Fenfluramine

Fenfluramine is an antiobesity medication that came into the U.S. market in the early 1970s. Fenfluramine is the racemic mixture of dexofenfluramine and levofenfluramine. Dexfenfluramine is the active form and is effective in one-half the dose of the racemic mixture. Fenfluramine is currently available in many countries throughout the world. Although structurally very similar to the noradrenergic drugs, these agents act by different mechanisms. Fenfluramine and dexfenfluramine are highly selective serotonin agonists that enhance serotonin release into nerve synapses and inhibit its reuptake. In a major study by the National Heart, Lung, and Blood Institute, the noradrenergic agent phentermine was combined with the serotonergic drug fenfluramine.

The concept of this medication was to increase the levels of serotonin, an important neurotransmitter in food intake regulation, in the brain. Serotonin is a monoamine neurotransmitter that is synthesized in serotonergic neurons in the central nervous system (CNS). Serotinon is believed to play an important role in the regulation of anger, aggression, body temperature, mood, sleep, vomiting, sexuality, and appetite. An increase of serotonin levels in the brain are thought to depresses the part of the CNS that regulates mood and appetite, leading to a decrease in food intake and subsequent weight loss.

However, this medication was withdrawn from the U.S. market in 1997 after reports of heart valve disease and pulmonary hypertension, a high pressure of blood moving into the lungs. Heart valves also have serotonin receptors, which regulate their growth. The distinctive valvular abnormality seen with fenfluramine is a thickening of the chordae tendinae in the heart. These are the thin, fibrous chords that lie within the heart muscle wall and contribute to the support of the tricuspid and mitral valves. These abnormalities seen in patients who take the medication have led it to be removed from use.

Consequently, the Food and Drug Administration (FDA), acting on new evidence about significant side effects associated with fenfluramine has asked the manufacturers to voluntarily withdraw both treatments for obesity from the market. The FDA recommended that patients using fenfluramine products stop taking them. Users of these products should contact their doctors to discuss their treatment. There is [Page 274]currently a seemingly endless pursuit for a medicinal cure to the drastic obesity epidemic in the United States and abroad. Further research with other serotonergic medications is under way and may change treatment measures for obesity in years to come.