37 Pharmacotherapy of Obesity, Anorexia, and Cachexia

Question 1

Behavioral Modification

• the mainstay of obesity management is centered on/
• Motivational interviewing techniques
• Most bariatric surgery programs require/

Answer 1

• the mainstay of obesity management is centered on
  
  • promoting lifestyle modifications that have two primary aims:
  • Improving the nutritional composition and decreasing the total caloric content of the diet
  • Increasing total caloric expenditures, ideally through increased aerobic exercise
• Motivational interviewing techniques
  
  • the most effective and durable interventions will have to take into account patient goals, beliefs, and preferences.
  • can be critical to assess patient readiness for and perceived barriers to change in a non-confrontational manner.
• Most bariatric surgery programs require participation in at least a 6 month diet and exercise program before being considered for surgical intervention.
  
  • having patients undergo a trial of a diet and exercise program does not “lose time” and can only be beneficial.
  • patients will benefit from a referral to a dietician who specializes in weight loss programs.

Question 2

Behavioral Modification

• Some simple dietary strategies to suggest to any obese patient:
  
  • Food substitutions
  • Portion control
• Restrictive diets
• The best approach to diet change
• joining the gym
• non-exercise activity thermogenesis (NEAT)

Answer 2

• Some simple dietary strategies to suggest to any obese patient:
  
  • Food substitutions: exchange sugary/soft drinks for water or drinks with artificial sweeteners/sugar substitutes; baked foods over fried foods; meal replacements with liquid nutritive shakes (i.e. one Slim Fast).
  • Portion control: At a restaurant, ask for ½ of a dish in a “to go” box before the meal is served
• Restrictive diets (South Beach, Ornish, Adkins, etc.) are often effective in the short run, but less durable in the long run.
• The best approach to diet change is to make healthy, balanced choices and watch portion size.
  
  • Weight Watchers and other “calorie counting” strategies tend to be effective long term approaches because they are not as restrictive, build awareness of healthy options, and reinforce a balanced dietary approach.
• Most patients view “joining the gym” as the only mechanism to obtain exercise.
  
  • Yet, caloric expenditure can be increased on a daily basis with several simple, and monetarily free, approaches.
  • Any increase in daily walking is a plus.
  • Patients can increase the number of daily steps by parking their car in the furthest part of lot, using stairs instead of the elevator, etc.
• Increasing non-exercise activity thermogenesis (NEAT) by purposely fidgeting / tapping feet under a desk during work, etc.
  
  • Ideally, patients should try to get aerobic exercise for 30 minutes most days of a week.
  • Swimming or aquaerobics/aquafitness programs are ideal for those with joint related problems.

Question 3

Pharmacotherapy of Obesity

• Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults recommends pharmacotherapy as an adjunct to lifestyle modification for/
• What would be an ideal drug for obesity
• thyroid hormone to treat obesity

Answer 3

• Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults recommends pharmacotherapy as an adjunct to lifestyle modification for
  
  • patients with a BMI ≥ 30 kg/m2 with no concomitant obesity-related risk factors or diseases;
  • patients with a BMI ≥ 27-29.9 kg/m2 with a major obesity-related comorbidity such as hypertension, diabetes, obstructive sleep apnea, etc.
• What would be an ideal drug for obesity
  
  • proven effect on fat loss, is well-tolerated during acute and chronic administration,
  • minimal or no physiological or psychological side effects,
  • affordable.
• thyroid hormone to treat obesity
  
  • undesirable side effects
  • there is no “specific” drug targets known to drive weight loss.

Question 4

Pharmacotherapy of Obesity:
Amphetamine-like compounds

• ?
• act as/
• potential for/
• Cocaine and amphetamines
• Sibutramine
  
  • acted as/
  • major effect

Answer 4

• boost general metabolism
• act as appetite suppressants (fairly effectively).
• potential for abuse, dependence, and cardiovascular events.
• Cocaine and amphetamines share a similar pharmacology
• Sibutramine was approved and withdrawn because of an increased risk of heart attack and stroke.
  
  • It also acted as a centrally acting monoamine-reuptake inhibitor.
  • The major effect of sibutramine was on satiety, which resulted in reduced food intake and weight loss.

Question 5

Pharmacotherapy of Obesity:
Sympathomimetics

• ?
• possible increase in/
• Only FDA-approved medications currently available for “short term use”:
  
  • drugs
  • mechanism
  • Side effects
• “Non-prescription” sympathomimetics:

Answer 5

• potent appetite suppressants,
• possible increase in general metabolism
• Only FDA-approved medications currently available for “short term use”:
  
  • Phentermine, Diethylpropion, Benzphetamine, Phendimetrazine.
  • Displace NE, or monoamines in general, from presynaptic vesicles
  • Side effects include increased blood pressure, dry mouth, constipation, dry skin, insomnia.
    
