42: Dieting Xenobiotics and Regimens

Obesity is a worldwide epidemic, and the United States has the largest proportion of a national population of overweight and obese individuals.¹²⁵ Nearly 68% of Americans are overweight (body mass index {BMI}, 25–29.9) and 35% are obese (BMI >30 kg/m²).^53,123 Even more alarming, the incidence of obesity in children between the ages of 6 and 19 years has tripled in the past 30 years.^12,124 As many as 17% of children aged 2 to 19 years of age are obese, and 31% of children are overweight.^12,123 There are conflicting data as to the exact number of deaths attributed to obesity annually; however, all of the studies agree that obesity results in excess mortality.^53,54 In 2009, the Centers for Disease Control and Prevention reported greater than 110,000 deaths due to obesity in the United States. The cost of obesity is staggering and is reported to be upward of $147 billion.²⁷ Obesity is linked to numerous health risks, including type 2 diabetes, hypertension, coronary heart disease,^12,24 metabolic syndrome,¹⁷⁰ and low back pain.¹⁴⁸ Obesity is considered a leading preventable health risk, second only to cigarette smoking. Genetic links including particular gene polymorphisms have been identified and are being pursued.¹¹⁶

Americans spend upward of $60 billion per year on weight loss therapies and modalities. Pharmacologic interventions typically result in a 5% to 10% weight loss, although a return to baseline upon drug cessation is common.⁴⁶ Surgical interventions consistently achieve substantial weight loss, causing up to a 30% reduction in weight, but they are not without complications.^2,20

One of the earliest accounts of weight loss therapy dates back to 10th century Spain. King Sancho I, who was obese, underwent successful treatment with a “theriaca” thought to contain plants and possibly opioids, administered with wine and oil. In addition, he was closely supervised and treated by a physician.⁷⁹

Currently, medicinal weight loss therapies (Table 42–1) are available as prescription medications (lorcaserin, phentermine, phentermine/­topiramate), nonprescription dietary supplements (Citrus aurantium, chitosan, Garcinia cambogia, caffeine), and nonprescription diet aids (orlistat). Numerous other prescription medications, including thyroid medications and metformin, have been used on an off-label basis for weight loss. Numerous xenobiotics are promoted as weight loss aids, many with no proven efficacy and some with serious toxicity.

The history of dieting xenobiotics is checkered. A number of weight loss therapies were withdrawn or banned by the Food and Drug Administration (FDA) because of serious adverse health effects (Table 42–2). Phenylpropanolamine,⁸⁷ fenfluramine-phentermine,³⁴ and sibutramine⁸² were withdrawn from the US market. The endocannabinoid receptor antagonists (rimonabant) never reached the US market. γ-Hydroxybutyric acid (GHB) and its congeners were initially sold as dietary supplements (Chap. 83) and promoted to body builders as a means to “convert fat into muscle” as a result of the effect of GHB on growth hormone. Because of toxicity and its association with drug-facilitated sexual assault, GHB is strictly controlled as a schedule I drug, with limited availability as a schedule III drug for narcolepsy (Xyrem). Clenbuterol is a long-acting β₂-adrenergic agonist. Because of the stimulant properties and lipolytic effects, clenbuterol is abused by body builders as an energy source and anoretic agent.⁷⁶ It has been touted by celebrities to be an effective diet aid (Chap. 40).

For the first time in many years, two new pharmaceutical preparations received FDA approval for weight loss in 2012. Phentermine/topiramate (Qsymia) and lorcaserin (Belviq) received FDA approval and became available late in 2012. Pharmacologically different, they show promise in the weight loss drug armamentarium. Other new pharmaceuticals are currently being investigated and likely to be presented to the FDA for consideration.

Dieting xenobiotics can be divided into classes based on one or more of the following mechanisms or action: (1) appetite suppression (anorectics), (2) alteration of food absorption or elimination, or (3) increased energy expenditure. The hypothalamus is the key site in the brain that regulates food intake, energy expenditure, satiety, and metabolism. Sympathomimetics, serotonergics, dinitrophenol, and bupropion/naltrexone all work pharmacologically on the hypothalamus for weight loss. The endocannabinoid receptors, namely CB1, are located in the brain and in the intestines, liver, pancreas, adipose tissue, and skeletal muscle.

Endocannabinoid receptor antagonists bind to CB1 receptors and cause weight loss via different mechanisms. Neurohormonal approaches at targeting weight loss are under investigation, with specific focus on leptin, amylin, ghrelin, and glucagon-like peptide-1 (GLP-1). Leptin is secreted from fat proportionate to the amount of lipids contained in the adipocyte, with women secreting more leptin than men. Leptin acts on the hypothalamus to decrease food intake, enhancing the metabolic rate and energy ­expenditure. Ghrelin is secreted by the stomach, and concentrations increase following fasting and just prior to meals. Ghrelin stimulates the hypothalamus and stimulates food intake. GLP-1 enhances glucose-induced insulin secretion while suppressing glucagon release (Fig. 42–1).^47,57

Although there has been improvement and advancements in the understanding and treatment of obesity, significant challenges remain. The ideal xenobiotic for weight loss has yet to be identified.

