Slide 8-19. The pharmacological actions of the available anti-obesity drugs is shown in this table. Dexfenfluramine and fenfluramine are no longer available. They were witdrawn by the FDA due to an association with cardiac valvular disease. All of these drugs work at a central level to affect the hypothalamic appetite centers with the exception of Orlistat, which acts in the gastrointestinal tract to inhibit triglyceride breakdown and absorption by about 30%.

Slide 8-20. Sibutramine is a non-selective norepinephrine and serotonin reuptake inhibitor. The normal release and reuptake of neurotransmitters from the synaptic space determines the amount of active neurotransmitter to bind to the postsynaptic receptor. By inhibiting the reuptake of norepinephrine and serotonin, this drug increases the concentration of both neurotransmitters in the synaptic space.

Slide 8-21. Phentermine is both a releaser of synaptic stores of norepinephrine and a reuptake inhibitor. It overrides the normal control mechanisms of synthesis-secretion coupling and has a pronounced effect on the levels of norepinephrine in the synapse by comparison to sibutramine. Physicians should be aware that in contrast to sibutramine, this drug is only approved for short term use in weight management.

Slide 8-22. Monoamine circuits in the hypothalamus governing feeding and satiety. Serotonin facilitates satiety without addictive potential. Norepinephrine inhibits feeding via the beta-adrenergic system without addictive potential. Dopamine inhibits feeding, but is associated with addictive potential.

Slide 8-23. Centrally acting antiobesity drugs share some similarities in chemical structure. Phentermine and amphetamines are structurally similar. Sibutramine has structural differences which confer unique properties of non-selective reuptake inhibition for both serotonin and norepinephrine.

Slide 8-24. Inhibition of lipases by Orlistat blocks systemic absorption of dietary fat. Up to one-third of ingested fat is excreted into the feces. Gastric and pancreatic lipases are the key enzymes that hydrolyze triglycerides into free fatty acids and monoglycerides, which are then absorbed. Orlistat inhibits these lipases.

Slide 8-25. After 1 year, Orlistat 120 mg tid, resulted in a weight loss of 8.8% compared to a mean weight loss of 5.8% in the placebo group (p<0.0001). After two years the subjects with a waist circumference greater than 39 inches had a mean loss of 2.3 inches in the Orlistat group compared with a mean loss of 1.1 inches in the placebo group.

Top of page