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HISTORY AND EPIDEMIOLOGY

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Methylxanthines are plant-derived alkaloids that include caffeine (1,3,7-trimethylxanthine), theobromine (3,7-dimethylxanthine), and theophylline (1,3-dimethylxanthine). They are so named because they are methylated derivatives of xanthine. Members of this group have very similar pharmacologic properties and clinical effects. Methylxanthines are used ubiquitously throughout the world, most commonly in beverages imbibed for their stimulant, mood-elevating, and fatigue-abating effects. Coffea arabica and related species are used to make coffee, a beverage rich in caffeine. Cocoa and chocolate are derived from the seeds of Theobroma cacao, which contains theobromine and to a lesser extent caffeine. Thea sinensis, a bush native to China but now cultivated worldwide, produces leaves from which various teas, rich in caffeine and containing small amounts of theophylline and theobromine, are brewed. Paullinia spp, commonly known as guarana, is a South American plant that produces berries with caffeine content much greater than that of coffee beans.

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Selective β2-adrenergic agonists have been developed for the treatment of bronchoconstriction. Their selectivity has improved therapy for bronchoconstriction, allowing avoidance of the adverse effects of the previously used therapies: epinephrine, an α- and β-adrenergic agonist, as well as isoproterenol, a β1- and β2-adrenergic agonist. All β2-adrenergic agonists have nearly identical clinical effects; the principal differences are their pharmacokinetics. This chapter does not examine each β2-adrenergic agonist individually but instead discusses them as a class. The β2-adrenergic agonists include albuterol, clenbuterol, bitolterol, formoterol, pirbuterol, salmeterol, terbutaline, and ritodrine.

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The American Association of Poison Control Centers (AAPCC) reported the following trends in methylxanthine exposures. Theophylline exposures, which previously caused thousands of poisonings and dozens of deaths annually, have remained rare. From 2007 to 2011, there were 300 to 400 exposures annually, representing how infrequently theophylline is now used therapeutically. Caffeine exposures continue to decrease at a slow and steady rate. In 1998, there were 7390 reported caffeine exposures. This number has steadily declined: from 2007, with 5448 caffeine exposures, to 2011, with 3667 exposures. Caffeine, as a component of energy drinks, has only recently been added to the National Poisoning Data System (NPDS) of the AAPCC. Included as subcategory of poisoning in 2010, there were 308 reported exposures. The following year, the number of reported exposures to caffeine-containing energy drinks increased to 1610 and exposures to caffeine-containing alcoholic beverages was 131.

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It is impossible to know the precise reasons, which may be related to underlying patient health as well as differences in toxicity, but the disparity between theophylline deaths and caffeine deaths is notable. The number of deaths resulting from theophylline remains at approximately one or two per year, and even though caffeine poisoning occurred much more frequently, during this same 5-year time period, there was only a single death attributed to caffeine toxicity in the United States.

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The number of β2-adrenergic agonist exposures has remained stable ...

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