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 is the only approved antidepressant for the treatment of bulimia. It is unclear whether the effectiveness of these compounds is due primarily to their antidepressant action or whether they are directly orexigenic (appetite stimulating). These compounds are ineffective for binge-eating disorder. Their mechanisms of action are discussed in Chapter 30.

Orexigenics

Similar to the goal for therapy with anorectic and bulimic patients is the need to stimulate appetite in individuals with cachexia. In concert with nutritional counseling, progestational agents such as megestrol acetate, corticosteroids such as dexamethasone, and anabolic steroids such as oxandrolone and nandrolone have been shown to stimulate appetite and cause weight gain in these patients. The mechanisms of action of these compounds are discussed in Chapters 39, 40 and Chapters 41.

In addition to steroids, the orally active cannabinoid agonist dronabinol is approved for promoting appetite in individuals with cachexia. Dronabinol is a Schedule III agent. Dronabinol, which is also used to prevent the nausea and vomiting associated with cancer chemotherapy in individuals who fail to respond to other antiemetics, produces a dose-related stimulation of appetite through activation of cannabinoid type 1 (CB₁) receptors in the hypothalamus and limbic forebrain and at peripheral afferent nerve terminals in the GI tract.

Anti-Obesity Agents

All centrally active anti-obesity drugs increase synaptic concentrations of biogenic amines in the CNS, leading to their anorectic effect. In addition, increases in peripheral amine levels may promote thermogenesis, contributing to weight loss. Although clinical studies have demonstrated that the use of these drugs produces more weight loss than placebo when used as an adjunct to a supervised diet and exercise routine, their effects were maximal during initial use, and continued treatment did not lead to further weight loss; as a matter of fact, weight regain usually occurs within 6 months after discontinuation. Unfortunately, it is unclear whether chronic use of these drugs continues to decrease mechanisms controlling appetite or whether tolerance develops. Further studies are needed to understand the loss of effectiveness after chronic use.

Orlistat has no effect on appetite-regulating pathways in the CNS, and as such, there is no potential for CNS tolerance or abuse. Continued treatment with orlistat increases the intake of low fat-containing foods and decreases high fat intake by patients, perhaps reflecting the desire to decrease the GI side effects that accompany its use. In addition to decreasing fat absorption, orlistat decreases cholesterol absorption and reduces plasma low-density lipoprotein cholesterol beyond that produced by weight loss alone in obese individuals, an added benefit of this drug.

Drugs for Anorexia and Bulimia

Anorexia nervosa, bulimia nervosa, and binge-eating disorder have multifactorial etiologies, and as such, drug therapy alone is likely to be ineffective. Studies indicate that antidepressants do not lead to the remission of bulimia, although a single course of drug is better than placebo. In addition, with continued treatment, patients have a high rate of relapse. Thus, although antidepressants have been shown to be efficacious for bulimia, their long-term utility remains to be determined.

Orexigenics

Weight gain in patients with cachexia may be achieved by increasing the appetite and caloric intake of these individuals. Megestrol has been found to be effective in increasing body weight, primarily reflecting increased fat weight rather than lean body mass. In contrast, the anabolic agents oxandrolone and nandrolone both promote appetite and physical activity and increase muscle anabolism and protein synthesis, decrease catabolism, and stimulate growth hormone and insulin-like growth factors. Thus the anabolic steroids increase lean body mass in men; the effectiveness of anabolic steroids has not been thoroughly evaluated in women.

Dronabinol produces a modest increase in weight gain relative to both megestrol and the anabolic steroids and may be additive with these other agents.

It is important to keep in mind that none of the orexigenic compounds have been shown to affect the course of either cancer or AIDS, but they do enhance the quality of life for patients with these diseases.

Anti-Obesity Agents

The centrally active anorexigenics have similar side-effect profiles, related to their ability to increase central and peripheral aminergic activity. Use is contraindicated in patients with a history of stroke, coronary artery disease, congestive heart failure, or arrhythmias. Sibutramine can increase both systolic and diastolic blood pressure, and baseline blood pressure should be obtained before therapy is initiated; regular monitoring is required thereafter.

These drugs should be used as monotherapy and are contraindicated in patients receiving sympathomimetic amines, tricyclic antidepressants, selective serotonin reuptake inhibitors, or MAO inhibitors because of documented cases of hypertensive crises. In addition, for compounds such as sibutramine that affect 5-HT, a 5-HT syndrome can be precipitated (see Chapter 30). A minimum drug-free period of 14 days is required for anyone using MAO inhibitors before therapy is initiated with these agents.

Glaucoma can be exacerbated as a result of the mydriasis produced by these agents and is also a contraindication to their use.

Increased insulin sensitivity has been reported in type 2 diabetics receiving diethylpropion, and thus careful monitoring of serum glucose, insulin, and oral hypoglycemic agents is required in these patients; sibutramine leads to better metabolic control in type 2 diabetics.

These drugs also cause insomnia and tremors and induce anxiety through their CNS actions. Because of their CNS stimulation, these drugs carry a potential for abuse. Although they have less abuse potential than amphetamine, they are contraindicated in abusers of cocaine, phencyclidine, and methamphetamine.

As a consequence of significant hepatic metabolism of these agents, a potential for drug interactions exists.

Orlistat is unique for treatment of obesity, as it does not carry a risk of cardiovascular side effects. Because its actions involve the GI system, its adverse effects are limited to this area. The most commonly reported GI complaints, which occur in as many as 80% of individuals, are most pronounced in the first 1 to 2 months and decline with continued use. Malabsorption of fat-soluble vitamins (A, D, E, and K) and β-carotene occur, but no notable changes in the pharmacokinetic profiles of other drugs

have been reported. Long-term use of orlistat has not resulted in any documented cases of serious reactions.

Side effects associated with use of the anti-obesity drugs are listed in the Clinical Problems Box.

Orexigenics

The adverse effects of the corticosteroids, progestational agents, and anabolic steroids are presented in Chapters 39, 40 and 41, respectively.

Dronabinol produces dose-related CNS effects including a “high” characterized by laughing, elation, altered time perception, and a heightened sensory awareness at low doses; memory impairment and depersonalization at moderate doses; and motor incoordination at high doses. Dronabinol may decrease seizure threshold and has variable effects on the cardiovascular system. Thus it should be used with caution in patients with a history of either seizure or cardiac disorders.