A number of drugs have been developed and marketed to replace amphetamines as appetite suppressants. These anorectic drugs include benzphetamine (Didrex®), diethylproprion (Tenuate®, Tepanil®), mazindol (Sanorex®, Mazanor®), phendimetrazine (Bontril®, Prelu-27®), and phentermine (lonamin®, Fastin®, Adipex®).  These substances are in Schedule III or IV of the CSA and produce some amphetamine-like effects. Of these diet pills, phentermine is the most widely prescribed and most frequently encountered on the illicit market. Two Schedule IV anorectics often used in combination with phentermine (phen-fen combo), fenfluramine and dexfenfluramine, were removed from the U.S. market due to heart valve problems.

Anorectic drugs are widely used for the treatment of obesity. They are thought to decrease appetite through their effects on catecholamine or 5-hydroxytryptamine (5-HT) levels in the brain. Their use has been associated with epidemics of pulmonary hypertension and the development of valvular heart disease, hypertension, stroke and digital or mesenteric ischemia. Understanding the mechanism of the cardiovascular toxicity of anorectic drugs is important because of the modern epidemic of obesity and the resulting plethora of new anorexigens, many of which share similar mechanisms with those that have previously caused cardiovascular disease. In addition, the mechanism by which anorexigens cause vascular disease has relevance to the etiology and treatment of pulmonary and systemic hypertension. Recent discoveries have clarified how the anorexigens cause vasoconstriction and hypertension. Most anorexigens directly inhibit voltage-gated K+ (KV) channels in vascular smooth muscle cells (SMCs). This reduced K+ efflux leads to depolarization, the opening of voltage-sensitive Ca2+ channels, an increase in intracellular Ca2+ and vasoconstriction. Endothelial dysfunction appears to be a predisposing factor for the development of anorectic-induced vascular complications. Vasoconstriction is weak at clinically relevant doses of anorectic drugs. However, when nitric oxide synthase is inhibited, vasoconstriction is significantly enhanced. Anorexigens are the only drugs in widespread clinical use that have KV-channel-blocking properties and it is probable that much of their cardiovascular toxicity relates to this mechanism. Investigators need to examine new anorexigens and other therapeutic molecules for inhibitory effects on KV channels, as this effect may be a marker of drugs that will elicit vascular complications.

Keywords: Anorexigens; Appetite; Sibutramine; Dexfenfluramine; Vascular tone; KV channels; Pulmonary hypertension

Abbreviations: 4-AP, 4-aminopyridine; BKCa channels, high conductance, Ca2+-activated K+ channels; BMPR-II, bone morphogenetic protein receptor II; [Ca2+]i, cytosolic calcium concentration; CHO cells, Chinese hamster ovary cells; EDHF, endothelium-dependent hyperpolarizing factor; Em, membrane potential; 5-HT, 5-hydroxytryptamine; KCa channels, Ca2+-sensitive K+ channels; KIR channels, inwardly rectifying K+ channels; KV channels, voltage-gated K+ channels; IPPHS, International Primary Pulmonary Hypertension Study; PAH, pulmonary arterial hypertension; SMCs, smooth muscle cells.

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