Obesity

• Obesity


  Individuals with a body mass index (BMI) of 30 kg/m2 or greater
• Causes of obesity


  • Genetics
  • Metabolism
  • Behavior
  • Environment
  • Culture
  • Socioeconomic status
• Potential candidate for pharmacologic treatment of obesity


  Individual with a BMI greater than 30 or greater than 27 with other comorbidities, such as hypertension and diabetes
• Drugs for obesity are considered effective if they demonstrate at least a 5% greater reduction in body weight as compared with placebo (no treatment)

  
• Anorexiants/Appetite suppressants


  Drugs that are used as appetite suppressants

  
• Phentermine and diethylpropion


  • CNS stimulants used as appetite suppressants
  • Increase release of norepinephrine and dopamine from nerve terminals
  • Inhibit reuptake of these neurotransmitters, thereby increasing levels in the brain
  • Increase in norepinephrine signals a "fight-or-flight" response, which decreases appetite

  
• Tolerance to the weight loss effect of anorexiants develops within weeks, and weight loss typically plateaus
• Anorexiants are classified as controlled substances due to the potential for dependence or abuse
• Adverse effects of anorexiants


  • Dry mouth
  • Headache
  • Insomnia
  • Constipation
  • Increased heart rate and blood pressure
• Anorexiants should be avoided in patients with a history of uncontrolled hypertension, cardiovascular disease, arrhythmias, heart failure, or stroke
• Concomitant use of anorexiants with monoamine oxidase inhibitors (MAOIs) or other sympathomimetics should be avoided

  
• Lipase inhibitor


  A class of anti-obesity drugs that inhibit gastric and pancreatic lipases, thus decreasing the breakdown of dietary fat into smaller molecules that can be absorbed

  
• Orlistat


  The only agent in the lipase inhibitor class, indicated for weight loss or chronic weight maintenance

  
• Administration of orlistat decreases fat absorption by approximately 30%, which is the main cause of weight loss

  
• Adverse effects of orlistat


  • Oily spotting
  • Flatulence with discharge
  • Fecal urgency
  • Increased defecation
• Orlistat is contraindicated in pregnancy and in patients with chronic malabsorption syndrome or cholestasis

  
• Orlistat can interfere with the absorption of fat-soluble vitamins and β-carotene, so patients should take a multivitamin supplement

  
• Orlistat can also interfere with the absorption of other medications, such as amiodarone, cyclosporine, and levothyroxine, and their clinical response should be monitored

  
• Glucagon-like peptide-1 (GLP-1) receptor agonists


  Injectable drugs indicated for chronic weight management, which reduce hunger and lead to decreased caloric intake and weight loss

  
• Liraglutide and semaglutide


  • GLP-1 receptor agonists
  • Liraglutide is dosed daily, semaglutide has a once-weekly dosing schedule
  • Also indicated for the treatment of type 2 diabetes

  
• Adverse effects of GLP-1 receptor agonists


  • Nausea and vomiting
  • Pancreatitis
  • Hypoglycemia
  • Acute gallbladder disease
  • Elevated heart rate
  • Suicidal ideation

  
• Serotonin agonists


  Drugs that act on serotonin receptors to reduce appetite

  
• Fenfluramine and dexfenfluramine, the first serotonin agonists used for weight loss, were withdrawn from the market due to an increase in potentially fatal adverse effects, including valvulopathy

  
• Lorcaserin


  A serotonin agonist with selectivity for the 5-HT2C serotonin receptor, used for chronic weight management

  
• Mechanism of action of lorcaserin


  • Selectively activates 5-HT2C receptors, which stimulates proopiomelanocortin (POMC) neurons, activating melanocortin receptors and decreasing appetite

  
• If a patient does not lose at least 5% of their body weight after 12 weeks of using lorcaserin, the drug should be discontinued

  
• Pharmacokinetics of lorcaserin


  • Extensively metabolized in the liver to two inactive metabolites, which are then eliminated in the urine
  • Not recommended in severe hepatic or renal impairment

  
• Adverse effects of lorcaserin


  • Nausea
  • Headache
  • Dry mouth
  • Dizziness
  • Constipation
  • Lethargy
  • Rare mood changes and suicidal ideation
  • Risk of serotonin syndrome or neuroleptic malignant syndrome

  
• Lorcaserin


  Selectively activates 5-HT2C receptors, which are almost exclusively found in the central nervous system

  
• Lorcaserin mechanism of action


  1. Activates 5-HT2C receptors

  2. Stimulates proopiomelanocortin (POMC) neurons

  3. Activates melanocortin receptors

  4. Causes a decrease in appetite

  
• If a patient does not lose at least 5% of their body weight after 12 weeks of use, the drug should be discontinued

  
• Pharmacokinetics of Lorcaserin


  • Extensively metabolized in the liver to two inactive metabolites
  • Eliminated in the urine
  • Not studied for use in severe hepatic impairment
  • Not recommended in severe renal impairment

  
• Adverse effects of Lorcaserin


  • Nausea
  • Headache
  • Dry mouth
  • Dizziness
  • Constipation
  • Lethargy

  
• Rare adverse effects include mood changes and suicidal ideation
• Use of Lorcaserin with selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, MAOIs, or other serotonergic drugs should be avoided

  
• Valvulopathy has been associated with the use of 5-HT2B receptor agonists, although the incidence was not significantly increased in studies of Lorcaserin

  
• Patients with a history of heart failure should use Lorcaserin with caution
• Phentermine and topiramate combination


  • Used for long-term treatment of obesity
  • Topiramate observed weight loss in patients
  • Phentermine added to counteract sedation and promote additional weight loss through appetite suppression

  
• If a patient does not achieve a 5% weight loss after 12 weeks on the maximum dose of the phentermine/topiramate combination, then use should be discontinued

  
• Topiramate has been associated with significant birth defects including cleft palate, and the combination of phentermine/topiramate is contraindicated in pregnancy