Treatment of Obesity and Eating Disorders

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Chapter 33 Treatment of Obesity and Eating Disorders

Abbreviations
CNS	Central nervous system
DA	Dopamine
GI	Gastrointestinal
5-HT	Serotonin
MAO	Monoamine oxidase
NE	Norepinephrine

Therapeutic Overview

Obesity has increased at an alarming rate in the United States during the past 30 years in all age groups. In adults 20 to 74 years of age, the prevalence of obesity has increased from 15% to 33%. Similar increases have been noted for children; the prevalence for those 2 to 5 years of age increased from 5% to 14%, for 6 to 9 years of age from 7% to 19%, and for those ages 12 to 19, prevalence has increased from 5% to 17%. Obesity is a significant risk factor for many common conditions including type 2 diabetes mellitus, hypertension, dyslipidemia, coronary artery disease, congestive heart failure, stroke, hepatic steatosis, sleep apnea, osteoarthritis, and endometrial, breast, prostate, and colon cancers. In addition, mortality rates from all causes increase with obesity. Weight reduction lowers the risk of morbidity and mortality and is currently accepted as one of the most preventable health risk factors. Drugs available currently for the short-term treatment of obesity include the sympathomimetics benzphetamine, diethylpropion, phentermine, and phendimetrazine, the amine reuptake inhibitor sibutramine, and the peripherally active gastrointestinal (GI) lipase inhibitor orlistat.

In contrast to obesity, anorexia nervosa and bulimia nervosa are commonly recognized eating disorders in which there is an exaggerated concern about body weight and shape. Although these disorders have been more prevalent in women between the ages of 12 and 25, increasing numbers of older women, men, and boys are exhibiting these illnesses. Anorexia is the more disabling and lethal, characterized by the obsessive pursuit of thinness that results in serious, even life-threatening weight loss. Bulimia differs from anorexia because many individuals are of normal body weight. Bulimic patients indulge in binge eating, followed by excessive inappropriate behavior to lose weight such as vomiting, the use of laxatives, or compulsive exercising. Anorexic and bulimic patients have common characteristics, and although the physiological disturbances from the latter are less severe than the former, both are associated with serious medical complications. Treatment involves the management of these complications and restoring and maintaining normal body weight through psychotherapy and pharmacotherapy with antidepressants.

Binge-eating disorder is characterized by binge eating, similar to bulimia, but these individuals do not exhibit any subsequent counteracting or weight-reduction behaviors. Although this disorder has been classified with

Therapeutic Overview
Obesity
Significant risk factors should be present before initiating drug therapy
Patients with concurrent diseases such as diabetes and hypertension require close monitoring
Exercise and a supervised dietary plan are essential
Centrally active drugs that enhance aminergic transmission may be of benefit
Peripherally active drugs that decrease fat absorption may be of benefit
Anorexia and Bulimia
Baseline medical and psychological assessment
Psychotherapy is cornerstone of treatment
Antidepressants may be of benefit
Cachexia
Associated with advanced cancers and AIDS
Corticosteroids, progestational agents, anabolic steroids, and stimulation of cannabinoid type 1 receptors stimulate appetite and weight gain

anorexia and bulimia, binge-eating disorder is manifest by approximately one third of obese patients enrolled in weight loss clinics; thus its relationship to obesity is beginning to be recognized.

Cachexia is not primarily an eating disorder but is a loss of appetite and weight as a consequence of cancer, infectious diseases such as AIDS, and other major chronic disorders. It is often very debilitating and is associated with weakness, a loss of fat and muscle, fatigue, decreased survival time, and diminished responses to cytotoxic therapeutic compounds. The orexigenic progestational agents, corticosteroids and anabolic steroids, and the orally active cannabinoid dronabinol stimulate appetite and cause weight gain in these patients.

The etiology of eating disorders and the involvement of developmental, social, and biological factors are beyond the scope of this chapter. The pharmacological treatment of eating disorders is presented in the Therapeutic Overview Box.

Mechanisms of Action

Anti-Obesity Agents

Drugs approved for the treatment of obesity include centrally active agents and the GI lipase inhibitor orlistat. The four sympathomimetics currently approved for the treatment of obesity include benzphetamine, diethylpropion, phentermine, and phendimetrazine. These drugs are β-phenethylamine derivatives structurally related to the biogenic amines norepinephrine (NE) and dopamine (DA) and to the stimulant amphetamine (Fig. 33-1). As a consequence of the latter, these agents have been deemed to have the potential for abuse and thus are classified by the U.S. DEA as Schedule III (benzphetamine and phendimetrazine) and Schedule IV (diethylpropion and phentermine) drugs, with diethylpropion and phentermine producing less central nervous system (CNS) stimulation than benzphetamine and phendimetrazine. All these agents are indicated for the short-term (up to 12 weeks) treatment of obesity and increase synaptic concentrations of NE or DA by promoting their release. These compounds are believed to suppress appetite through effects on the satiety center in the hypothalamus rather than effects on metabolism.

FIGURE 33–1 Structures of the centrally active drugs to treat obesity compared with the endogenous neurotransmitters NE and DA, and amphetamine.

Sibutramine is a unique agent that induces weight loss by both suppressing appetite and increasing thermogenesis. Sibutramine and its two active metabolites inhibit the reuptake of NE, DA, and serotonin (5-HT), with the metabolites more potent than the parent compound. Although the contribution of the CNS versus peripheral actions of sibutramine is unknown, studies have shown that sibutramine leads to improved lipid measures as evidenced by increased high-density lipoprotein cholesterol, decreased waist-to-hip ratios, and enhanced glycemic control in individuals with type 2 diabetes. Sibutramine is classified as a Schedule IV drug and is approved for long-term use in obese individuals.

Orlistat is the only weight-loss drug that does not suppress appetite. Rather, orlistat binds to and inhibits the enzyme lipase in the lumen of the stomach and small intestine, thereby decreasing the production of absorbable monoglycerides and free fatty acids from triglycerides. Orlistat is a synthetic derivative of lipstatin, a naturally occurring lipase inhibitor produced by Streptomyces toxytricini. Normal GI lipases are essential for the dietary absorption of long-chain triglycerides and facilitate gastric emptying and secretion of pancreatic and biliary substances. Because the body has limited ability to synthesize fat from carbohydrates and proteins, most accumulated body fat in humans comes from dietary intake. Orlistat reduces fat absorption up to 30% in individuals whose diets contain a significant fat component. Reduced fat absorption translates into significant calorie reduction and weight loss in obese individuals. In addition, the lower luminal free fatty acid concentrations also reduce cholesterol absorption, thereby improving lipid profiles. Orlistat is not a controlled substance, is approved for the long-term treatment of obesity, and is now available over the counter.

Drugs for Anorexia and Bulimia

Based on evidence that individuals with anorexia and bulimia are prone to mood disturbances, the pharmacological treatment of these disorders has focused on use of antidepressants. Evidence supports the efficacy of these compounds for treatment of bulimia. Antidepressants in all classes including the tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and selective serotonin reuptake inhibitors have been shown to be equally efficacious. However, because of side effects associated with the use of tricyclic antidepressants and MAO inhibitors (Chapter 30), selective serotonin reuptake inhibitors may be considered first-line agents. Antidepressants reduce binge eating, vomiting, and depression and improve eating habits in bulimia but do not affect poor body image. Imipramine, desipramine, phenelzine, amitriptyline, and trazodone have all been used with some success, but currently fluoxetine

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