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![THANK YOU
Eat and drink, but be not excessive. Indeed, He does
not like those who commit excess.”
[Quran Sûrah al-A`râf: 31]](https://image.slidesharecdn.com/obesity-150220093357-conversion-gate02/85/Obesity-42-320.jpg)
Uploaded byFardan Qadeer
Obesity
This document provides an overview of obesity including its epidemiology, classification, medical complications, etiology, management, and pharmacotherapy. Some key points: - Over 1.9 billion adults worldwide are overweight, with over 600 million being obese according to WHO 2014 data. - Obesity is classified based on BMI and carries increased risks for conditions like cardiovascular disease and diabetes. - Its causes are multifactorial including genetic, metabolic, behavioral and environmental factors. Leptin plays an important role in regulating appetite and weight. - Treatment involves lifestyle changes like diet and exercise as well as pharmacotherapy. Approved obesity drugs include orlistat, lorcaserin, phentermine, and liraglutide
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Obesity
- 1. OBESITY Pathophysiology and Management FardanQadeer Resident, Department of Pharmacology ELMC&H Moderator: Dr. Ali Ahmad
- 2. OVERVIEW EPIDEMIOLOGY CLASSIFICATION OF OBESITY MEDICALCOMPLICATIONS OF OBESITY ETIOLOGY MANAGEMENT OF OBESITY PHARMACOTHERAPY
- 3. According to theWHO(2014) more than 1.9 billion adults, 18 years and older, were overweight. Of these over 600 million were obese. Overall, about 13% of the world’s adult population (11% of men and 15% of women) were obese in 2014.
- 5. WHO defines obesityas “abnormal or excessive fat accumulation.” The Obesity is classified according to the BMI:
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- 7. ETIOLOGY It may besimply attributed as the imbalance between energy intake and energy output however it has a more complex and multifactorial etiology. Possible factors in the development of obesity include the following: Race, sex, and age factors Ethnic and cultural factors Metabolic factors Genetic factors Psychological factors Endocrine factors Dietary habits Level of inactivity Psychological factors
- 9. THE REGULATION OFBODY WEIGHT This process is tightly regulated by a homeostatic system that integrates inputs from a number of internal sensors and external factors. Important components of the system include the following: •Hormones that signal the status of fat stores (e.g. leptin). •Hormones released from the gut during feeding that convey sensations of hunger (e.g. ghrelin), satiety (e.g. CCK) or satiation (e.g. PYY3-36).
- 10. THE REGULATION OFBODY WEIGHT •This hormonal information together with neural gustatory, olfactory and viscerosensory input is integrated in the hypothalamus. •Two groups of opposing neurons in the arcuate nucleus sense hormonal and other signals. Those secreting POMC/CART products promote feeding while those secreting NPY/AgRP inhibit feeding. •The net output from this process is relayed to other sites in the brain stem motor nuclei that control feeding behaviour.
- 11. LEPTIN: ITS ROLEIN OBESITY Friedman and his colleagues in 1994 identified a protein leptin. When recombinant leptin was administered in animals it strikingly reduced food intake and body weight. It had a similar effect when injected directly into the lateral or the third ventricle, implying that it acted on the regions of the brain that control food intake and energy balance. LEPTIN ARCUATE NUCLEUS Glucocorticoi ds insulin oestrogens Beta adrenergic stimulation + -
- 12. ADIPONECTIN A peptide hormonemade by adipocytes in response to high fat reserves: Increases FA uptake by myocytes and the rate of FA oxidation. Slows FA synthesis in the liver. Slows gluconeogenesis in the liver. Adiponectin is the only adipose-specific protein known to date that is negatively regulated in obesity Adiponectin levels are significantly reduced among obese subjects in comparison with lean control subjects
- 14. GUT HORMONES PYY- PeptideYY 1. Secreted from L cells of GI tract 2. Reduces food intake Ghrelin 1. Mainly secreted from stomach 2. A potent Orexigenic Cholecystokinin 1. Mainly secreted in duodenum 2. Decreasing meal size and duration both
- 17. THE PATHOGENESIS LEPTIN DISORDER Insufficient amounts of this hormone. resistance to leptin Defect in leptin carriage, transport into the CNS, Leptin receptor defect in the hypothalamus (as occurs in db/db mice) Postreceptor signalling
- 18. Mediators other thanleptin are certainly implicated in obesity. TNF-α, and cytokines that can relay information from fat tissue to brain, is increased in the adipose tissue of the obese individuals. Reduced insulin sensitivity of muscle and fat, alterations in the function of specific nuclear receptors, such as PPARα, β and γ, may play a role in obesity.
