Appetite suppressants, cardiac valve disease and combination pharmacotherapy

Abstract

The prevalence of obesity in the United States is a major health problem associated with significant morbidity, mortality, and economic burden. Although obesity and drug addiction are typically considered distinct clinical entities, both diseases involve dysregulation of biogenic amine neuron systems in the brain. Thus, research efforts to develop medications for treating drug addiction can contribute insights into the pharmacotherapy for obesity. Here, we review the neurochemical mechanisms of selected stimulant medications used in the treatment of obesity and issues related to fenfluramine-associated cardiac valvulopathy. In particular, we discuss the evidence that cardiac valve disease involves activation of mitogenic serotonin 2B (5-HT2B) receptors by norfenfluramine, the major metabolite of fenfluramine. Advances in medication discovery suggest that novel molecular entities that target 2 different neurochemical mechanisms, that is, "combination pharmacotherapy," will yield efficacious antiobesity medications with reduced adverse side effects.

Figure 1

Mechanism of biogenic amine transporter (BAT) reuptake inhibitors. Reuptake inhibitors increase synaptic transmitter concentrations by binding to BAT proteins and blocking the recapture of previously released biogenic amine transmitters.

Figure 2

Mechanism of biogenic amine transporter (BAT) substrate-type releasers. Releasers increase synaptic transmitter concentrations by a two pronged mechanism: 1) they promote biogenic amine efflux out of the cell by reversing the normal direction of transporter activity, and 2) they disrupt the storage of biogenic amines in vesicles by interacting with vesicular monoamine transporters (VMAT). The disruption of biogenic amine storage increases the cytoplasmic concentrations of amines available for release.

Figure 3

Chemical structures of commonly prescribed anorectic medications. With the exception of sibutramine, these medications are substituted phenylethylamine analogs, related to amphetamine. Fenfluramines are no longer available for clinical use.

Figure 4

In vivo metabolism of selected drugs to form potent 5-HT_2B receptor agonists. In each case illustrated, N-demethylation or N-deethylation produces bioactive metabolites that display much greater agonist activity at 5-HT_2B receptors when compared to their corresponding parent compounds.