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CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 289

Treatment of Obesity

It is said that much of the world is experiencing an “epidemic that bypasses the stomach and upper small intestine (but not
of obesity.” This statement is based on statistics showing that in simple restrictive banding) rapidly reverses some aspects of the
the USA and many other countries, 30–40% of the population metabolic syndrome even before significant loss of weight. Even a
is above optimal weight, and that the excess weight (especially 5–10% loss of weight is associated with a reduction in blood pres-
abdominal fat) is often associated with the metabolic syndrome sure and improved glycemic control. Gastrointestinal flora also
and increased risks of cardiovascular disease and diabetes. Since influence metabolic efficiency, and research in mice suggests that
eating behavior is an expression of endocrine, neurophysiologic, altering the microbiome can lead to weight gain or loss.
and psychological processes, prevention and treatment of obe- Until approximately 15 years ago, the most popular and
sity are challenging. There is considerable scientific and financial successful appetite suppressants were the nonselective 5-HT 2
interest in developing pharmacologic therapy for the condition. agonists fenfluramine and dexfenfluramine. Combined with
Although obesity can be defined as excess adipose tissue, phentermine as Fen-Phen and Dex-Phen, they were moderately
it is currently quantitated by means of the body mass index effective. However, these 5-HT 2 agonists were found to cause pulmo-
2
(BMI), calculated from BMI = weight (in kilograms)/height (in nary hypertension and cardiac valve defects and were withdrawn.
meters). Using this measure, the range of normal BMI is defined Older drugs still available in the USA and some other countries
as 18.5–24.9; overweight, 25–29.9; obese, 30–39.9; and morbidly include phenylpropanolamine, benzphetamine, amphetamine,
obese (ie, at very high risk), ≥40. (Underweight persons, ie, those methamphetamine, phentermine, diethylpropion, mazindol, and
with a BMI < 18, also have an increased [but smaller] risk of health phendimetrazine. These drugs are all amphetamine mimics
problems.) Some extremely muscular individuals may have a BMI and are central nervous system appetite suppressants; they are
higher than 25 and no excess fat; however, the BMI scale gener- generally helpful only during the first few weeks of therapy. Their
ally correlates with the degree of obesity and with risk. A second toxicity is significant and includes hypertension (with a risk of
metric, which may be an even better predictor of cardiovascular cerebral hemorrhage) and addiction liability.
risk, is the ratio of waist measurement to body height; cardiovas- Liraglutide, lorcaserin, orlistat, and phentermine are the
cular risk is lower if this ratio is less than 0.5. Experts consider drug only single-agent drugs currently approved in the USA for the treat-
therapy to be justified in patients with increased risk factors and a ment of obesity. In addition, combination agents (phentermine
BMI ≥ 27 and in those without comorbidities but with a BMI ≥ 30. plus topiramate and naltrexone plus bupropion) are available.
Although the cause of obesity can be simply stated as energy These drugs have been intensely studied, and some of their prop-
intake (dietary calories) that exceeds energy output (resting erties are listed in Table 16–5. Clinical trials and phase 4 reports
metabolism plus exercise), the actual physiology of weight con- suggest that these agents are modestly effective for the duration of
trol is extremely complex, and the pathophysiology of obesity therapy (up to 1 year) and are probably safer than the single-agent
is still poorly understood. Many hormones and neuronal mecha- amphetamine mimics. However, they do not produce more than
nisms regulate intake (appetite, satiety), processing (absorption, a 5–10% loss of weight. Mirabegron, a β 3 adrenoceptor agonist
conversion to fat, glycogen, etc), and output (thermogenesis, approved for the treatment for overactive bladder (see Chapter 9),
muscle work). The fact that a large number of hormones reduce is of possible future interest because β 3 agonists activate brown
appetite might appear to offer many targets for weight-reducing fat to consume more energy. Sibutramine and rimonabant were
drug therapy, but despite intensive research, no available phar- marketed for several years but were withdrawn because of increas-
macologic therapy has succeeded in maintaining a weight loss ing evidence of cardiovascular and other toxicities.
of over 10% for 1 year. Furthermore, the social and psychological Because of the low efficacy and the toxicity of the available
aspects of eating are powerful influences that are independent drugs, intensive research continues. Because of the redundancy
of or only partially dependent on the physiologic control mecha- of the physiologic mechanisms for control of body weight, it
nisms. In contrast, bariatric (weight-reducing) surgery readily seems likely that polypharmacy targeting multiple pathways will
achieves a sustained weight loss of 10–40%. Furthermore, surgery be needed to achieve success.

effective nonbenzodiazepine anxiolytic (see Chapter 22). Appe- characterized by an aura of variable duration that may involve nausea,
tite suppression appears to be associated with agonist action at vomiting, visual scotomas or even hemianopsia, and speech abnor-
5-HT receptors in the central nervous system, and dexfenflu- malities; the aura is followed by a severe throbbing unilateral headache
2C
ramine, a selective 5-HT agonist, was widely used as an appetite that lasts for a few hours to 1–2 days. “Common” migraine lacks the
suppressant but was withdrawn because of cardiac valvulopathy. aura phase, but the headache is similar. After more than a century of
Lorcaserin, a 5-HT agonist, is approved by the FDA for use as intense study, the pathophysiology of migraine is still poorly under-
2C
a weight-loss medication (see Box: Treatment of Obesity). stood. Although the symptom pattern and duration of prodrome
and headache vary markedly among patients, the severity of migraine
5-HT 1D/1B Agonists & Migraine Headache headache justifies vigorous therapy in the great majority of cases.
The 5-HT 1D/1B agonists (triptans, eg, sumatriptan) are used almost Migraine involves the trigeminal nerve distribution to intra-
exclusively for migraine headache. Migraine in its “classic” form is cranial (and possibly extracranial) arteries. These nerves release