- 19. Proopiomelanocorti n (POMC) Alpha-MSH melanocor tin receptor 4 Geneticdefects in POMC production and mutations in the MC4 gene are described as monogenic causes of obesity in humans Reduce dietary intakeData suggest that up to 5% of children who are morbidly obese have MC4 or POMC mutations Most common identifiable genetic defects associated with obesity in humans Prohormone convertase Genetic factors are presumed to explain 40-70% of the variance in obesity. Genome-wide association studies have found a robust number of genetic susceptibility loci associated with obesity. THE GENETIC FACTORS
- 20. Leptin deficiency Rare casesof humans with congenital leptin deficiency caused by mutations in the leptin gene have been identified. (The involved band is at 7q31.) PPAR-gamma PPAR-gamma is a transcription factor that is involved in adipocyte differentiation. All humans with mutations of the receptor (at band 3p25) described so far have had severe obesity.
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- 22. DIET AND OBESITY Variousanimal models have shown that high fat diet causes obesity. Similar observations are seen with High carbohydrate diet Hence, a diet rich in carbohydrate plus fats in definitely implicated for obesity.
- 23. OBESITY IN DISEASE Obesityis a common feature in various endocrine disorders: Hypothyroidism Cushing’s Syndrome Pseudohypoparathyroidism Growth hormone deficiency
- 24. TREATMENT OF OBESITY Thefirst weapons in the fight against obesity are diet and exercise. Unfortunately, these often fail or show only short-term efficacy, leaving only surgical techniques (such as gastric stapling or bypass) or drug therapy as a viable alternative. Surgery is much more effective than currently licensed drugs.
- 25. DIETARY MODIFICATION Ensure lowcalorie diet for moderate weight loss: Nutrient Recommended Intake Calories Approximately 500 to 1,000 kcal/day reduction from usual intake Total fat 30 percent or less of total calories Saturated fatty acids 8 to 10 percent of total calories Monounsaturated fatty acids Up to 15 percent of total calories Polyunsaturated fatty acids Up to 10 percent of total calories Carbohydrate 55 percent or more of total calories Protein Approximately 15 percent of total calories
- 26. PHYSICAL ACTIVITY Physical activityshould be an integral part of weight loss therapy and weight maintenance. Initially, moderate levels of physical activity for 30 to 45 minutes, 3 to 5 days per week, should be encouraged. Example Walking 13/4 miles in 35 minutes (20 min/mile) Bicycling 5 miles in 30 minutes Running 11/2 miles in 15 minutes(15 min/mile) Swimming laps for 20 minutes
- 27. PHARMACOTHERAPY Currently, the 3major groups of drugs used to manage obesity are as follows: Centrally acting medications that impair dietary intake Medications that act peripherally to impair dietary absorption Medications that increase energy expenditure
- 28. ORLISTAT Orlistat is agastrointestinal and pancreatic lipase inhibitor that induces weight loss by inhibiting dietary fat
- 29. ORLISTAT Indication: Indicated inpatients with pretreatment BMI >30 kg/m², or BMI >27 kg/m² in presence of other risk factors or diseases (eg, HTN, DM, hyperlipidemia) Dose:120 mg PO q8hr with each fat-containing meal Side effects: Oily spotting (5%) Flatulence, Fatty/oily stool ,Increased defecation, Fecal incontinence, Nausea, Vomiting, Reduced absorption of fat soluble vitamins and beta-carotene Serious interaction: Orlistat decreases levels of cyclosporine by inhibition of GI absorption
- 30. LORCASERIN It decrease foodconsumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic pro- opiomelanocortin neurons located in the hypothalamus.
