The Pharmacology of Obesity

1. The Pharmacology of Obesity Dr. haninosama

2. Definition of Obesity • 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)

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

4. Indications for Drug Therapy in Obesity A combined intervention of behavior therapy, dietary changes and increased physical activity should be maintained for at least 6 months before considering pharmacotherapy. • Failure of diet and exercise alone • BMI of 30 kg/m² or more or a BMI of 27 kg/m² or more with comorbid condition • Understand that drug therapy is adjunctive to lifestyle intervention • Have realistic expectations about weight loss goals and outcomes • Demonstrate readiness for change • Are unable to lose/maintain weight with lifestyle change alone • Comply with medication use • Have no medical or psychiatric contraindications

5. Potential Strategies for Anti-Obesity Drug Action • Reducing food intake. • Blocking nutrient absorption • Increasing thermogenesis. • Modulating fat metabolism/storage. • Modulating the central regulation of body weight.

6. ADDITIONAL CONSIDERATIONS WHEN USING ANTI-OBESITY DRUGS • Weight loss drugs should never be used without continued concomitant lifestyle modifications and as part of a comprehensive weight loss program. • Continual assessment of drug therapy for efficacy and safety is necessary. • If the drug is efficacious in helping the patient to lose and/or maintain weight loss and there are no serious adverse effects, it can be continued. • If not, it should be discontinued.

7. 1. Sibutramine Mechanism of action: • Was developed originally as antidepressant • Inhibit reuptake of serotonin and norepinephrine at nerve terminals increasing their concentration at postsynaptic receptors in the brain that affect food intake • It is also thought to stimulate energy expenditure

8. Pharmacokinetics • Rapidly absorbed from the GI • Extensively metabolized by CYP 3A4 to active metabolites • With dietary advise this drug is expected to cause loss 5-7% of the body weight but this tend to be regained after the drug is stopped

9. Indications and precautions • Patients with BMI of 27% who have CVS disease or BMI >30 with or without CVS disease • It should be discontinued • if weight loss at 3monts of starting the drug is <5% of the initial weight • the patient regained 3kg after previous weight loss • Should not be given more than one year • Sibutramine is taken once daily with or without food.

10. Contraindications and D/I • sibutramine should not be used by patients who have: • uncontrolled hypertension • coronary heart disease • congestive heart failure • Arrhythmias • stroke • severe renal or liver dysfunction • obesity from endocrine disease • Major eating or psychiatric disorder • Should not be given with TCA because of CNS toxicity

11. Side Effects • dry mouth, constipation, headache, insomnia, increased blood pressure, tachycardia, sweating, altered taste. • Should monitor all patients twice weekly in the first 3 months for hypertension • Should take in the morning to avoid insomnia

12. 2. Orlistat (Xenical) Mechanism of action: • Pancreatic lipase inhibitor that blocks the absorption of up to one third of ingested fat. (normally 5% of fat is not absorbed) • Weight loss is due to calories loss but drug related adverse effects also contribute by diminishing the food intake • Patients who adhere to a low calorie diet and take orlistat lost an average of 9-10kg after one year (compared to 6kg on placebo)

13. Orlistat is taken 3 times daily with meals, if the meal is missed or contain no fat the dose of orlistat should be omitted • Treatment should be proceed beyond 3 month only if lost >5% of the initial body weight and beyond 6 month if lost >10% should not normally exceed one year and never 2 years Indications • Aged 18-75 • Who have lost 2.5kgbody weight by dieting and increasing physical activity in the previous month • Patients with BMI of 27% who have CVS disease or BMI >30 with or without CVS disease

14. Side effects • Because it blocks intestinal absorption of fat it can result in diarrhea and steatorrhea (liquid oily stools), urgency, abdominal pain. This is minimized by maintaining a strict low fat diet (<30% of diet) • Mal-absorption of fat soluble vitamins C/I • Chronic intestinal malabsorption • Cholestasis

15. Investigational Agents for Treatment of Obesity

16. 1. Topiramate • Topiramate is antiepileptic drug approved by the FDA as an antiseizure medication. • When reports surfaced that patients enrolled in initial trials of the drug and also in clinical practice were experiencing unexpected weight loss, the effects of the drug on weight began to be studied. • Mechanism for weight loss is still poorly understood

17. 2. Leptin • Naturally occurring hormone that plays a role in satiety and weight maintenance. • Produced in adipocytes • Its role in weight regulation is related to its effects on the hypothalamus, where it leads to: • satiety • decreased food intake • increased energy expenditure in the periphery • Weight loss was relatively modest.

18. Other drugs withdrawn from the market • Phentermine, fenfluramnie dexfenfluramine • Were formerly prescribed appetite suppressants • Stimulate NE release • They cause cardiac valve disease and pulmonary hypertension