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INTRODUCTION

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HISTORY AND EPIDEMIOLOGY

Methylated derivatives of xanthine, or methylxanthines, are plant-derived alkaloids that include caffeine (1,3,7-trimethylxanthine), theobromine (3,7-dimethylxanthine), and theophylline (1,3-dimethylxanthine). Members of this group share pharmacologic properties and clinical effects. The naturally occurring methylxanthines caffeine and theobromine are used ubiquitously throughout the world. Caffeine is most commonly contained in beverages imbibed for their stimulant, mood-elevating, and fatigue-abating effects. The plant 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 shrub 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.

Selective β2-adrenergic agonists were developed for the treatment of bronchoconstriction. Their receptor selectivity improved therapy for patients with reversible airways disease, 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. Most selective β2-adrenergic agonists are pharmacodynamically similar, with similar clinical effects; the principal differences are their pharmacokinetics. Clenbuterol and ritodrine have unique toxicities distinct from other β2-adrenergic agonists. This chapter does not examine each β2-adrenergic agonist individually but instead discusses them as a class, with a separate discussion of the unique toxicities of clenbuterol and ritodrine. The β2-adrenergic agonists in the United States include arformoterol, albuterol, clenbuterol, bitolterol, formoterol, levalbuterol, metaproterenol, pirbuterol, ritodrine, salmeterol, terbutaline, although numerous others are used outside the United States.

The American Association of Poison Control Centers (AAPCC) follows trends in methylxanthine and β2-adrenergic agonists exposures in National Poisoning Data System (NPDS). Theophylline exposures, which previously caused thousands of poisonings and dozens of deaths annually, have remained uncommon and are continuing to decrease in frequency. From 2012 to 2015, there were approximately 200 exposures annually, consistent with how infrequently theophylline is now used therapeutically. Caffeine exposures continue to slowly decrease. In 1998, there were 7,390 reported caffeine exposures, with a steady decline: from 2007 with 5,448 exposures, to 2011 with 3,667 exposures, and to 2015 with 3,598 exposures. Caffeine is an important component of many energy drinks, and these have only been included as a subcategory of poisoning in NPDS since 2010, when there were 308 reported exposures. In 2015, the number of reported exposures to caffeine-containing energy drinks increased to 1,161, and exposures to caffeine-containing alcoholic beverages was 150.

The number of selective β2-adrenergic agonist exposures is decreasing, with approximately 6,500 cases annually from 2012 to 2015, which is a decrease from the past 5 ...

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