Although controversial, certain sympathomimetic amines still carry official indications for short-term weight reduction (Table 42–1). Sympathomimetic amines share a β-phenylethylamine parent structure and include phentermine, diethylpropion, and mazindol, which are restricted as schedule IV drugs and carry warnings that advise prescribers to limit use to only a few weeks. Phentermine/topiramate extended release (Qsymia) was recently approved.^6,11 Regardless of their source and legal status, sympathomimetics generally share a spectrum of toxicity and produce adverse effects similar to amphetamines (Chap. 76).

Pharmacology

Sympathomimetic amines that act at α- and β-adrenergic receptors are clinically effective in promoting weight loss but have numerous side effects that limit their clinical use. Soon after its introduction as a pharmaceutical for nasal congestion in the 1930s, the prototype sympathomimetic drug amphetamine (Fig. 42–2) was noted to cause weight loss (Chap. 76). The weight loss effect of amphetamine was also readily apparent in early animal studies, although tolerance to the anorectic effects was also noted.¹⁵⁸ The primary mechanism of action of the weight loss effects of sympathomimetic drugs is central nervous system (CNS) stimulation, resulting from increased release of norepinephrine and dopamine.¹⁵⁵ The effects include direct suppression of the appetite center in the hypothalamus and reduced taste and olfactory acuity, leading to decreased interest in food. Increased energy and euphoriant effects of the stimulants also contribute to weight loss. However, tachyphylaxis occurs, and the rate of weight loss diminishes within a few weeks of initiating therapy.⁴⁹ Significant side effects and abuse potential severely limit the therapeutic use of this class of drugs.

Adverse Effects

Absence of polar hydroxyl groups from a sympathomimetic amine increases its lipophilicity; therefore, unsubstituted or predominantly alkyl group ­substituted compounds (eg, amphetamine, ephedrine, phenylpropanolamine {PPA}) have greater CNS activity. Mild cardiovascular and CNS stimulant effects include headache, tremor, sweating, palpitations, and insomnia. More severe effects that may occur after overdose of sympathomimetic amines include anxiety, agitation, psychosis, seizures, palpitations, and chest pain.^145,164

Hypertension is common following overdose and occasionally following therapeutic use. Patients may present with confusion and altered mental status as a result of hypertensive encephalopathy. Reflex bradycardia after exposure to xenobiotics with predominantly α-adrenergic agonist effects may accompany the hypertension and provides a clue to the diagnosis. Children may be at especially high risk for hypertensive episodes because of the relatively significant dose per kilogram of body weight from even a single tablet. Other manifestations include chest pain, palpitations, tachycardia, syncope, hypertension, mania, psychosis, convulsions, and coronary vasospasm.^129,180

Clinically significant hypertension should be treated aggressively with either phentolamine, a rapidly acting α-adrenergic antagonist or nicardipine. Analogous to the management of cocaine toxicity, β-adrenergic antagonists should be avoided because the resultant unopposed α-adrenergic agonist effects may lead to greater vasoconstriction and hypertension.⁵ Agitation, tachycardia, and seizures should be treated initially with benzodiazepines.

Herbal Sympathomimetic Products

Since ephedra was banned, herbal weight loss supplements have been reformulated. Many now contain an extract of bitter orange (C. aurantium), a natural source of the sympathomimetic amine synephrine, often in combination with caffeine, theophylline, willow bark (containing salicylates), diuretics, and other constituents. The dried fruit peel of bitter orange is a traditional remedy for gastrointestinal ailments. The predominant constituents, p-synephrine (Fig. 42–2) and octopamine, are structurally similar to epinephrine and norepinephrine. The isomer m-synephrine (phenylephrine or Neo-Synephrine) is used extensively as a vasopressor and nasal decongestant. Although the physiologic actions of synephrine are not fully characterized, it appears to interact with amine receptors in the brain and acts at peripheral α₁-adrenergic receptors, resulting in vasoconstriction and increased blood pressure.⁵⁸ Some evidence indicates that synephrine may also have β₂-adrenergic agonist activity,¹³⁹ which could increase lipolysis. β₂-Adrenergic agonists were found to have remarkable antiobesity effects in rodents; however, effects in human are not as profound. Octopamine stimulates lipolysis in rats, hamsters, and dogs, although this effect was not seen in human fat cells.^24,58

Nearly 2% of 4140 Californians surveyed had used a C. aurantium–containing product several times a week.⁹² Adverse effects associated with use of C. aurantium–containing weight loss products are reported, including tachydysrhythmias,⁵² cerebral ischemia in a 38 year-old man,¹⁶ exercise induced syncope, and QTc interval prolongation in a 22 year-old woman,¹¹⁹ and a possible case of myocardial infarction in a 55 year-old woman.¹²¹

Raspberry ketone, 4-(4-hydroxyphenyl)-2-butanone, is promoted to induce weight loss and is available as a supplement. Structurally similar to synephrine, its purported effects on weight loss are similar. The amount of raspberry ketone in a typical dose of a dietary supplement is equal to the amount derived from 40 kilograms of raspberries. Studies in rats show an increase in lipolysis and alteration in lipid metabolism.^117,129 Toxicity is not yet described in the literature, although clinical effects would be expected to be similar to other sympathomimetics.

