Fenfluramine
Encyclopedia
Fenfluramine is a drug that was part of the Fen-Phen
anti-obesity medication (the other drug being phentermine
). Fenfluramine was introduced on the U.S. market in 1973. It is the racemic
mixture of two enantiomer
s, dextrofenfluramine
and levofenfluramine. It increases the level of the neurotransmitter
serotonin
, a chemical that regulates mood, appetite and other functions. Fenfluramine causes the release
of serotonin
by disrupting vesicular
storage of the neurotransmitter, and reversing serotonin transporter function. The end result is a feeling of fullness and loss of appetite.
disease, and pulmonary hypertension
, including a condition known as cardiac fibrosis
. After the US withdrawal of fenfluramine, it was also withdrawn from other markets around the world.
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 agonist of 5-HT2B 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-HT2B 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.
Fen-phen
The drug combination fenfluramine/phentermine, usually called fen-phen, is an anti-obesity treatment that utilizes two anorectics. Fenfluramine, its S-enantiomer dexfenfluramine, and a few other serotonin agonists were shown to cause potentially fatal pulmonary hypertension and heart valve...
anti-obesity medication (the other drug being phentermine
Phentermine
Phentermine, a contraction of "phenyl-tertiary-butylamine", is a psychostimulant drug of the phenethylamine class, chemically related to amphetamine. It is used medically as an appetite suppressant....
). Fenfluramine was introduced on the U.S. market in 1973. It is the racemic
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
mixture of two enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
s, dextrofenfluramine
Dexfenfluramine
Dexfenfluramine, marketed as dexfenfluramine hydrochloride under the name Redux, is a serotoninergic anorectic drug: it reduces appetite by increasing the amount of extracellular serotonin in the brain...
and levofenfluramine. It increases the level of the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, a chemical that regulates mood, appetite and other functions. Fenfluramine causes the release
Releasing agent
A releasing agent , or simply releaser, is a drug that induces the release of a neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs use neurotransmitter release to exert their psychological and...
of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
by disrupting vesicular
Synaptic vesicle
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
storage of the neurotransmitter, and reversing serotonin transporter function. The end result is a feeling of fullness and loss of appetite.
Withdrawal due to heart disease
The drug was withdrawn from the U.S. market in 1997 after reports of heart valveHeart valve
A heart valve normally allows blood flow in only one direction through the heart. The four valves commonly represented in a mammalian heart determine the pathway of blood flow through the heart...
disease, and pulmonary hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
, including a condition known as cardiac fibrosis
Cardiac fibrosis
Cardiac fibrosis refers to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts.Fibrocyte cells normally secrete collagen, and function to provide structural support for the heart...
. After the US withdrawal of fenfluramine, it was also withdrawn from other markets around the world.
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
Norfenfluramine
Norfenfluramine is a psychoactive drug which functions as a serotonin releasing agent and potent 5HT2B receptor agonist. The action of norfenfluramine on 5HT2B receptors on heart valves leads to a characteristic pattern of heart failure following proliferation of cardiac fibroblasts on the...
stimulate serotonin receptors, this may have led to the valvular abnormalities found in patients using fenfluramine. In particular norfenfluramine is a potent agonist of 5-HT2B receptors
5-HT2B receptor
5-hydroxytryptamine receptor 2B, also known as HTR2B, is a 5-HT2 receptor, but also denotes the human gene encoding it.-Function:...
, 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-HT2B 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.
See also
- 3-Fluoroethamphetamine3-Fluoroethamphetamine3-Fluoroethamphetamine is a stimulant drug which acts as a releaser of the monoamine neurotransmitters noradrenaline, dopamine and serotonin...
- 3,4-MethylenedioxyethamphetamineMethylenedioxyethylamphetamine3,4-Methylenedioxy-N-ethylamphetamine is an entactogen, psychedelic, and stimulant of the phenethylamine and amphetamine chemical classes....
- 4-MethoxyethamphetamineParamethoxyethylamphetaminepara-Methoxyethylamphetamine , is a stimulant drug related to PMA. PMEA reputedly produces similar effects to PMA, but is considerably less potent and seems to have slightly less tendency to produce severe hyperthermia, at least at low doses...
- EthylamphetamineEthylamphetamineEthylamphetamine , also known as etilamfetamine or N-ethylamphetamine, is a stimulant drug of the phenethylamine and amphetamine chemical classes...
- NorfenfluramineNorfenfluramineNorfenfluramine is a psychoactive drug which functions as a serotonin releasing agent and potent 5HT2B receptor agonist. The action of norfenfluramine on 5HT2B receptors on heart valves leads to a characteristic pattern of heart failure following proliferation of cardiac fibroblasts on the...
- BenfluorexBenfluorexBenfluorex is an anorectic and hypolipidemic agent that is structurally related to fenfluramine. Two clinical studies have shown it may improve glycemic control and decrease insulin resistance in people with poorly controlled type 2 diabetes; However Servier is suspected of having marketed Mediator...