Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 33 Treatment of Obesity and Eating Disorders

MAJOR DRUG CLASSES

Anti-obesity agents

Sympathomimetics

Amine reuptake inhibitor

Pancreatic lipase inhibitor

Drugs for anorexia and bulimia

Antidepressants

Orexigenics

Progestational Agents

Corticosteroids

Anabolic Steroids

Cannabinoid receptor agonist

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 sympathomimeticsbenzphetamine, 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

Abbreviations

CNS

Central nervous system

DA

Dopamine

GI

Gastrointestinal

5-HT

Serotonin

MAO

Monoamine oxidase

NE

Norepinephrine

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 includebenzphetamine, 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.

image

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 asmegestrol 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 3940 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.

Pharmacokinetics

All centrally acting anorectic drugs are well absorbed from the GI tract and reach peak plasma levels within two hours. However, they differ somewhat in their pharmacokinetic profiles (Table 33-1).

TABLE 33–1 Selected Pharmacokinetic Parameters

Drug

t1/2 (hrs)

Metabolism and Elimination

Benzphetamine

-

M, R

Diethylpropion

4-8 for metabolites

M, R

Phendimetrazine

1.9 for immediate-release preparation

M, R

 

10 for sustained-released preparation

 

Phentermine

19-24

R

Sibutramine

14-18 for metabolites

M, R

M, Metabolized; R, renal.

Most of the sympathomimetics undergo extensive first-pass metabolism. Benzphetamine is metabolized to two para-hydroxylated derivatives that are excreted in urine within 24 hours, whereasdiethylpropion is metabolized via N-dealkylation and reduction, producing active metabolites with half-lives of approximately 4 to 8 hours that are excreted mainly by the kidneys.

Phentermine and phendimetrazine are available in both immediate- and sustained-release formulations. Phentermine is not metabolized, and 70% to 80% of an administered dose is excreted unchanged by the kidneys. Phendimetrazine is metabolized by the liver and excreted by the kidneys with an apparent t1/2 of 1.9 and 9.8 hours for the immediate- and slow-release preparations, respectively.

Sibutramine is inactive and undergoes extensive first-pass hepatic metabolism to its active mono-and di-desmethyl metabolites, which are further metabolized by CYP3A4 and excreted by the kidneys. As a consequence of the metabolism of sibutramine by CYP3A4, changes in plasma levels of the parent compound and its metabolites may be expected when it is used with agents that inhibit this enzyme such as ketoconazole, erythromycin, and cimetidine.

Orlistat is not absorbed to any appreciable extent, is metabolized in the GI tract to two inactive metabolites, and is excreted primarily in the feces.

Dronabinol is nearly completely absorbed after oral administration. It undergoes extensive first-pass hepatic metabolism, has high lipid solubility with a large (10 L/kg) apparent volume of distribution, and is 97% bound to plasma proteins. Hepatic metabolism yields both active and inactive metabolites, with 11-OH-delta-9-THC representing the primary active metabolite, which reaches plasma levels equal to that of the parent compound. Dronabinol and its metabolites are excreted in both urine and feces, with biliary excretion representing the primary route. Dronabinol has a terminal half-life of 25 to 36 hours.

The pharmacokinetics of the antidepressants are discussed in Chapter 30; those of the corticosteroids are discussed in Chapter 39, those of the progestational agents in Chapter 40, and those of the anabolic steroids in Chapter 41.

Relationship of Mechanisms of Action to Clinical Response

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.

Pharmacovigilance: Side-Effects, Clinical Problems, and Toxicity

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

CLINICAL PROBLEMS

Benzphetamine, Diethylpropion, Phentermine, Phendimetrazine

Dry mouth, headaches, nervousness, insomnia

Sibutramine

Constipation, insomnia, headache, dry mouth

Tachycardia and hypertension

Orlistat

Decreased absorption of fat-soluble vitamins

Soft and oily stools and anal leakage

Cramping, diarrhea, flatulence

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 3940 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.

New Horizons

The potential to develop new drugs to affect eating behaviors is increasing as our understanding of the basic pathways and neurotransmitters involved expands. Currently, most research is focused on treatment of obesity, which has become a national epidemic and is linked with a high rate of morbidity and mortality from other causes. Anorexia and bulimia are less well understood, and psychotherapy remains the cornerstone of therapy. However, as the role of specific neurotransmitters becomes more clearly defined, new treatment options may become available. Preliminary studies suggest that the 5-HT antagonist cyproheptadine may lead to weight gain in non-bulimic anorexic patients.