Phentermine/Topiramate

Phentermine is a sympathomimetic that still retains an FDA indication for short-term weight loss. It increases release of norepinephrine, which serves as an appetite suppressant via the effects on the hypothalamus. Topiramate has been on the US market for years for a variety of conditions including seizure disorder and migraine headaches. Weight loss is a demonstrated side effect of topiramate when used for these indications.⁸⁹ The mechanism of weight loss induced by topiramate remains speculative and is likely a combination of decreased caloric intake, increased energy expenditure, and decreased energy efficiency.^6,59

Phentermine/topiramate controlled release (Qsymia) is approved for long term management of weight loss. The FDA recommends discontinuation if 5% of body weight is not lost within 24 weeks of therapy initiation.^32,33 The clinical trials evaluating the efficacy of phentermine/­topiramate, were short term studies performed in approximately 4000 patients.^6,11,59 In all of these trials, there was a substantial decline in body fat (upward of 10%) as well as improvement in other metabolic parameters, including lipid control and glucose regulation. In addition, blood pressure declined in all three trials. Adverse events appeared mild, although there were increases in heart rate and complaints of somnolence. There appears to be an increased risk of congenital malformations, particularly orofacial clefts, when taken during the first trimester of pregnancy.⁵⁷ Because topiramate is a carbonic anhydrase inhibitor, it can decrease serum bicarbonate resulting in a nonanion gap metabolic acidosis.¹⁴⁶

Although there have been no documented cases of overdose of this combination product, its toxicity can be extrapolated from the known toxicities of the individual components. Phentermine toxicity is described in detail above. Topiramate toxicity causes CNS depression, dizziness, ataxia, a nonanion gap metabolic acidosis, and hypokalemia^17,106,146 (Chap. 48).

Xenobiotics that affect central release and reuptake of serotonin are approved for a number of indications, including depression, anxiety, nicotine addiction, migraine headache, and premenstrual dysphoric syndrome. Serotonin is believed to have a role in appetite suppression, which is due to the effect on the hypothalamic serotonin 5-HT_2C receptor, as well as the 5-HT_1A,5-HT_1B, and 5-HT₆ receptors.^{67,68, and 69,71} Serotonin receptor effects may also enhance energy expenditure. The serotonin agonists have been associated with cardiac valvulopathy (5-HT_2B receptor), hallucinations (5-HT_2A receptor), and pulmonary hypertension (5-HT_1B), as well as serotonin toxicity.

Lorcaserin (Belviq), approved by the FDA in 2012, is a novel selective agonist at the 5-HT_2C receptor.^9,50,80,109 This novel selectivity for the 5-HT_2C receptor conceivably may permit weight loss with minimal risk of significant toxicity as recognized with other serotonergics.⁶⁸ Lorcaserin neither stimulates the release of norepinephrine, dopamine, or serotonin, nor does it inhibit the reuptake of these neurotransmitters.^67,68

Lorcaserin 10 mg twice daily showed a significant reduction in body fat (5.8 ± 0.2 kg) compared to placebo (2.2 ± 0.1 kg) after 52 weeks of therapy in 3182 subjects. In addition to the weight loss achieved in 1 year, the subjects maintained their body weight for 1 year.¹⁵³ No increase in the incidence of cardiac valvulopathy was demonstrated in the 2-year follow up in the subjects receiving lorcarserin.¹⁵³ In all of the clinical trials, the adverse events were minimal and included dizziness, headache, and nausea.^{50,75,84,136,153}

There have been no cases of overdose documented to date. Expected clinical toxicity includes nausea, vomiting, dizziness, and headache. In large overdoses, receptor selectivity is typically lost, suggesting that large overdoses of lorcaserin would cause effects from agonism at other serotonergic receptors. Serotonin toxicity may occur after overdose (Chap. 75).

Management of the toxic effects mediated by serotonin receptors should address the specific clinical effects. Benzodiazepines may be useful for tachycardia and hypertension. Rapid identification and management of serotonin toxicity is essential to prevent associated morbidity and mortality (Chap. 75).

Fat Absorption Blockers

Orlistat (Xenical) was approved by the FDA in 1999 for treatment of obesity. In 2007, orlistat (Alli) became available as a nonprescription formulation. The availability may pose an abuse potential for patients with eating disorders, and abuse should be considered in patients presenting with related adverse events. Orlistat is the only FDA approved drug that alters the absorption, distribution, and metabolism of food. Orlistat is a potent inhibitor of gastric and pancreatic lipase, thus reducing lipolysis and increasing fecal fat excretion.²⁵ The drug is not systemically absorbed but exerts its effects locally in the gastrointestinal tract. It inhibits hydrolysis of dietary triglycerides and reduces absorption of the products of lipolysis, monoglycerides, and free fatty acids. Several clinical trials demonstrate that orlistat reduces gastrointestinal fat absorption by as much as 30%.¹⁷⁷ When taken in association with a calorie restricted diet, weight loss of approximately 10% body weight can be achieved in 1 year.¹⁵¹ Orlistat is associated with a modestly lower weight gain over a 3 year period when compared to placebo (4.6 kg versus 7 kg, respectively).¹³⁷

