Anti-obesity drugs Tomáš Goněc 22.4.2014 Obesity severe world-wide spread disease increases DM II, cardiovascular risk, osteoporosis Body mass index (BMI) = body weight [kg] / (body height [m])2 Obesity definition (WHO): BMI 20-25 normal BMI 25-30 overweight BMI 30-40 obesity BMI >40 severe obesity Visceral obesity: waistline > 80cm (F) or > 94cm (M) Anti-obesity therapy  low-energy diet  aerobic exercise  farmacotherapy Anti-obesity drugs  Central (Anorectics) - inhibits centre of appetite in brain - increase sympathetic tonus  Peripheral - inhibits digestion and/or absorption of lipids and carbohydrates - accelerates their metabolism Central anorectics - decreases appetite - causes feeling full - increases lipolysis Mechanism of action: - indirect central adrenergic stimulants - indirect 5-HT mimetics - cannabinoid receptor 1 antagonists Amphetamine derivatives R 1 NH R 2 CH3 Structure-activity relationships: R1: -H, -OH or 3,4- -OCH2OR2: methyl, ethyl - increases catecholamine synaptic release Amphetamine derivatives Amphetamine Metamphetamine (Pervitine) Tenamfetamine -withdrawed from market due to habit and toleration Fenfluramine -withdrawed from market due to severe cardiovascular side-effects NH2 CH3 NH CH3 CH3 NH2 CH3 O O CF3 N H Amphetamine synthesis Metamphetamine synthesis Amphetamine derivatives Fentermine used as resinate (complex with resine polymer) Mazindole NH2 CH3CH3 N N OH Cl Fentermine synthesis Mazindole synthesis Serotonine-Noradranaline Reuptake Inhibitors (SNRIs) Antidepressants with anorectic activity Venlafaxine Duloxetine Serotonine-Noradranaline Reuptake Inhibitors (SNRIs) CH3 CH3 N CH3 CH3 Cl Sibutramine widely used in therapy, manifesting several cardiovascular side-effects Sibutramine synthesis Selective Serotonine Reuptake Inhibitors (SSRIs) Antidepressants with anorectic activity Fluoxetine Sertraline Cannabinoid receptor CB1 inhibitors N N Cl NH N O CH3 Cl Cl Rimonabant Antagonism on the cerebral CB1 receptors decreases appetite and overall food income Rimonabant synthesis Peripheral anti-obesity drugs Acarbose α-glucosidase inhibitor – carbohydrates are not digested in the intestine Peripheral anti-obesity drugs Orlistat both ventricular and pancreatic lipase inhibitor - lipids are not digested in all digestive organs Important side-effect: undigested lipids causes diarrhoea