Rimonabant is a newly developed anti-obesity drug; it is available in 18 countries but has not yet received approval by the U.S. Food and Drug Administration. Rimonabant is a CB1 cannabinoid receptor antagonist, with actions opposite to that of the orexigenic agent dronabinol. CB1 receptors are present throughout the brain in feeding-related areas, on fat cells, and in the GI tract. Evidence indicates that rimonabant has a dual mechanism to decrease food intake and increase energy expenditure, the latter perhaps mediated by an induced increase in adiponectin, the fat cell hormone associated with sensitivity to insulin. Rimonabant does not alter blood pressure or heart rate, increases high-density lipoprotein cholesterol, and decreases triglycerides and fasting insulin levels, leptin, and C-reactive protein. Rimonabant has failed to receive approval for use in the United States based on the increased incidence of reported psychiatric side effects in clinical trials including depression, anxiety, and sleep problems.

Orexigenic signals appear to be redundant in the body and involve numerous peptides, hormones, and neurotransmitters. When body fat stores decrease, serum concentrations of leptin (secreted by adipocytes) and insulin (secreted by the pancreas) decrease. Concurrently, endocrine cells within the stomach secrete ghrelin. Alterations in these hormones are sensed in the arcuate nucleus of the hypothalamus and stimulate production of orexigenic signals involving agouti-related protein, neuropeptide Y (NPY), galanin, and melanin-concentrating hormone. These are potential targets for drug development. NPY and galanin stimulate food consumption, each with different effects on intake of energy sources such as protein, fat, and carbohydrates.

Leptin has been extensively studied, and obese individuals have been shown to be leptin resistant. Axokine is an injectable weight loss drug in clinical trials. It is an analog of ciliary neurotrophic factor that signals the satiety center in the brain to decrease food intake by activating the central leptin pathway distal to the leptin receptor. Inhibitors of tyrosine phosphatase-IB, an enzyme involved in leptin resistance, have shown promise in preclinical trials to increase leptin receptor sensitivity, similar to effects of sulfonylureas on insulin receptors.

Other approaches include ghrelin receptor antagonists to block central stimulation of appetite. However, preliminary results with ghrelin and ghrelin antagonists have been disappointing.

In addition to ongoing drug development for central or peripheral inhibition of appetite, research is also targeting thermogenesis. Specific β3 adrenergic receptor agonists would stimulate breakdown of fat for energy metabolism by directly activating adipocytes yet avoiding sympathetic stimulation and cardiovascular effects.

As obesity has rapidly become a major health and economic issue, development of better drugs to combat this epidemic may become a dominant strategy in treatment and prevention of many diseases associated with obesity.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Anti-obesity Drugs

Benzphetamine (Didrex)

Diethylpropion (Tenuate, Tepanil)

Phentermine (Adipex-P, Anoxine, Fastin, Ionamin, Obenix, Obephen, Oby-Cap, Oby-Trim, Phentercot, Phentride, Pro-Fast, Teramine, Zantryl)

Phendimetrazine (Bontril, Plegine, Prelu-2, X-Trozine)

Sibutramine (Meridia, Reductil)

Orlistat (Xenical, Alli)

Drugs for Anorexia and Bulimia

Antidepressants

Orexigenics

Megestrol (Megace)

Oxandrolone (Anavar, Oxandrin)

Nandrolone (Deca-Durabolin, Durobolin)

Dronabinol (Marinol)

FURTHER READING

Bray GA, Greenway FL. Pharmacological treatment of the overweight patient. Pharmacol Revs. 2007;59:151-184.

Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacology. Pharmacol Revs. 2006;58:389-462.

SELF-ASSESSMENT QUESTIONS

1. A 47-year-old obese man with a history of hypertension and angina requires pharmacological intervention for weight loss. Which of the following drugs would be best for this patient?

A. Diethylpropion

B. Fluoxetine

C. Orlistat

D. Phentermine

E. Sibutramine

2. A 23-year-old anorexic patient requires drug therapy to assist her with weight maintenance. Which of the following drugs would have the least risk of cardiovascular complications?

A. Fluoxetine

B. Amitriptyline

C. Desipramine

D. Imipramine

E. Phenelzine

3. Which of the following agents is not absorbed into the systemic circulation and has its actions locally in the gastrointestinal tract?

A. Amitriptyline

B. Dronabinol

C. Phentermine

D. Orlistat

E. Sibutramine

4. Which of the following is an agonist at cannabinoid type 1 receptors in both the brain and gastrointestinal tract?

A. Benzphetamine

B. Rimonabant

C. Dronabinol

D. Sibutramine

E. Phentermine