The Pharmacology of Obesity

1. The Pharmacology of Obesity CH 31

2. LEARNING OBJECTIVES • Epidemic of obesity • Why treat obesity? • Pathophysiology of Obesity • Pharmacology of obesity • Pharmacology of drugs currently approved for treatment of obesity • Pharmacology of investigational agents • Non pharmacological methods Dietary and nutritional recommendations Physical activity and other lifestyle changes Surgical options for weight loss

3. The Epidemic of Obesity

4. Obesity Trends* Among U.S. AdultsBRFSS, 1985 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

5. Obesity Trends* Among U.S. AdultsBRFSS, 2001 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

6. Prevalence of Obesity More than 30% of adults in the US are overweight or obese, and this percentage is rising. Percentage of people with BMI ≥ 30 in the US in 2005 CDC’s Behavioral Risk Factor Surveillance System.

7. Why Treat Obesity? • 300,000 deaths a year, making it 2nd only to smoking as a cause of death • Contributes or causes to many other health problems including: • Type 2 Diabetes Mellitus • Coronary Artery Disease • Degenerative Joint Disease • Certain Types of Cancer

9. Pathophysiology of Obesity

10. The role of peripheral hormones and other mediators in the regulation of energy balance and fat stores • . The primary level of hypothalamic control is vested in two groups of neurons, with opposing actions, in the arcuate nucleus (ARC). In one group, the peptides neuropeptide Y (NPY) and agouti-related protein (AgRP) are co-localised; the other contains the polypeptides prepro-opiomelanocortin (POMC) and cocaine- and amphetamine-related transcript (CART), which release α-melanocyte-stimulating hormone (MSH). Blood-borne hormones arising from the gastrointestinal (GI) tract or adipose tissue are sensed by receptors on vagal and other afferents and are relayed through the nucleus tractus solitarius to modify the activity of these neuronal circuits. The influence of hormones on each neuronal group is indicated. Hormones (e.g. leptin) arise from the peripheral blood and influence the ARC neurons directly or indirectly through neuronal signals; mediators (e.g. 5HT, orexin) originate within the central nervous system itself. Activation of the NPY/AgRP group by, for example, a fall in leptin or an increase in ghrelin levels results in increased food intake and decreased energy expenditure. In the POMC/CART group of neurons, increased leptin or other hormone levels triggered by overfeeding produces a predominately inhibitory effect on feeding behaviour. A number of other hormones such as cholecystokinin (CCK) and amylin also alter the properties of the ARC neurons although the mechanism is not clear. GLP-1, glucagon-like peptide-1.

11. Obesity • Obesity is a multifactorial disorder of energy balance, in which long-term calorie intake exceeds energy output. • It is characterized by an excessive body mass index (BMI; weight in kg divided by the square of height in m). • A subject with a BMI of 18.5-25 kg/m2 is considered as having a healthy body weight, one with a BMI of 25-30 kg/m2 as overweight, and one with a BMI > 30 kg/m2 as obese. • A BMI of 40 or above indicates that a person is morbidly obese. This can increases a person's risk of death from any cause by 50% to 150%.

12. Obesity is a growing problem in most rich nations; the incidence-at present approximately 30% in the USA and 15-20% in Europe-is increasing. • A BMI > 30 kg/m2 significantly increases the risk of type 2 diabetes, hypercholesterolaemia, hypertension, ischaemic heart disease, gallstones and some cancers.

13. BMI 25-29.9 (Grade 1, overweight) • BMI 30-39.9 (Grade 2, obese) • BMI > 40 (Grade 3, Morbidly obese) • Increased visceral fat • Waist > 94 cm in men (waist-to-hip > 0.95) • Waist > 80 cm in women (waist-to-hip >0.8)

14. Pharmacology of Obesity Potential Strategies for Anti-Obesity Drug Action Indication C.I Pharmacology of Drugs Currently Approved for Treatment of Obesity Pharmacology of investigational agents

15. Potential Strategies for Anti-Obesity Drug Action • Reducing food intake. Either amplify effects of signals/factors that inhibit food intake or block signals/factors that augment food intake • Blocking nutrient absorption (especially fat or carbohydrates) in the intestine. • Increasing thermogenesis. Either increase metabolism and dissipate food energy as heat or increase energy expenditure through the enhancement of physical activity. • Modulating fat metabolism/storage. Regulate fat synthesis/breakdown by making appropriate adjustments to food intake or energy expenditure. • Modulating the central regulation of body weight. Either alter the internal set point or modulate the signals presented regarding fat stores.

16. INDICATIONS FOR USE OF OBESITY DRUGS • A combined intervention of behavior therapy, dietary changes and increased physical activity should be maintained for at least 6 months before considering pharmacotherapy.