Orlistat should be taken only in conjunction with meals that have a high fat content; it should not be consumed in the absence of food intake. Adverse effects correlate with the amount of dietary fat consumption and include abdominal pain, oily stool, fecal incontinence, fecal urgency, flatus, and increased defecation. Systemic effects, which are rare due to the lack of systemic absorption,^51,115,162 include cholestatic hepatitis and hepatocellular necrosis,^115,162 but there is an inconsistent demonstration of a temporal relationship. In a cohort of nearly 16,000 patients in England, although there were no cases of serious hepatotoxicity, there were reports of aminotransferase elevations. Two of the cases were deemed as causally related to orlistat, and one had evidence of aminotransferase elevations and elevations on rechallenge.¹³² Concomitant use of natural fibers (6 g of psyllium mucilloid dissolved in water) may reduce the gastrointestinal side effects of orlistat.²⁶ Because orlistat reduces absorption of fat soluble food constituents, daily ingestion of a multivitamin supplement containing vitamins A, D, and K, and β-carotene is advised to prevent resultant deficiency. Pancreatitis⁴ and oxalate nephropathy¹⁴⁹ are rarely reported after orlistat use. Currently, there are no reported intentional overdoses of orlistat. There are limited data regarding unintentional pediatric exposure to orlistat, and the toxicity appears to be limited to mild gastrointestinal effects.¹²² In overdose and/or misuse, treatment should be responsive to clinical manifestations.

Chitosan is a weight loss dietary supplement derived from exoskeletons of marine crustaceans. It is thought to act similarly to orlistat by binding to dietary lipids in the gastrointestinal tract and reducing breakdown and absorption of fat. Animal models describe an increase in fecal fat excretion in rats administered chitosan when they are fed high-fat diets.⁴¹ The efficacy of chitosan in humans is disputed.^60,112,113 Some evidence indicates that chitosan may decrease total serum cholesterol concentration in overweight people, but the majority of clinical studies indicate chitosan is ineffective for weight loss in the absence of dietary and lifestyle modifications.¹⁴⁷ It is estimated that in the presence of chitosan, it would take more than 7 months to lose 1 pound of body fat.⁶⁰ Chitosan is contraindicated in people with shellfish allergy.

Dietary Fibers

Glucomannan is a dietary fiber consisting of glucose and mannose, which is derived from konjac root, a traditional Japanese food. Edible forms of glucomannan include konjac jelly and konjac flour, which are mixed with liquid prior to ingestion. Purified glucomannan is available in capsule form and is found in various proprietary products marketed for weight loss. On contact with water, glucomannan swells to approximately 200 times its original dry volume, turning into a viscous liquid. It lowers blood cholesterol and glucose concentrations and decreases systolic blood pressure,^7,167 but significant weight loss benefits are not demonstrated.⁹⁵ Following several reports of esophageal obstruction, glucomannan tablets were withdrawn from the market in Australia in 1985.⁷³ Serious adverse effects are not described with encapsulated glucomannan, presumably because slower dissolution allows for gastrointestinal transit prior to expansion. Glucomannan capsules are available as a nutritional supplement in the United States, although adequate safety and efficacy studies are not published.

Dinitrophenol

One of the earliest attempts at a pharmaceutical treatment for obesity was 2,4-dinitrophenol (DNP), which was popularized as a weight loss adjuvant in the 1930s.^64,160 This chemical, which is used in dyes, wood preservatives, herbicides, and explosives, was never approved as a drug product. DNP was legally available as a dietary supplement prior to enactment of the US Federal Food, Drug, and Cosmetic Act of 1938 and thus remained legal. By increasing metabolic energy expenditure, it reportedly produces weight loss of 1 to 2 pounds per week in doses of 200 to 300 mg per day.^31,64 DNP increases metabolic work by uncoupling oxidative phosphorylation in the mitochondria. Through this mechanism, the hydrogen ion gradient that allows ATP synthesis is destroyed and ATP production is stopped, though oxidative metabolism in the Krebs cycle continues (Chap. 13). This mechanism results in inefficient substrate utilization, and the resulting energy loss is dissipated as heat. This wastes calories but also elevates temperature and, occasionally, life-threatening hyperthermia can occur.¹⁵⁹ In fact, DNP was reportedly administered to Russian soldiers during World War II to keep them warm during winter battles.⁶⁴ Symptoms related to DNP toxicity include malaise, skin rash, headache, diaphoresis, thirst, and dyspnea. Severe toxic effects include hyperthermia, hepatotoxicity, agranulocytosis, respiratory failure, coma, and death.^15,96,159 Delayed-onset cataracts were a frequent and serious complication of DNP use.¹⁵

Epidemic use of DNP occurred in Texas in the 1980s when industrial DNP was used at a physician’s weight loss center. The physician distributed DNP under the trade name, Mitcal. The fatality of a wrestler following an intentional overdose in 1984 led a Texas court to stop the use of this practice.⁹⁶ DNP continues to reappear sporadically as a weight loss treatment, and cases of serious toxicity still are reported.^64,127 Management should emphasize rapid cooling (Chap. 30). Benzodiazepines should also be used as an adjunct therapy for management of delirium and seizures.

