ABSTRACT
Anorectic drugs have been used for more than 30 years as an aid in weight reduction
for obese persons. The use of aminorex, an amphetamine analog that increases norepinephrine
levels in the central nervous system, led to an epidemic of primary pulmonary hypertension
(PPH) in Europe in the late 1960s and early 1970s. The use of fenfluramine and later
dexfenfluramine [drugs that inhibit 5-hydroxytryptamine (5-HT) release and reuptake
and increases 5-Ht and thus 5-HT secretion in the brain] was associated with a second
epidemic of PPH. All of these drugs have been voluntarily withdrawn from the market.
The pathogenesis of PPH in patients treated with these agents is uncertain, but recent
evidence suggests that potassium channel abnormalities and vasoactive and proliferative
properties of 5-HT may play a role. There is increasing experimental evidence suggesting
that aminorex, fenfluramine and dexfenfluramine inhibit 4-aminopyridine-sensitive
currents in potassium channels resulting in vasoconstriction in pulmonary resistance
vessels and perhaps smooth muscle cell proliferation. 5-HT causes pulmonary artery
vasoconstriction and smooth muscle cell proliferation. Its levels are known to be
high in those with fenfluramine-induced PPH. However, a firm cause-and-effect relationship
has not yet been established. One potentially beneficial effect of the epidemics of
anorectic-related PPH is that it may have provided important insights into the causes
of PPH unrelated to anorectic agents.
KEY INDEXING TERMS
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Article info
Footnotes
EDM is supported by the Alberta Heritage Foundation, Alberta Lung Association, and American Heart Association (Minnesota affiliate). EKW is supported by a VA grant and the American Heart Association (Minnesota affiliate).
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Copyright
© 2001 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.