- 31. LORCASERIN Indication: Indicated inpatients with pretreatment BMI >30 kg/m², or BMI >27 kg/m² in presence of other risk factors or diseases (eg, HTN, DM, hyperlipidemia) Dose: 10 mg PO q12h Side effects: Interactions:Almotriptan, Amitriptyline, bupropion >10% Uncommon Headache (16.8%) Upper respiratory tract infection (13.7%) Nasopharyngitis (13%) Dizziness (8.5%) Nausea (8.3%) Fatigue (7.2%) Diarrhea (6.5%) Urinary tract infection (6.5%) Back pain (6.3%) Constipation (5.8%)
- 32. SYMPATHOMIMETIC AMINE Phentermine Diethylpropion Phendimetrazine Benzphetamine Phentermine/topiram ate Sympathomimetic amine increasesthe release and reuptake of norepinephrine and dopamine. Its anorexiant effect occurs as a result of satiety-center stimulation in hypothalamic and limbic areas of the brain.
- 33. SYMPATHOMIMETIC AMINE Side effects: Dysuria,Excitement, Hair loss, Headache, Hypertension, Tremor, Urticaria, Primary pulmonary hypertension, Psychotic disorder Serious interaction: Amoxapine, Cabergoline, Citalopram, Clomipramine Contraindication: Arteriosclerosis, cardiovascular disease, moderate-to-severe hypertension, glaucoma, agitation, hyperthyroidism, history of drug abuse Not approved for long-term use
- 34. BUPROPION AND NALTREXONE Combination mayregulate activity in the dopamine reward system of the brain that helps control food cravings and overeating behaviours Bupropion Increases dopamine activity in the brain, which appears to lead to a reduction in appetite and increase in energy expenditure by increasing activity of pro- opiomelanocortin (POMC) neurons Naltrexone Blocks opioid receptors on the POMC neurons, preventing feedback inhibition of these neurons and further increasing POMC activity
- 35. LIRAGLUTIDE Liraglutide was approvedby the FDA on December 23, 2014 for treatment for obesity in adults with some related comorbidity. Liraglutide (NN2211) is a long-acting glucagon-like peptide-1 receptor agonist. Thyroid cancer concern: Liraglutide caused a statistically significant increase in thyroid tumors in rats. The clinical relevance of these findings is unknown.
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- 38. Target Drug Company Mechanismof action Status Central neuropeptide signaling Melanocortin receptor MK-0493 Merck Selective MC4R agonist, increasing MC3/4R signaling Phase II completed RM-493 Rhythm Selective MC4R agonist, increasing MC3/4R signaling Phase II NPY MK-0557 Merck Y5 receptor antagonist, NPY blocker Phase II completed Velneperit (S- 2367) Shionogi USA Y5 receptor antagonist, NPY blocker Phase III
- 39. Target Drug Company Mechanismof action Status Monoamine neurotransmis sion Dopamine / norepinephrin e / serotonin Contrave (bupropion / naltrexone) Orexigen Norepinephrin e/dopamine reuptake inhibitor Phase III completed NDA submission Intestinal peptide hormone signaling GLP Byetta® (exenatide) Amylin GLP1R agonist, GLP- 1 mimicking Phase III OXM Qxyntomoduli n (OXY-RPEG) Prolor GLP1R agonist, OXM mimicking Phase I recruiting Thiakis / GLP1R
- 40. Target Drug Company Mechanismof action Status Pancreatic hormone signaling PP PP1420 Wellcome Trust Pancreatic polypeptide analog Phase I completed Amylin Davalintide (AC2307) Amylin Amylin mimicking Phase II Adipose tissue hormone signaling Leptin Metreleptin Amylin / Takeda Leptin receptor agonist Phase III recruiting Inhibition of lipase Pancreatic lipase Cetilistat (ATL-962) Alizyme / Takeda / Norgine Pancreatic lipase inhibitor, inhibiting Phase III completed
- 41. SURGICAL MANAGEMENT Weight losssurgery is an option for weight reduction in patients with clinically severe obesity, i.e., a BMI ≥40, or a BMI ≥ 35 with comorbid condition(morbid obesity)
- 42. THANK YOU Eat anddrink, but be not excessive. Indeed, He does not like those who commit excess.” [Quran Sûrah al-A`râf: 31]