Endocannabinoid Receptor Antagonists

In the past decade, the endocannabinoid system (ECS) and its involvement in weight loss sparked excitement and potential for novel xenobiotics. Endocannabinoids, which are the natural ligand for the cannabinoid receptor, have diverse effects on metabolic functions.⁷⁷ The ECS contributes to the regulation of food intake, body weight, and energy balance, and it may have a role in inflammation and neuropathic pain.^{83,141,169,174} It has long been known that tetrahydrocannabinol, the active principle in marijuana (Cannabis sativa), stimulates appetite and is an effective antiemetic (Chap. 77).^29,131

Several CB1 receptor antagonists showed promise in both animal and human studies of weight loss. Rimonabant was approved for therapeutic use in Europe and clinical trials in the United States were performed. Clinical studies note that these xenobiotics showed a significant and sustained reduction in body weight.¹³⁵ There was also improvement in insulin resistance with a decline in plasma leptin, insulin, and free fatty acid concentrations, presumably due to the upregulation of the peripheral ECS system in diabetes.^74,140 In the clinical trials there was a significant increase in adverse events, including anxiety and depression in the rimonabant groups. This led to a delay in the FDA’s approving this product for therapeutic use. Shortly after approval in Europe, it became evident that the effects of anxiety and depression were far greater than initially expected. Rimonabant was never approved by the FDA, and other Phase III studies, including those involving other endocannabinoid receptor antagonists (eg, tranabant), were terminated early. Rimonabant was removed from the European market. Centrally acting CB1 antagonists proved to have an unfavorable risk–benefit relationship. However, peripherally acting CB1 antagonists have shown some promise for weight loss, and further research is currently underway.^48,65

Naltrexone/Bupropion

Naltrexone is an opioid receptor antagonist that is currently approved by the FDA for the treatment of alcohol and opioid dependence.¹⁶⁸ Bupropion is a norepinephrine and dopamine reuptake inhibitor that is approved for both depression and smoking cessation, and it is known to cause weight loss at therapeutic doses. The combination of naltrexone and bupropion is effective in inducing weight loss and is beneficial in other addictive disorders. The mechanisms by which naltrexone/bupropion cause weight loss is not completely understood.¹⁶⁸ Proopiomelanocortin (POMC)-producing neurons in the hypothalamus are stimulated with bupropion, and naltrexone inhibits the opioid mediated POMC autoinhibition. This combination of stimulation and inhibition of the negative feedback loop on POMC neurons is believed to facilitate ongoing weight loss. Additionally, it is believed that there is synergism with naltrexone and bupropion in midbrain dopamine areas resulting in decreased food intake, presumably through modulation of mesolimbic reward systems.^63,86,168

This potential synergistic effect has resulted in promising effects. A new drug application for the combination product of Naltrexone SR/Bupropion SR (Contrave/NB32) was submitted to the FDA in 2010.¹³ The Contrave Obesity Research Program consists of four 56-week, randomized, double-blind, placebo-controlled Phase III trials.^63,168 The combination of naltrexone plus bupropion in these studies demonstrated a 5% to 15% weight reduction.¹⁶⁸ The naltrexone SR 32 mg/bupropion 360 mg/day per arm resulted in significantly greater weight loss and had improvements in markers of cardiovascular risk. The combination was generally well tolerated, with nausea and headache most frequently reported.^63,168 There was no increased depression or suicidality in the treatment groups.

The FDA has mandated a clinical trial evaluating cardiovascular risk of naltrexone SR 32 mg/bupropion SR 360 mg in subjects with underlying cardiovascular risk factors. The status of the FDA approval of this combination therapy is pending the results of the current clinical trial. It is unclear if the combination drug will receive FDA approval despite its promising results on weight reduction.

Adverse events from this product result from the known toxicity of each individual xenobiotic. Naltrexone is generally expected to be safe and well tolerated in opioid naive patients; however, it will cause prolonged opioid withdrawal symptoms in opioid tolerant patients and will significantly reduce the efficacy of opioids if they are required. Bupropion toxicity is well described in the literature. Seizures may occur after bupropion at doses greater than 450 mg per day.^38,145 The amount of bupropion available in this formulation is of particular concern as is the potential for misuse/overdose. Bupropion toxicity is discussed in detail in Chap. 75.

Alternative Pharmaceutical Approaches

In an attempt to find the perfect therapeutic alternative for weight loss, there is an continuing approach to utilize currently approved xenobiotics for weight loss. Similar to topiramate, xenobiotics that are known to cause weight loss at therapeutic doses such as metformin, bupropion, and zonisamide, continue to be investigated for both label and off label use. Combination therapy aimed at multiple systems likely will prove most efficacious. Although these xenobiotics may provide a beneficial weight loss, each of them has their own inherent toxicities. Metformin can cause a metabolic acidosis with elevated lactate concentration, particularly in patients with underlying kidney dysfunction and after large intentional overdoses (Chap. 53). Zonisamide, an adjunct anticonvulsant that is not used commonly, is associated with adverse events including CNS depression and hypersensitivity^120,175 (Chap. 48).

