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Anti-Obesity Drugs: Mechanisms and Side Effects
- 4. OBESITY • Defined as an excess of body fat. • Surrogate marker for body fat content Body Mass Index. • BMI= Weight (in kg) Height (in m2) • BMI not a direct estimate of adiposity; large muscle mass.
- 5. OBESITY • Can also be defined as, • 25% or greater total body fat- men • 35% or greater- women • Estimation of % of total body fat: • Measurement of skin fold thickness • Bioelectrical impedance • Underwater weighing
- 6. BODY MASS INDEX BODY MASS INDEX VALUES(kg/m2) NORMAL 18.5- 24.9 OVERWEIGHT 25-29.9 CLASS I OBESITY 30-34.9 CLASS II OBESITY 35-39.9 CLASS III OBESITY (EXTREME) > 40 According to National Institute of Health:
- 8. EPIDEMIOLOGY • Obesity “Killer lifestyle disease” • According to WHO, • 1.2 billion people classified overweight worldwide • 3% of Indian population- obese • Lancet India is just behind US and China among top 10 countries with highest number of obese.
- 9. OBESITY • Obesity results from greater energy intake than energy expenditure. • 9.3 Cal 1gm fat is stored. • Fat adipocytes SC tissue; IP cavity; liver & other tissues.
- 11. OBESITY • Infancy; childhood hyperplastic obesity number of adipocytes • Adults Hypertrophic obesity size of adipocytes • Extremely obese size and number of adipocytes contains double amount of lipids as a lean person
- 16. OBESITY AND GENETICS • 20-25% • How genes contribute to obesity??? • One/ more abnormality of pathway regulating feeding center • Abnormality of energy expenditure and fat storage
- 17. PATHOPHYSIOLOGY
- 18. • Neural centers regulating appetite, feeding, behavior and energy status: Hypothalamus; the amygdala; nucleus tractus solitarius (NTS). • Lateral nuclei hypothalamus feeding center • Ventromedial nuclei satiety center
- 19. • Arcuate nucleus floor of 3rd ventricle in hypothalamus key site. • These centers possess high density receptors for neurotransmitters and hormones.
- 29. • Orlistat- pancreatic lipase inhibitor • Sibutramine- serotonin-norepinephrine reuptake inhibitor • Rimonobant- cannabinoid type-1 receptor antagonist
- 30. Newer drugs approved by FDA • Lorcaserin- June 2012 • Phentermine & Topiramate ER- July 2012 • Naltrexone & Bupropion- Sept 2014 • Liraglutide- Dec 2014
- 31. ORLISTAT • Reversible inhibitor of lipase- inhibits absorption of dietary fats • Empirical formula- C29H53NO5 • Molecular weight- 495.7 • FDA approved- April 1999
- 32. ORLISTAT- MECHANISM OF ACTION • Exerts therapeutic activity- lumen of stomach and small intestine • Covalent bond active serine residue site- gastric; pancreatic lipase • Inactivated enzyme inhibits hydrolysis of dietary fat (TG) to absorbable free fatty acids and monoglycerides.
- 33. • Undigested TG unabsorbed caloric deficit positive effect on weight control. • Therapeutic dose- 120 mg TID- fat absorption inhibited by 30%
- 34. ORLISTAT- ADR • Fatty/oily stool • Flatus with discharge • Fecal incontinence • Increased defecation • Abdominal cramps
- 35. SIBUTRAMINE • Serotonin-norepinephrine reuptake inhibitor • Empiric formula- C17H29Cl2NO • Molecular weight- 334.33 • FDA approved- November 1997
- 36. SIBUTRAMINE- MOA • Inhibits reuptake of serotonin; norepinephrine at hypothalamic sites • Increases levels of these substances- enhances satiety • Reduction in waist circumference • Decrease in plasma TG and VLDL • Increase in HDL • Dose- 5-15 mg/day
- 37. SIBUTRAMINE- ADR • Dry mouth • Constipation • Insomnia • Increased BP; Heart rate
- 38. RIMONABANT • Cannabinoid type-1 receptor antagonist • Developed for smoking cessation; facilitate weight loss • Initially used in pts with BMI> 30kg/m2 • Frequent adverse effects most notably severe depression risk of suicide this drug is no longer used clinically
- 39. LORCASERIN • Serotonin 2C receptor agonist • Selectively activates serotonin 2C receptors in brain promotes satiety • Indicated as an adjunct to low calorie diet and increased physical activity • BMI> 27 kg/m2 associated with weight-related comorbid condition or BMI >30kg/m2
- 40. LORCASERIN • Dose- 10 mg twice daily • ADR- • Headache, dizziness, fatigue • Nausea, dry mouth • Constipation • Backache • Cough • Hypoglycemia
- 41. QSYMIA • Combination of Phentermine & Topiramate ER. • Phentermine mediates release of catecholamine's in hypothalamus reduced appetite; decreased food consumption • Topiramate precise mechanism unknown • Dose- start 3.75mg/23mg daily for 14 days; increase to 7.5mg/46mg once daily. • After 12 weeks, <3% weight loss discontinue
- 42. QSYMIA- ADR • Paresthesia • Dizziness • Insomnia • Constipation • Dry mouth
- 43. CONTRAVE • Naltrexone & Bupropion • Schedule for treatment: • Week 1 1 tab- morning • Week 2 1 tab- morning & evening • Week 3 2 tab- morning; 1 tab- evening • Week 4 2 tab- morning & evening • After 12 weeks, <5% weight loss discontinue
- 44. CONTRAVE- MOA • Effect on 2 separate areas of brain • Hypothalamus • Mesolimbic dopamine circuit • Exact neurochemical effects not known
- 45. CONTRAVE- ADR • Nausea, vomiting • Headache, dizziness, insomnia • Dry mouth • Constipation • Has potential to cause suicidal thoughts & behaviors.
