Diet Drugs and Death

It has been known for quite awhile that drug-induced valvulopathy is an issue for fenfluramines (diet drugs).

Fenfluramine, which was sold as Pondimin, Ponderax and Adifax, was one part of a two drug combination sold as Fen-Phen for anti-obesity.  Fenfluramine was removed from the U.S. market in 1997 following reports of heart valve disease and pulmonary hypertension.    The other medication in the diet combination was phentermine.

Fenfluramine is a mixture of dextrofenfluramine and levofenfluramine (i.e. it's racemic mixture of two enantiomoers).  It causes an increase in the neurotransmitor serotonin.  Serotonin is known to be responsible for mood and appetite.  The increase in serotonin leads to the sensation of feeling full and not hungry.  It is postulated that fenfluramine, a sympathomimetic amine, causes release of serotonin and inhibits the reuptake of serotonin.  High levels of serotonin are found to decrease appetite in humans.

Fenfluramine, however, has "off-target" effects via activation of 5-hydroxytryptamine (5-HT) 2B receptor (5-HT2BR) expressed on heart valve leaflets.  This leads to a growth on the heart valves, leaving them structurally changed and incapable of closing properly.  Clinically, this can be detected by cardiovascular symptoms, which include a heart murmur, shortness of breath (dyspnea), edema, chest pain, congestive heart failure (CHF), palpitations, as well as supraventricular tachycardia. These symptoms are well described in the New England Journal of Medicine.

Macroscopic appearance: anterior leaflet 
of the mitral valve
 with thickened and retractile insertion 
of the chordae tendineae.

It is postulated that fenfluramine, a sympathomimetic amine, causes release of serotonin and inhibits the reuptake of serotonin.  As noted above, high levels of serotonin are found to decrease appetite in humans.  Elevated serotonin is also associated with acute or chronic pulmonary hypertension from pulmonary vasoconstriction or cardiac valve fibrosis (endocardial fibrosis) from overstimulation of serotonic growth receptors on fibrocytes.  Additionally increased serotonin levels are a factor in retroperitoneal fibrosis.

Serotonin is an intense pulmonary vasoconstrictor that stimulates proleferation of vascular smooth muscle by interacting synergistically with platelet-derived growth factor.