18
Prescribing Obesity Medications
Mechanisms of Action
The majority of individuals tend to regain weight upon
discontinuation of obesity medications. Therefore, long-term
therapy is advised.
➤ The hypothalamus is the primary site for appetite control, but
limbic and brainstem regions also influence eating behavior.
➤ Phentermine promotes adrenergic signaling. The mechanism of
action of topiramate is not fully understood; however, it is thought
to enhance gamma-aminobutyric acid (GABA) transmission.
➤ Bupropion is a dopamine and norepinephrine reuptake inhibitor,
exerting its effects within both the limbic system and the
hypothalamus. One proposed mechanism is the increased release
of α-MSH, which subsequently reduces appetite through the
activation of the melanocortin-4 receptor in the hypothalamus.
α-MSH is secreted by neurons that produce POMC.
➤ Naltrexone, an opioid antagonist, inhibits feedback mechanisms,
thereby facilitating increased release of α-MSH. One example is
through blocking beta-endorphin, a product of POMC, whose
feedback on the POMC neuron reduces α-MSH release.
➤ GLP-1 RAs interact with GLP-1 receptors in the brainstem which
activate GLP-1 activity in the hypothalamus and other areas of the
brain to decrease appetite. GLP-1 RAs do not traverse the blood-
brain barrier; however, they can access certain brain regions
through circumventricular organs.
➤ Tirzepatide is a dual GIP and GLP-1 receptor agonist. Its central
effects on appetite regulation appear less specific than those of
selective GLP-1 RAs.
➤ The role of GIP in lipid metabolism remains uncertain. Although
GIP has been characterized as fat-anabolic, lipolysis can persist
in the absence of insulin. In animal models, GIP antagonism
can prevent or attenuate obesity. Conversely, it has been
hypothesized that chronic GIP agonism may produce functional
antagonism via desensitization, but findings are mixed.
➤ Orlistat exerts its effects by inhibiting the activities of pancreatic
and gastric lipase, which leads to an approximate 30% reduction
in fat absorption. Unabsorbed fats can result in the presence of
oily stools and can also bind to intestinal calcium, consequently
enhancing oxalate absorption.