17. CONTRAINDICATIONS OR CAUTIONS TO THE USE OF OBESITY DRUGS • Pregnancy or lactation • Unstable cardiac disease • Uncontrolled hypertension (SBP >180, DBP > 110 mmHg) • Unstable severe systemic illness • Unstable psychiatric disorder or history of anorexia • Other drug therapy, if incompatible (eg MAO inhibitors, migraine drugs, adrenergic agents, arrhythmic potential) • Closed angle glaucoma (caution) • General anesthesia

18. General Drug therapy Appetite suppressants • Adrenergic agents (e.g. amphetamine, methamphetamine, phenylpropanol amine, phentermine) • Serotonergic agents (e.g. fenfluramine, dexfenfluramine, SSRIs like sertraline, fluoxetine) Thermogenic agents • ephedrine, caffeine New ones • Sibutramine ; Orlistat

19. Clinical uses of antiobesity drugs • The main treatment of obesity is a suitable diet and increased exercise. • Orlistat , which causes fat malabsorption, is considered for severely obese individuals, especially with additional cardiovascular risk factors (e.g. diabetes mellitus, hypertension). • Many centrally acting appetite suppressants have been withdrawn because of addiction, pulmonary hypertension or other serious adverse effects. Sibutramine is one possible adjunctive treatment of severely obese individuals.

21. Drugs removed from market • Fenfluramine • Dexfenfluramine • Phenylpropanolamine

22. Pharmacology of Drugs Currently Approved for Treatment of Obesity

23. Sibutramine Non-selective inhibitor of neuronal reuptake of serotonin and norepinephrine: appetite suppressant

24. Sibutramine Blocks Neuronal Monoamine (Serotonin, Norepinephrine, Dopamine) Reuptake X S S = Monoamine = Sibutramine

25. Mechanism of Action • Sympathomimetic amine-Appetite Suppressant -Centrally acting neurotransmitter reuptake inhibitor- serotonin,norepinephrine and dopamine -Early satiety -Increase in energy expenditure

26. Sibutramine, • originally intended as an antidepressant, has shown promise in the treatment of obesity. • The drug inhibits the reuptake of serotonin and noradrenaline at the hypothalamic sites that regulate food intake. • Its main effects are to reduce food intake and cause dose-dependent weight loss

27. Sibutramine enhances satiety and is reported to produce a reduction in waist circumference (i.e. a reduction in visceral fat), a decrease in plasma triglycerides and very low-density lipoproteins, but an increase in high-density lipoproteins. • Causes a beneficial effects on hyperinsulinaemia a • There is some evidence that the weight loss is associated with higher energy expenditure, possibly through an increase in thermogenesis mediated by the sympathetic nervous system.

28. Sibutramine Indications Among obese patients who should undergo drug therapy, sibutramine works best for those who: • Experience difficulty controlling food intake • Do not feel full • Think about food a lot • Do not have increased cardiovascular disease risk or multiple risk factors • Are younger Sibutramine is taken once daily with or without food.

29. Side Effects • Sibutramine increases heart rate ,tachycardia and blood pressure. Regular monitoring of these parameters is essential, and the drug is C.I if C.V. disease is present or if the systolic or diastolic pressure is raised by 10 mmHg or more. • dry mouth, constipation and insomnia, anxiety, headache, depression, risk of serotonin syndrome in combination with other CNS drugs. • Should take in the morning to avoid insomnia • Interactions with drugs that are metabolised by one of the P450 isoenzymes can occur.

30. Sibutramine

31. Orlistat Pancreatic lipase inhibitor: fat malabsorption

33. M.O.A • Orlistat reacts with serine residues at the active sites of gastric and pancreatic lipases, irreversibly inhibiting the enzymes and thereby preventing the breakdown of dietary fat to fatty acids and glycerols. • It therefore causes a dose-related decrease in fat absorption and a corresponding increase in faecal fat excretion that plateaus at some 30% of dietary fat. • Given with a low-calorie diet in obese individuals, it produces a modest but consistent loss of weight compared with in placebo-treated control subjects.

34. Orlistat Indications Among obese patients who meet the criteria for anti-obesity drug therapy, orlistat is most likely to benefit those who: • Do not feel hungry • Are not preoccupied with food • Eat out or order-in often • Have increased cardiovascular disease risk or multiple cardiovascular risk factors • Are older • Take multiple medications Orlistat is taken 3 times daily with meals

35. Orlistat is also reported to be • effective in patients suffering from type 2 diabetes and other complications of obesity • to reduce leptin levels • to reduce blood pressure • to protect against weight loss-induced changes in biliary secretion • to delay gastric emptying and gastric secretion • to improve several important metabolic parameters • and not to interfere with the release or action of thyroid and other important hormones • It does not induce changes in energy expenditure.