Future Targets for Xenobiotic Development

The desire to identify new biochemical pathways and pharmacologic approaches to weight loss began in antiquity. Research continues to evolve in an ongoing effort to determine the underlying etiology of obesity as well as develop new, more advanced pharmacologic interventions (Table 42–3).^3,29,69 Gut peptides play an important physiologic role in normal gastrointestinal functions, including cessation of meals. Some gut peptides affect feeding control and show promise in the treatment of obesity.^{36,69,108,116}

Leptin and the leptin gene are being explored as a basis for obesity and as a therapeutic strategy.^28,78 Much of the enthusiasm about the potential role for leptin as an antiobesity therapy has subsided because leptin administration does not induce the expected response on weight control and is transient.^134,142,161 In fact, obese people have elevated leptin concentrations, and obesity is believed to cause leptin resistance in the brain.⁴⁷ Amylin is cosecreted from the β islet cells in the pancreas and contributes to short-term energy regulation. The combination of leptin and amylin reduce food intake and body weight even in the setting of leptin resistance.¹⁶¹ Pramlintide acetate (a synthetic analog of amylin) and metreleptin (a recombinant analog of leptin) combination therapy has been studied in animals and humans for weight loss with promising results. The combination therapy was stalled in Phase II clinical trials because of safety concerns. It remains unclear if this potential combination therapy and novel approach will be continued in drug development.¹⁶¹ This suggests that combination therapy in the management of obesity is increasingly important.

Ghrelin antagonists are also suggested as a possible adjunct therapy for weight loss. Ghrelin is a growth hormone releasing agent produced by the stomach that stimulates appetite.^93,94,163 Data suggest that ghrelin and leptin work together to stimulate food consumption.^39,107 Ghrelin antagonists may decrease the increased appetite that often occurs with dietary modifications for weight loss and such agents are under investigation.¹¹⁶ Neuropeptide Y, a peptide found in the arcuate and paraventricular nucleus of the hypothalamus, is a potent central appetite stimulant.

GLP-1 is produced in the brain and distal intestine. During a meal, GLP-1 concentrations increase and remain elevated for several hours after. GLP-1 inhibits food intake, inhibits glucagon secretion, decreases gastric acid secretion, and delays gastric emptying. Exendin-4, extracted from the venom of the Gila monster, is a pharmaceutically available GLP-1 agonist, exenatide (Byetta), and is approved by the FDA for diabetes mellitus. It decreases food intake and produces a 2 to 5 kilogram sustained weight loss. Extended release exenatide (Bydureon) is available and has an FDA approved indication for type 2 diabetes. It is dosed every 7 days, and although it does not have an FDA approved indication for weight loss, it will likely be used off-label for weight loss. Acute overdoses of exenatide are rarely reported; however, the potential for hypoglycemia remains a significant concern, although it has not yet been reported.^30,31

Peptide YY is similar to GLP-1 and has been investigated for weight loss. Preliminary data suggest that intranasal peptide YY failed to induce a significant body weight reduction when compared to placebo and had a high incidence of nausea and vomiting.¹¹⁶

Because β₂-adrenergic receptors mediate lipolysis in adipose tissue, β₂-selective agonists also are under investigation to enhance weight loss.¹³⁹ Future drug therapy may target these genes, receptors, and proteins to modify metabolism. As obesity research proceeds and the biologic basis for obesity is defined, new approaches and mechanisms for therapy may be identified.¹⁹

Hypocaloric Diets and Cathartic/Emetic Abuse

Starvation, as well as abuse of laxatives, syrup of ipecac, diuretics, and anorectics, has led to morbidity and mortality, often in young patients.^56,81 Fad diets and laxative abuse should be strongly considered in young people with unexplained salt and water depletion, syncope, hypokalemia, and metabolic alkalosis. A variety of extreme calorie-restricted diets resulting in profound weight loss were very popular in the late 1970s, but reports of a possible association between these diets and sudden death followed.¹⁵⁰ Myocardial atrophy was a consistent finding on autopsy. Torsade de pointes and other ventricular dysrhythmias may have occurred as a result of hypokalemia^150,154 and protein-­calorie malnutrition are proposed as causes of death.^{45,150, 154}

Following the negative reports and FDA warnings, the enthusiasm for liquid protein diets waned. Several current diets (Atkin’s plan, South Beach diet) advocate intake of high protein, high fat, and low carbohydrates while allowing unlimited amounts of meat, fish, eggs, and cheese. Lack of carbohydrates induces ketosis, which results in salt and water depletion, giving the user the appearance of rapid weight loss. With rehydration and resumption of a normal diet, weight gain generally occurs. In addition, salt and water depletion may cause orthostatic hypotension and ureterolithiasis. Atherosclerosis and hypercholesterolemia may occur as a result of substitution of high-calorie, high fat foods for carbohydrates. Despite the rapid weight loss early on with these diets, once carbohydrates are reintroduced, weight gain occurs rapidly and significantly.⁴⁶

Dieter’s teas that contain combinations of herbal laxatives, including senna and Cascara sagrada, can produce profound diarrhea, salt and water depletion, and hypokalemia. They are associated with sudden death, presumably as a result of cardiac dysrhythmias. Despite FDA warnings of the dangers of these weight loss regimens, dieter’s teas remain available in retail stores that sell nutritional supplements and are easily accessible to adolescents.

