Drug Topics - November 10, 2008 - (Page 46)

Continuing Education COMPLICATIONS OF OBESITY Orlistat Orlistat is unlike any other weight-loss medication in that its mechanism of action is to inhibit gastrointestinal lipases.47 Orlistat is currently available by prescription at a 120 mg dose and over the counter at half the prescription strength. This agent is a chemically synthesized, hydrogenated derivative of lipstatin, a natural product of Streptomyces toxytricini. It binds to gastric and pancreatic lipases in the gut lumen and blocks the digestion of dietary fat by preventing lipase from interacting with its lipid target. This results in about one-third of dietary fat remaining unabsorbed. Orlistat does not affect the action of systemic lipases or lipases located in other organ systems because it is minimally (<1%) absorbed from the gastrointestinal tract. The longest study to look at orlistat’s effect on the prevention of type 2 diabetes in obese patients is the Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) study.48 This four-year, multi-center, randomized control trial included more than 3,000 obese subjects and compared orlistat therapy plus lifestyle intervention to placebo plus lifestyle intervention in people with either normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). Participants were prescribed a reduced-calorie diet of approximately 800 kcal/ day deﬁcit, 30% calories from fat, and less than 300 mg cholesterol/day. The study found that orlistat plus lifestyle changes signiﬁcantly reduced the incidence of type 2 diabetes and improved weight loss. Orlistat therapy resulted in a 37% reduction in the cumulative incidence of new-onset type 2 diabetes, primarily by preventing the development of diabetes in patients who had impaired glucose tolerance. Side effects that patients may experience include ﬂatulence with discharge, fecal urgency, fecal incontinence, steatorrhea, diarrhea, and increased defecation.47 The adverse effects of orlistat often serve as a motivation for patients to avoid foods high in fat. Minimizing fat intake helps to lessen adverse effects, which generally occur early in treatment and can diminish or disappear as treatment is continued. However, some patients may continue to experience side effects six months or more into treatment. Psyllium has been reported to be an effective ﬁber adjunct to reduce some of the GI side effects associated with orlistat. Orlistat can interfere with the absorption of lipophilic medications such as cyclosporine; therefore close monitoring and dose adjustment may be required. Because orlistat may block the absorption of vitamin K, an increase in international normalized ratio may occur with warfarin treatment. Patients are also advised to supplement the fat-soluble vitamins A, D, E, and K. Rimonabant Rimonabant, the ﬁrst CB-1 cannabinoid receptor antagonist to reach the market, reduces food intake and increases adiponectin through the CB-1 receptor on fat cells. This is thought to increase insulin sensitivity and reduce risk associated with metabolic syndrome. While initially approved for use in more than 30 European, South American, and Asian W W W.D R U GTO P I C S .C O M into two categories: appetite suppressants and lipase inhibitors. Agents that are approved for short-term use include benzphetamine, phendimetrazine, diethylpropion, mazindol, and phentermine.42 The most commonly used of these is phentermine. The other prescription medications mentioned have not been studied as well and have not had the same utility in clinical practice. Consequently, the only short-term agent this article will focus on is phentermine. Phentermine Phentermine, a noradrenergic agent, acts as an appetite suppressant.43 Phentermine hydrochloride was approved by the FDA in 1973 for short-term use of a few weeks to a few months by obese patients. Phentermine suppresses the appetite by stimulating the release of norepinephrine and dopamine, thereby causing a decrease in gastric secretion and an increase in energy levels. It is theorized to cause signiﬁcant increases in blood pressure, palpitations, and arrhythmias. Consequently, phentermine’s use is not advised in hypertensive patients and those with unstable cardiovascular function. Other common adverse effects are constipation, dry mouth, and nervousness. Evening dose administration should be avoided because of the possibility of insomnia. As with all adrenergic agents, a minimum washout period of 14 days is suggested if patients are taking a monoamine oxidase inhibitor (MAOI) to avoid excessive sympathomimetic effects. Dosing is commonly one 37.5 mg capsule in the morning. Use is not advisable in patients with hypertension or in those with a history of drug abuse as phentermine may be physically and psychologically addictive. Sibutramine Sibutramine is one of two medications that the FDA has approved for long-term use (typically up to a year and possibly longer) for weight loss.44 Sibutramine works by inhibiting the reuptake mainly of norepinephrine and serotonin, and to a lesser extent dopamine.45 In addition, its active metabolites also inhibit the reuptake of norepinephrine and serotonin. Unfortunately, many obese patients possess several conditions that are considered contraindications to the use of sibutramine. Studies have found that compared to those taking placebo, patients treated with sibutramine had a signiﬁcant increase in SBP and DBP of approximately 1 to 3 mmHg and also experienced an increase in pulse of 4 to 5 beats per minute.46 For patients who already have hypertension or borderline high blood pressure, this can be a concern, since it may be difﬁcult to achieve and maintain blood-pressure control.46 It is imperative that blood pressure and heart rate be monitored regularly throughout therapy. Patients whose hypertension becomes uncontrolled or who develop hypertension or tachycardia during treatment may need to either decrease their dose or discontinue therapy altogether. 46 DRUG TOPICS N OV. 10, 2008 http://WWW.DRUGTOPICS.COM

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Drug Topics - November 10, 2008 Contents Up Front Up Front in Depth Letters Rx Care Government Community Practice First Responders Clinical Practice Self-Care FDA Safety Page Weighing the Complications of Obesity New Products Viewpoint

Drug Topics - November 10, 2008

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