36. Unwanted effects • Abdominal cramps, flatus with discharge and faecal incontinence can occur, as can intestinal borborygmi (rumbling) and oily spotting. Surprisingly, in view of the possibility of these antisocial effects occurring the drug is well tolerated. • Supplementary therapy with fat-soluble vitamins may be needed, and there has been a report of decreased absorption of contraceptive pills. • No significant drug interactions have been noted, except in the case of ciclosporin , where reduced absorption of the latter drug has been reported

37. Metformin •  hepatic gluconeogenesis and glucose production;  hepatic insulin sensitivity •  food intake •  fat stores ,improves lipid profiles • 25 % reduction in cumulative 3 yr incidence of T2DM in adults;  CV morbidity & mortality in adults w/ T2DM

38. Side effects • Transient abdominal discomfort or diarrhea • Lactic acidosis (rare) in adults with chronic cardiac, hepatic, renal or GI disease. • Urinary losses of B vitamins: use daily MVI in all metformin patients • **Approved for obesity +Type 2 diabetes mellitus; not yet approved for obesity

39. New FDA approved lorcaserin hydrochloride to treat some overweight or obese adults Acts by activating the serotonin 2C receptor in the brain. Activation of this receptor may help a person eat less and feel full after eating smaller amounts of food. The most common side effects in non-diabetic patients are headache, dizziness, fatigue, nausea, dry mouth, and constipation, and in diabetic patients are low blood sugar (hypoglycemia), headache, back pain, cough, and fatigue.

40. Pharmacology of investigational agents

41. THC Δ9-tetrahydrocannabinol (THC) is the active principle of cannabis, and took off with the discovery of 1-specific cannabinoid receptors-termed CB receptors 2- endogenous ligands (endocannabinoids),

42. Cannabis  Main active constituent is Δ9-tetrahydrocannabinol (THC) Actions on the central nervous system include both depressant and psychotomimetic effects. Causes euphoria and a feeling of relaxation, with sharpened sensory awareness. Leads to impairment of learning, memory and motor performance, including impaired driving ability. THC also shows analgesic and antiemetic activity, as well as causing catalepsy and hypothermia in animal tests. Peripheral actions include vasodilatation, reduction of intraocular pressure and bronchodilatation. Cannabinoids are less liable than opiates, nicotine or alcohol to cause dependence but may have long-term psychological effects.

43. The endocannabinoid system Cannabinoid receptors (CB1, CB2) are G-protein coupled Activation of CB1 inhibits adenylyl cyclase and calcium channels, and activates potassium channels, inhibiting synaptic transmission. The peripheral receptor (CB2) is expressed mainly in cells of the immune system. . Endogenous ligands for CB receptors are known as endocannabinoids. They are eicosanoid mediators The best-established endocannabinoids are anandamide and 2-arachidonoyl glycerol (2-AG), which have many roles, including functioning as 'retrograde' mediators passing information from postsynaptic to presynaptic neurons. The main enzyme that inactivates anandamide is fatty acid amide hydrolase (FAAH). A putative 'endocannabinoid membrane transporter' may transport cannabinoids from postsynaptic neurons, where they are synthesised, to the synaptic cleft, where they access CB1 receptors, and into presynaptic terminals, where 2-AG is metabolised.

44. FAAH 'knockout' mice have an increased brain content of anandamide and an increased pain threshold; selective inhibitors of FAAH have analgesic and anxiolytic properties, implicating endocannabinoids in nociception and anxiety. Rimonabant, an antagonist at CB1 receptors, causes sustained weight loss and may promote abstinence from tobacco.

45. Pharmacology of investigational agentsRimonabant • Cannabinoid-1 receptor blocker • Reduces over activation of the central & peripheral endocannabinoid system • 3045 pts with BMI>27 and HTN or dyslipidemia • Most common side effect was nausea • It was licensed in Europe for treating obesity, but was withdrawn because of psychiatric problems including depression.

46. Potential and actual clinical uses of cannabinoid agonists and antagonists • Cannabinoid agonists and antagonists are undergoing evaluation for a wide range of possible indications, including the following. Agonists: • - glaucoma (to reduce pressure in the eye) • - nausea/vomiting associated with cancer chemotherapy • - cancer and AIDS (to reduce weight loss) • - neuropathic pain • - head injury • - Tourette's syndrome • - Parkinson's disease (to reduce involuntary movements caused as an adverse effect of L-dopa • Antagonists: • - obesity • - tobacco dependence • - drug addiction • - alcoholism.

47. Non pharmacological methods

48. Weight Loss Surgery Option for limited number of patients with clinically severe obesity. • BMI >40 or >35 with comorbid conditions • Reserved for patients in whom medical therapy has failed • Gastric restriction or gastric bypass Integrated program must be in place before and after surgery.

49. Gastric Bypass • Gastrojejunostomy impairs rapid gastric emptying • Create 15-30 ml gastric pouch

50. Advantages: • Significant weight loss or lower BMI (~33%) one year post-op; generally sustainable (14 year • Deterrence to carbohydrate ingestion • Enhanced satiety