    • abuse potential.
• “Non-prescription” sympathomimetics:
  
  • Caffeine and ephedrine

Question 6

Pharmacotherapy of Obesity:
Serotonergic receptor agonists

• Fenfluramine
• Lorcaserin (Belviq)
• Buspirone (Buspar)

Answer 6

• Fenfluramine
  
  • 5-HT2B receptor agonist
  • withdrawn for causing an unusual heart valvular disorder and an increased risk of pulmonary hypertension.
• Lorcaserin (Belviq)
  
  • binds selectively to central 5-HT2C receptors (with “very little activity at 5-HT2B receptors”)
  • increases satiety and decreases hunger.
• Buspirone (Buspar)
  
  • approved for anxiety and depression management;
  • 5HT-1A receptor agonist with a good safety record.
  • currently being evaluated as an appetite suppressant useful for weight loss.

Question 7

Pharmacotherapy of Obesity:
Combination medications

• Phentermine-topiramate (Qsymia)
• Buproprion / Natrexone (Contrave)
  
  • naltrexone,

Answer 7

• Phentermine-topiramate (Qsymia)
  
  • use is based primarily on the observation that patients on topiramate found that they lost weight.
  • Side effects include: cognitive dysfunction, depression, anxiety, suicidal ideation; acute angle glaucoma (topiramate effect).
• Buproprion / Natrexone (Contrave)
  
  • combines a 5HT-1A agonist (buproprion) with an opiate-receptor antagonist (naltrexone).
  • naltrexone,
    
    • therapy for alcohol and opiate addication, may have benefits in the treatment of impulse control disorders in general (i.e. kleptomania, compulsive gambling, and trichotillomania).
    • the hedonic impact of eating was blunted
    • an effect of naltrexone on the reinforcement aspect of eating in obese individuals fits with concepts of obesity as a form of addiction (to food).

Question 8

Pharmacotherapy of Obesity:
Drugs that alter metabolism or absorption:
Orlistat

• approved for/
• ?
• needs to be taken/
• essentially/
• blocks/
• efficacy
• Systemic side effects/
• major side effects
• can interfere with/
• can potentiate/

Answer 8

• approved for long term weight loss programs.
• a gastric and pancreatic lipase inhibitor,
• needs to be taken along with meals.
• essentially “not-absorbed” (bioavailability <1%)
• blocks a major first step in fat digestion (mimicking exocrine pancreatic insufficiency).
• effective approach leading 5-10% average weight loss.
• Systemic side effects are minimal,
• the major side effects are gastrointestinal, as undigested fat leads to fatty/oily stool, fecal urgency, and possible fecal incontinence.
  
  • Fat soluable vitamin deficiency is possible.
• can interfere with the absoption of other medications such as amiodarone and cyclosporine,
• can potentiate warfarin by blocking absorption of vitamin K.

Question 9

Pharmacotherapy of Obesity

• Cannabinoid receptor blockers (Rimonabant)
• New drugs under development
• The first surgery expressly for the purpose of weight loss (bariatric surgery)

Answer 9

• Cannabinoid receptor blockers (Rimonabant)
  
  • suppress appetite.
  • high rates of depression and suicidal behaviors
• New drugs under development
  
  • Selective 5-HT2C/1B receptor agonists
  • Leptin and Ghrelin for weight maintenance/prevent relapse.
  • Analogs of GI peptides: GLP-1 (exenatide) and PYY.
• The first surgery expressly for the purpose of weight loss (bariatric surgery)
  
  • high rates of early post-operative complications
  • later severe complications due to malnutrition,
  • sustained weight loss
  • resolution of metabolic derangements associated with obesity.

Question 10

Surgical Approaches to Weight Loss:
Adjustable lap-band surgery (p.27-28)

• ?
• mechanism
• Advantages
• Disadvantages

Answer 10

• An inflatable band is placed 1-2 cm below the GE junction to create a ~30 mL gastric pouch.
• a purely “restrictive” mechanism,
  
  • intake is limited to small meals due to the size of the pouch.
• Advantages:
  
  • “reversible” and “adjustable” (there is a subcutaneous port through which the band can be made tighter or looser);
  • can be placed laparoscopically;
  • no high risk of malnutrition
• Disadvantages:
  
  • high rate (30%) of complications necessitating removal (band slippage, pouch dilation, band erosion).

Question 11

Surgical Approaches to Weight Loss:
Sleeve gastrectomy (longitudinal gastric resection) (p.30)

• ?
• mechanism
• Advantages
• Disadvantage

Answer 11

• A “gastric tube” is created by resecting the greater curvature of the stomach, thereby reducing the distensibility and volume of the stomach.
  
