The Pharmacology of Dexfenfluramine

Abstract

This chapter focuses on the pharmacology of anti-obesity drug dexfenfluramine. The dexfenfluramine molecule resembles d-amphetamine in that it contains a substituted phenylethylamine moiety. It is a serotoninergic agent that acts in three ways to enhance serotonin-mediated neurotransmission in the brain. Dexfenfluramine has no sympathomimetic properties; its administration tends to lower blood pressure, not raise it. The principal metabolite of dexfenfluramine, comprising perhaps 33% of the total fenfluramine in brains of people taking the drug, is dexnorfenfluramine. This compound has important pharmacological properties, mediating two of the three processes through which dexfenfluramine enhances serotonin-mediated neurotransmission. It releases serotonin from presynaptic terminals directly into synapses, and it also activates the postsynaptic 5-HT-2C receptors that probably underlie the drug's weight-reducing effects. Dexfenfluramine itself acts as a serotonin-reuptake blocker. The weight loss associated with dexfenfluramine treatment principally reflects decreased food intake; the drug also probably causes a small increase in calorie utilization. It decreases food consumption in two ways: it first speeds the onset of satiety, and second, it selectively suppresses the desire of many patients to overeat carbohydrates. Unlike the amphetamines, it apparently does not significantly reduce dietary protein intake, a desirable property for a drug that can be administered in a long term.