NCPA C.E. Processing Ctr.; 405 Glenn Drive, Suite 4; Sterling, VA. 20164 ______Last 4 digits of SSN MM-DD of birth ______Name ______Pharmacy name ______Address ______City State ZIP ______Phone number (store or home) ______Store e-mail (if avail.) Date quiz taken

Quiz: Shade in your choice a b c d e a b c d e 1. q q q q q 11. q q q q q 2. q q q q q 12. q q q q q 3. q q q q q 13. q q q q q 4. q q q q q 14. q q q q q 5. q q q q q 15. q q q q q

6. q q q q q 16. q q q q q 7. q q q q q 17. q q q q q 8. q q q q q 18. q q q q q 9. q q q q q 19. q q q q q 10. q q q q q 20. q q q q q

Quiz: Circle your choice 21. Is this program used to meet your mandatory C.E. requirements? a. yes b. no 22. Type of pharmacist: a. owner b. manager c. employee 23. Age group: a. 21–30 b. 31–40 c. 41–50 d. 51–60 e. Over 60 24. Did this article achieve its stated objectives? a. yes b. no 25. How much of this program can you apply in practice? a. all b. some c. very little d. none

How long did it take you to complete both the reading and the quiz? ______minutes

NCPA® is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCPA has assigned two contact hours (0.2 CEU) of continuing education credit to this article. Eligibility to receive continuing education xiv america’s Pharmacist | June 2009 credit for this article expires three years from the month published.