- 46. LIRAGLUTIDE • Glucagon like peptide 1 receptor agonist. • A physiological regulator of appetite; calorie intake • GLP-1 receptor- present in several areas of brain regulating appetite. • Dose- 3mg subcutaneously
- 47. LIRAGLUTIDE- ADR • Hypoglycemia • Nausea, vomiting • Constipation • Dyspepsia • Fatigue, Dizziness • Pain abdomen
- 48. OTHER TRIALS • Beloranib- May 2015, Phase II trial
- 49. BARIATRIC SURGERY • Most effective long-term treatment for obesity • Several approaches used- performed laproscopically • Goal- disrupting release of ghrelin and other peptides enhancing satiety
- 50. • Complications: • Post-operative respiratory problems, wound infection • Staple leaks, stomal stenosis, • Marginal ulcers and venous thrombosis
Notas del editor
- High BMI may also be due to large muscle mass.
- These methods are rarely used in clinical practice; Hence BMI is the only method to assess obesity. Abdominal circumference >102cm in men and >88 in women Waist hip ratio >1 in men and >0.85 in women obesity
- The Western Pacific Region Office of WHO recommends that, amongst Asians, BMI > 23.0 is overweight and > 25.0 is obese.
- Obesity important cause of preventable death worldwide A study published in the noted medical journal Lancet says India is just behind US and china in this global hazard list of top 10 countries with highest number of obese people.
- Metabolic syndrome is a disorder of energy utilization and storage, diagnosed by a co-occurrence of three out of five of the following medical conditions: abdominal (central) obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein (HDL) levels
- Once a person is obese and attains a stable weight energy intake = energy expenditure. For weight loss, energy intake should be less than energy expenditure.
- Sensation of hunger- craving for food; rhythmic contractions of stomach; restlessness; Sensation of appetite- desire for food; helps to choose quality of food to be eaten. Both these feelings are influenced by hypothalamus. Satiety centre- gives sense of nutritional satisfaction- inhibits feeding centre; In case of complete satiety- even in presence of highly appetizing food, the person refuses it.
- Also, the paraventricular nucleus, dorsomedial nucleus and arcuate nucleus play an important role in feeding regulation. Hormones and neurotransmitters are released from GIT and adipose tissue in stimulation to food intake. These converge into the arcuate nucleus
- Arcuate nucleus 2 types of neurons to control appetite & energy expenditure 1) anorexigenic POMC & CART; 2) orexigenic NPY/AGRP POMC release MSH acts on melanocortin receptors in PVN (MCR 3 and 4) activation of MCR decreased food intake and increased energy expenditure. This is mediated by activation of neuronal pathways projecting from PVN to nucleus tractus solitaries Defective signaling of this pathway is associated with obesity. Mutations of MCR-4 is the main cause for obesity and accounts for 5-6% of early onset obesity in children. AGRP inhibits MSH natural antagonist of MCR 3 and 4 increases food intake When energy stores deplete activation of orexigenic neurons release of NPY stimulates appetite.
- 2 major clinical trial sustained weight loss of 9-10% over 2 years
- Increases the levels of these substances in the synaptic cleft and enhances satiety
- Phentermine- a sympathomimetic; topiramate- antiepileptic Indicated in adjunct to low calorie diet and increased physical activity. BMI > 27 and if associated with other comorbidity. BMI> 30
- Naltrexone- an opioid antagonist Bupropion- an inhibitor of neuronal reuptake of dopamine and norepinephrine Indications same as previous drugs
- Indications same as other drugs
- After 12 weeks study, sustained progressive dose dependent weight loss of up to 11 kg from baseline Reduced hunger; food intake. Reduced total, LDL, Tg and increased HDL levels
- Vertical banded gastroplasty- Also known as stomach stapling; A small stomach pouch 15-30 ML capacity is created using bands/staples. At the bottom of the pouch is a small hole through which contents flow into the remainder of stomach and GIT Roux-en-Y gastric bypass- Stomach is divided into 2 pouches and small intestine is rearranged to connect to both.