Anorectic drugs and pulmonary hypertension from the bedside to the bench

Anorectic drugs have been used for more than 30 years as an aid in weight r eduction for obese persons. The use of aminorex, an amphetamine analog that increases norepinephrine levels in the central nervous system, led to an e pidemic 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 epi demic of PPH. All of these drugs have been voluntarily withdrawn from the m arket. The pathogenesis of PPH in patients treated with these agents is unc ertain, but recent evidence suggests that potassium channel abnormalities a nd vasoactive and proliferative properties of 5-HT may play a role. There i s increasing experimental evidence suggesting that aminorex, fenfluramine a nd 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 vaso constriction and smooth muscle cell proliferation. Its levels are known to be high in those with fenfluramine-induced PPH. However, a firm cause-and-e ffect relationship has not yet been established. One potentially beneficial effect of the epidemics of anorectic-related PPH is that it may have provi ded important insights into the causes of PPH unrelated to anorectic agents .