Fenfluramine

Withdrawal due to heart disease

The drug was withdrawn from the U.S. market in 1997 after reports of heart valve disease and pulmonary hypertension, including a condition known as cardiac fibrosis. It was subsequently withdrawn from other markets around the world. It was banned in India in 1998.

The distinctive valvular abnormality seen with fenfluramine is a thickening of the leaflet and chordae tendineae. One mechanism used to explain this phenomenon involves heart valve serotonin receptors, which are thought to help regulate growth. Since fenfluramine and its active metabolite norfenfluramine stimulate serotonin receptors, this may have led to the valvular abnormalities found in patients using fenfluramine. In particular norfenfluramine is a potent inhibitor of the re-uptake of 5-HT into nerve terminals. 5-HT_2B receptors. Fenfluramine and its active metabolite norfenfluramine affect the 5-HT_2B receptors which are plentiful in human cardiac valves. The suggested mechanism by which fenfluramine causes damage is through over or inappropriate stimulation of these receptors leading to inappropriate valve cell division. Supporting this idea is the fact that this valve abnormality has also occurred in patients using other drugs that act on 5-HT_2B receptors.

According to a study of 5743 former users conducted by a plaintiff's expert cardiologist, damage to the heart valve continued long after stopping the medication. Of the users tested, 20 percent of women, and 12 percent of men were affected. For all ex-users, there was a sevenfold increase of chances of needing surgery for faulty heart valves caused by the drug.

Other adverse effects and recreational use potential

There have been reports associating fenfluramine with depression, psychosis, exacerbation of pre-existing psychosis (schizophrenia), and sleep disturbances. These effects may be mediated by serotonergic neurotoxicity/depletion of serotonin with chronic administration and/or activation 5-HT_2A receptors. In overdose, fenfluramine can result in serotonin syndrome and death. Unlike various other amphetamine derivatives, fenfluramine is reported to be dysphoric, "unpleasantly lethargic", and non-addictive. However, it has been reported to be used recreationally at high doses ranging between 80 and 400 mg, which have been described as producing euphoria, amphetamine-like effects, sedation, and hallucinogenic effects, along with anxiety, nausea, diarrhea, and sometimes panic attacks, as well as depressive symptoms once the drug had worn off. At high doses (e.g., 240 mg, or between 200–600 mg), fenfluramine induces a psychedelic state resembling that produced by lysergic acid diethylamide (LSD). While fenfluramine binds only very weakly to the 5-HT₂ receptors, its active metabolite norfenfluramine binds to and activates the 5-HT_2B and 5-HT_2C receptors with high affinity and the 5-HT_2A receptor with moderate affinity; as such, indirect (via induction of serotonin release) and/or direct activation of the 5-HT_2A receptor would be expected to be responsible for the psychedelic effects of the drug at sufficient doses.

Synthesis

Prepn: L. G. Beregi et al., FR M1658; eidem, US 3198833 (1963, 1965 both to Sci. Union et Cie Soc. Franc. Recherche Méd.). Prepn of optical isomers: eidem, US 3198834 (1965 to Sci. Union et Cie Soc. Franc. Recherche Med.).