Chronic laxative use can result in an atonic colon (“cathartic bowel”) and development of tolerance, with the subsequent need to increase dosing to achieve catharsis. Because cathartics do not decrease food absorption, they have limited effects on weight control.¹⁰ Various test methods can be used to detect laxative abuse.⁴⁰ Phenolphthalein can be detected as a pink or red coloration to stool or urine following alkalinization. Colonoscopy reveals the benign, pathognomonic “melanosis coli,” the dark staining of the colonic mucosa secondary to anthraquinone laxative abuse. The combination of misuse/abuse of laxatives in conjunction with orlistat has the potential to cause severe diarrhea and subsequent fluid and electrolyte imbalances. Now that orlistat is readily available, there is a greater likelihood of these two xenobiotics being used together.³⁵

Chronic use of syrup of ipecac to induce emesis by patients with eating disorders, such as bulimia nervosa, leads to the development of cardiomyopathy, subsequent dysrhythmias, and death.^56,128 Emetine, a component of syrup of ipecac, is the alkaloid responsible for the severe myopathy. Chronic administration of syrup of ipecac results in tolerance to the emetic effects and increased systemic absorption of emetine.¹²⁸ Emetine can be detected in serum by high pressure liquid chromatography or thin-layer chromatography. It persists for weeks to months after chronic ingestion. In 2003, an FDA advisory committee recommended that the nonprescription drug status of syrup of ipecac be rescinded because of its use by patients with bulimic disorders.

Several herbal remedies for weight loss have resulted in serious toxicity. In France, germander (Teucrium chamaedrys) supplements taken for weight loss resulted in seven cases of hepatotoxicity.⁹⁹ A “slimming regimen” first prescribed in a weight loss clinic in Belgium produced an epidemic of progressive kidney disease, known as Chinese herb nephropathy, when botanical misidentification led to the substitution of Stephania tetrandra with the nephrotoxic plant Aristolochia fangji.¹⁶⁵ The toxic constituent, identified as aristolochic acid, has been implicated in numerous cases of kidney failure and urothelial carcinoma.¹⁰⁴ A case of profound digitalis toxicity occurred with a laxative regimen contaminated with Digitalis lanata.¹⁵² Contamination of herbal products remains a concern today due to the lack of standardization of manufacturing processes. Until regulation of herbal products is improved and manufacturing practices worldwide are standardized, sporadic reports of herb-related toxicity likely will continue (Chaps. 28 and 45).

Sympathomimetics

PPA, a sympathomimetic amine (Fig. 42–2), was available until 2000 as a nonprescription diet aid (eg, Dexatrim, Acutrim). It is both a direct-acting xenobiotic, via stimulation of α-adrenergic receptors, and an indirect-acting xenobiotic, through release of norepinephrine. Both of these actions cause a net increase in blood pressure when given in high doses. PPA-induced anorexia is mediated via α-adrenergic receptors in the hypothalamus.¹⁷² PPA was voluntarily withdrawn after its use was linked to increased risk of hemorrhagic stroke in women.⁸²

Reported toxicity associated with PPA generally results from severe hypertension.¹³⁰ A comprehensive review of more than 100 case reports of adverse drug effects involving PPA revealed 24 intracranial hemorrhages, 8 seizures, and 8 fatalities between 1965 and 1990.^62,97 Some adverse events occurred following ingestion of diet preparations that contained both PPA and caffeine, which have pharmacokinetic and pharmacodynamic interactions.^90,98 Cardiac toxicity, although less common, was reported in two young patients who suffered myocardial injury following therapeutic daily dosing in one and acute overdose in the other.¹⁰¹

Ephedrine

Ephedra (Ephedra sinica), or Ma-huang, is a plant that contains six sympathomimetic amines, known collectively as ephedra alkaloids. The two primary alkaloids are ephedrine and pseudoephedrine (Fig. 42–2). Ephedra was popular as a weight loss dietary supplement until the FDA banned ephedra-containing products in April 2004 because of cases of serious cardiovascular toxicity^72,176 and acute hepatitis.¹¹⁸ In a review of 140 adverse events reported to MedWatch following use of ephedra, 31% of the cases were considered to be definitely or probably related to the use of ephedra supplements, including four strokes, five cardiac arrests, two myocardial infarctions, and three fatalities.⁷² In 2005, there was concern that the FDA ban would be overturned and ephedra would once again be available. But, in 2006, the US Court of Appeals upheld the FDA’s final rule to ban ephedra. Despite this ban, ephedra still can be obtained from practitioners of complementary medicine as a traditional Chinese herbal medicine for short-term treatment of wheezing and nasal congestion associated with asthma, allergies, and colds. Synthetic ephedrine is still available, behind the pharmacy counter, as a nonprescription medication (eg, Primatene tablets) for asthma.

