Chapter 186

Methylxanthines (including theophylline, theobromine, caffeine, and nicotine) are plant-derived alkaloids with ubiquitous use in beverages (caffeine in coffee and soda), foods (theobromine in chocolate), tobacco products (nicotine), and medications (theophylline and caffeine). They have shared pharmacologic properties and very similar pharmacodynamic effects. Newer methylxanthine derivatives include pentoxifylline (an anti-inflammatory) and doxofylline.1

### Epidemiology

Theophylline (1,3-dimethylxanthine) and its water-soluble salt, aminophylline, were used extensively in the past for the treatment of asthma and chronic obstructive pulmonary disease. However, theophylline’s use has declined due to its narrow therapeutic window and the development of safer agents. The number of theophylline toxicity cases reported to the American Association of Poison Control Centers decreased from 2609 exposures with 20 deaths in 1997 to only 357 exposures with 2 deaths in 2008.2,3 Theophylline is still used in patients with debilitating bronchospastic disease, particularly outside the U.S., and has been studied for the treatment of other diseases, including acute mountain sickness and contrast-induced nephropathy.4–6

Theobromine (3,7-dimethylxanthine) is found in the seeds of Theobroma cacao, from which chocolate and cocoa are derived; Commelia thea, from which teas are steeped; and is an ingredient in numerous “energy drinks.” There are very few cases of human toxicity, but it has been associated with atrial fibrillation.7

Caffeine (1,3,7-trimethylxanthine), also a methylxanthine and structural analog of adenosine, is the most commonly used psychoactive drug in the world and the only one that can be legally purchased by children. It is found at varying amounts in beverages and “energy-enhanced” foods, such as candy bars, potato chips, and oatmeal (Table 186-1).8 Other uses for caffeine include apnea of prematurity, analgesic adjuncts, appetite suppression for weight loss, sleep prevention, and diuresis. In 2008, the American Association of Poison Control Centers received reports of 4852 caffeine exposures with one death.3 Many “energy drinks” also use guarana, which contains relatively high concentrations of caffeine and other methylxanthines.9

Table 186-1 Caffeine Content of Various Products

### Pharmacology

Theophylline is usually taken orally, although its absorption may be affected by food. It is available via elixir, or extended-release and controlled-release tablets. Despite being designed for once-daily dosing, controlled-release tablets can result in erratic or rapid absorption. Theophylline can also be administered IV as aminophylline. Caffeine is most commonly consumed PO; however, it can be administered PR or parenterally (IV, IM, or SC).

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