Physicians who prescribe appetite-control drugs
should plan to continue therapy for at least 5 to 10 years. (It's either
that or plan for long-term drug therapy for obesity-related disorders such
as hypertension, hyperlipidemia, and diabetes.)
Centrally acting drugs that promote weight loss include agents that act at
adrenergic receptors in the brain (e.g., sympathomimetic amines such as
amphetamine) and agents that act at serotonergic receptors (e.g.,
fenfluramine, fluoxetine). Although most serotonergics are approved only as
antidepressants, they do induce weight loss in the short term. Weight loss
slows after the first few months, is minimal by the 6th to 10th months, and
is maintained only so long as the drug is taken, with immediate reversal of
the weight loss upon drug discontinuation. The sympathomimetic amines
(Schedule IV, low abuse potential) include phentermine (Fastin/SmithKline
Beecham), mazindol (Sanorex/Sandoz, Mazanor/Wyeth-Ayerst), and
diethylpropion (Tenuate/Marion Merrell Dow). One sympathomimetic amine with
no abuse potential is phenylpropanolamine. Generally safe and efficacious,
phenylpropanolamine can cause transient hypertensive reactions (although
obese persons appear to be the least sensitive to the pressor effects of the
drug, presumably because of higher baseline blood pressure). Patients taking
any sympathomimetic should be monitored for hypertensive effects and
associated risks. It should be noted that obesity itself increases the risk
of stroke (both hemorrhagic and thrombotic), and weight loss reduces this
risk.

Several promising anorectics are under investigation. One is d-fenfluramine
(not to be confused with the racemic mixture, d/l-fenfluramine, available in
the United States as Pondimin). Although d-fenfluramine induces weight loss,
no reduction in food intake or increase in energy expenditure appears to
account for the loss, suggesting that the drug acts by potentiating the
thermic effects of food. Also under investigation is sibutramine, a
monoamine that blocks the reuptake of norepinephrine and, to a lesser
extent, serotonin and dopamine. Other promising agents include
chlorocitrate, which inhibits gastric emptying, and tetrahydrolipstatin,
which inhibits gastrointestinal lipase, thus blocking hydrolysis of
triglycerides, decreasing absorption of ingested fat, and increasing fecal
fat content.

Until the biochemists and pharmacologists come up with the ideal anorectic,
combination therapy with existing agents is a good approach to treating
obesity.