Serotonergics

Sibutramine blocks the reuptake of both serotonin and norepinephrine, but it does not promote neuronal release of serotonin. Its clinical effects include reduced appetite and increased satiety. Its effectiveness in producing weight loss was demonstrated in several randomized, double-blind studies.^{37,42,100,105} It also decreased binge-eating when compared to placebo.¹⁷³

Shortly after approval, reports of serious adverse events, including cardiovascular toxicity, emerged. Sibutramine use was associated with psychosis,^14,103,157 hypertension, cardiac ischemia, dysrhythmias,¹³² and death.¹³² The increased risk of nonfatal myocardial infarction and nonfatal stroke in patients led to the withdrawal of sibutramine from the US market in the fall of 2010.⁸²

The serotonergics dexfenfluramine (Redux) and fenfluramine (Pondimin), used in the treatment of obesity, were withdrawn because of postmarketing reports of serious cardiac effects associated with their therapeutic use.^{18,21,34,44,171} The diet drug combination known as Fen-Phen (fenfluramine and phentermine {an amphetamine derivative}) was popular in the 1990s because of the presumed improved side-effect profile and efficacy achieved with lower doses of each drug. This drug combination was never approved by the FDA for treatment of obesity. Because of an unusual and serious cardiac valvulopathy in women taking Fen-Phen, fenfluramine was withdrawn from the market in 1997.³⁴ All of the women presented with new heart murmurs and either right- or left-sided valvular abnormalities. Eight of the 24 women also developed pulmonary hypertension. Several required cardiac surgery and were found to have plaquelike encasement of the leaflets and chordae, with preservation of valvular structure. These pathologic findings are identical to those described in patients with ergotamine-induced valvular disease and in those with carcinoid valvulopathy. Although subsequent studies confirmed this association, the reported magnitude of risk associated with these drugs has varied.^85,88,171 Regression of these valvular lesions with cessation of the drugs is reported,²² and limited evidence indicates that the valvular effects are milder than initially described.⁶¹

Primary pulmonary hypertension has been described in association with fenfluramine and dexfenfluramine since 1981.^{8,21,44,111,138} Primary pulmonary hypertension in association with another anorectic, aminorex fumarate, was previously reported in Europe.⁶⁶ In one multicenter case control study of patients with primary pulmonary hypertension, use of anorectics such as dexfenfluramine and fenfluramine for more than 3 months was associated with a 30-fold increased risk of primary pulmonary hypertension in these patients compared with nonusers.¹ Several theories are proposed to explain the mechanism of pulmonary toxicity of these anorectics,²¹ namely, serotonin-mediated constriction of pulmonary arteries,¹¹⁰ serotonin-mediated platelet aggregation, and vasoconstriction in the lungs leading to microembolization, elevated pulmonary vascular resistance, and pulmonary hypertension.¹¹¹

Guar Gum

Guar gum is derived from the bean of the Cyamopsis psorabides plant and is a hygroscopic polysaccharide that expands 10- to 20-fold in the stomach, forming a gelatinous mass. The purpose of ingesting guar was to cause gastric distension and create the sensation of satiety, thereby decreasing appetite and food intake. Unfortunately, the use of guar gum resulted in numerous cases of esophageal and small bowel obstruction in patients with both preexisting anatomical lesions such as strictures and in individuals with normal gastrointestinal anatomy. It was withdrawn from the market in 1992.¹⁰²

Although not a specific toxicologic concern, it is imperative to mention surgical interventions for management of obesity. Surgical interventions to manage obesity have increased in frequency over the past years and may provide a long-term solution for obesity. Roux-en-Y gastric bypass, laparoscopic adjustable banding, and biliary-pancreatico diversion with duodenal switch are the most commonly described techniques.^2,20,43 The health of these patients is of particular concern because absorption of vitamins, minerals, and drugs is altered.^{91,114,133,144,166} Pharmacokinetics of orally administered medications may also be altered.^133,144 Consideration of drug properties should be examined closely prior to initiation in this patient population.⁹¹

• Obesity is a major health concern and a significant cause of preventable diseases and sequelae. Unproven weight loss modalities are associated with treatment failure and the potential for significant adverse events.

• Some common themes exist; combination drug therapy likely provides the best weight loss; and toxicity from proven and unproven treatments remains a significant concern.

• A balanced weight loss plan that encompasses decreased caloric intake with increased energy expenditure through exercise should be ­encouraged.

• Clinicians should be aware of the lack of regulation of most available diet remedies and should report adverse events involving these products to poison control centers and to the FDA MedWatch system so that appropriate regulatory actions can be taken to prevent further instances of toxicity.

• A historical review of compounds used as weight loss agents readily uncovers numerous examples of poorly conceived drug regimens, popular misunderstanding of the benefits and risk of the drugs involved, and relatively poor postmarketing surveillance leading to unnecessary morbidity and mortality.

Acknowledgment

Christine Haller, MD, and Jeanmarie Perrone, MD, contributed to this chapter in previous editions.

References