  • works by decreasing ghrelin production (removes oxyntic cells) and promoting general sense of satiety
• a “restrictive” mechanism, in that meal size would be limited.
• Advantages:
  
  • can be performed laparoscopically with little risk of “leak” (easy to use staple device to cut off the greater curvature).
• Disadvantage:
  
  • Irreversible;
  • lower rate of resolution of DM2 and long term weight loss than other techniques.
  • promote GERD via gastric stasis or increased gastric pressures after eating.

Question 12

Surgical Approaches to Weight Loss:
Roux-en-Y gastric bypass (p.25)

• initially/
• effects
• ?
• Advantages
• Disadvantages

Answer 12

• initially only an “open” procedure,
  
  • most gastric bypass surgeries have been done laparoscopically.
• leads to several alterations including “restrictive”, malabsoprtive, and “anorexic” effects.
• a small gastric pouch is separated from the remainder of the stomach, and a distal loop of jejunum is cut and anastomosed to the pouch to “receive food”.
  
  • The remaining stomach, duodenum, and jejunum are left in continuity (“the biliary-pancreatic limb” that drains secretions and digestive enzymes), to another anastomosis with the bypassed jejunum (“Roux limb”) where food is finally mixed with digestive enzymes.
  • The Roux limb “bypasses” healthy small intestine due to lack of digestion, and therefore various degrees of malabsorption can be induced based on the length of this segment.
  • ileal exposure to nutrients stimulates the “ileal brake” mechanisms where GLP-1 and PYY are released by L cells. This leads to a decreased appetite.
• Advantages:
  
  • best outcomes for significant weight loss
  • metabolic benefits (resolution of DM2, improved lipid profile, and sometimes resolved HTN).
  • an “anti-reflux” surgery.
• Disadvantages:
  
  • Irreversible;
  • anastomotic ulcers /breakdown are not uncommon and may require revision surgery;
  • micronutrients deficiency is common (thiamine, iron, B12)
  • require life-time replacement strategies (including IV administration).

Question 13

Eating Disorders

• two primary forms of eating disorders
  
  • Anorexia nervosa
  • Bulemia (“bulimia nervosa”)
• Both eating disorders

Answer 13

• two primary forms of eating disorders:
  
  • Anorexia nervosa
    
    • “nervous inability to eat”.
    • primarily restrictive pattern with little intake.
  • Bulemia (“bulimia nervosa”)
    
    • pattern of overeating / binging, typically following by intense feelings of guilt and purging (either by vomiting, laxative use, etc.).
• Both eating disorders
  
  • lie on a spectrum, and often patients shift between patterns over time.
  • share several features including unrealistic fears of weight gain, voluntary weight loss (more pronounced in anorexia), and a conspicuous distortion of body image.
  • seen in both men and women, but the vast majority (90%) are young females.

Question 14

Eating Disorders

• Anorexia nervosa
  
  • incidence
  • can cause/
  • leads to serious long-term health complications, including/
• Etiology of Anorexia Nervosa and Bulemia
  
  • a combination of/
  • At the biological level/

Answer 14

• Anorexia nervosa
  
  • a growing problem among adolescent females between 14-18 years of age.
    
    • The incidence has doubled in the United States since 1970.
  • can cause premature death.
    
    • It has one of the highest mortality rates of any psychiatric disorder.
  • leads to serious long-term health complications, including congestive heart failure, sudden death, growth retardation, dental problems, constipation, stomach rupture, swelling of the salivary glands, anemia and other abnormalities of the blood, loss of kidney function, and osteoporosis.
• Etiology of Anorexia Nervosa and Bulemia
  
  • a combination of cultural-social, psychological, and biological factors
  • At the biological level, alterations of the function of serotoninergic and other neuronal systems involved in reward are implicated in the pathogenesis of anorexia nervosa, with an overlap in comorbidity with mood disorders and drug abuse.

Question 15

Eating Disorders:
Diagnostic Criteria

• Restricted calorie intake/
• Intense/
• Disturbed/
• Restrictive type
• Binge-eating/Purging type

Answer 15

• Restricted calorie intake not sufficient to maintain body weight at or above a minimal normal for height and age.
  
  • Weight loss leading to less than 85% of expected body weight.
  • Lack of weight gain with growth leading to less than 85% of expected weight.
• Intense fear of weight gain or becoming fat, despite being under weight.
• Disturbed weight and shape perception.
  
  • Undue influence of body weight or shape on self-evaluation.
  • Denial of seriousness of current low body weight.
• Restrictive type: During episodes, the patient does not regularly engage in binge eating or purging. Food intake is extremely limited.
• Binge-eating/Purging type: During current episodes, the patient regularly engages in binge eating or purging, without any prolonged periods of fasting.

Question 16

Eating Disorders

• Clinical Consequences of Anorexia Nervosa
  
  • Psychiatric comorbidity
  • Medical complications
    
    • Hematologic and electrolyte abnormalities
    • Gastrointestinal complications
    • Long-term complications
• Treatment Objectives for Anorexia Nervosa:

Answer 16

• Clinical Consequences of Anorexia Nervosa
  
  • Psychiatric comorbidity: depression, anxiety, obsessions/rituals/OCD behaviors; drug abuse.
  • Medical complications:
    
    • Hematologic and electrolyte abnormalities: hypokalemia, hypochloremia, elevated serum bicarbonate, metabolic acidosis, arrhythmias, congestive heart failure
    • Gastrointestinal complications: constipation, gastritis, esophageal erosions, stomach rupture
    • Long-term complications: osteoporosis, death
• Treatment Objectives for Anorexia Nervosa:
  
  • Weight restoration
  • Changing dysfunctional attitudes
  • Normalization of eating pattern
  • Correction of physical complications
  • Weight maintenance/preventing relapse

Question 17

Treatment of Eating Disorders

• cornerstone of therapy
• Other psychological interventions
• The most challenging part of eating disorder therapy
• Medication therapies for eating disorders

Answer 17

• The cornerstone of therapy is psychological intervention with Cognitive Behavioral Therapy (CBT).
• Other psychological interventions
  
  • such as family therapy, insight-oriented therapy, and supportive psychotherapy
  • inherent parts of management which have demonstrated to be beneficial in younger patients and preventing relapse.
  • Often, these therapies occur in outpatient settings in those with less critical degrees of weight loss.
  • However, it may need to occur as a part of a commitment to inpatient psychiatric care.
  • psychiatrists often collaborate with gastroenterologists to assist in feeding strategies (i.e. feeding tubes).
• The most challenging part of eating disorder therapy is to maintain weight in the long term and to prevent relapse in outpatient settings.
• Medication therapies for eating disorders
  
  • Historically, the most effective medications have been the SSRIs (particularly fluoxetine [Prozac]), used in combination with CBT.
  • atypical antipsychotic medications such as olanzapine (Zyprexa) may be beneficial.

Question 18

Cachexia

• characterized by/
• occurs in patients with/
• Underlying Mechanisms of Cachexia
• Clinical Consequences of Cachexia

Answer 18

• characterized by involuntary weight loss, lean body mass wasting, fatigue, weakness, and anorexia (significant loss of appetite).
• occurs in patients with cancer (the “cancer anorexia-cachexia syndrome”), certain infectious diseases (e.g. tuberculosis, HIV/AIDS), some autoimmune disorders, congestive heart failure and liver failure, among others.
• Underlying Mechanisms of Cachexia
  
  • The metabolic and inflammatory abnormalities resulting from these diseases drive increased circulating cytokines including TNFα (originally called “cachexin”), IFN, IL-1, and IL-6.
  • Decreased caloric intake and malabsorption are secondary contributors to the cachexia syndrome in some disorders.
  • The psychologic impact of chronic illness also plays an important role in amplifying symptoms, and patients often become severely depressed.
• Clinical Consequences of Cachexia
  
  • Decreased survival
  • Increased complications of surgery, radiotherapy, and chemotherapy
  • Weakness, anorexia, chronic nausea
  • Psychological distress in patient and family

Question 19

Cachexia

• Treatment Options
• Nutritional Intake
• Pharmacotherapy of Cachexia
  
  • Appetite stimulants
  • Serotoninergic and Noradrenergic agents
  • Anti-emetics
  • Muscle growth stimulation
  • Block Cytokine production

Answer 19

• Treatment Options
  
  • treating the underlying condition,
  • supportive treatments for cachexia /anorexia include improving nutritional intake, supportive counseling and medications.
• Nutritional Intake
  
  • Patients may not tolerate large meals, but often can handle liquids.
  • substitute nutrient dense liquids (Ensure, Boost, Ensure Clear) for less nutritionally useful liquids (water, apple juice).
  • High protein gels are also helpful supplements.
  • If patients are severely debilitated and/or have altered mental status, or other issues precluding oral intake, then tube feeding may be required if it is compatible with goals of care.
  • incorporate patient taste preferences into the diet plan.
  • Many patients describe altered taste or smell, and they develop easy food aversions due to poor experiences.
• Pharmacotherapy of Cachexia
  
  • Appetite stimulants: Cannabinoids (dronabinol), glucocorticoids (Prednisone), progestins (megestrol acetate [Megace])
  • Serotoninergic and Noradrenergic agents: SSRIs/SNRIs, mirtazapine (Remeron)
  • Anti-emetics: ondansetron (Zofran)
  • Muscle growth stimulation: Anabolic hormones (testosterone), Growth Hormone; eicosapentaenoic acid
  • Block Cytokine production: melatonin, thalidomide